In the US, nutraceuticals are marketed under the Dietary Supplement and Health Education Act of 1994 (DSHEA). Consequently, scientific data supporting claimed benefit(s) are not always available for nutraceuticals as they are for traditional pharmaceuticals since nutraceuticals are not regulated as drugs. Consumers should also note that rigid quality control standards are not required for nutraceuticals; substantial variability can occur in both the potency and the purity of these products. Monographs on nutraceuticals are included in CP when reliable clinical data are available. The information presented below is condensed from the best clinical data we could find.
Description: St. John's wort, Hypericum perforatum, is an aromatic perennial native to Europe, parts of Africa and Asia, and the western US. Its yellow flowers are especially bright on June 24, the traditional birthday of St. John the Baptist, hence the name "St. John's wort". Other names include "goat weed" or "klamath weed". The leaves and flowering tops of Hypericum perforatum yield about 0.1% hypericin, pseudohypericin, and related naphthodianthrones. Flavonoids such as amentoflavone, luteolin, kaempferol, and quercetin and the glycosides hyperoside and rutinoside have also been identified in the plant.
St. John's wort is widely used in Europe for treatment of depression, dysthymia, and sleep disturbances. The German Commission E has recognized St. John's wort as a "modestly effective" antidepressant. Two meta-analysis published in 1996 and 2000 , respectively, revealed that St. John's wort did possess clinical antidepressant effects; however, most studies reviewed contained at least one methodological error. In 2002, the results of a multicenter trial conducted by the US National Institute of Mental Health (NIMH) were reported. The trial compared treatment with St. John's wort (as LI 160(TM) extract), sertraline (an SSRI) and placebo in patients with moderate major depressive disorder. While St. John's wort was no more effective than placebo in the patients studied, sertraline was also no more effective than placebo, and experts have criticized the trial design as having a lack of sufficient sensitivity.
A phase I study of synthetic hypericin for the treatment of HIV infection was reported in 1999; the study failed to demonstrate anti-retroviral activity or positive changes in CD4+ counts, and further clinical trials were halted. Oral synthetic hypericin is being investigated as a treatment for glioblastoma. Initial phase II studies in glioblastoma were completed by Nexell (formerly VIMRx, Inc.) in 1998 under the name "VIMRxyn(R)", but it is uncertain if further phase II and III trials are planned. St. John's wort has been used historically for insomnia and has been applied topically after maceration to promote healing of minor burns or wounds. Because of its photodynamic activity, topical application of synthetic hypericin (topical VimRxyn(R)) in combination with light therapy is being investigated for the treatment of psoriasis, cutaneous T-cell lymphoma, and verruca vulgaris.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Potency for nutraceutical products can vary substantially from manufacturer to manufacturer. The use of standardized product from a reliable manufacturer is recommended.
Route-Specific Administration
Oral Administration
-St. John's wort is available in a variety of dosage forms, including capsules, extracts, tablets, and teas.
-Administer dosage with water at mealtimes.
Some St. John's wort preparations are a combination of several herbs. Only adverse reactions pertaining to St. John's wort as monotherapy are discussed in this monograph.
The effects of St. John's wort on an electocardiogram (ECG) have been compared to imipramine in a double-blind, placebo controlled trial. Doses of up to 1800 mg/day of hypericum extract were given. Patients administered imipramine showed the characteristic prolongation of PR, QRS and QTc intervals at the end of 6 weeks. Patients receiving St. John's wort did not show adverse effects on cardiac conduction as evidenced by ECG recordings in this trial.
In Germany, more than 20 million people have taken St. John's wort for more than a year without noting severe side effects. In one study of 3250 adult patients treated with St. John's wort (hypericum extract LI 160) in primary care settings, the following ADRs were documented: GI irritation or dyspepsia (0.6%); allergic reactions like urticaria or swelling (0.5%); drowsiness (0.4%) and descriptions of anxiety or restlessness (0.3%). Only 1.5% of patients required discontinuation of therapy due to adverse effects. In a meta-analysis of studies of St. John's wort, 19.8% of patients receiving this herb experienced side effects compared to 52.8% of patients receiving standard antidepressants. Abdominal pain or discomfort, headache, orgasm dysfunction (anorgasmia), increased urinary frequency, and xerostomia have been reported commonly in other trials. In some surveys of patients taking St. Johns' wort, restlessness has led to sleep disturbances, like insomnia. In some studies, the short-term use of a hypnotic (e.g., zolpidem), has been prescribed during the initial few weeks of treatment. Similar to the SSRIs, sexual dysfunction, ejaculation dysfunction (i.e., delayed ejaculation) or orgasm dysfunction have been reported with the use of St. John's wort. St. John's wort has also been associated with withdrawal effects similar to those seen with antidepressants; withdrawal symptoms include headache, nausea, anorexia, thirst, chills, weight loss, dizziness, insomnia, paresthesias, confusion, and fatigue.
When exposed to light, hypericins, the photoactive components of St. John's wort produce substances that may damage skin cells, causing pigment changes and other symptoms. St. John's wort has been shown to cause phototoxicity in grazing animals that consume the plant. In some cases, these reactions in animals have been severe. Similar photosensitivity reactions have been reported in humans upon ingestion of St. John's wort and exposure to UV light. In a phase I study of IV and oral hypericin in HIV-infected patients, 48% of the 30 patients discontinued treatment due to severe cutaneous photosensitivity. The eythematous rashes in these patients were associated with painful dysesthesia in the areas exposed to sunlight. Another case report described an acute peripheral neuropathy occurring upon exposure to sunlight in a 35 year old woman taking St. John's wort in doses of 500 mg per day. After 4 weeks of ingesting the herb, the woman began to have 'stinging' pain of the face, hands, arms and legs. She had a worsening of symptoms after sun-bathing, and sought medical attention. No skin pigmentation changes were present, but symptoms were consistent with nerve damage. After discontinuing use of the St. John's wort, the woman's symptoms slowly resolved over a course of 2 months. There is theoretical concern regarding an increased risk for cataracts due to the effects of the hypericin constituent, which might damage ocular lens proteins.
In vitro studies have suggested that use of St. John's wort may cause a risk for reduced fertility or infertility. The herb appears to inhibit sperm penetration of oocytes, decrease sperm viability, and cause potential sperm mutations when tested via in vitro fertilization methods. These findings may have important implications for couples attempting to conceive. Further research is needed to delineate these findings, as well as the activity of St. John's wort on in vivo conception.
One case report exists in the literature of a patient who experienced symptoms of mania (e.g., racing and disorganized thoughts, aggressive behavior, insomnia, irritability, and hostility) 10 days after initiating St. John's wort therapy. After the tincture was discontinued, the hypomanic symptoms resolved within 48 hours. Similar reactions are known to occur in some patients taking traditional antidepressants. Practitioners should be aware that similar effects may occur with the use of St. John's wort, Hypericum perforatum.
In a few reported cases, St. John's wort has been associated with serotonin syndrome. Serotonin syndrome is a range of signs and symptoms that can rarely, in its most severe form, resemble neuroleptic malignant syndrome. Symptoms may include nausea/vomiting, sedation, dizziness, diaphoresis (sweating), facial flushing, mental status changes, myoclonia, restlessness, shivering, and elevated blood pressure. If serotonin syndrome becomes evident during St. John's wort treatment, the herb and any other serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Some St. John's wort preparations are a combination of several herbs. Only contraindications and precautions pertaining to St. John's wort are discussed in this monograph. St. John's wort has not been evaluated by the Food and Drug Administration. Products containing St. John's wort are not intended to diagnose, treat, cure, or prevent any disease. Consumers should also be informed that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products.
St. John's wort, Hypericum perforatum, would be contraindicated in anyone with a previous hypersensitivity to the herb or product in which the herb was a component.
Several studies have suggested that St. John's wort may not be effective for the treatment of moderate to severe major depressive disorder. Self-treatment of depression is not recommended for most individuals. The decision to self-treat depression for 6 weeks with St. John's wort should be weighed against the possibility of the depression coexisting with another medical condition (e.g., thyroid disease, neurological disease). Caution should be used when patients are being treated for other psychiatric diseases (e.g., anxiety, mania, psychosis, etc.) by a health care professional. St. John's wort could interfere with prescribed therapies, such as MAOI therapy (see Drug Interactions). The possibility of a suicide attempt is inherent in patients with depressive symptoms. Patients with suicidal ideation and who are at high risk for suicide attempt should not be treated with St. John's wort, as efficacy for severe depression has not been established.
Due to limited scientific data, St. John's wort is not recommended for use during pregnancy. In animals, hypericum extract has caused contractions of uterine muscles. Related hypericum species (not St. John's wort) were used by Native Americans as abortifacients. In vitro data suggest that St. John's wort may induce infertility in couples trying to conceive (see Adverse Reactions). In one case report, a woman used St. John's wort (900 mg/day) during her 24th week of gestation until the day prior to delivery. The pregnancy was unremarkable except for late onset thrombocytopenia. She delivered a healthy infant, and began to breast-feed her newborn. The neonate required brief phototherapy for jaundice on postnatal day 5. The woman re-initiated St. John's wort on the 20th day post-partum at a lower dosage, and continued to breast-feed. The infant had normal behavioral and physical examinations at 1 month of age. Animal studies evaluating other serotonergic antidepressants have shown that down-regulation of serotonin receptors occurs in the fetal cortex and that these changes can be present for a period of time after birth; the effect on neurological development is unknown. The applicability of any of these findings to humans is also unknown. Neonates exposed to other serotonergic antidepressants (e.g., SSRIs, SNRIs) late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Symptoms have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of SSRIs and SNRIs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome. Until more data become available, the physician should carefully consider the potential risks and benefits of treatment if recommending St. John's wort during pregnancy. In addition, patients considering use of St. John's wort during pregnancy should be informed that rigid quality control standards are not required for dietary supplements and substantial variability can occur in both the potency and the purity of these products, which may inadvertently expose the developing fetus to unintended doses and/or contaminants.
Due to limited scientific data, St. John's wort is not recommended for use during breast-feeding. It is uncertain if the herb is excreted in human milk. In addition, patients considering use of St. John's wort should be informed that rigid quality control standards are not required for nutraceuticals and substantial variability can occur in both the potency and the purity of these products, which may inadvertently expose the infant to unintended doses and/or contaminants. Although the American Academy of Pediatrics (AAP) does not make specific recommendations regarding use of St. John's wort during breast-feeding, the AAP cautions that psychotropic medications affect neurotransmitter function in the developing central nervous system, and therefore, the accurate prediction of long-term adverse effects may not be possible. In one observational cohort study examining the safety of St. John's wort during breast-feeding, 33 women taking St. John's wort were followed and compared to 2 control groups (101 disease-matched women and 33 non-disease controls). There were 2 cases of colic, 2 cases of drowsiness, and 1 case of lethargy among infants in the St. John's wort group compared to 1 case of colic in each of the comparator groups. No significant differences were identified between groups in infant weight over the first year of life or maternal breast milk production. In a separate study, plasma and breast milk concentrations of hyperforin (an active component of St. John's wort) were assessed in 5 mothers who began 900 mg/day of St. John's wort while breast-feeding. Milk:plasma ratios of hyperforin ranged from 0.04-0.13. The relative mean infant dose was 0.9-2.5% of the maternal dose. Of the two infants in whom plasma levels were obtained, the infant plasma levels were 0.17% and 0.15% of the respective maternal levels. No side effects were noted in any of the infants studied (age range: 10-22 weeks). One case report describes a woman who used St. John's wort (900 mg/day) during her 24th week of gestation until the day prior to delivery. She delivered a healthy infant, and initiated breast-feeding. The neonate required brief phototherapy for jaundice on postnatal day 5. The woman re-initiated St. John's wort on the 20th day post-partum at a lower dosage, and continued to breast-feed; the infant had normal behavioral and physical examinations at 1 month of age. A pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum; these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Since photosensitivity has been reported with St. John's wort, patients should minimize sunlight (UV) exposure while using this herbal product. Protective clothing and sunscreens should be utilized. The use of sunlamps or tanning booths is not recommended.
The electrocardiographic effects of St. John's wort have been compared to imipramine in a multicenter controlled trial. Patients receiving St. John's wort did not show adverse effects on cardiac conduction as evidenced by ECG recordings in this trial. However, until the pharmacologic and pharmacokinetic actions of St. John's wort are fully elucidated, it should be used cautiously by patients with hypertension, cardiac disease, heart transplant, or cerebrovascular disease. In addition, serious drug interactions may occur between St. John's wort and medications used to treat these conditions, including anticoagulant therapy (see Drug Interactions).
Until the routes of elimination of St. John's wort are known, the herb should be used cautiously by patients with hepatic disease, organ transplant, renal disease or renal impairment. In addition, serious drug interactions may occur between St. John's wort and medications used to treat some of these conditions (see Drug Interactions).
Due to lack of clinical safety and efficacy data, St. John's wort should be used with caution in children. A qualified health care professional should be consulted prior to use of this herb.
St. John's wort should not be used to treat human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).Human studies have failed to demonstrate anti-retroviral activity or positive changes in CD4+ counts from the use of St. John's wort. There was no synergy in these studies with currently available anti-HIV therapies. In addition, serious drug interactions between St. John's wort and HIV protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been reported; these interactions may compromise the effectiveness of anti-retroviral therapy and lead to increased rates of HIV drug-resistance (see Drug Interactions).
Patients should inform their surgeon and anesthesiologist of the use of St. John's wort prior to scheduling surgery. St. John's wort, Hypericum perforatum, may intensify or prolong the effects of general anesthetics, as well as interact with many medications used perioperatively (see Drug Interactions). Based on estimated half-lives for this herb, this herb should be discontinued at least 5 days before the surgical procedure. It may be wise to discontinue this herb 2-3 weeks prior to an elective procedure, when possible.
For the treatment of mild to moderate depression*:
Oral dosage:
Adults: 300 mg PO three times per day is a common initial dose. A St. John's Wort (SJW) standardized extract, such as 0.3% hypericin or alternatively, the LI 160 extract, has been used in most double-blind, placebo-controlled trials in Germany and by the US National Institute of Mental Health (NIMH). Titration up to a range of 900 mg/day-1500 mg/day PO, given in three divided doses, has been allowed in many trials according to efficacy and tolerance. Assess clinical response after at least 4 weeks. While St. John's wort may be be more effective than placebo in treating mild to moderate depression, the herb is probably not effective for moderate to severe major depressive disorder (MDD). Hamilton Depression Rating Scale (HAM-D) or Clinical Global Impression Severity (CGI-S) changes often do not find differences in efficacy in mild to moderate depression for SJW versus the selective serotonin reuptake inhibitors (SSRIs); however, in some trials neither type of treatment exhibits better response rates over placebo, likely due to high placebo response rates. Some studies highlight the ongoing concerns with placebo response rates in antidepressant studies which have recently been estimated to be as high as 35-45%. St. John's wort may cause side effects such as frequent urination, anorgasmia, and swelling; additionally, St. John's wort exhibits many clinically significant drug-drug interactions.
For the relief of inflammation due to minor burns*:
Topical dosage (oil):
Adults: Macerate the flowering tops of the fresh plant in olive, sunflower, or wheatgerm oil and apply topically, as directed and suggested by herbal texts.
Maximum Dosage Limits:
No specific maximum dosage information is available.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it is not known if dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it is not known if dosage adjustments are needed.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with St. John's Wort, Hypericum perforatum as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. St. John's Wort is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Abemaciclib: (Major) Avoid coadministration of St Johns Wort with abemaciclib due to decreased exposure to abemaciclib and its active metabolites, which may lead to reduced efficacy. Abemaciclib is a CYP3A4 substrate and St Johns Wort is a strong CYP3A4 inducer. The amount of individual constituents in various St Johns Wort products may alter the inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by approximately 70% in healthy subjects.
Abiraterone: (Major) Avoid coadministration of abiraterone with St. John's Wort if possible due to decreased plasma concentrations of abiraterone. If concomitant use is unavoidable, increase the dosing frequency of abiraterone to twice daily. Reduce the dose back to the previous dose and frequency if St. John's Wort is discontinued. Abiraterone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and St. Johns Wort. If coadministration cannot be avoided, increase the acalabrutinib dose to 200 mg PO twice daily. Decreased acalabrutinib exposure may occur. Acalabrutinib is a CYP3A4 substrate; St. Johns Wort is a strong CYP3A4 inducer. In healthy subjects, the Cmax and AUC values of acalabrutinib were decreased by 68% and 77%, respectively, when acalabrutinib was coadministered with another strong CYP3A4 inducer for 9 days.
Acetaminophen: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Aspirin: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Aspirin; Diphenhydramine: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Caffeine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of dihydrocodeine with St. John's Wort can result in lower dihydrocodeine concentrations, greater dihydronorcodeine concentrations, and less metabolism by CYP2D6 with resulting lower dihydromorphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when dihydrocodeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of dihydrocodeine and signs of opioid withdrawal; consider increasing the dose of dihydrocodeine as needed. If St. John's Wort is discontinued, consider a dose reduction of dihydrocodeine and frequently monitor for signs of respiratory depression and sedation. Dihydrocodeine is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Chlorpheniramine: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Dextromethorphan; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Dichloralphenazone; Isometheptene: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Diphenhydramine: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Guaifenesin; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Hydrocodone: (Moderate) Concomitant use of hydrocodone with St. John's Wort can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If St. John's Wort is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Ibuprofen: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with St. John's wort is necessary; consider increasing the dose of oxycodone as needed. If St. John's wort is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additive serotonergic effects are also possible with this drug-herb combination. Caution and careful monitoring, particularly during treatment initiation and dose adjustment, is recommended due to the potential for serotonin syndrome. Serotonin syndrome may occur within the recommended dosage range. Discontinue St. John's wort if serotonin syndrome is suspected. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Pamabrom; Pyrilamine: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acetaminophen; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Acitretin: (Major) Because of the teratogenic potential of acitretin, the coadministration of St. John's wort, Hypericum perforatum and acitretin should be avoided in females who are using hormonal contraceptives as their primary form of birth control. St. John's wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. Breakthrough bleeding and pregnancies have been reported following coadministration of St. John's Wort and hormonal contraception. It is thought that St. John's wort induces hormone metabolism via induction of the hepatic CYP3A4 isoenzyme. It is possible that, as with other CYP3A4 inducers, St. John's wort could also reduce the therapeutic efficacy of non-oral combination contraceptives or progestin-only contraceptives (i.e., norgestrel, levonorgestrel, and medroxyprogesterone).
Acrivastine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Adagrasib: (Major) Avoid concurrent use of adagrasib and St. John's wort due to the risk of decreased adagrasib exposure which may reduce its efficacy. Adagrasib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced adagrasib exposure by more than 66%.
Afatinib: (Major) Increase the daily dose of afatinib by 10 mg as tolerated if the concomitant use with St. Johns Wort is necessary; resume the previous dose of afatinib 2 to 3 days after discontinuation of St. Johns Wort. Afatinib is a P-glycoprotein (P-gp) substrate and St. Johns Wort is a P-gp inducer; coadministration may decrease plasma concentrations of afatinib. Pre-treatment with another strong P-gp inducer decreased afatinib exposure by 34%.
Alfentanil: (Major) St. John's wort (Hypericum perforatum) may increase the risk for serotonin syndrome when combined with alfentanil, and may also intensify or prolong the effects of general anesthetics. The onset of serotonergic symptoms generally occurs within several hours to a few days of concomitant use, but may occur later. Monitor the patient closely if use of St. John's Wort is reported pre-operatively. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that, if possible, patients should stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions. If use together is necessary and serotonin syndrome is suspected, discontinue alfentanil.
Almotriptan: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Alosetron: (Moderate) Alosetron is metabolized by hepatic cytochrome P450 enzymes CYP2C9, CYP3A4, and CYP1A2. Inducers of these enzymes, such as St. John's Wort, can reduce the systemic exposure to alosetron by increasing the metabolism of the drug.
Alpelisib: (Major) Avoid coadministration of alpelisib with St. John's Wort due to decreased exposure to alpelisib which could decrease efficacy. Alpelisib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer.
Alprazolam: (Moderate) Monitor for reduced efficacy of alprazolam and signs of benzodiazepine withdrawal if coadministration with St. John's Wort is necessary. Alprazolam is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. When given with St. John's Wort, the half-life of alprazolam is reduced and clearance is increased. Reduced alprazolam concentrations may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Aminolevulinic Acid: (Major) St. John's wort has been reported to increase the phototoxicity associated with photosensitizing agents used in photodynamic therapy. Although interactions have not been reported, in theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs.
Amiodarone: (Moderate) Monitor for a decrease in amiodarone efficacy during concomitant use of amiodarone and St. John's wort. Concomitant use may decrease amiodarone exposure. Amiodarone is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Amitriptyline: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Atorvastatin: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine. (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Coadministration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including atorvastatin.
Amlodipine; Benazepril: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Celecoxib: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Olmesartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Amoxapine: (Minor) It is not known if additive pharmacodynamic effects could occur as a result of coadministration of St. John's wort with amoxapine. Therefore, coadministration of St. John's wort with amoxapine therapy is not usually recommended.
Amoxicillin; Clarithromycin; Omeprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%. (Moderate) St. John's Wort appears to induce CYP3A4 and may lead to increased systemic clearance of clarithromycin, a CYP3A4 substrate. Additionally, clarithromycin may increase serum concentrations of St. John's Wort due to CYP3A4 inhibition. Postmarketing reports of interactions have been noted.
Amphetamine: (Moderate) Coadministration of St. John's Wort with amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Amphetamine; Dextroamphetamine Salts: (Moderate) Coadministration of St. John's Wort with amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Amphetamine; Dextroamphetamine: (Moderate) Coadministration of St. John's Wort with amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Apixaban: (Major) Avoid the concomitant administration of apixaban and herbal medications that are both strong inducers of CYP3A4 and P-gp, such as St. John's Wort, Hypericum perforatum. Concomitant administration of apixaban and St. John's wort results in decreased exposure to apixaban and an increase in the risk of stroke.
Apremilast: (Major) The coadministration of apremilast and St. John's Wort is not recommended. Apremilast is a substrate of CYP3A4; St. John's Wort is a strong CYP3A4 inducer. Coadministration of rifampin, another strong CYP3A4 inducer, with a single dose of apremilast resulted in a decrease in apremilast AUC and Cmax by 72% and 43%, respectively. A reduction in systemic exposure of apremilast may be seen with coadministration of apremilast and St. John's Wort which may result in a loss of efficacy of apremilast.
Aprepitant, Fosaprepitant: (Major) Avoid the concurrent use of St. John's Wort, Hypericum perforatum with aprepitant due to substantially decreased exposure of aprepitant. If these drugs must be coadministered, monitor for a decrease in the efficacy of aprepitant. After administration, fosaprepitant is rapidly converted to aprepitant and shares the same drug interactions. St. John's Wort is a strong CYP3A4 inducer and aprepitant is a CYP3A4 substrate. When a single dose of aprepitant (375 mg, or 3 times the maximum recommended dose) was administered on day 9 of a 14-day rifampin regimen (a strong CYP3A4 inducer), the AUC of aprepitant decreased approximately 11-fold and the mean terminal half-life decreased by 3-fold.
Aripiprazole: (Major) Recommendations for managing aripiprazole and St. John's wort vary by aripiprazole dosage form. For aripiprazole oral dosage forms, double the usual dose over 1 to 2 weeks. For extended-release aripiprazole injections administered monthly (Abilify Maintena) and every 2 months (Abilify Asimtufii), avoid concomitant use. Concomitant use may decrease aripiprazole exposure and reduce efficacy. Aripiprazole is CYP3A substrate; St. John's wort is a strong CYP3A inducer. (Major) Recommendations for managing aripiprazole and St. John's wort vary by aripiprazole dosage form. For extended-release aripiprazole lauroxil injections (Aristada), increase the 441 mg dose to 662 mg; no adjustments are necessary for other dosages. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Concomitant use may decrease aripiprazole exposure and reduce efficacy. Aripiprazole is CYP3A substrate; St. John's wort is a strong CYP3A inducer.
Artemether; Lumefantrine: (Contraindicated) Concomitant use of St. John's wort, Hypericum perforatum and artemether; lumefantrine is contraindicated. St. John's wort is an inducer of CYP3A4 and both components of artemether; lumefantrine are substrates of this isoenzyme; therefore, coadministration may lead to decreased artemether; lumefantrine concentrations and possible reduction in antimalarial activity.
Articaine; Epinephrine: (Moderate) Monitor blood pressure during concomitant use of epinephrine and St. John's Wort. Patients receiving St. John's Wort may experience severe, prolonged hypertension when given epinephrine. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the pressor effects of epinephrine.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine.
Aspirin, ASA; Caffeine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer. (Minor) Carisoprodol is metabolized via CYP2C19. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. If carisoprodol is combined with an inducer of CYP2C19 such as St. John's Wort, Hypericum perforatum, the potential exists for increased metabolism of carisoprodol. Theoretically, carisoprodol plasma concentrations could be decreased, and meprobamate (active metabolite) plasma concentrations could be increased. The clinical significance of this interaction is unknown.
Aspirin, ASA; Omeprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Aspirin, ASA; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with St. John's wort is necessary; consider increasing the dose of oxycodone as needed. If St. John's wort is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additive serotonergic effects are also possible with this drug-herb combination. Caution and careful monitoring, particularly during treatment initiation and dose adjustment, is recommended due to the potential for serotonin syndrome. Serotonin syndrome may occur within the recommended dosage range. Discontinue St. John's wort if serotonin syndrome is suspected. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Atazanavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Atazanavir; Cobicistat: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer. (Contraindicated) Coadministration of St. John's Wort, Hypericum perforatum with cobicistat is contraindicated. St. John's Wort induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided.
Atogepant: (Major) Avoid use of atogepant and St. John's wort when atogepant is used for chronic migraine. Use an atogepant dose of 30 or 60 mg PO once daily for episodic migraine if coadministered with St. John's wort. Concurrent use may decrease atogepant exposure and reduce efficacy. Atogepant is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer resulted in a 60% reduction in atogepant overall exposure and a 30% reduction in atogepant peak concentration.
Atorvastatin: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Coadministration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including atorvastatin.
Avacopan: (Major) Avoid concomitant use of avacopan and St. John's Wort due to the risk of decreased avacopan exposure which may reduce its efficacy. Avacopan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased avacopan overall exposure by 93%.
Avanafil: (Major) Coadministration of avanafil with St. John's Wort is not recommended by the manufacturer of avanafil due to the potential for decreased avanafil efficacy. Avanafil is a CYP3A substrate and St. John's Wort is a CYP3A inducer. Although the potential effect of CYP inducers on the pharmacokinetics of avanafil has not been evaluated, plasma concentrations may decrease.
Avapritinib: (Major) Avoid coadministration of avapritinib with St. John's Wort due to the risk of decreased avapritinib efficacy. Avapritinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of avapritinib by 92% and 74%, respectively.
Avatrombopag: (Major) In patients with chronic immune thrombocytopenia (ITP), increase the starting dose of avatrombopag to 40 mg PO once daily when used concomitantly with St. John's Wort. In patients starting St. John's Wort while receiving avatrombopag, monitor platelet counts and adjust the avatrombopag dose as necessary. Dosage adjustments are not required for patients with chronic liver disease. Avatrombopag is a CYP2C9 and CYP3A4 substrate, and dual moderate or strong inducers such as St. John's Wort decrease avatrombopag exposure, which may reduce efficacy.
Axitinib: (Major) Avoid coadministration of axitinib with St. Johns Wort due to the risk of decreased efficacy of axitinib. Selection of a concomitant medication with no or minimal CYP3A4 induction potential is recommended. Axitinib is a CYP3A4/5 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4/5 inducer significantly decreased the plasma exposure of axitinib in healthy volunteers.
Bedaquiline: (Major) Avoid concurrent use of St. John's Wort with bedaquiline. St. John's Wort may induce CYP3A4 metabolism resulting in decreased bedaquiline systemic exposure (AUC) and possibly reduced therapeutic effect.
Belumosudil: (Major) Increase the dosage of belumosudil to 200 mg PO twice daily when coadministered with St. John's wort. Belumosudil is a CYP3A4 substrate and St. John's wort is a strong CYP3A inducer; concomitant use may result in decreased belumosudil exposure and reduced belumosudil efficacy. Coadministration with another strong CYP3A inducer decreased belumosudil exposure by 72% in healthy subjects.
Benzhydrocodone; Acetaminophen: (Moderate) Concurrent use of benzhydrocodone with St. John's Wort may decrease hydrocodone plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to opioid agonists. If concomitant use is necessary, consider increasing the benzhydrocodone dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Discontinuation of St. John's Wort may increase the risk of increased opioid-related adverse reactions, such as fatal respiratory depression. If St. John's Wort is discontinued, consider a benzhydrocodone dosage reduction and monitor patients for respiratory depression and sedation at frequent intervals. Benzhydrocodone is a prodrug of hydrocodone. St. John's Wort is a strong inducer of CYP3A4, an isoenzyme partially responsible for the metabolism of hydrocodone. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Contraindicated) Concurrent use of methylene blue and St. John's Wort, hypericum perforatum should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and St. John's Wort increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving St. John's Wort, it is advisable to discontinue the St. John's Wort and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to stop the St. John's Wort for at least 2 weeks prior to methylene blue treatment.
Benzphetamine: (Moderate) Coadministration of St. John's Wort with amphetamines may increase the risk of serotonin syndrome. At high doses, amphetamines can increase serotonin release, as well as act as serotonin agonists. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly at initiation of treatment, after a dose increase, or the addition of other serotonergic medications. Discontinue serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Berotralstat: (Major) Avoid coadministration of berotralstat with St. John's Wort. Concurrent use may decrease berotralstat exposure, leading to reduced efficacy. Berotralstat is a P-gp substrate and St. John's Wort is a P-gp inducer.
Betrixaban: (Major) Avoid the concomitant administration of betrixaban and St. John's wort. Concomitant administration of betrixaban and St. John's wort results in decreased plasma concentrations of betrixaban that may be insufficient to achieve the intended therapeutic effect. Betrixaban is a P-glycoprotein (P-gp) substrate and St. John's wort is a P-gp inducer.
Bexarotene: (Major) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs such as retinoids.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Major) Administering tenofovir alafenamide with St. John's wort is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure. (Major) Concomitant use of bictegravir and St. John's Wort is not recommended as coadministration may result in decreased bictegravir plasma concentrations, which may result in the loss of therapeutic efficacy and development of resistance. Bictegravir is a substrate of CYP3A4; St. John's Wort is a strong inducer of CYP3A4.
Bortezomib: (Minor) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including bortezomib.
Bosentan: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4. Coadministration of St. John's wort could decrease the efficacy of some medications metabolized by this enzyme, such as bosentan. Clinicians should observe patients closely if St. John's wort is used.
Bosutinib: (Major) Avoid concomitant use of bosutinib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as St. John's Wort, as a large decrease in bosutinib plasma exposure may occur.
Brentuximab vedotin: (Minor) Concomitant administration of brentuximab vedotin and potent CYP3A4 inducers, like St. John's wort, Hypericum perforatum may decrease the exposure of monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin. MMAE is a CYP3A4 substrate and St. John's wort, Hypericum perforatum is a potent CYP3A4 inducer. It may be advisable for patients to avoid St. John's wort when receiving brentuximab vedotin treatment.
Brexpiprazole: (Major) Because brexpiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the brexpiprazole dose be doubled over 1 to 2 weeks when a strong CYP3A4 inducer, such as St. John's Wort, is added to brexpiprazole therapy. When the CYP3A4 inducer is withdrawn from the combination therapy, the brexpiprazole dose should be reduced to the original level over 1 to 2 weeks.
Brigatinib: (Major) Avoid coadministration of brigatinib with St. John's Wort due to decreased plasma exposure to brigatinib which may result in decreased efficacy. Brigatinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the AUC and Cmax of brigatinib by 80% and 60%, respectively.
Brivaracetam: (Major) Co-administration of brivaracetam with St. John's Wort, Hypericum perforatum may decrease brivaracetam plasma concentrations, likely because of CYP2C19 induction by St. John's Wort. When metabolized, brivaracetam undergoes hydroxylation that is mediated by CYP2C19. During drug interaction studies, co-administration of brivaracetam with rifampin, another CYP2C19 inducer, decreased brivaracetam plasma concentrations by 45%. The dose of brivaracetam should be increased by up to 100% in patients in patients taking concomitant rifampin, and similar consideration may be warranted when brivaracetam is used with St. John's Wort.
Bromocriptine: (Moderate) Caution and close monitoring are advised if bromocriptine and St. John's Wort are used together. Concurrent use may decrease the plasma concentrations of bromocriptine resulting in loss of efficacy. Bromocriptine is extensively metabolized by the liver via CYP3A4; St. John's Wort is a strong inducer of CYP3A4.
Brompheniramine; Dextromethorphan; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Brompheniramine; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent.
Brompheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Bupivacaine; Epinephrine: (Moderate) Monitor blood pressure during concomitant use of epinephrine and St. John's Wort. Patients receiving St. John's Wort may experience severe, prolonged hypertension when given epinephrine. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the pressor effects of epinephrine.
Bupivacaine; Lidocaine: (Moderate) Concomitant use of systemic lidocaine and St. John's Wort may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; St. John's Wort induces CYP3A4.
Buprenorphine: (Moderate) The use of St. John's wort with buprenorphine is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of buprenorphine and also for signs of opioid withdrawal in patients who have developed physical dependence to buprenorphine. Buprenorphine is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Also monitor patients for the emergence of serotonin syndrome; both agents have serotonergic activity. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Buprenorphine; Naloxone: (Moderate) The use of St. John's wort with buprenorphine is not recommended. If coadministration cannot be avoided, monitor for decreased efficacy of buprenorphine and also for signs of opioid withdrawal in patients who have developed physical dependence to buprenorphine. Buprenorphine is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Also monitor patients for the emergence of serotonin syndrome; both agents have serotonergic activity. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Butalbital; Acetaminophen: (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Butalbital; Acetaminophen; Caffeine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer. (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Butalbital; Aspirin; Caffeine; Codeine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer. (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine.
Cabotegravir; Rilpivirine: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Cabozantinib: (Major) Avoid coadministration of cabozantinib with St. Johns Wort due to the risk of decreased cabozantinib exposure which could affect efficacy. If concomitant use is unavoidable, increase the dose of cabozantinib. For patients taking cabozantinib tablets, increase the dose of cabozantinib by 20 mg (e.g., 60 mg/day to 80 mg/day; 40 mg/day to 60 mg/day); the daily dose should not exceed 80 mg. For patients taking cabozantinib capsules, increase the dose of cabozantinib by 40 mg (e.g., 140 mg/day to 180 mg/day or 100 mg/day to 140 mg/day); the daily dose should not exceed 180 mg. Resume the cabozantinib dose that was used prior to initiating treatment with St. Johns Wort 2 to 3 days after discontinuation of St. Johns Wort. Cabozantinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer, although the effect varies widely and is preparation-dependent. Coadministration with another strong CYP3A4 inducer decreased single-dose cabozantinib exposure by 77%.
Caffeine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine.
Caffeine; Sodium Benzoate: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
Capivasertib: (Major) Avoid coadministration of capivasertib with St. John's Wort due to decreased capivasertib exposure and risk of decreased efficacy. Capivasertib is a CYP3A substrate; St. John's Wort is a strong CYP3A inducer. Coadministration of another strong CYP3A inducer is predicted to decrease the capivasertib overall exposure by 70%.
Capmatinib: (Major) Avoid coadministration of capmatinib and St. John's Wort due to the risk of decreased capmatinib exposure, which may reduce its efficacy. Capmatinib is a CYP3A substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased capmatinib exposure by 67%.
Capsaicin; Metaxalone: (Moderate) Concomitant use of metaxalone and St. John's Wort may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Carbamazepine: (Moderate) Monitor carbamazepine concentrations closely during coadministration of St. John's Wort; carbamazepine dose adjustments may be needed. Concomitant use may decrease carbamazepine concentrations. Carbamazepine is a CYP3A4 substrate and St. John's Wort is a CYP3A4 inducer.
Cariprazine: (Major) Cariprazine and its active metabolites are extensively metabolized by CYP3A4. Concurrent use of cariprazine with CYP3A4 inducers, such as St. John's Wort, has not been evaluated and is not recommended because the net effect on active drug and metabolites is unclear.
Carisoprodol: (Minor) Carisoprodol is metabolized via CYP2C19. The formation of meprobamate (active metabolite of carisoprodol) is catalyzed by CYP2C19. If carisoprodol is combined with an inducer of CYP2C19 such as St. John's Wort, Hypericum perforatum, the potential exists for increased metabolism of carisoprodol. Theoretically, carisoprodol plasma concentrations could be decreased, and meprobamate (active metabolite) plasma concentrations could be increased. The clinical significance of this interaction is unknown.
Celecoxib; Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with St. John's wort is necessary; consider increasing the dose of tramadol as needed. If St. John's wort is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ceritinib: (Major) Avoid concomitant use of ceritinib with St. Johns Wort as ceritinib exposure may be decreased, which may reduce its efficacy. Ceritinib is a CYP3A substrate and St. Johns Wort is a strong CYP3A inducer. Coadministration with a strong CYP3A inducer decreased ceritinib exposure by 70%.
Cetirizine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Chlordiazepoxide: (Major) St. John's Wort may induce the hepatic CYP3A4 metabolism of chlordiazepoxide which is metabolized by oxidation. It would be prudent to avoid co-administration of St. John's Wort with chlordiazepoxide. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
Chlordiazepoxide; Amitriptyline: (Major) St. John's Wort may induce the hepatic CYP3A4 metabolism of chlordiazepoxide which is metabolized by oxidation. It would be prudent to avoid co-administration of St. John's Wort with chlordiazepoxide. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort. (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Chlordiazepoxide; Clidinium: (Major) St. John's Wort may induce the hepatic CYP3A4 metabolism of chlordiazepoxide which is metabolized by oxidation. It would be prudent to avoid co-administration of St. John's Wort with chlordiazepoxide. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer.
Chlorpheniramine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with St. John's Wort can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If St. John's Wort is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Chlorpheniramine; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent.
Chlorpheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Cilostazol: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes, including cilostazol.
Cisapride: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including cisapride.
Citalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering citalopram and St. John's wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Clarithromycin: (Moderate) St. John's Wort appears to induce CYP3A4 and may lead to increased systemic clearance of clarithromycin, a CYP3A4 substrate. Additionally, clarithromycin may increase serum concentrations of St. John's Wort due to CYP3A4 inhibition. Postmarketing reports of interactions have been noted.
Clindamycin: (Moderate) Monitor for loss of clindamycin efficacy with coadministration of St. John's Wort as concurrent use may decrease clindamycin exposure. In the presence of strong CYP3A4 inducers, monitor for loss of clindamycin effectiveness. Clindamycin is a CYP3A4 substrate; St. John's Wort is a strong inducer of CYP3A4.
Clomipramine: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Clonazepam: (Moderate) Monitor patients for decreased clonazepam efficacy when coadministered with St. John's Wort. Adjust clonazepam dosage if clinically warranted. Clonazepam is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. When clonazepam is used with other strong CYP3A4 inducers, a reduction of clonazepam concentration of approximately 38% has been reported.
Clorazepate: (Major) St. John's Wort may induce the hepatic CYP3A4 metabolism of clorazepate which is metabolized by oxidation. It would be prudent to avoid co-administration of St. John's Wort with clorazepate. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
Clozapine: (Major) Concomitant use of clozapine, a CYP3A4 substrate, with strong CYP3A4 inducers, including St. John's Wort, Hypericum perforatum, is not recommended; however, if this combination is necessary, monitor for decreased effectiveness with consideration for increasing the clozapine dose if clinically warranted. St. John's Wort is also a CYP1A2 inducer, which may further increase the elimination of clozapine.
Cobicistat: (Contraindicated) Coadministration of St. John's Wort, Hypericum perforatum with cobicistat is contraindicated. St. John's Wort induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided.
Cobimetinib: (Major) Avoid the concurrent use of cobimetinib with St. John's Wort, Hypericum perforatum due to decreased cobimetinib efficacy. Cobimetinib is a CYP3A substrate in vitro; St. John's Wort is a strong inducer of CYP3A. Based on simulations, cobimetinib exposure would decrease by 83% when coadministered with a strong CYP3A inducer.
Cocaine: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with drugs with sympathomimetic-like actions, like cocaine.
Cod Liver Oil: (Moderate) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs such as retinoids.
Codeine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Codeine; Phenylephrine; Promethazine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with St. John's Wort can decrease codeine levels, resulting in less metabolism by CYP2D6 and decreased morphine concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor for reduced efficacy of codeine and signs of opioid withdrawal; consider increasing the dose of codeine as needed. If St. John's Wort is discontinued, consider a dose reduction of codeine and frequently monitor for signs or respiratory depression and sedation. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties. St. John's Wort is a strong CYP3A4 inducer.
Conjugated Estrogens: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Bazedoxifene: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Conjugated Estrogens; Medroxyprogesterone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and St. John's Wort; decreased copanlisib exposure and loss of efficacy may occur. Copanlisib is a CYP3A substrate; St. John's Wort is a strong CYP3A inducer. The AUC and Cmax values of copanlisib decreased by 60% and 12%, respectively, when a single IV dose of copanlisib 60 mg was administered following 12 days of another strong CYP3A4 inducer in a drug interaction study in patients with cancer.
Crizotinib: (Major) Avoid coadministration of crizotinib with St. John's Wort due to decreased plasma concentrations of crizotinib, which may result in decreased efficacy. Crizotinib is primarily metabolized by CYP3A and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the crizotinib AUC and Cmax at steady state by 84% and 79%, respectively.
Cyclosporine: (Contraindicated) Clinical interactions between cyclosporine and St. John's wort, Hypericum perforatum have been reported. It appears that St. John's wort may increase the metabolism of cyclosporine through induction of the hepatic CYP3A4 isoenzyme. Clinically, decreased cyclosporine concentrations resulting from the concurrent administration of St. John's wort have led to reports of acute heart transplant rejection. A similar report of subtherapeutic cyclosporine concentrations has been noted in a kidney-pancreas transplant patient who self-medicated with St. John's wort. Graft loss has occurred. St. John's wort in all forms, including teas, should be avoided in patients treated with cyclosporine.
Dabigatran: (Major) In general, avoid coadministration of dabigatran with P-gp inducers, such as St. John's Wort, Hypericum perforatum. Concomitant administration of dabigatran and rifampin, another P-gp inducer, resulted in a significant decrease in dabigatran AUC and Cmax.
Daclatasvir: (Contraindicated) Concomitant use of daclatasvir with St. John's Wort, Hypericum perforatum is contraindicated due to the potential for hepatitis C treatment failure. Coadministration may result in reduced systemic exposes to daclatasvir. St. John's Wort is a potent inducer of the hepatic isoenzyme CYP3A4; daclatasvir is a substrate of this isoenzyme.
Dapsone: (Moderate) Monitor for an increase in hemolysis if coadministration of dapsone with St. John's Wort is necessary; dapsone efficacy may also be compromised. Dapsone is a CYP3A4 metabolite and St. John's Wort is a strong CYP3A4 inducer. Strong CYP3A4 inducers may increase the formation of dapsone hydroxylamine, a metabolite associated with hemolysis. Coadministration with another strong CYP3A4 inducer decreased dapsone levels by 7-fold to 10-fold; in leprosy, this reduction has not required a change in dosage.
Daridorexant: (Major) Avoid concomitant use of daridorexant and St. John's Wort. Coadministration may decrease daridorexant exposure which may reduce its efficacy. Daridorexant is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer decreased daridorexant overall exposure by over 50%.
Darolutamide: (Major) Avoid coadministration of darolutamide with St. John's Wort due to the risk of decreased darolutamide plasma concentrations which may decrease efficacy. St. John's Wort is a P-glycoprotein (P-gp) inducer and a strong inducer of CYP3A4; darolutamide is a CYP3A4 substrate. Concomitant use with another combined P-gp and strong CYP3A4 inducer decreased the mean AUC and Cmax of darolutamide by 72% and 52%, respectively.
Darunavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Darunavir; Cobicistat: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer. (Contraindicated) Coadministration of St. John's Wort, Hypericum perforatum with cobicistat is contraindicated. St. John's Wort induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer. (Contraindicated) Coadministration of St. John's Wort, Hypericum perforatum with cobicistat is contraindicated. St. John's Wort induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided. (Major) Administering tenofovir alafenamide with St. John's wort is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
Dasatinib: (Major) Avoid coadministration of dasatinib and St. John's wort due to the potential for decreased dasatinib exposure and reduced efficacy. Consider an alternative to St. John's wort with less potential for enzyme induction. If coadministration cannot be avoided, consider an increased dose of dasatinib and monitor for toxicity. Dasatinib is a CYP3A4 substrate; St. John's wort is a strong CYP3A4 inducer. Concurrent use of another strong CYP3A4 inducer decreased the mean Cmax and AUC of dasatinib by 81% and 82%, respectively.
Deflazacort: (Major) Avoid concomitant use of deflazacort and St. John's Wort. Concurrent use may significantly decrease concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in loss of efficacy. Deflazacort is a CYP3A4 substrate; St. John's Wort is a strong inducer of CYP3A4. Administration of deflazacort with multiple doses of rifampin (a strong CYP3A4 inducer) resulted in geometric mean exposures that were approximately 95% lower compared to administration alone.
Delavirdine: (Contraindicated) St. John's wort appears to be an inducer of hepatic cytochrome P450 enzymes, particularly CYP3A4 and, it is expected that St. John's wort may significantly decrease the plasma concentrations of delavirdine. Such reductions in plasma concentrations of delavirdine could lead to HIV treatment failures or the development of viral-resistance. St. John's wort in all forms, including teas, should be avoided in HIV patients treated with delavirdine.
Desipramine: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Desloratadine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Desogestrel; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Desvenlafaxine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Dexamethasone: (Moderate) Monitor for decreased efficacy of dexamethasone if coadministration with St. John's wort is necessary; consider increasing the dose of dexamethasone if clinically appropriate. Dexamethasone is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Dexlansoprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Dexmethylphenidate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering methylphenidate derivatives and St. John's Wort. There are rare reports of serotonin syndrome occurring during use of other serotonergicagents and methylphenidate or its derivatives. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Dextroamphetamine: (Moderate) Coadministration of St. John's Wort with amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Bupropion: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Dextromethorphan; Guaifenesin; Pseudoephedrine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Dextromethorphan; Quinidine: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4. Coadministration of St. John's wort could decrease the efficacy of some medications metabolized by this enzyme, such as quinidine. Clinicians should observe patients closely if St. John's wort is used. (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Diazepam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with St. John's Wort is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and St. John's Wort is a CYP3A4 inducer.
Dienogest; Estradiol valerate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Diethylpropion: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
Digoxin: (Moderate) Consider if St. John's Wort supplementation is appropriate in patients receiving digoxin. Monitor serum digoxin concentrations before starting St. John's Wort. Continue monitoring during concomitant treatment and increase the digoxin dose by 20 to 40% as necessary. Conversely, the discontinuation of St. John's wort could lead to increased digoxin exposure and potential toxicity. An interaction between St. John's wort, Hypericum perforatum and digoxin has been studied. After the achievement of steady-state digoxin levels, 25 healthy volunteers received digoxin (0.25 mg/day) either with placebo or with St. John's wort extract (900 mg/day),patients receiving St. John's Wort had a reduction in digoxin AUC of approximately 25%. Digoxin trough concentrations and Cmax decreased by 33% and 26%, respectively. St. John's wort appears to induce the P-glycoprotein intestinal drug transporter, which extrudes digoxin back into the GI tract and results in decreased systemic bioavailability.
Diltiazem: (Major) Avoid coadministration of diltiazem and St. John's wort if possible due to the potential for decreased plasma concentrations of diltiazem. Diltiazem is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered diltiazem plasma concentrations to undetectable.
Diphenhydramine; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent.
Disopyramide: (Major) Hepatic microsomal enzyme-inducing agents, such as St. John's wort, have the potential to accelerate the hepatic metabolism of disopyramide (CYP3A4 substrate). Patients should be monitored for loss of disopyramide activity. In addition, disopyramide doses may need to be reduced if these agents are stopped and disopyramide therapy is continued. Serum disopyramide concentrations should be monitored closely if hepatic enzyme inducers are either added or discontinued during disopyramide therapy.
Dobutamine: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions.
Docetaxel: (Major) Avoid coadministration of docetaxel with St. John's Wort due to decreased plasma concentrations of docetaxel. Docetaxel is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Concomitant use with St. John's Wort increased docetaxel metabolism by 2.6-fold to 32-fold.
Dofetilide: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by CYP3A4, such as dofetilide. Clinicians should observe patients closely if St. John's wort is used.
Dolutegravir: (Major) Avoid concurrent use of dolutegravir with St. John's Wort, Hypericum perforatum as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. St. John's Wort is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Lamivudine: (Major) Avoid concurrent use of dolutegravir with St. John's Wort, Hypericum perforatum as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. St. John's Wort is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Dolutegravir; Rilpivirine: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Avoid concurrent use of dolutegravir with St. John's Wort, Hypericum perforatum as coadministration may result in decreased dolutegravir plasma concentrations. Currently, there are insufficient data to make dosing recommendations; however, predictions regarding this interaction can be made based on the drugs metabolic pathways. St. John's Wort is an inducer of CYP3A, dolutegravir is partially metabolized by this isoenzyme.
Donepezil: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including donepezil.
Donepezil; Memantine: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including donepezil.
Dopamine: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines, such as dopamine and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions.
Doravirine: (Contraindicated) Concurrent administration of doravirine and St. John's Wort is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Contraindicated) Concurrent administration of doravirine and St. John's Wort is contraindicated due to decreased doravirine exposure, resulting in potential loss of virologic control. At least a 4-week cessation period is recommended before initiating treatment with doravirine. Doravirine is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer.
Doxepin: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Doxercalciferol: (Moderate) Although these interactions have not been specifically studied, hepatic enzyme inducers, such as St. John's Wort, may affect the 25-hydroxylation of doxercalciferol and may necessitate dosage adjustments of doxercalciferol.
Doxorubicin Liposomal: (Major) St. John's Wort, Hypericum perforatum, is a potent inducer of CYP3A4 and a moderate P-glycoprotein (P-gp) inducer; doxorubicin is a major substrate of both CYP3A4 and P-gp. Inducers of CYP3A4 and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of St. John's Wort and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Doxorubicin: (Major) St. John's Wort, Hypericum perforatum, is a potent inducer of CYP3A4 and a moderate P-glycoprotein (P-gp) inducer; doxorubicin is a major substrate of both CYP3A4 and P-gp. Inducers of CYP3A4 and/or P-gp may decrease the concentration of doxorubicin and compromise the efficacy of chemotherapy. Avoid coadministration of St. John's Wort and doxorubicin if possible. If not possible, monitor doxorubicin closely for efficacy.
Dronabinol: (Moderate) Use caution if coadministration of dronabinol with St. John's Wort, Hypericum perforatum is necessary, and monitor for a decrease in the efficacy of dronabinol. Dronabinol is a CYP2C9 and 3A4 substrate. St. John's Wort is a strong inducer of CYP3A4 and a moderate CYP2C9 inducer; however, the amount of individual constituents in various products may alter the inhibiting or inducing effects, making drug interactions unpredictable. Concomitant use may result in decreased plasma concentrations of dronabinol.
Dronedarone: (Major) The concomitant use of dronedarone and CYP3A4 inducers should be avoided. Dronedarone is metabolized by CYP3A. St. John's Wort, Hypericum perforatum induces CYP3A4. Coadministration of CYP3A4 inducers, such as St. John's Wort, with dronedarone may result in reduced plasma concentration and subsequent reduced effectiveness of dronedarone therapy.
Drospirenone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Estetrol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Drospirenone; Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Drospirenone; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Duloxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Duvelisib: (Major) Avoid coadministration of duvelisib with St. John's Wort. Coadministration may decrease the exposure of duvelisib, which may reduce the efficacy of duvelisib. Duvelisib is a CYP3A substrate; St. John's Wort is a strong CYP3A inducer. In drug interaction studies, coadministration of duvelisib with another strong CYP3A inducer for 7 days decreased duvelisib Cmax and AUC by 66% and 82%, respectively.
Edoxaban: (Moderate) Coadministration of edoxaban and St. John's Wort, Hypericum perforatum may result in decreased concentrations of edoxaban. Edoxaban is a P-glycoprotein (P-gp) substrate and St. John's Wort is a P-gp inducer. Decreased concentrations of edoxaban may occur during concomitant use of St. John's Wort; monitor for decreased efficacy of edoxaban.
Efavirenz: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and efavirenz is contraindicated. When coadministered, there is a potential for treatment failure and the development of efavirenz or NNRTI resistance. St. John's Wort is a strong inducer of CYP3A4, which is partially responsible for the metabolism of efavirenz. Coadministration may result in decreased efavirenz serum concentrations, which could cause impaired virologic response.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and efavirenz is contraindicated. When coadministered, there is a potential for treatment failure and the development of efavirenz or NNRTI resistance. St. John's Wort is a strong inducer of CYP3A4, which is partially responsible for the metabolism of efavirenz. Coadministration may result in decreased efavirenz serum concentrations, which could cause impaired virologic response.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and efavirenz is contraindicated. When coadministered, there is a potential for treatment failure and the development of efavirenz or NNRTI resistance. St. John's Wort is a strong inducer of CYP3A4, which is partially responsible for the metabolism of efavirenz. Coadministration may result in decreased efavirenz serum concentrations, which could cause impaired virologic response.
Elacestrant: (Major) Avoid concurrent use of elacestrant and St. John's Wort due to the risk of decreased elacestrant exposure which may reduce its efficacy. Elacestrant is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced elacestrant overall exposure by 86%.
Elagolix: (Moderate) Concomitant use of elagolix and St. John's Wort may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; St. John's Wort is a strong inducer of CYP3A.
Elagolix; Estradiol; Norethindrone acetate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination. (Moderate) Concomitant use of elagolix and St. John's Wort may result in decreased concentrations of elagolix; monitor for decreased efficacy with coadministration. Elagolix is a CYP3A substrate; St. John's Wort is a strong inducer of CYP3A.
Elbasvir; Grazoprevir: (Contraindicated) Concurrent administration of elbasvir; grazoprevir with St. John's Wort, Hypericum perforatum is contraindicated. St. John's Wort is a strong CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together is expected to significantly decrease the plasma concentrations of both elbasvir and grazoprevir, and may result in decreased virologic response.
Eletriptan: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Elexacaftor; tezacaftor; ivacaftor: (Major) Coadministration of elexacaftor; tezacaftor; ivacaftor with St. John's Wort is not recommended as concurrent use may decrease exposure of elexacaftor; tezacaftor; ivacaftor. Elexacaftor, tezacaftor, and ivacaftor are CYP3A4 substrates (ivacaftor is a sensitive CYP3A4 substrate). Coadministration of a strong CYP3A4 inducer significantly decreased ivacaftor exposure by 89%; elexacaftor and tezacaftor exposures are expected to also decrease during coadministration of strong CYP3A4 inducers. (Major) Coadministration of ivacaftor with St. John's Wort is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and St. John's Wort together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of St. John's Wort, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
Eliglustat: (Major) Coadministration of eliglustat and St. John's Wort, Hypericum perforatum significantly decreases eliglustat exposure and is not recommended in extensive, intermediate, or poor metabolizers of CYP2D6. St. John's Wort is a strong CYP3A inducer, and eliglustat is a CYP3A substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of St. John's Wort, Hypericum perforatum with cobicistat is contraindicated. St. John's Wort induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided. (Major) Administering tenofovir alafenamide with St. John's wort is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure. (Major) Coadministration of St. John's Wort, Hypericum perforatum with elvitegravir is not recommended. St. John's Wort induces CYP3A4; elvitegravir is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of St. John's Wort, Hypericum perforatum with cobicistat is contraindicated. St. John's Wort induces CYP3A4; cobicistat is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of cobicistat and of the simultaneously administered protease inhibitors (atazanavir or darunavir), leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided. (Major) Coadministration of St. John's Wort, Hypericum perforatum with elvitegravir is not recommended. St. John's Wort induces CYP3A4; elvitegravir is a substrate of this enzyme. Concurrent use may result in significant decreases in the plasma concentrations of elvitegravir, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. St. John's Wort in all forms, including teas, should be avoided.
Empagliflozin; Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and St. John's wort if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Empagliflozin; Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and St. John's wort if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine. (Major) Administering tenofovir alafenamide with St. John's wort is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Emtricitabine; Tenofovir alafenamide: (Major) Administering tenofovir alafenamide with St. John's wort is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
Encorafenib: (Major) Avoid concomitant use of encorafenib and St. John's wort. Concurrent use may decrease encorafenib exposure which may reduce its efficacy. Encorafenib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Entrectinib: (Major) Avoid coadministration of entrectinib with St. John's Wort due to decreased entrectinib exposure and risk of decreased efficacy. Entrectinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the entrectinib AUC by 77% in a drug interaction study.
Enzalutamide: (Major) Avoid coadministration of St. John's Wort with enzalutamide if possible due to decreased enzalutamide exposure which may compromise efficacy. If concomitant use is unavoidable, increase the dose of enzalutamide from 160 mg to 240 mg once daily; the original dose of enzalutamide may be resumed when St. John's Wort is discontinued. Enzalutamide is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the composite AUC of enzalutamide plus N-desmethyl enzalutamide by 37%.
Ephedrine: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions.
Ephedrine; Guaifenesin: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions.
Epinephrine: (Moderate) Monitor blood pressure during concomitant use of epinephrine and St. John's Wort. Patients receiving St. John's Wort may experience severe, prolonged hypertension when given epinephrine. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the pressor effects of epinephrine.
Eplerenone: (Minor) St. John's Wort is a CYP3A4 inducer and causes a small (30%) decrease in eplerenone AUC. It is not known if the interaction is clinically significant. Advise patients to avoid this herbal dietary supplement. If a patient is using St. John's Wort with eplerenone, monitor the patient closely for evidence of decreased efficacy.
Eravacycline: (Major) Increase the dose of eravacycline to 1.5 mg/kg IV every 12 hours when coadministered with a strong CYP3A4 inducer, such as St John's Wort, Hypericum perforatum. Concomitant use of strong CYP3A4 inducers decreases the exposure of eravacycline, which may reduce its efficacy. When eravacycline was administered with a strong CYP3A4/3A5 inducer, the eravacycline AUC was decreased by 35% and its clearance was increased by 54%.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and St. John's wort due to the risk of decreased plasma concentrations of erdafitinib resulting in decreased efficacy. Erdafitinib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Ergotamine; Caffeine: (Moderate) Inducers of CYP1A2, such as St. John's wort, Hypericum perforatum, may induce the hepatic oxidative metabolism of caffeine.
Erlotinib: (Major) Avoid coadministration of erlotinib with St. John's Wort if possible due to the risk of decreased erlotinib efficacy. If concomitant use is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals as tolerated (maximum dose, 450 mg). Erlotinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer, although the amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased erlotinib exposure by 58% to 80%.
Escitalopram: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering escitalopram and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Esomeprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Estazolam: (Moderate) St. John's Wort is a hepatic inducer and can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, possibly leading to reduced benzodiazepine concentrations.
Esterified Estrogens: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Esterified Estrogens; Methyltestosterone: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Levonorgestrel: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Norethindrone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Norgestimate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estradiol; Progesterone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estrogens affected by CYP3A inducers: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Estropipate: (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Eszopiclone: (Major) Potent inducers of CYP3A4, such as St. John's Wort, may increase the rate of eszopiclone metabolism.
Ethanol: (Minor) Since some compounds in St. John's wort may potentially inhibit MAO, and some beverages that contain alcohol may contain tyramine, it may be prudent to avoid concomitant use of alcohol and St. John's Wort.
Ethinyl Estradiol; Norelgestromin: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norethindrone Acetate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethinyl Estradiol; Norgestrel: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Ethotoin: (Major) Avoid if possible; St. John's wort could decrease the efficacy of hydantoins metabolized by CYP450 enzymes, including hydantoins as St. John's wort induces CYP2C9 and other CYP450 enzymes. Clinicians should observe patients closely if St. John's wort is used; careful monitoring of anticonvulsant drug concentrations may be needed.
Ethynodiol Diacetate; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Etomidate: (Contraindicated) St. John's wort, Hypericum perforatum, may intensify or prolong the effects of general anesthetics; profound hypotension has also been reported. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that patients stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
Etonogestrel: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Etonogestrel; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Etravirine: (Major) St. John's wort should not be administered with etravirine as it may significantly decrease the plasma concentrations of etravirine. Such reductions in plasma concentrations of etravirine could lead to HIV treatment failures or the development of viral-resistance. St. John's wort appears to be an inducer of hepatic cytochrome P450 enzymes, particularly CYP3A4. Etravirine is a CYP3A4 substrate.
Everolimus: (Major) Avoid coadministration of everolimus with St. Johns Wort due to the risk of decreased efficacy of everolimus. If concomitant use is unavoidable, coadministration requires a dose increase for some indications and close monitoring for others. For oncology indications and tuberous sclerosis complex (TSC)-associated renal angiomyolipoma, double the daily dose using increments of 5 mg or less; multiple increments may be required. For patients with TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated partial-onset seizures, assess the everolimus whole blood trough concentration 2 weeks after initiation of St. Johns Wort and adjust the dose as necessary to remain in the recommended therapeutic range. Also closely monitor everolimus whole blood trough concentrations in patients receiving everolimus for either kidney or liver transplant and adjust the dose as necessary to remain in the recommended therapeutic range. Everolimus is a sensitive CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of everolimus by 63%. For indications where everolimus trough concentrations are monitored, the addition of a second strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dose modification.
Exemestane: (Major) If coadministration of exemestane with St. John's Wort is necessary, increase the dose of exemestane to 50 mg once daily after a meal. Exemestane is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer, although the amount of individual constituents of various St. John's Wort products may alter its inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased exemestane exposure by 54%.
Ezetimibe; Simvastatin: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, CYP1A2, and potentially CYP2C9. Co-administration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including simvastatin.
Fedratinib: (Major) Avoid coadministration of fedratinib with St. John's Wort as concurrent use may decrease fedratinib exposure which may result in decreased therapeutic response. Fedratinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of fedratinib with another strong CYP3A4 inducer decreased the overall exposure of fedratinib by 81%.
Felodipine: (Major) St. John's wort appears to induce the metabolism of the calcium-channel blockers, such as felodipine, apparently by the induction of the CYP3A4 isoenzyme leading to reduced clinical efficacy. The metabolism of calcium channel blockers may also be increased.
Fenfluramine: (Major) Avoid concurrent use of fenfluramine and St. John's Wort due to the risk of decreased fenfluramine plasma concentrations, which may reduce its efficacy. Concomitant use may also increase the risk for serotonin syndrome. If concomitant use is necessary, monitor for decreased fenfluramine efficacy and serotonin syndrome. Fenfluramine is a CYP1A2, CYP2B6, and CYP3A substrate and St. John's Wort is a CYP1A2, CYP2B6, and strong CYP3A inducer.
Fentanyl: (Moderate) Consider an increased dose of fentanyl and monitor for evidence of opioid withdrawal if coadministration with St. John's wort is necessary. If St. John's wort is discontinued, consider reducing the fentanyl dosage and monitor for evidence of respiratory depression. Coadministration of a strong CYP3A4 inducer like St. John's wort with fentanyl, a CYP3A4 substrate, may decrease exposure to fentanyl resulting in decreased efficacy or onset of withdrawal symptoms in a patient who has developed physical dependence to fentanyl. Fentanyl plasma concentrations will increase once the inducer is stopped, which may increase or prolong the therapeutic and adverse effects, including serious respiratory depression. Additive serotonergic effects are also possible with this drug-herb combination. Caution and careful monitoring, particularly during treatment initiation and dose adjustment, is recommended due to the potential for serotonin syndrome. Serotonin syndrome may occur within the recommended dosage range. Discontinue fentanyl if serotonin syndrome is suspected. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Monitor the patient closely if use of St. John's wort is reported pre-operatively. The American Society of Anesthesiologists has recommended that, if possible, patients should stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
Fexinidazole: (Major) Avoid concurrent use of fexinidazole and St. John's Wort. Coadministration may increase the risk for fexinidazole-related adverse effects including QT prolongation. Concomitant use may enhance the conversion of fexinidazole to its active metabolites. Higher metabolite concentrations have been associated with increased risk of QT prolongation. Fexinidazole is converted to its active metabolites via CYP3A and St. John's Wort is a strong CYP3A inducer.
Fexofenadine: (Minor) St. John's Wort may increase, decrease, or not change the plasma concentrations and AUC of fexofenadine. The mechanisms proposed have included CYP3A4 induction and/or altered P-glycoprotein efflux transport of fexofenadine. The clinical importance of this theoretical interaction has not been established; further study is needed.
Fexofenadine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure. (Minor) St. John's Wort may increase, decrease, or not change the plasma concentrations and AUC of fexofenadine. The mechanisms proposed have included CYP3A4 induction and/or altered P-glycoprotein efflux transport of fexofenadine. The clinical importance of this theoretical interaction has not been established; further study is needed.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil with St. John's wort in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of St. John's wort due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Finerenone: (Major) Avoid concurrent use of finerenone and St. John's Wort due to the risk for decreased finerenone exposure which may reduce its efficacy. Finerenone is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased overall exposure to finerenone by 90%.
Flibanserin: (Major) The concomitant use of flibanserin with CYP3A4 inducers significantly decreases flibanserin exposure compared to the use of flibanserin alone. Therefore, concurrent use of flibanserin and St. John's Wort, Hypericum perforatum, a strong CYP3A4 inducer, is not recommended.
Fluoxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering fluoxetine and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Flurazepam: (Moderate) Monitor patients for decreased efficacy of flurazepam if coadministration with St. John's Wort is necessary. Concurrent use may decrease flurazepam exposure. Flurazepam is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Fluvoxamine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering fluvoxamine and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Food: (Major) Advise patients to avoid cannabis use if they are taking St. John's wort. Concomitant use may decrease the concentration of some cannabinoids and alter their effects. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and St. John's wort is a strong CYP3A inducer. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inducer decreased THC, 11-OH-THC, and CBD peak exposures by 36%, 87%, and 52% respectively. (Minor) Since some compounds in St. John's wort may potentially inhibit MAO, the ingestion of tyramine-containing foods, like aged or smoked meats, yeast, cheeses, pickled herring, should be minimized when using St. John's wort.
Fosamprenavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Fosphenytoin: (Major) Avoid if possible; St. John's wort could decrease the efficacy of hydantoins metabolized by CYP450 enzymes, including hydantoins as St. John's wort induces CYP2C9 and other CYP450 enzymes. Clinicians should observe patients closely if St. John's wort is used; careful monitoring of anticonvulsant drug concentrations may be needed.
Fostamatinib: (Major) Avoid the concomitant use of fostamatinib with St. John's Wort. Concomitant use of fostamatinib with a strong CYP3A4 inducer decreases exposure to the major active metabolite, R406. R406 is extensively metabolized by CYP3A4; St. John's Wort is a strong CYP3A4 inducer. Concomitant use of fostamatinib with another strong CYP3A4 inducer decreased R406 AUC by 75% and Cmax by 59%.
Fostemsavir: (Contraindicated) Concomitant use of fostemsavir and St. John's Wort is contraindicated. Use of these drugs together may significantly decrease the plasma concentrations of temsavir, the active moiety of fostemsavir, thereby increasing the risk for HIV treatment failure or development of viral resistance. Temsavir is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Frovatriptan: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Fruquintinib: (Major) Avoid coadministration of fruquintinib with St. John's wort due to decreased fruquintinib exposure and risk of decreased efficacy. Fruquintinib is a CYP3A substrate; St. John's wort is a strong CYP3A inducer. Coadministration of a strong CYP3A inducer decreased fruquintinib exposure by 65%.
Futibatinib: (Major) Avoid concurrent use of futibatinib and St. John's wort. Concomitant use may decrease futibatinib exposure, which may reduce its efficacy. Futibatinib is a substrate of CYP3A and P-gp; St. John's wort is a dual P-gp and strong CYP3A inducer. Coadministration with another dual P-gp and strong CYP3A inducer decreased futibatinib exposure by 64%.
Ganaxolone: (Major) Avoid concurrent use of ganaxolone and St. John's Wort due to the risk of decreased ganaxolone efficacy. If concomitant use is unavoidable, consider increasing ganaxolone dose without exceeding the maximum daily dose. Ganaxolone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ganaxolone overall exposure by 68%.
Gefitinib: (Major) Increase the dose of gefitinib to 500 mg PO once daily if coadministration with St John's Wort is necessary. If St John's Wort is discontinued, gefitinib at a dose of 250 mg once daily may be resumed 7 days later. Gefitinib is a CYP3A4 substrate and St John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer reduced gefitinib exposure by 83%.
Gemifloxacin: (Major) Use St. John's Wort with caution in patients who are also taking drugs known to be photosensitizers, such as gemifloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Gilteritinib: (Major) Avoid coadministration of gilteritinib and St. John's Wort due to the potential for decreased gilteritinib exposure and risk of decreased efficacy. Gilteritinib is a P-gp and CYP3A4 substrate; St. John's Wort is a combined P-gp and strong CYP3A4 inducer. Coadministration of another combined P-gp and strong CYP3A4 inducer decreased the gilteritinib AUC by 70% in a drug interaction study.
Glasdegib: (Major) Avoid coadministration of glasdegib and St. John's wort due to the potential for decreased glasdegib exposure and risk of decreased efficacy. Glasdegib is a CYP3A4 substrate; St. John's wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the glasdegib AUC by 70% in a drug interaction study.
Glecaprevir; Pibrentasvir: (Major) Coadministration of glecaprevir with St. John's Wort is not recommended due to the potential loss of efficacy of glecaprevir. Glecaprevir is a substrate of CYP3A4 and P-glycoprotein (P-gp); St. John's Wort is a CYP3A4/P-gp inducer. Coadministration may decrease plasma concentrations of glecaprevir. (Major) Coadministration of pibrentasvir with St. John's Wort is not recommended due to the potential loss of efficacy of pibrentasvir. Pibrentasvir is a substrate of P-glycoprotein (P-gp); St. John's Wort is an inducer of P-gp. Coadministration may decrease plasma concentrations of pibrentasvir.
Green Tea: (Minor) Some, but not all, green tea products contain caffeine. Medications that may induce caffeine metabolism via induction of the hepatic CYP1A2 isoenzyme include St. John's wort, Hypericum perforatum.
Guaifenesin; Hydrocodone: (Moderate) Concomitant use of hydrocodone with St. John's Wort can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If St. John's Wort is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Guaifenesin; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent.
Guaifenesin; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Guanfacine: (Major) St. John's Wort, Hypericum perforatum may significantly decrease guanfacine plasma concentrations. FDA-approved labeling for extended-release (ER) guanfacine recommends that, if these agents are taken together, doubling the recommended dose of guanfacine should be considered; if St John's Wort is added in a patient already receiving guanfacine, this escalation should occur over 1 to 2 weeks. If St. John's Wort is discontinued, decrease the guanfacine ER dosage back to the recommended dose over 1 to 2 weeks. Specific recommendations for immediate-release (IR) guanfacine are not available. Guanfacine is primarily metabolized by CYP3A4, and St. John's Wort is a strong CYP3A4 inducer.
Halobetasol; Tazarotene: (Moderate) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs such as retinoids.
Haloperidol: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and could decrease the efficacy of some medications metabolized by these enzymes including haloperidol.
Homatropine; Hydrocodone: (Moderate) Concomitant use of hydrocodone with St. John's Wort can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If St. John's Wort is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Hydantoins: (Major) Avoid if possible; St. John's wort could decrease the efficacy of hydantoins metabolized by CYP450 enzymes, including hydantoins as St. John's wort induces CYP2C9 and other CYP450 enzymes. Clinicians should observe patients closely if St. John's wort is used; careful monitoring of anticonvulsant drug concentrations may be needed.
Hydrocodone: (Moderate) Concomitant use of hydrocodone with St. John's Wort can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If St. John's Wort is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Hydrocodone; Ibuprofen: (Moderate) Concomitant use of hydrocodone with St. John's Wort can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If St. John's Wort is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of hydrocodone with St. John's Wort can decrease hydrocodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. It is recommended to avoid this combination when hydrocodone is being used for cough. If coadministration is necessary, monitor for reduced efficacy of hydrocodone and signs of opioid withdrawal; consider increasing the dose of hydrocodone as needed. If St. John's Wort is discontinued, consider a dose reduction of hydrocodone and frequently monitor for signs or respiratory depression and sedation. Hydrocodone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Hydromorphone: (Moderate) If concomitant use of hydromorphone and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Contraindicated) Concurrent use of methylene blue and St. John's Wort, hypericum perforatum should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and St. John's Wort increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving St. John's Wort, it is advisable to discontinue the St. John's Wort and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to stop the St. John's Wort for at least 2 weeks prior to methylene blue treatment.
Ibrexafungerp: (Major) Avoid concurrent administration of ibrexafungerp with St. John's Wort. Use of these drugs together is expected to significantly decrease ibrexafungerp exposure, which may reduce its efficacy. Ibrexafungerp is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer.
Ibrutinib: (Major) Avoid the concomitant use of ibrutinib and St. John's Wort; ibrutinib plasma concentrations may decrease. Ibrutinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ibrutinib exposure by more than 10-fold.
Ibuprofen; Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with St. John's wort is necessary; consider increasing the dose of oxycodone as needed. If St. John's wort is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additive serotonergic effects are also possible with this drug-herb combination. Caution and careful monitoring, particularly during treatment initiation and dose adjustment, is recommended due to the potential for serotonin syndrome. Serotonin syndrome may occur within the recommended dosage range. Discontinue St. John's wort if serotonin syndrome is suspected. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Ibuprofen; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Idelalisib: (Contraindicated) Avoid concomitant use of idelalisib, a CYP3A4 substrate, with a strong CYP3A4 inducer such as St. John's Wort, Hypericum perforatum, as idelalisib exposure may be significantly reduced and efficacy compromised.
Ifosfamide: (Moderate) Closely monitor for increased ifosfamide-related toxicities (e.g., neurotoxicity, nephrotoxicity) if coadministration with St. John's Wort is necessary; consider adjusting the dose of ifosfamide as clinically appropriate. Ifosfamide is metabolized to its active alkylating metabolites by CYP3A4. St. John's Wort is a strong CYP3A4 inducer; however, the amount of individual constituents in various products of St. John's Wort may alter the inducing effects, making drug interactions unpredictable. Concomitant use may increase the formation of the neurotoxic/nephrotoxic ifosfamide metabolite, chloroacetaldehyde.
Imatinib: (Major) Avoid coadministration of imatinib and St. John's Wort if possible due to decreased plasma concentrations of imatinib. If concomitant use is unavoidable, increase the dose of imatinib by at least 50%, carefully monitoring clinical response; imatinib doses up to 1,200 mg per day (600 mg twice daily) have been given to patients receiving concomitant strong CYP3A4 inducers. Imatinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased imatinib clearance by 3.8-fold, which significantly decreased the mean Cmax and AUC of imatinib.
Imipramine: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Indinavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Infigratinib: (Major) Avoid concurrent use of infigratinib and St. John's Wort. Coadministration may decrease infigratinib exposure resulting in decreased efficacy. Infigratinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of infigratinib by 56%.
Iobenguane I 131: (Major) Discontinue St. John's Wort for at least 5 half-lives before the administration of the dosimetry dose or a therapeutic dose of iobenguane I-131. Do not restart St. John's Wort until at least 7 days after each iobenguane I-131 dose. Drugs that reduce catecholamine uptake or deplete catecholamine stores, such as St. John's Wort, may interfere with iobenguane I-131 uptake into cells and interfere with dosimetry calculations resulting in altered iobenguane I-131 efficacy.
Irinotecan Liposomal: (Major) Avoid administration of St. Johns Wort during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. St. Johns Wort is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Irinotecan: (Major) Avoid administration of St. Johns Wort during treatment with irinotecan and for at least 2 weeks prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates. St. Johns Wort is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers substantially reduced exposure to irinotecan or SN-38 in both adult and pediatric patients. An appropriate starting dose for patients taking irinotecan with strong CYP3A4 inducers has not been defined.
Isavuconazonium: (Contraindicated) Concomitant use of isavuconazonium with St. John's Wort is contraindicated due to the potential for decreased isavuconazole serum concentrations and treatment failure. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate of hepatic isoenzyme CYP3A4; St. John's Wort is a strong inducer of this enzyme. According to the manufacturer, coadministration of isavuconazole with strong CYP3A4 inducers is contraindicated. There was a 97% decrease in isavuconazole serum concentrations when coadministered with rifampin, another strong CYP3A4 inducer.
Isocarboxazid: (Contraindicated) St. John's wort, Hypericum perforatum should not be used concurrently with monoamine oxidase inhibitors (MAOIs) because of the possibility of serotonin syndrome. In patients receiving nonselective MAOs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Isoflurane: (Major) St. John's wort, Hypericum perforatum, may intensify or prolong the effects of general anesthetics; profound hypotension has also been reported. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that patients stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
Isoproterenol: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions.
Isradipine: (Major) St. John's wort appears to induce the metabolism of the calcium-channel blockers, such as isradipine, apparently by the induction of the CYP3A4 isoenzyme leading to reduced clinical efficacy. The metabolism of calcium channel blockers may also be increased.
Istradefylline: (Major) Avoid coadministration of istradefylline with St. John's Wort as istradefylline exposure and efficacy may be reduced. St. John's Wort is a strong inducer. Istradefylline exposure was decreased by 81% when administered with a strong inducer in a drug interaction study.
Itraconazole: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's wort could decrease the efficacy of some medications metabolized by these enzymes including itraconazole.
Ivabradine: (Major) Avoid coadministration of ivabradine and St. John's wort. Ivabradine is primarily metabolized by CYP3A4; St. John's wort induces CYP3A4. Coadministration may decrease the plasma concentrations of ivabradine resulting in the potential for reduced efficacy of ivabradine.
Ivacaftor: (Major) Coadministration of ivacaftor with St. John's Wort is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with St. John's Wort due to decreased plasma concentrations of ivosidenib. Ivosidenib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer is predicted to decrease ivosidenib exposure at steady-state by 33%.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and St. John's Wort due to decreased plasma concentrations of ixabepilone, which may reduce its efficacy. If concomitant use is unavoidable, gradually increase the dose of ixabepilone as tolerated from 40 mg/m2 to 60 mg/m2 and infuse over 4 hours; monitor carefully for ixabepilone-related toxicities. Ixabepilone is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased ixabepilone exposure by 43%.
Ixazomib: (Major) Avoid the concomitant use of ixazomib and St. John's Wort; ixazomib levels may be significantly decreased and its efficacy reduced. Ixazomib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. In subjects who received ixazomib with another strong CYP3A4 inducer, the ixazomib Cmax and AUC values were decreased by 54% and 74%, respectively.
Ketoconazole: (Major) Avoid St. John's Wort for 2 weeks before and during treatment with ketoconazole. Concomitant use may decrease ketoconazole exposure and reduce ketoconazole efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole. Ketoconazole is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer.
Lansoprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Lansoprazole; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%. (Moderate) St. John's Wort appears to induce CYP3A4 and may lead to increased systemic clearance of clarithromycin, a CYP3A4 substrate. Additionally, clarithromycin may increase serum concentrations of St. John's Wort due to CYP3A4 inhibition. Postmarketing reports of interactions have been noted.
Lapatinib: (Major) Avoid coadministration of lapatinib with St. Johns Wort due to decreased plasma concentrations of lapatinib. If concomitant use is unavoidable, gradually titrate the dose of lapatinib from 1,250 mg per day to 4,500 mg per day in patients receiving concomitant capecitabine (HER2-positive metastatic breast cancer), and from 1,500 mg per day to 5,500 mg per day in patients receiving concomitant aromatase inhibitor therapy (HR-positive, HER2-positive breast cancer) based on tolerability. If St. Johns Wort is discontinued, reduce lapatinib to the indicated dose. Lapatinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased lapatinib exposure by 72%.
Larotrectinib: (Major) Avoid coadministration of larotrectinib with St. John's wort due to decreased larotrectinib exposure and risk of decreased efficacy. If coadministration cannot be avoided, double the larotrectinib dose. If St. John's wort is discontinued, resume the original larotrectinib dose after 3 to 5 elimination half-lives of St. John's wort. Larotrectinib is a CYP3A4 substrate; St. John's wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the larotrectinib AUC by 81% in a drug interaction study.
Lasmiditan: (Moderate) Serotonin syndrome may occur during coadministration of lasmiditan and St. John's Wort. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly after a dose increase or the addition of other serotonergic medications to an existing regimen. Discontinue all serotonergic agents if serotonin syndrome occurs and implement appropriate medical management.
Ledipasvir; Sofosbuvir: (Major) Avoid coadministration of ledipasvir with potent inducers of intestinal P-glycoprotein (P-gp), such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease ledipasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate with inducers of P-gp, such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
Lefamulin: (Major) Avoid coadministration of lefamulin with St. John's Wort unless the benefits outweigh the risks as concurrent use may decrease lefamulin exposure and efficacy. Lefamulin is a CYP3A4 and P-gp substrate; St. John's Wort is a P-gp and strong CYP3A4 inducer. Coadministration of a combined P-gp and strong CYP3A4 inducer decreased the mean AUC of oral and intravenous lefamulin by 72% and 28%, respectively.
Lemborexant: (Major) Avoid coadministration of lemborexant and St. John's Wort as concurrent use may decrease lemborexant exposure which may reduce efficacy. Lemborexant is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer.
Lenacapavir: (Contraindicated) Concurrent use of lenacapavir and St. John's wort is contraindicated due to the risk of decreased lenacapavir exposure which may result in loss of therapeutic effect and development of resistance. Lenacapavir is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced lenacapavir overall exposure by 84%.
Leniolisib: (Major) Avoid concomitant use of leniolisib and St. John's wort. Concomitant use may decrease leniolisib exposure which may reduce its efficacy. Leniolisib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced leniolisib overall exposure by 78%.
Letermovir: (Major) Concurrent administration of letermovir and St. John's Wort is not recommended. Use of these drugs together may decrease letermovir plasma concentrations, resulting in a potential loss of letermovir efficacy. Letermovir is a substrate of the drug transporter P-glycoprotein (P-gp). St. John's Wort induces P-gp.
Leuprolide; Norethindrone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levamlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Levoketoconazole: (Major) Avoid St. John's Wort for 2 weeks before and during treatment with ketoconazole. Concomitant use may decrease ketoconazole exposure and reduce ketoconazole efficacy. If coadministration cannot be avoided, monitor for decreased efficacy of ketoconazole. Ketoconazole is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer.
Levomilnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Levonorgestrel: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Levonorgestrel; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Levorphanol: (Moderate) If concomitant use of levorphanol and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Lidocaine: (Moderate) Concomitant use of systemic lidocaine and St. John's Wort may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; St. John's Wort induces CYP3A4.
Lidocaine; Epinephrine: (Moderate) Concomitant use of systemic lidocaine and St. John's Wort may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; St. John's Wort induces CYP3A4. (Moderate) Monitor blood pressure during concomitant use of epinephrine and St. John's Wort. Patients receiving St. John's Wort may experience severe, prolonged hypertension when given epinephrine. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the pressor effects of epinephrine.
Lidocaine; Prilocaine: (Moderate) Concomitant use of systemic lidocaine and St. John's Wort may decrease lidocaine plasma concentrations. Higher lidocaine doses may be required; titrate to effect. Lidocaine is a CYP3A4 and CYP1A2 substrate; St. John's Wort induces CYP3A4.
Linagliptin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and St. John's wort if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Linagliptin; Metformin: (Moderate) Monitor for a decrease in linagliptin efficacy during concomitant use of linagliptin and St. John's wort if coadministration is required. Concomitant use may decrease linagliptin exposure. Linagliptin is a CYP3A and P-gp substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with a strong CYP3A and P-gp inducer reduced linagliptin overall exposure by 0.6-fold.
Linezolid: (Contraindicated) Linezolid should generally not be administered to patients taking serotonergic agents, such as St. John's wort, Hypericum perforatum, due to the potential for serious CNS reactions, such as serotonin syndrome. The FDA recommends that if linezolid must be administered to patients already taking serotonergic agents due to life-threatening conditions, the serotonergic agent should be discontinued immediately and the patient should be monitored for emergence of symptoms of CNS toxicity for two weeks, or until 24 hours after the last dose of linezolid, whichever comes first. For non-emergent situations, most serotonergic drugs should be stopped at least 2 weeks prior to instituting linezolid therapy. Treatment with serotonergic agents may resume 24 hours after the discontinuation of linezolid. Linezolid is an antibiotic that is also a reversible, non-selective MAO inhibitor. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Lisdexamfetamine: (Moderate) Coadministration of St. John's Wort with amphetamines may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Lithium: (Moderate) Coadministration of paroxetine and lithium may increase the risk of serotonin syndrome. If serotonin syndrome occurs, all serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Lonafarnib: (Contraindicated) Coadministration of lonafarnib and St. John's Wort is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Lopinavir; Ritonavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Loratadine; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Lorcaserin: (Moderate) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, St. John's Wort. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
Lorlatinib: (Contraindicated) Coadministration of lorlatinib with St. Johns Wort is contraindicated due to the risk of severe hepatotoxicity as well as decreased lorlatinib exposure which may reduce its efficacy. Discontinue St. Johns Wort for 3 plasma half-lives prior to initiating therapy with lorlatinib. Lorlatinib is a CYP3A substrate and St. Johns Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased lorlatinib exposure by 85% and caused severe (grade 3 or 4) hepatotoxicity in 83% of patients.
Lovastatin: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system. Co-administration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including lovastatin.
Lumacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with St. John's Wort is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Concomitant use of St. John's Wort, Hypericum perforatum and lumacaftor; ivacaftor is not recommended. St. John's Wort may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Ivacaftor is a substrate of CYP3A, and St. John's Wort is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor.
Lumacaftor; Ivacaftor: (Major) Concomitant use of St. John's Wort, Hypericum perforatum and lumacaftor; ivacaftor is not recommended. St. John's Wort may decrease the therapeutic effect of lumacaftor; ivacaftor by significantly decreasing the systemic exposure of ivacaftor. Ivacaftor is a substrate of CYP3A, and St. John's Wort is a potent CYP3A inducer. In a pharmacokinetic study, coadministration of lumacaftor; ivacaftor with rifampin, another potent CYP3A inducer, decreased ivacaftor exposure by 57%, with minimal effect on the exposure of lumacaftor.
Lumateperone: (Major) Avoid coadministration of lumateperone and St. John's wort as concurrent use may decrease lumateperone exposure which may reduce efficacy. Lumateperone is a CYP3A4 substrate; St. John's wort is a strong CYP3A4 inducer. Coadministration of lumateperone with a strong CYP3A4 inducer decreased lumateperone overall exposure by greater than 30-fold.
Lurasidone: (Contraindicated) Concurrent use of lurasidone with strong CYP3A4 inducers, such as St. John's Wort, is contraindicated. Lurasidone is primarily metabolized by CYP3A4. Decreased blood concentrations of lurasidone are expected when the drug is co-administered with inducers of CYP3A4.
Lurbinectedin: (Major) Avoid coadministration of lurbinectedin and St. Johns Wort due to the risk of decreased lurbinectedin exposure which may reduce its efficacy. Lurbinectedin is a CYP3A substrate and St. Johns Wort is a strong CYP3A inducer.
Macimorelin: (Major) Discontinue St. John's Wort, Hypericum and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can significantly decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and St. John's Wort is a strong CYP3A4 inducer.
Macitentan: (Major) Avoid coadministration of macitentan and St. John's Wort, Hypericum perforatum. St. John's Wort is a strong inducer of CYP3A4. Coadministration with macitentan significantly reduces macitentan exposure.
Maraviroc: (Major) Concomitant use of maraviroc and St. John's wort, Hypericum perforatum or products containing St. John's wort is not recommended. St. John's wort is expected to substantially decrease maraviroc concentrations; reductions in plasma concentrations could lead to HIV treatment failures or the development of viral-resistance. St. John's wort in all forms, including teas, should be avoided in HIV-infected patients treated with maraviroc.
Maribavir: (Major) Avoid concomitant use of maribavir and St. John's Wort. Coadministration may decrease maribavir exposure resulting in reduced virologic response. Maribavir is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the exposure of maribavir by 60%.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with St. John's Wort due to risk for reduced mavacamten efficacy. Concomitant use decreases mavacamten exposure. Mavacamten is a CYP2C19 and CYP3A substrate and St. John's Wort is a moderate CYP2C19 inducer and strong CYP3A inducer. The impact that a CYP3A inducer may have on mavacamten overall exposure varies based on the patient's CYP2C19 metabolizer status. Concomitant use of a strong CYP3A inducer is predicted to decrease mavacamten overall exposure by 69% and 87% in poor and normal CYP2C19 metabolizers, respectively.
Medroxyprogesterone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Mefloquine: (Moderate) Mefloquine is metabolized by CYP3A4. St. John's Wort is an inducer of CYP3A4, and may increase the metabolism of mefloquine and reduce mefloquine plasma concentrations if coadministered.
Meperidine: (Moderate) Monitor for reduced efficacy of meperidine and signs of opioid withdrawal if coadministration with St. John's Wort is necessary; these effects may be more pronounced with St. John's Wort as it can induce multiple CYP enzymes. Consider increasing the dose of meperidine as needed. If St. John's Wort is discontinued, consider a dose reduction of meperidine and frequently monitor for signs of respiratory depression and sedation. Meperidine is a substrate of CYP3A4 and CYP2B6; St. John's Wort is a CYP3A4 and CYP2B6 inducer. Concomitant use can decrease meperidine exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Metaxalone: (Moderate) Concomitant use of metaxalone and St. John's Wort may increase the risk for serotonin syndrome. Monitor patients for serotonin syndrome if concomitant use is necessary.
Metformin; Repaglinide: (Moderate) Coadministration of St. John's Wort and repaglinide may decrease the serum concentration of repaglinide; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. St. John's Wort is a CYP3A4 inducer and repaglinide is a CYP3A4 substrate. Monitor for the possibility of reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Methadone: (Moderate) Monitor for reduced efficacy of methadone and signs of opioid withdrawal if coadministration with St. John's Wort is necessary; these effects may be more pronounced with St. John's Wort as it can induce multiple CYP enzymes. Consider increasing the dose of methadone as needed. If St. John's Wort is discontinued, consider a dose reduction of methadone and frequently monitor for signs of respiratory depression and sedation. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, and CYP2C9. St. John's Wort is a CYP3A4, CYP2B6, CYP2C19, and CYP2C9 inducer. Concomitant use can decrease methadone exposure resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Methamphetamine: (Moderate) Coadministration of St. John's Wort with amphetamines may increase the risk of serotonin syndrome. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome.
Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Contraindicated) Concurrent use of methylene blue and St. John's Wort, hypericum perforatum should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and St. John's Wort increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving St. John's Wort, it is advisable to discontinue the St. John's Wort and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to stop the St. John's Wort for at least 2 weeks prior to methylene blue treatment.
Methohexital: (Major) St. John's wort, Hypericum perforatum, may intensify or prolong the effects of general anesthetics; profound hypotension has also been reported. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that patients stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
Methoxsalen: (Major) St. John's wort has been reported to increase the phototoxicity associated with photosensitizing agents used in photodynamic therapy. Although interactions have not been reported, in theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs.
Methylene Blue: (Contraindicated) Concurrent use of methylene blue and St. John's Wort, hypericum perforatum should generally be avoided due to the potential for serotonin syndrome. Methylene blue is a thiazine dye that is also a potent, reversible inhibitor of the enzyme responsible for the catabolism of serotonin in the brain (MAO-A) and St. John's Wort increases central serotonin effects. Cases of serotonin syndrome have been reported, primarily following administration of standard infusions of methylene blue (1 to 8 mg/kg) as a visualizing agent in parathyroid surgery, in patients receiving selective serotonin reuptake inhibitors, serotonin/norepinephrine reuptake inhibitors, or clomipramine. It is not known if patients receiving other serotonergic psychiatric agents with intravenous methylene blue are at a comparable risk or if methylene blue administered by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. Published interaction reports between intravenously administered methylene blue and serotonergic psychiatric agents have documented symptoms including lethargy, confusion, delirium, agitation, aggression, obtundation, myoclonus, expressive aphasia, hypertonia, pyrexia, elevated blood pressure, seizures, and/or coma. Serotonin syndrome is characterized by rapid development of various symptoms such as hyperthermia, hypertension, myoclonus, rigidity, hyperhidrosis, incoordination, diarrhea, mental status changes (e.g., confusion, delirium, or coma), and in rare cases, death. If emergent treatment with methylene blue is required in a patient receiving St. John's Wort, it is advisable to discontinue the St. John's Wort and monitor the patient for symptoms of CNS toxicity for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. During non-emergent use of methylene blue, it is advisable to stop the St. John's Wort for at least 2 weeks prior to methylene blue treatment.
Methylergonovine: (Moderate) Monitor for a decrease in methylergonovine efficacy during concomitant use of methylergonovine and St. John's wort. Concomitant use may decrease methylergonovine exposure. Methylergonovine is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Methylphenidate Derivatives: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering methylphenidate derivatives and St. John's Wort. There are rare reports of serotonin syndrome occurring during use of other serotonergicagents and methylphenidate or its derivatives. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Methylphenidate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering methylphenidate derivatives and St. John's Wort. There are rare reports of serotonin syndrome occurring during use of other serotonergicagents and methylphenidate or its derivatives. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Midazolam: (Major) St. John's Wort induces the hepatic CYP3A4 metabolism of midazolam which is metabolized by oxidation. St. John's Wort, in doses of 900 mg/day, reduces the AUC of oral midazolam by about 50%. It would be prudent to avoid co-administration of St. John's Wort with midazolam. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
Midodrine: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and St. Johns Wort as midostaurin exposure may be decreased, which may reduce its efficacy. Midostaurin is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased the exposure of midostaurin and its metabolites CGP62221 and CGP52421 by 96%, 92%, and 59%, respectively.
Mifepristone: (Major) Avoid the use of potent CYP3A inducers such as St. John's wort with mifepristone due to the potential for reduced mifepristone exposure and reduced efficacy. It is not known if lowered mifepristone serum levels would lead to reduced response or therapeutic failure. If use together is medically necessary, monitor the patient closely to ensure the proper therapeutic response is obtained.
Milnacipran: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Mirtazapine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering mirtazapine with St. John's Wort. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Mitapivat: (Major) Avoid coadministration of mitapivat with St. John's Wort due to decreased mitapivat efficacy. Coadministration decreases mitapivat concentrations. Mitapivat is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased mitapivat overall exposure by 91% to 95%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and St. John's Wort. Coadministration may decrease mobocertinib exposure resulting in decreased efficacy. Mobocertinib is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Use of a strong CYP3A inducer is predicted to decrease the overall exposure of mobocertinib and its active metabolites by 92%.
Modafinil: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
Monoamine oxidase inhibitors: (Contraindicated) St. John's wort, Hypericum perforatum should not be used concurrently with monoamine oxidase inhibitors (MAOIs) because of the possibility of serotonin syndrome. In patients receiving nonselective MAOs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Montelukast: (Minor) St. John's Wort may reduce the systemic exposure of montelukast. However, dosage adjustment is not likely to be needed. If used together, the manufacturer recommends monitoring for proper montelukast effectiveness as a precaution. St. John's Wort is a strong CYP3A inducer. Montelukast is metabolized by CYP2C8 (primary), and also CYP2C9 and CYP3A4.
Morphine: (Moderate) If concomitant use of morphine and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Morphine; Naltrexone: (Moderate) If concomitant use of morphine and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Moxifloxacin: (Moderate) Use St. John's Wort with caution in patients who are also taking drugs known to be photosensitizers, such as moxifloxacin, as concomitant use may augment phototoxicity. Patients should take care and use proper techniques to limit sunlight and UV exposure of treated areas.
Nalbuphine: (Moderate) If concomitant use of nalbuphine and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Naldemedine: (Major) Avoid coadministration of naldemedine with strong CYP3A4 inducers. Naldemedine is metabolized primarily by the CYP3A enzyme system. Strong CYP3A4 inducers, such as St. John's Wort, significantly decrease plasma naldemedine concentrations and may decrease the efficacy of naldemedine treatment.
Naloxegol: (Major) Coadministration of naloxegol with St. John's Wort is not recommended due to the potential for decreased naloxegol efficacy. Naloxegol is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased naloxegol exposure by 89%.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for decreased efficacy of nab-paclitaxel if coadministration with St. John's Wort is necessary due to the risk of decreased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and St. John's wort as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and St. John's wort is a strong CYP3A and P-gp inducer.
Naproxen; Esomeprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Naproxen; Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Naratriptan: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Nateglinide: (Moderate) Monitor for nateglinide efficacy and glycemic control. St. John's Wort, Hypericum perforatum is a hepatic enzyme inducer of CYP2C9 and thus may reduce the hypoglycemic action of nateglinide, a CYP2C9 substrate.
Nefazodone: (Moderate) Concurrent use of nefazodone and St. John's wort may increase the risk of serotonin syndrome or decrease the efficacy of nefazodone. Inform patients of the possible risk for serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. In addition, monitor for decreased efficacy of nefazodone if coadministration with St. John's wort is necessary. Concomitant use may decrease nefazodone exposure. Nefazodone is a primary CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nefazodone and hydroxynefazodone exposure by almost 95%.
Nelfinavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Neratinib: (Major) Avoid concomitant use of St. Johns Wort with neratinib due to decreased efficacy of neratinib. Neratinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased neratinib exposure by 87%, while exposure to active metabolites M6 and M7 were reduced by 37% to 49%. Concomitant use with other strong inducers of CYP3A4 may also decrease neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Major) Netupitant is mainly metabolized by CYP3A4. Avoid coadministration of netupitant in patients who are chronically using a strong CYP3A4 inducer, such as St. John's Wort, Hypericum perforatum. A strong CYP3A inducer can decrease the efficacy of netupitant by substantially reducing plasma concentrations of netupitant; however, the amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable.
Nevirapine: (Major) Concomitant use of nevirapine and St. John's Wort is not recommended. Concurrent use may decrease the plasma concentrations of nevirapine leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Nevirapine is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased nevirapine exposure by greater than 50%.
Nicardipine: (Major) St. John's wort appears to induce the metabolism of the calcium-channel blockers, such as nicardipine, apparently by the induction of the CYP3A4 isoenzyme leading to reduced clinical efficacy. The metabolism of calcium channel blockers may also be increased.
NIFEdipine: (Major) Avoid coadministration of nifedipine and St. John's Wort, Hypericum perforatum, and consider alternative therapy if possible. If coadministration is necessary, monitor the patient closely for desired cardiovascular effects on heart rate, blood pressure, or chest pain. The FDA-approved labeling for some nifedipine products contraindicates coadministration with strong CYP3A4 inducers, while other manufacturers classify the recommendation as a warning. Nifedipine is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration of nifedipine with another strong CYP3A4 inducer reduced the AUC and Cmax of nifedipine by approximately 70%.
Nilotinib: (Major) Avoid the concomitant use of nilotinib and St. John's Wort; significantly decreased nilotinib exposure and reduced nilotinib efficacy may occur. Nilotinib is a CYPA4 substrate and St. John's Wort is a strong CYP3A4 inducer. In a drug interaction study, coadministration with another strong CYP3A4 inducer decreased nilotinib exposure by approximately 80%.
Nimodipine: (Major) St. John's wort appears to induce the metabolism of the calcium-channel blockers, such as nimodipine, apparently by the induction of the CYP3A4 isoenzyme leading to reduced clinical efficacy. The metabolism of calcium channel blockers may also be increased.
Nintedanib: (Major) Have patients avoid use of St. John's Wort, Hypericum perforatum supplements during nintedanib treatment as this herb is likely to decrease exposure to nintedanib and compromise its efficacy. St. John's Wort is a potent dual CYP3A4 and P-glycoprotein (P-gp) inducer; nintedanib is a P-gp substrate and a minor substrate of CYP3A4. In drug interaction studies, administration of a dual P-gp and CYP3A4 inducer with nintedanib decreased the AUC of nintedanib by 50%.
Niraparib; Abiraterone: (Major) Avoid coadministration of abiraterone with St. John's Wort if possible due to decreased plasma concentrations of abiraterone. If concomitant use is unavoidable, increase the dosing frequency of abiraterone to twice daily. Reduce the dose back to the previous dose and frequency if St. John's Wort is discontinued. Abiraterone is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased abiraterone exposure by 55%.
Nirmatrelvir; Ritonavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer. (Contraindicated) Ritonavir-boosted nirmatrelvir is contraindicated for use within 2 weeks of administering St. John's Wort; consider an alternative COVID-19 therapy. Coadministration may decrease nirmatrelvir exposure resulting in reduced virologic response. The risk for reduced efficacy may persist following St. John's Wort discontinuation. Nirmatrelvir is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer.
Nirogacestat: (Major) Avoid concomitant use of nirogacestat and St. John's wort. Concurrent use may decrease nirogacestat exposure which may reduce its efficacy. Nirogacestat is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to reduce nirogacestat overall exposure by 85%.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with St. John's Word due to the possibility for decreased plasma concentrations of nisoldipine. Alternative antihypertensive therapy should be considered. Nisoldipine is a CYP3A4 substrate and St. John's Word is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer lowered nisoldipine plasma concentrations to undetectable levels.
Norepinephrine: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics or drugs with sympathomimetic-like actions.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Norethindrone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Norethindrone; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Norgestimate; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Norgestrel: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Nortriptyline: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Olanzapine: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and could decrease the efficacy of some medications metabolized by these enzymes including olanzapine.
Olanzapine; Fluoxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering fluoxetine and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated. (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and could decrease the efficacy of some medications metabolized by these enzymes including olanzapine.
Olanzapine; Samidorphan: (Major) Avoid the concurrent use of samidorphan and St. John's Wort; decreased samidorphan exposure and loss of efficacy may occur. Samidorphan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant use of another strong CYP3A inducer reduced samidorphan exposure by 73%. (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system and could decrease the efficacy of some medications metabolized by these enzymes including olanzapine.
Olaparib: (Major) Avoid coadministration of olaparib with St. Johns Wort due to the risk of decreasing the efficacy of olaparib. Olaparib is a CYP3A substrate and St. Johns Wort is a strong CYP3A4 inducer; concomitant use may decrease olaparib exposure. Coadministration with another strong CYP3A inducer decreased the olaparib Cmax by 71% and the AUC by 87%.
Oliceridine: (Moderate) Monitor for reduced efficacy of oliceridine and signs of opioid withdrawal if coadministration with St. John's Wort is necessary; consider increasing the dose of oliceridine as needed. If St. John's Wort is discontinued, consider a dose reduction of oliceridine and frequently monitor for signs of respiratory depression and sedation. Oliceridine is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease the plasma concentrations of oliceridine; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Also monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Olutasidenib: (Major) Avoid concurrent use of olutasidenib and St. John's wort due to the risk of decreased olutasidenib exposure which may reduce its efficacy. Olutasidenib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced olutasidenib exposure by approximately 80%.
Omaveloxolone: (Major) Avoid concurrent use of omaveloxolone and St. John's wort. Concurrent use may decrease omaveloxolone exposure which may reduce its efficacy. Omaveloxolone is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Omeprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Omeprazole; Amoxicillin; Rifabutin: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Omeprazole; Sodium Bicarbonate: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Ondansetron: (Minor) St. John's Wort may reduce the efficacy of ondansetron by decreasing its systemic exposure; however, based on available data, no ondansetron dosage adjustment is recommended. If used together, monitor patients for antiemetic efficacy. St. John's Wort is a strong CYP3A inducer. Ondansetron is a substrate for CY1A2, CYP2D6, and CYP3A4, with CYP3A4 playing a predominant role in ondansetron turnover. During pharmacokinetic studies, patients treated with strong CYP3A inducers (i.e., phenytoin, carbamazepine, rifampin) and ondansetron had significantly increased ondansetron clearance, resulting in significant reductions in AUC, Cmax, and half-life. However, these changes in ondansetron exposure are not thought to be clinically relevant.
Osilodrostat: (Major) Monitor cortisol concentration and patient's signs and symptoms during coadministration of osilodrostat and St. John's Wort. Concurrent use may decrease osilodrostat exposure and reduce its efficacy; an increase in osilodrostat dose may be necessary. After discontinuation of St. John's Wort, monitor cortisol concentration and patient's signs and symptoms; a reduction in osilodrostat dose may be needed. Osilodrostat is a CYP3A4 and CYP2B6 substrate and St. John's Wort is a strong CYP3A4 inducer and also induces CYP2B6.
Osimertinib: (Major) Avoid coadministration of St. John's Wort with osimertinib due to decreased plasma concentrations of osimertinib which may lead to reduced efficacy. If concomitant use is unavoidable, increase the dose of osimertinib to 160 mg once daily. If St. John's Wort is discontinued, reduce the dose of osimertinib to 80 mg once daily after a washout period of 3 weeks. Osimertinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer, although the effect varies widely and is preparation-dependent. Coadministration with another strong CYP3A4 inducer decreased osimertinib exposure by 78%.
Ospemifene: (Moderate) Coadministration of St. John's Wort, Hypericum perforatum and ospemifene may decrease the systemic exposure of ospemifene, which may decrease the clinical effect. If possible, the patient should avoid St John's Wort while taking ospemifene. Ospemifene is a substrate of CYP3A4, CYP2C9, and CYP2C19, and St. John's Wort is a strong inducer of CYP3A4 and an inducer of CYP2C19. Administration of another mixed CYP inducer with ospemifene decreased the systemic exposure of ospemifene by 58%.
Oxcarbazepine: (Moderate) Monitor MHD, the active metabolite of oxcarbazepine, concentrations during oxcarbazepine dosage titration if St. John's Wort and oxcarbazepine are used concurrently. A dose adjustment of oxcarbazepine may be required after initiation, dosage modification, or discontinuation of St. John's Wort. St. John's Wort is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased plasma concentrations of MHD by 25% to 40%.
Oxycodone: (Moderate) Monitor for reduced efficacy of oxycodone and signs of opioid withdrawal if coadministration with St. John's wort is necessary; consider increasing the dose of oxycodone as needed. If St. John's wort is discontinued, consider a dose reduction of oxycodone and frequently monitor for signs of respiratory depression and sedation. Oxycodone is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease oxycodone levels; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. Additive serotonergic effects are also possible with this drug-herb combination. Caution and careful monitoring, particularly during treatment initiation and dose adjustment, is recommended due to the potential for serotonin syndrome. Serotonin syndrome may occur within the recommended dosage range. Discontinue St. John's wort if serotonin syndrome is suspected. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death.
Oxymorphone: (Moderate) If concomitant use of oxymorphone and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Ozanimod: (Major) Coadministration of ozanimod with St. John's Wort is not recommended due to the potential for hypertensive crisis. If coadministration is necessary, closely monitor patients for hypertension. An active metabolite of ozanimod inhibits MAO-B, which may increase the potential for hypertensive crisis. St. John's Wort may increase blood pressure by increasing serotonin concentrations.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with St. John's Wort is contraindicated due to decreased pacritinib exposure which may impair efficacy. Pacritinib is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased pacritinib exposure by 87%.
Palbociclib: (Major) Avoid coadministration of St. Johns Wort with palbociclib due to decreased plasma concentrations of palbociclib, which may result in decreased efficacy. Palbociclib is primarily metabolized by CYP3A4 and St. Johns Wort is a strong CYP3A4 inducer, although the amount of individual constituents in various products may alter the inducing effects, making drug interactions unpredictable. In a drug interaction trial, coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of palbociclib by 85% and 70%, respectively.
Paliperidone: (Major) It may be necessary to increase the dose of oral paliperidone during coadministration of a strong inducer of both CYP3A4 and P-gp, such as St. John's Wort. Conversely, a reduction in oral paliperidone dose may be needed upon discontinuation of the inducer. Avoid using a strong inducer of CYP3A4 and/or P-gp if possible during the 1-month injectable dosing interval of Invega Sustenna or the 3-month injectable dosing interval of Invega Trinza. If use of a strong inducer is required in patients receiving injectable paliperidone, consider management with oral paliperidone. Paliperidone is a P-gp substrate, with minor contributions in metabolism by CYP3A4 and CYP2D6.
Palovarotene: (Major) Avoid concomitant use of palovarotene and St. John's wort. Concurrent use may decrease palovarotene exposure which may reduce its efficacy. Palovarotene is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced palovarotene overall exposure by 11%.
Panobinostat: (Major) Avoid the concomitant use of panobinostat and St. John's Wort; panobinostat levels may be significantly decreased and its efficacy reduced. St. John's Wort is a strong CYP3A4 inducer and panobinostat is a CYP3A4 substrate. Using a physiologically-based pharmacokinetic model, the systemic exposure was estimated to be decreased by 70% when a strong CYP3A inducer was co-administered with panobinostat.
Pantoprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Paricalcitol: (Moderate) Serum concentrations of paricalcitol may be reduced when administered with drugs known to induce the CYP3A4 enzyme, such as St. John's Wort. Dosage adjustments of paricalcitol may be required. Clinicians should monitor plasma PTH and serum calcium and phosphorous concentrations with this combination.
Paroxetine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering paroxetine and St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Pazopanib: (Moderate) Pazopanib is a substrate for CYP3A4 and P-glycoprotein (Pgp). Plasma pazopanib concentrations may be decreased by concurrent administration with a CYP3A4 and Pgp inducer such as St. John's Wort, Hypericum perforatum. Use caution if chronic use of CYP3A4 and Pgp inducers and pazopanib can not be avoided.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and St. Johns Wort due to the risk of decreased pemigatinib exposure which may reduce its efficacy. Pemigatinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pemigatinib exposure by 85%.
Perampanel: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with St. John's Wort due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of St. John's Wort occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. St. John's Wort is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
Perindopril; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Perphenazine; Amitriptyline: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Pexidartinib: (Major) Avoid coadministration of pexidartinib with St. John's Wort as concurrent use may decrease pexidartinib exposure which may result in decreased therapeutic response. Pexidartinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased pexidartinib exposure by 65%.
Phendimetrazine: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
Phenelzine: (Contraindicated) St. John's wort, Hypericum perforatum should not be used concurrently with monoamine oxidase inhibitors (MAOIs) because of the possibility of serotonin syndrome. In patients receiving nonselective MAOs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Phentermine: (Moderate) The concomitant use of St. John's Wort with phentermine may increase the risk for serotonin syndrome. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Phentermine; Topiramate: (Moderate) The concomitant use of St. John's Wort with phentermine may increase the risk for serotonin syndrome. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent.
Phenytoin: (Major) Avoid if possible; St. John's wort could decrease the efficacy of hydantoins metabolized by CYP450 enzymes, including hydantoins as St. John's wort induces CYP2C9 and other CYP450 enzymes. Clinicians should observe patients closely if St. John's wort is used; careful monitoring of anticonvulsant drug concentrations may be needed.
Photosensitizing agents (topical): (Major) St. John's wort has been reported to increase the phototoxicity associated with photosensitizing agents used in photodynamic therapy. Although interactions have not been reported, in theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs.
Pimavanserin: (Major) The use of St. John's Wort with pimavanserin should be avoided. Because pimavanserin is primarily metabolized by CYP3A4 and CYP3A5, the manufacturer recommends avoiding use of strong CYP3A4 inducers, such as St. John's Wort. Strong inducers of CYP3A4 can reduce pimavanserin exposure, potentially decreasing the effectiveness of pimavanserin.
Pirtobrutinib: (Major) Avoid concurrent use of pirtobrutinib and St. John's wort due to the risk of decreased pirtobrutinib exposure which may reduce its efficacy. Pirtobrutinib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced pirtobrutinib overall exposure by 71%.
Pitolisant: (Major) Monitor for loss of pitolisant efficacy after initiation of St. John's Wort. Increase to double the original daily dose of pitolisant over 7 days in patients stable on 8.9 mg or 17.8 mg once daily (i.e., 17.8 mg or 35.6 mg, respectively). Decrease the pitolisant dose by half if St. John's Wort is discontinued. Pitolisant is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of strong CYP3A4 inducers decreases pitolisant exposure by 50%.
Polatuzumab Vedotin: (Moderate) Monitor for decreased polatuzumab vedotin efficacy during coadministration of St. John's Wort due to the risk of decreased exposure to the cytotoxic component of polatuzumab vedotin, MMAE. MMAE is metabolized by CYP3A4; St. John's Wort is a strong CYP3A4 inducer. Strong CYP3A4 inducers are predicted to decrease the exposure of MMAE by 63%.
Pomalidomide: (Moderate) Use pomalidomide and St. John's Wort, Hypericum perforatum, together with caution; decreased pomalidomide exposure may occur resulting in reduced pomalidomide effectiveness. Pomalidomide is a CYP1A2 substrate and St. John's Wort is a CYP1A2 inducer.
Ponatinib: (Major) Avoid coadministration of ponatinib with St. Johns Wort due to decreased plasma concentrations of ponatinib. If concomitant use is unavoidable, monitor for reduced efficacy of ponatinib. Ponatinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased ponatinib exposure by 62%.
Ponesimod: (Major) Avoid concurrent use of ponesimod and St. John's Wort and monitor for decreased ponesimod efficacy if use is necessary. Ponesimod is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer that may decrease ponesimod exposure.
Porfimer: (Major) Avoid coadministration of porfimer with St. Johns Wort due to the risk of increased photosensitivity. All patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like St. Johns Wort may increase the risk of a photosensitivity reaction.
Posaconazole: (Major) Posaconazole and St. John's Wort, Hypericum perforatum should be coadministered with caution due to a potential for altered posaconazole plasma concentrations. St. John's Wort is an inducer of the drug efflux protein, P-glycoprotein, for which posaconazole is a substrate. This interaction may cause alterations in the plasma concentrations of posaconazole, ultimately resulting in a risk of decreased efficacy and breakthrough fungal infections.
Pralsetinib: (Major) Avoid coadministration of St. Johns wort with pralsetinib due to the risk of decreased pralsetinib exposure which may reduce its efficacy. If concomitant use is unavoidable, double the current dose of pralsetinib starting on day 7 of coadministration. After St. Johns wort has been discontinued for at least 14 days, resume the pralsetinib dose taken prior to initiating St. Johns wort. Pralsetinib is a CYP3A substrate and St. Johns wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the pralsetinib AUC by 68%.
Praziquantel: (Contraindicated) Concomitant use of praziquantel and St. John's wort is contraindicated due to the risk of decreased praziquantel exposure which may reduce its efficacy. Praziquantel is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. In a crossover study with a 2-week washout period, administration of praziquantel followed by another strong CYP3A inducer resulted in undetectable plasma concentrations of praziquantel in 7 out of 10 subjects. When praziquantel was administered 2 weeks after discontinuation of the strong inducer, the mean praziquantel AUC was 23% lower than when praziquantel was given alone.
Pretomanid: (Major) Avoid coadministration of pretomanid with St. John's Wort as concurrent use may decrease pretomanid exposure which may lead to decreased efficacy. Pretomanid is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased pretomanid exposure by 66%.
Prilocaine; Epinephrine: (Moderate) Monitor blood pressure during concomitant use of epinephrine and St. John's Wort. Patients receiving St. John's Wort may experience severe, prolonged hypertension when given epinephrine. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the pressor effects of epinephrine.
Progesterone: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Progestins: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin).
Promethazine; Dextromethorphan: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when administering dextromethorphan with St. John's Wort. Inform patients of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose adjustments. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Promethazine; Phenylephrine: (Major) St. John's wort may have MAOI-like activities, and could potentially increase the cardiac stimulation and vasopressor effects of the sympathomimetics. St. John's wort should be used cautiously with any sympathomimetic agent.
Propofol: (Major) St. John's wort, Hypericum perforatum, may intensify or prolong the effects of propofol; profound hypotension has also been reported. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that patients stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
Protease inhibitors: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Proton pump inhibitors: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Protriptyline: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Pseudoephedrine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Pseudoephedrine; Triprolidine: (Moderate) Monitor blood pressure during concomitant use of pseudoephedrine and St. John's Wort. St. John's Wort has been shown to weakly inhibit monoamine oxidase and may potentiate the effects of pseudoephedrine on blood pressure.
Quazepam: (Major) St. John's Wort may induce the hepatic metabolism of quazepam which is metabolized by oxidation. It would be prudent to avoid co-administration of St. John's Wort with quazepam.
Quetiapine: (Major) If possible, avoid use of St. John's wort with quetiapine due to a potential for decreased quetiapine efficacy. Coadministration may significantly decrease quetiapine exposure. If St. John's wort must be used, the quetiapine dose may need to be increased based on clinical response. Quetiapine is a sensitive CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer increased the mean oral clearance of quetiapine by 5-fold.
Quinidine: (Major) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4. Coadministration of St. John's wort could decrease the efficacy of some medications metabolized by this enzyme, such as quinidine. Clinicians should observe patients closely if St. John's wort is used.
Quinine: (Moderate) Quinine is a substrate of P-glycoprotein (PGP) and CYP3A4, and St. John's Wort, Hypericum perforatum is an inducer of PGP and CYP3A4. Monitor patients for decreased efficacy of quinine if these drugs are given together.
Quizartinib: (Major) Avoid concomitant use of St. John's wort with quizartinib due to the risk of decreased quizartinib exposure which may reduce its efficacy. Quizartinib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer.
Rabeprazole: (Major) Avoid concomitant use of St. John's wort with the proton pump inhibitors (PPIs) as PPI exposure may be decreased, reducing their efficacy. PPIs are CYP3A4 and CYP2C19 substrates and St. John's wort is a strong CYP3A4 and CYP2C19 inducer. For example, coadministration of omeprazole with St. John's wort decreased omeprazole plasma concentrations by approximately 40%.
Ranolazine: (Contraindicated) Ranolazine is contraindicated in patients receiving drugs known to be CYP3A inducers including St. John's wort, Hypericum perforatum. Induction of CYP3A metabolism could lead to decreased ranolazine plasma concentrations and decreased efficacy.
Rasagiline: (Contraindicated) St. John's wort should not be used concurrently with MAOIs (i.e., rasagiline) or drugs that possess MAOI-like activity because of the possibility of severe hyperpyretic or hypertensive crises, convulsions, or death. In addition, St. John's wort appears to potentiate serotonin by inhibiting its neuronal reuptake. Since serotonin is deaminated by monoamine oxidase type A, administration of non-selective MAOIs concurrently with St. John's wort could potentially lead to a serious reaction known as 'serotonin syndrome.' At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Red Yeast Rice: (Moderate) Since certain red yeast rice products (i.e., pre-2005 Cholestin formulations) contain lovastatin, clinicians should use red yeast rice cautiously in combination with drugs known to interact with lovastatin. CYP3A4 inducers can theoretically reduce the effectiveness of HMG-CoA reductase activity via induction of CYP3A4 metabolism. Examples of CYP3A4 inducers include St. John's Wort, Hypericum perforatum.
Regorafenib: (Major) Avoid coadministration of regorafenib with St. John's Wort due to decreased plasma concentrations of regorafenib and increased plasma concentrations of the M-5 active metabolite, which may lead to decreased efficacy. Regorafenib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the mean AUC of regorafenib by 50% and increased the mean AUC of M-5 by 264%; no change in the mean AUC of M-2 was observed.
Relugolix: (Major) Avoid concurrent use of relugolix and St. John's Wort. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If St. John's Wort is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and St. John's Wort is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%.
Relugolix; Estradiol; Norethindrone acetate: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Avoid concurrent use of relugolix and St. John's Wort. Concurrent use may decrease relugolix exposure and compromise the efficacy of relugolix therapy. If concurrent use is unavoidable, increase the relugolix maintenance dose to 240 mg once daily. If St. John's Wort is discontinued resume the recommended relugolix treatment dose of 120 mg once daily. Relugolix is a P-glycoprotein (P-gp) and CYP3A substrate and St. John's Wort is a P-gp and strong CYP3A inducer. Concurrent use of another P-gp and strong CYP3A inducer decreased relugolix overall exposure by 55%. (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Remifentanil: (Moderate) If concomitant use of remifentanil and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Repaglinide: (Moderate) Coadministration of St. John's Wort and repaglinide may decrease the serum concentration of repaglinide; if coadministration is necessary, repaglinide dosage adjustment may be required and an increased frequency of glucose monitoring is recommended. St. John's Wort is a CYP3A4 inducer and repaglinide is a CYP3A4 substrate. Monitor for the possibility of reduced effectiveness of repaglinide and possible symptoms indicating hyperglycemia.
Repotrectinib: (Major) Avoid coadministration of repotrectinib with St. John's Wort due to decreased repotrectinib exposure and risk of decreased efficacy. Repotrectinib is a CYP3A substrate; St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased repotrectinib overall exposure by 92%.
Ribociclib: (Major) Avoid coadministration of St. Johns Wort with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. However, the amount of individual constituents in various St. Johns Wort products may alter the inhibiting or inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
Ribociclib; Letrozole: (Major) Avoid coadministration of St. Johns Wort with ribociclib due to decreased ribociclib exposure resulting decreased efficacy. Ribociclib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. However, the amount of individual constituents in various St. Johns Wort products may alter the inhibiting or inducing effects, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer decreased ribociclib exposure in healthy subjects by 89%.
Rilpivirine: (Contraindicated) Concurrent use of St. John's Wort, Hypericum perforatum and rilpivirine is contraindicated. When coadministered, there is a potential for treatment failure and/or the development of rilpivirine or NNRTI resistance. St. John's wort appears to be an inducer of CYP3A4, which is primarily responsible for the metabolism of rilpivirine. Coadministration may result in decreased rilpivirine serum concentrations, which could cause impaired virologic response to rilpivirine.
Riluzole: (Moderate) Coadministration of riluzole with St. John's Wort may result in decreased riluzole efficacy. In vitro findings suggest decreased riluzole exposure is likely. Riluzole is a CYP1A2 substrate and St. John's Wort is a CYP1A2 inducer.
Rimegepant: (Major) Avoid coadministration of rimegepant with St. John's Wort; concurrent use may significantly decrease rimegepant exposure which may result in loss of efficacy. Rimegepant is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration of rimegepant with another strong CYP3A4 inducer decreased rimegepant exposure by 80%.
Riociguat: (Major) Strong inducers of CYP3A (e.g., rifampin, phenytoin, carbamazepine, phenobarbital or St. John's Wort) may significantly reduce riociguat exposure. Dosage adjustment recommendations are not available when strong CYP3A inducers are co-administered with riociguat.
Ripretinib: (Major) Avoid coadministration of ripretinib with St. John's Wort. Coadministration may decrease the exposure of ripretinib and its active metabolite (DP-5439), which may decrease ripretinib anti-tumor activity. Ripretinib and DP-5439 are metabolized by CYP3A4 and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased ripretinib exposure by 61% and decreased DP-5439 exposure by 57%.
Risperidone: (Moderate) Monitor for a decrease in risperidone efficacy during concomitant use of risperidone and St. John's Wort and increase risperidone dosage as appropriate based on response. For patients receiving long-acting risperidone dosage forms, supplemental oral risperidone may be required. Concomitant use may decrease risperidone exposure. Risperidone is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced risperidone overall exposure by 50%.
Ritlecitinib: (Moderate) Monitor for a decrease in ritlecitinib efficacy during concomitant use of ritlecitinib and St. John's wort. Concomitant use may decrease ritlecitinib exposure. Ritlecitinib is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced ritlecitinib overall exposure by 0.56-fold.
Ritonavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Rivaroxaban: (Major) Avoid concomitant use of rivaroxaban with combined P-glycoprotein and strong CYP3A4 inducers such as St. John's Wort, due to decreased efficacy and an increased risk for thrombotic events. Consider increasing the rivaroxaban dose if St. John's Wort must be used. In a drug interaction study, coadministration of rivaroxaban (20 mg single dose) with a combined P-glycoprotein and strong CYP3A4 inducer led to an approximate 50% decrease in rivaroxaban AUC and 22% decrease in Cmax.
Rizatriptan: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Roflumilast: (Major) Coadminister roflumilast and St. John's wort, Hypericum perforatum cautiously as this may lead to reduced systemic exposure to roflumilast. St. John's wort induces CYP3A4 and roflumilast is a CYP3A4 substrate. In pharmacokinetic study, administration of a single dose of roflumilast in patients receiving another CYP3A4 inducer, rifampin, resulted in decreased roflumilast Cmax and AUC, as well as increased Cmax and decreased AUC of the active metabolite roflumilast N-oxide.
Rolapitant: (Contraindicated) Avoid the use of rolapitant with chronic administration of St. John's Wort, Hypericum perforatum. Rolapitant is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. When another strong CYP3A4 inducer, rifampin (600 mg once daily), was administered for 7 days before and 7 days after a single dose of rolapitant (180 mg), the mean Cmax and AUC of rolapitant were decreased by 30% and 85%, respectively; additionally, the mean half-life decreased from 176 hours to 41 hours. Significantly reduced plasma concentrations and decreased half-life can decrease the efficacy of rolapitant.
Romidepsin: (Major) The concomitant use of romidepsin, a CYP3A4 substrate, and St. John's Wort, Hypericum perforatum a strong CYP3A4 inducer, may result in significantly altered romidepsin plasma exposure. Therefore, avoid using romidepsin with potent CYP3A4 inducers if possible.
Ruxolitinib: (Moderate) Monitor patients frequently and adjust the ruxolitinib dose based on safety and efficacy if coadministered with St. John's Wort; decreased ruxolitinib exposure is possible. Ruxolitinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration of another strong CYP3A4 inducer decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. The relative exposure to ruxolitinib's active metabolites increased approximately 100%.
Safinamide: (Contraindicated) Safinamide is contraindicated for use with St. John's Wort due to the risk of serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. At least 14 days should elapse between the discontinuation of safinamide and the initiation of St. John's Wort. Patients should be instructed to discuss the use of any vitamins or herbal supplements with their heatlh care provider prior to the initiation of any new medication.
Saquinavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Segesterone Acetate; Ethinyl Estradiol: (Major) As with other CYP3A4 inducers, St. John's wort may reduce the therapeutic efficacy of progestin-only contraceptives or other progestin-based hormonal therapies. Patients should report irregular menstrual bleeding or other hormone-related symptoms to their health care providers if they are taking St. John's wort concurrently with their hormones. Avoidance of St. John's wort is recommended. This interaction does not apply to vaginal preparations of progesterone (e.g., Crinone, Endometrin). (Major) Women taking both estrogens and St. John's Wort should report breakthrough bleeding to their prescribers. If used for contraception, an alternate or additional form of contraception should be considered in patients prescribed St. John's Wort. Higher-dose hormonal regimens may be indicated where acceptable or applicable. The alternative or additional contraceptive agent may need to be continued for 1 month after discontinuation of St. John's Wort. Patients taking these hormones for other indications may need to be monitored for reduced clinical effect while on St. John's Wort, with dose adjustments made based on clinical efficacy. Estrogens are CYP3A4 substrates and St. John's Wort is a strong CYP3A4 inducer. Concurrent administration may increase estrogen elimination.
Selegiline: (Contraindicated) Concomitant use of selegiline and St. John's wort is contraindicated due to the risk of serotonin syndrome.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and St. John's Wort due to the risk of decreased selpercatinib exposure which may reduce its efficacy. Selpercatinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selpercatinib exposure by 87%.
Selumetinib: (Major) Avoid coadministration of selumetinib and St. John's Wort due to the risk of decreased selumetinib exposure which may reduce its efficacy. Selumetinib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased selumetinib exposure by 51%.
Serdexmethylphenidate; Dexmethylphenidate: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering methylphenidate derivatives and St. John's Wort. There are rare reports of serotonin syndrome occurring during use of other serotonergicagents and methylphenidate or its derivatives. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Serotonin norepinephrine reuptake inhibitors: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Serotonin-Receptor Agonists: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Sertraline: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering sertraline and St. John's Wort. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome, particularly during treatment initiation and dose increases. If serotonin syndrome occurs, serotonergic drugs should be discontinued and appropriate medical treatment should be initiated.
Sevoflurane: (Major) St. John's wort, Hypericum perforatum, may intensify or prolong the effects of sevoflurane; profound hypotension has also been reported. In one report, the authors recommend that patients should discontinue taking St. John's Wort at least 5 days prior to anesthesia. The American Society of Anesthesiologists has recommended that patients stop taking herbal medications at least 2 to 3 weeks before surgery to decrease the risk of adverse reactions.
Sildenafil: (Moderate) Monitor for decreased efficacy of sildenafil if coadministration with St. John's Wort is necessary as concurrent use may decrease sildenafil exposure. Sildenafil is a sensitive CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Concomitant administration of strong CYP3A inducers is expected to substantially decrease plasma concentrations of sildenafil.
Simvastatin: (Moderate) St. John's Wort appears to induce several isoenzymes of the hepatic cytochrome P450 enzyme system, including CYP3A4, CYP1A2, and potentially CYP2C9. Co-administration of St. John's Wort could decrease the efficacy of some medications metabolized by these enzymes including simvastatin.
Siponimod: (Major) Concomitant use of siponimod and St. John's Wort is not recommended due to a significant decrease in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; St. John's Wort is a moderate CYP2C9/strong CYP3A4 dual inducer. Coadministration with another moderate CYP2C9/strong CYP3A4 dual inducer decreased siponimod exposure by 57%.
Sirolimus: (Major) Avoid concomitant use of sirolimus and St. John's wort as use may decrease sirolimus exposure and efficacy. Sirolimus is a CYP3A and P-gp substrate and St. John's wort is a strong CYP3A and P-gp inducer. Concomitant use of another strong CYP3A and P-gp inducer decreased sirolimus overall exposure by 82%.
Sodium Oxybate: (Major) St. John's wort, Hypericum Perforatum may reduce the neuronal uptake of monoamines and should be used cautiously with sympathomimetics.
Sofosbuvir: (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate with inducers of P-gp, such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy.
Sofosbuvir; Velpatasvir: (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate with inducers of P-gp, such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as St. John's wort, Hypericum perforatum. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a P-gp and CYP3A4 substrate.
Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Avoid coadministration of sofosbuvir, a P-glycoprotein (P-gp) substrate with inducers of P-gp, such as St. John's Wort, Hypericum perforatum. Taking these drugs together may significantly decrease sofosbuvir plasma concentration, potentially resulting in loss of antiviral efficacy. (Major) Avoid coadministration of velpatasvir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as St. John's wort, Hypericum perforatum. Taking these drugs together may significantly decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a P-gp and CYP3A4 substrate. (Major) Avoid coadministration of voxilaprevir with inducers of P-glycoprotein (P-gp) and CYP3A4, such as St. John's wort, Hypericum perforatum. Taking these drugs together may significantly decrease voxilaprevir plasma concentrations, potentially resulting in loss of antiviral efficacy. Voxilaprevir is a P-gp and CYP3A4 substrate.
Sonidegib: (Major) Avoid the concomitant use of sonidegib and St. John's Wort; sonidegib exposure may be significantly decreased and its efficacy reduced. Sonidegib is a CYP3A substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration of a strong CYP3A4 inducer decreased the geometric mean Cmax and AUC of sonidegib by 54% and 72%, respectively.
Sorafenib: (Major) Avoid coadministration of sorafenib with St. John's Wort due to decreased plasma concentrations of sorafenib. Sorafenib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased sorafenib exposure by 37%.
Sotorasib: (Major) Avoid concurrent use of sotorasib and St. John's Wort. Coadministration may decrease sotorasib exposure resulting in decreased efficacy. Sotorasib is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC of sotorasib by 51%.
Sparsentan: (Major) Avoid concomitant use of sparsentan and St. John's wort due to the risk for decreased sparsentan exposure which may reduce its efficacy. Sparsentan is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer is predicted to decrease sparsentan overall exposure by 47%.
Stiripentol: (Major) Avoid coadministration of stiripentol with St. John's Wort. If concurrent use is necessary, increase the dose of stiripentol. Coadministration may decrease stiripentol plasma concentrations resulting in a decrease in efficacy. Stiripentol is metabolized by CYP3A4, CYP1A2, and CYP2C19; St. John's Wort is a strong inducer of CYP3A4, and an inducer of CYP2C19 and CYP1A2.
Sufentanil: (Major) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if St. John's Wort must be administered. Consider an increased dose of sufentanil injection and monitor for evidence of opioid withdrawal and serotonin syndrome if coadministration with St. John's Wort is necessary. If St. John's Wort is discontinued, consider reducing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of respiratory depression. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system like St. John's Wort has resulted in serotonin syndrome. In addition, sufentanil is a CYP3A4 substrate, and coadministration with a CYP3A4 inducer like St. John's Wort can decrease sufentanil concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence.
Sumatriptan: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Sumatriptan; Naproxen: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Sunitinib: (Major) Avoid coadministration of St. Johns Wort with sunitinib if possible due to decreased exposure to sunitinib which could decrease efficacy. If concomitant use is unavoidable, consider increasing the daily dose of sunitinib to a maximum of 87.5 mg for patients with GIST or RCC, and to a maximum of 62.5 mg for patients with pNET; monitor carefully for toxicity. Sunitinib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Because the amount of individual constituents in various St. Johns Wort products may alter the inducing effects, drug interactions are unpredictable. Coadministration with another strong CYP3A4 inducer decreased exposure to sunitinib and its primary active metabolite by 46%.
Suvorexant: (Moderate) Monitor for decreased efficacy of suvorexant if coadministration with St. John's Wort is necessary. Suvorexant is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A inducer decreased suvorexant exposure by 77% to 88%.
Tacrolimus: (Major) St. John's Wort, Hypericum perforatum may increase the metabolism of tacrolimus through induction of the hepatic CYP3A4 isoenzyme and decreased serum concentrations of tacrolimus would be expected if St. John's Wort was co-administered. St. John's Wort in all forms, including teas, should be avoided in patients treated with tacrolimus.
Tadalafil: (Major) Avoid coadministration of tadalafil with St. John's wort in patients with pulmonary hypertension due to decreased plasma concentrations of tadalafil. In patients with erectile dysfunction and/or benign prostatic hyperplasia, consider the potential for loss of efficacy of tadalafil during concurrent administration of St. John's wort due to reduced tadalafil exposure. Tadalafil is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased tadalafil exposure by 88%.
Tamoxifen: (Major) Avoid coadministration of St. Johns wort with tamoxifen due to decreased exposure to tamoxifen which may affect efficacy. Tamoxifen is a CYP3A4 substrate and St. Johns wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the AUC and Cmax of tamoxifen by 86% and 55%, respectively.
Tapentadol: (Moderate) If concomitant use of tapentadol and St. John's Wort is warranted, monitor patients for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tasimelteon: (Major) Concurrent use of tasimelteon and strong inducers of CYP3A4, such as St. John's Wort, hypericum perforatum, should be avoided. Because tasimelteon is partially metabolized via CYP3A4, a large decrease in exposure is possible with the potential for reduced efficacy. During administration of tasimelteon with another potent inducer of CYP3A4, tasimelteon exposure decreased by about 90%.
Tazarotene: (Moderate) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs such as retinoids.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with St. John's Wort as concurrent use may decrease tazemetostat exposure, which may reduce its efficacy. Tazemetostat is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Tedizolid: (Minor) Caution is warranted with the concurrent use of tedizolid and St. John's wort, Hypericaum perforatum due to the theoretical risk of serious CNS reactions, such as serotonin sydrome. Animal studies did not predict serontoneric effects with tedizolid. However, tedizolid is an antibiotic that is a weak reversible, non-selective MAO inhibitor and monoamine oxidase type A deaminates serotonin; therefore, coadministration theoretically could lead to serious reactions including serotonin syndrome or neuroleptic malignant syndrome-like reactions. Serotonin syndrome is characterized by rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome.
Telmisartan; Amlodipine: (Moderate) Closely monitor blood pressure if coadministration of amlodipine with St. John's Wort is necessary. Amlodipine is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. No information is available on the quantitative effects of CYP3A inducers on amlodipine; however, concomitant use may result in decreased plasma concentrations of amlodipine.
Temsirolimus: (Major) Avoid coadministration of temsirolimus with St. Johns Wort due to the risk of decreased plasma concentrations of the primary active metabolite of temsirolimus (sirolimus). Temsirolimus is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer; however, the amount of individual constituents in various products may alter the inducing effects of St. Johns Wort, making drug interactions unpredictable. Coadministration with another strong CYP3A4 inducer had no significant effect on the AUC or Cmax of temsirolimus, but decreased the AUC and Cmax of the active metabolite, sirolimus, by 56% and 65%, respectively.
Teniposide: (Moderate) Monitor patients for reduced efficacy of teniposide if coadministration with St. John's Wort is necessary. Teniposide is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers reduced plasma concentrations of teniposide.
Tenofovir Alafenamide: (Major) Administering tenofovir alafenamide with St. John's wort is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
Tenofovir Alafenamide: (Major) Administering tenofovir alafenamide with St. John's wort is not recommended. Taking these drugs together is expected to decrease tenofovir plasma concentrations, which may increase the potential for resistance and HIV treatment failure.
Tezacaftor; Ivacaftor: (Major) Coadministration of ivacaftor with St. John's Wort is not recommended due to decreased plasma concentrations of ivacaftor. Ivacaftor is a sensitive CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer significantly decreased ivacaftor exposure by approximately 9-fold. (Major) Do not administer tezacaftor; ivacaftor and St. John's Wort together; coadministration may reduce the efficacy of tezacaftor; ivacaftor. Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by the concomitant use of St. John's Wort, a strong CYP3A inducer; both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate). Coadministration of ivacaftor with a strong CYP3A inducer decreased ivacaftor exposure 89%.
Theophylline, Aminophylline: (Major) St. John's wort induces the metabolism o aminophylline and a decrease in theophylline plasma concentrations may occur. Higher doses of aminophylline may be required to achieve the desired effect. Discontinuation of St. John's Wort in a patient on aminophylline may result in theophylline toxicity. Close monitoring of drug concentrations and clinical status of the patient is recommended. Iinteractions with St. John's wort have been reported. St. John's wort appears to increase the metabolism of aminophylline through induction of the hepatic CYP1A2 isoenzyme. (Moderate) Higher doses of theophylline may be required to achieve the desired effect during coadministration of St. John's Wort. Monitor theophylline concentrations and clinical status of patient closely. St. John's Wort induces the metabolism of theophylline through induction of the hepatic CYP1A2 isoenzyme and a decrease in theophylline plasma concentrations may occur. Discontinuation of St. John's Wort in a patient on theophylline may result in theophylline toxicity.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and St. John's Wort if possible; increased metabolism to the active thiotepa metabolite may result in increased thiotepa toxicity (e.g., infection, bleeding, skin toxicity). Consider an alternative agent with no or minimal potential to induce CYP3A4. If coadministration is necessary, monitor patients for signs and symptoms of thiotepa toxicity. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; St. John's Wort is a strong CYP3A4 inducer.
Tiagabine: (Moderate) Monitor for potential reduction in tiagabine efficacy if administered concomitantly with St. John's Wort, Hypericum perforatum. St. John's Wort is a potent inducer of CYP3A4 isoenzyme and tiagabine is a substrate for CYP3A4. Increased metabolism of tiagabine may occur when St. John's Wort is administered concomitantly.
Ticagrelor: (Major) Avoid the concomitant use of ticagrelor and strong CYP3A4 inducers, such as St. John's Wort, Hypericum perforatum. Ticagrelor is a substrate of CYP3A4/5 and concomitant use with St. John's Wort may substantially decrease ticagrelor exposure which may decrease the efficacy of ticagrelor.
Tipranavir: (Contraindicated) Coadministration of protease inhibitors and St. John's wort is contraindicated due to the risk of decreased plasma concentrations of the antiviral agents, leading to a reduction of antiretroviral efficacy and the potential development of viral resistance. Protease inhibitors are CYP3A4 substrates and St. John's wort is a strong CYP3A4 inducer.
Tivozanib: (Major) Avoid concomitant use of tivozanib with St. Johns Wort due to decreased plasma concentrations of tivozanib, which may reduce its efficacy. Tivozanib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the overall exposure of tivozanib by 52%.
Tofacitinib: (Major) Coadministration of tofacitinib and St. John's Wort, Hypericum perforatum is not recommended due to the potential for a loss of response or reduced clinical response to tofacitinib. Tofacitinib is a CYP3A4 substrate; St. John's Wort, Hypericum perforatum is a strong CYP3A4 inducer. Tofacitinib exposure is decreased when coadministered with strong CYP3A4 inducers. In one study, the mean AUC and Cmax of tofacitinib were decreased by 84% and 74%, respectively when administered with another strong CYP3A4 inducer.
Tolvaptan: (Major) Avoid concurrent use of tolvaptan and St. John's Wort due to the risk for decreased tolvaptan plasma concentrations and reduced efficacy. Tolvaptan is a sensitive CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased tolvaptan exposure by 85%.
Toremifene: (Major) Avoid coadministration of St. John's Wort with toremifene due to decreased plasma concentrations of toremifene which may result in decreased efficacy. Toremifene is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with strong CYP3A4 inducers lowers steady-state serum concentrations of toremifene.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with St. John's Wort due to the risk of decreased trabectedin exposure. Trabectedin is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the systemic exposure of a single dose of trabectedin by 31% compared to a single dose of trabectedin given alone.
Tramadol: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with St. John's wort is necessary; consider increasing the dose of tramadol as needed. If St. John's wort is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome.
Tramadol; Acetaminophen: (Moderate) Monitor for reduced efficacy of tramadol and signs of opioid withdrawal if coadministration with St. John's wort is necessary; consider increasing the dose of tramadol as needed. If St. John's wort is discontinued, consider a dose reduction of tramadol and frequently monitor for seizures, serotonin syndrome, and signs of respiratory depression and sedation. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Tramadol is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Concomitant use with CYP3A4 inducers can decrease tramadol concentrations; this may result in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence. The concomitant use of opioids with other drugs that affect the serotonergic neurotransmitter system has resulted in serotonin syndrome. (Minor) St. John's wort, Hypericum perforatum induces cytochrome P450 1A2. About 10 to 15% of the acetaminophen dose undergoes oxidative metabolism via cytochrome P450 isoenzymes CYP2E1, 3A4 and 1A2, which produces the hepatotoxic metabolite, N-acetyl-p-benzoquinonimine. Thus, theoretically St. John's wort might increase the risk of acetaminophen-induced hepatotoxicity by increasing the metabolism of acetaminophen to NAPQI.
Trandolapril; Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with St. John's Wort is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Tranylcypromine: (Contraindicated) St. John's wort, Hypericum perforatum should not be used concurrently with monoamine oxidase inhibitors (MAOIs) because of the possibility of serotonin syndrome. In patients receiving nonselective MAOs in combination with serotoninergic agents there have been reports of serious, sometimes fatal, reactions. At least 2 weeks should elapse between discontinuation of one agent and initiation of therapy with the other.
Trazodone: (Moderate) Coadministration of trazodone and St. John's Wort may increase the risk of serotonin syndrome. Serotonin syndrome has been reported with both drugs when taken alone, but especially when coadministered with other serotonergic agents. Inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs.
Triazolam: (Moderate) Monitor for withdrawal symptoms or lack of triazolam efficacy if coadministration with St. John's Wort is necessary. Consider appropriate dose adjustment of triazolam if clinically indicated. Triazolam is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer.
Tricyclic antidepressants: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Trimipramine: (Moderate) Monitor patients for the emergence of serotonin syndrome or for loss of tricyclic antidepressant (TCA) efficacy if concomitant use of TCAs and St. John's wort is warranted. The concomitant use of TCAs with other serotonergic drugs has resulted in serotonin syndrome. Also monitor patients for reduced efficacy of TCAs if used together. TCAs are metabolized by several hepatic isoenzymes, including CYP3A and CYP1A2 and St. John's wort is a strong inducer of these enzymes.
Tryptophan, 5-Hydroxytryptophan: (Moderate) Due to the risk of serotonin syndrome, use St. John's wort with caution in combination with tryptophan supplements. There may be an increased risk of serotonin syndrome when St. John's Wort is given in combination with L-tryptophan. There is a case report of serotonin syndrome in a patient who took tryptophan and high doses of St. John's wort in combination.
Tucatinib: (Major) Avoid coadministration of tucatinib and St. John's Wort due to the risk of decreased tucatinib exposure which may reduce its efficacy. Tucatinib is a CYP3A4 and CYP2C8 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with a strong CYP3A4/moderate CYP2C8 inducer decreased tucatinib exposure by 50%.
Ubrogepant: (Major) Avoid the coadministration of ubrogepant and St. John's Wort as concurrent use may decrease ubrogepant exposure and reduce the efficacy. Ubrogepant is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer resulted in an 80% reduction in ubrogepant exposure.
Ulipristal: (Major) Avoid administration of ulipristal with drugs or herbal/dietary supplements that induce CYP3A4. Ulipristal is a substrate of CYP3A4 and St. John's Wort is a CYP3A4 inducer. Concomitant use may decrease the plasma concentration and effectiveness of ulipristal.
Upadacitinib: (Major) Coadministration of upadacitinib with St. John's Wort is not recommended as upadacitinib exposure may be decreased leading to reduced therapeutic effect. Upadacitinib is CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. Concurrent use of a strong CYP3A4 inducer decreased upadacitinib exposure by 61%.
Valbenazine: (Major) Co-administration of strong CYP3A4 inducers, such as St. John's Wort, and valbenazine, a CYP3A4 substrate, is not recommended. Strong CYP3A4 inducers can decrease systemic exposure of valbenazine and its active metabolite compared to the use of valbenazine alone. Reduced exposure of valbenazine and its active metabolite may reduce efficacy.
Vandetanib: (Major) Avoid coadministration of vandetanib with St. Johns Wort due to unpredictably decreased plasma concentrations of vandetanib and increased concentrations of the active metabolite. Vandetanib is a CYP3A4 substrate and St. Johns Wort is a strong CYP3A4 inducer. Concomitant use with another strong CYP3A4 inducer decreased the geometric mean AUC of vandetanib by 40%; the geometric mean AUC and Cmax of N-desmethylvandetanib increased by 266% and 414%, respectively.
Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and St. John's Wort; significantly decreased vemurafenib exposure may occur resulting in reduced vemurafenib efficacy. Consider the use of an alternative agent. If use with St. John's Wort cannot be avoided, increase the vemurafenib dose by 240 mg (as tolerated). If St. John's Wort is discontinued, the previous (lower) vemurafenib dose may be resumed 2 weeks after the last St. John's Wort dose. Vemurafenib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. In a drug interaction study, the vemurafenib AUC value decreased by 40% (90% CI, 24% to 53%) when a single 960-mg vemurafenib dose was administered with another strong CYP3A4 inducer; the vemurafenib Cmax was not changed.
Venetoclax: (Major) Avoid the concomitant use of venetoclax and St. John's wort; venetoclax levels may be significantly decreased and its efficacy reduced. Venetoclax is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Consider alternative agents. In a drug interaction study in healthy subjects (n = 10), the venetoclax Cmax and AUC values were decreased by 42% and 71%, respectively, following the co-administration of multiple doses of a strong CYP3A4 inducer.
Venlafaxine: (Moderate) Because of the potential risk and severity of serotonin syndrome, caution should be observed when coadministering St. John's wort and serotonin norepinephrine reuptake inhibitors (SNRIs). Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome, particularly at treatment initiation or with dose increases. If serotonin syndrome occurs, serotonergic agents should be discontinued and appropriate medical treatment should be initiated.
Verapamil: (Moderate) Monitor blood pressure and heart rate if coadministration of verapamil with St. John's Wort is necessary. Concomitant use may decrease plasma concentrations of verapamil. Verapamil is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer.
Verteporfin: (Moderate) Use caution if coadministration of verteporfin with St. Johns Wort is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like St. Johns Wort may increase the risk of a photosensitivity reaction.
Vilazodone: (Moderate) Consider increasing the dose of vilazodone up to 2-fold over 1 to 2 weeks (maximum, 80 mg per day) based on clinical response if coadministration with St. John's Wort is necessary for more than 14 days. After discontinuation of St. John's Wort, resume the previous vilazodone dose over 1 to 2 weeks. Also, inform patients taking this combination of the possible increased risk and monitor for the emergence of serotonin syndrome. Discontinue all serotonergic agents and initiate symptomatic treatment if serotonin syndrome occurs. Vilazodone is primarily metabolized by CYP3A4 and St. John's Wort is a strong CYP3A4 inducer. Decreased plasma concentrations of vilazodone are expected if vilazodone is used concomitantly with strong CYP3A4 inducers.
Vincristine Liposomal: (Moderate) St. John's Wort, Hypericum perforatum induces both CYP3A4 and P-glycoprotein (P-gp), and may decrease serum concentrations of drugs metabolized by this enzyme, such as vincristine. If these drugs are used together, monitor for possible decreased efficacy of vincristine.
Vincristine: (Moderate) St. John's Wort, Hypericum perforatum induces both CYP3A4 and P-glycoprotein (P-gp), and may decrease serum concentrations of drugs metabolized by this enzyme, such as vincristine. If these drugs are used together, monitor for possible decreased efficacy of vincristine.
Vitamin A: (Moderate) In theory it is possible that additive photosensitizing effects may result from the concomitant use of St. John's wort with other photosensitizing drugs such as retinoids.
Voclosporin: (Major) Avoid coadministration of voclosporin with St. John's Wort. Coadministration may decrease voclosporin exposure resulting in decreased efficacy. Voclosporin is a sensitive CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased voclosporin exposure by 87%.
Vonoprazan: (Major) Avoid concomitant use of vonoprazan and St. John's Wort due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Vonoprazan; Amoxicillin: (Major) Avoid concomitant use of vonoprazan and St. John's Wort due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer.
Vonoprazan; Amoxicillin; Clarithromycin: (Major) Avoid concomitant use of vonoprazan and St. John's Wort due to decreased plasma concentrations of vonoprazan, which may reduce its efficacy. Vonoprazan is a CYP3A substrate and St. John's Wort is a strong CYP3A inducer. Vonoprazan exposures are predicted to be 80% lower when coadministered with a strong CYP3A4 inducer. (Moderate) St. John's Wort appears to induce CYP3A4 and may lead to increased systemic clearance of clarithromycin, a CYP3A4 substrate. Additionally, clarithromycin may increase serum concentrations of St. John's Wort due to CYP3A4 inhibition. Postmarketing reports of interactions have been noted.
Vorapaxar: (Major) Avoid coadministration of vorapaxar and St. John's Wort. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with St. John's Wort, a strong CYP3A inducer.
Voriconazole: (Contraindicated) Concomitant use of voriconazole with St. John's Wort is contraindicated. Voriconazole is metabolized by the CYP3A4 and CYP2C9 isoenzymes, and St. John's wort is known to be an inducer of CYP3A4 and CYP2C9; coadministration results in significantly reduced plasma levels of voriconazole. A study in healthy volunteers who were given multiple oral doses of St. John's wort for 15 days followed by a single 400 mg oral dose of voriconazole, showed a 59% decrease in mean voriconazole exposure. However, coadministration of single oral doses of St. John's wort and voriconazole had no appreciable effect on voriconazole AUC. Long-term use of St. John's wort could lead to reduced voriconazole exposure.
Vortioxetine: (Major) Due to the potential for additive effects on serotonin concentrations and possible CYP induction by St. John's wort, it is advisable to avoid combining St. John's wort, Hypericum perforatum with vortioxetine. Interactions between vortioxetine and serotonergic agents can lead to serious reactions including serotonin syndrome. Serotonin syndrome is characterized by the rapid development of hyperthermia, hypertension, myoclonus, rigidity, autonomic instability, mental status changes (e.g., delirium or coma), and in rare cases, death. Cases of serotonin syndrome reactions have been documented when other serotonergic antidepressants (e.g., SSRIs) were used concurrently with St. John's wort. In addition, patients may experience a decreased response to vortioxetine when CYP inducers such as St. John's Wort are co-administered. Vortioxetine is extensively metabolized by CYP isoenzymes, primarily CYP2D6 and by CYP3A4 and other isoenzymes to a lesser extent. The manufacturer recommends that the practitioner consider an increase in dose of vortioxetine when a strong CYP inducer is co-administered for more than 14 days. In such cases, the maximum recommended dose of vortioxetine should not exceed three times the original dose. When the inducer is discontinued, the dose of vortioxetine should be reduced to the original level within 14 days.
Voxelotor: (Major) Avoid coadministration of voxelotor and St. John's Wort as concurrent use may decrease voxelotor exposure and lead to reduced efficacy. If coadministration is unavoidable, increase voxelotor dosage to 2,500 mg PO once daily in patients 12 years and older. In patients 4 to 11 years old, weight-based dosage adjustments are recommended; consult product labeling for specific recommendations. Voxelotor is a substrate of CYP3A; St. John's Wort is a strong CYP3A inducer. Coadministration of voxelotor with a strong CYP3A inducer is predicted to decrease voxelotor exposure by up to 40%.
Warfarin: (Moderate) Closely monitor the INR if coadministration of warfarin with St. John's Wort is necessary as concurrent use may decrease the exposure of warfarin leading to reduced efficacy. St. John's Wort is a CYP1A2, moderate CYP2C9, and strong CYP3A4 inducer and the enantiomers of warfarin are substrates of CYP1A2/CYP2C9/CYP3A4. In one report, a decreased INR occurred in 7 patients previously stabilized on warfarin. The interactions occurred within 1 week to 1 month of St. John's wort coadministration. Conversely, if St. John's wort is discontinued in a patient stabilized on warfarin, frequent monitoring and dosage adjustment may be necessary to avoid an increased INR or risk of bleeding.
Zaleplon: (Moderate) Monitor for decreased efficacy/ineffectiveness of zaleplon if coadministration with St. John's Wort is necessary. Zaleplon is a CYP3A4 substrate and St. John's Wort is a strong CYP3A4 inducer. Although CYP3A4 is normally a minor metabolizing enzyme of zaleplon, coadministration with another strong CYP3A4 inducer reduced zaleplon exposure by approximately 80%. An alternative non-CYP3A4 substrate hypnotic agent may be considered in patients taking strong CYP3A4 inducers.
Zanubrutinib: (Major) Avoid the concomitant use of zanubrutinib and St. John's Wort. Coadministration may result in decreased zanubrutinib exposure and reduced efficacy. Zanubrutinib is a CYP3A4 substrate; St. John's Wort is a strong CYP3A4 inducer. The AUC of zanubrutinib was decreased by 93% when coadministered with another strong CYP3A4 inducer.
Zolmitriptan: (Moderate) Although unlikely to occur during monotherapy with serotonin-receptor agonists ("triptans"), coadministration with serotonergic agents like St. John's Wort may increase the risk for serotonin syndrome. Inform the patient of the increased risk and monitor for the emergence of serotonin syndrome.
Zolpidem: (Major) Avoid use of St. John's wort with zolpidem is possible; use of St. John's wort is not recommended as concurrent use may decrease plasma concentrations of zolpidem and lead to loss of hypnotic efficacy. Zolpidem is a CYP3A4 substrate and St. John's wort is a strong CYP3A4 inducer. Coadministration with St. John's wort decreased the mean AUC of zolpidem by 30%.
Zonisamide: (Major) Zonisamide is metabolized by hepatic cytochrome P450 enzyme 3A4. Inducers of CYP3A4, including St. John's wort, can reduce the systemic exposure to zonisamide by increasing the metabolism of the drug.
Zuranolone: (Major) Avoid concomitant use of zuranolone and St. John's wort. Concurrent use may decrease zuranolone exposure which may reduce its efficacy. Zuranolone is a CYP3A substrate and St. John's wort is a strong CYP3A inducer. Concomitant use with another strong CYP3A inducer reduced zuranolone overall exposure by 85%.
There is much debate over the exact mechanism of action of St. John's wort, particularly in the treatment of depression. Hypericin, one of the active ingredients, is used as a marker for standardization of processing. Other naphthodianthrones (e.g., pseudohypericin), the flavonoids (e.g., quercetin), and hyperforin are thought to be needed in combination with hypericin for antidepressant clinical effects. Trials in Germany have focused on hyperforin, which is found primarily in the stamens and other reproductive parts of the plant, as a major contributor to antidepressant activity. It is postulated that the final activity of St. John's wort is the result of cumulative actions on a variety of neurotransmitters and steroid hormones.
-Neuropharmacology: Although it is not possible at this time to identify with certainty the active antidepressant principle(s) in St. John's wort, clinically, an antidepressant effect has been documented.
Animal data indicate that hypericum extract (LI 160(TM)) can inhibit serotonin uptake by postsynaptic receptors. Serotonin receptors are down-regulated in this process, leading to increased serotonin levels. Hypericum extract may also interfere with presynaptic serotonin uptake. Hypericum has also been reported to increase synaptic dopamine concentrations, possibly through inhibition of dopamine-beta-hydroxylase. Hyperforin, a component of hypericum extract, enhances the extracellular levels of serotonin, dopamine, norepinephrine, and the excitatory amino acid glutamate, probably as a consequence of neuronal uptake inhibition. The effects of hyperforin on serotonin are similar to, but less potent than, the SSRI class of antidepressants. Unlike the SSRI antidepressants, hyperforin is a non-competitive reuptake inhibitor; it affects the pre-synaptic sodium channels that control reuptake transporter activity.
Quercetin and xanthones contained in the leaves and roots of the St. John's wort plant have been shown to inhibit monoamine oxidase (MAO) in rat brain in vitro studies. Hypericin does not have any significant inhibition of MAO types A and B in the human nervous system when administered at recommended clinical dosages. MAO inhibition alone appears to be an insufficient explanation of antidepressant effects of St. John's wort. The relative MAO inhibitory action of St. John's wort is currently thought to be less significant than that which occurs with commonly prescribed MAOIs (e.g., isocarboxazid, phenelzine, tranylcypromine).
Active ingredients such as xanthone, quercetin, and rutoside have weak inhibitory actions on catechol-O-methyl transferase (COMT). However, there is no evidence at this time that COMT-inhibition is a significant contributor to the activity of St. John's wort.
St. John's wort may increase the nighttime production of melatonin. Relaxant effects seen on EEG are similar to the tricyclic antidepressants. Other actions of St. John's wort include weak affinity for NMDA receptors and GABA receptors in vitro.
St. John's wort may exhibit peripheral pharmacologic effects. Via inhibitory actions on cytokines (e.g., interleukin-6), St. John's wort may help regulate cortisol production and release, which may contribute to antidepressant activity.
-Phototoxic and Cytotoxic actions: Human keratinocytes treated with St. John's wort exhibit photodynamic effects similar to psoralen when exposed to UV light. Clinical phototoxicity results in adverse drug reactions such as sunburn, rashes, and dysesthesia. These actions have led to the investigation of synthetic hypericin in combination with light for the therapy of various pathologic skin conditions.
Hypericin is an inhibitor of cellular protein kinase C activity, and may exhibit anti-angiogenic activity. The activity of hypericin in vitro against glioma cells exposed to light has led to the clinical investigation of the action of oral synthetic hypericin against glioma-cell migration. Clinically, effects against glioblastoma have been observed in vivo.
-Antiviral and Antibacterial Actions: Antiviral effects of hypericin and pseudohypericin have been demonstrated in mice. Specific viruses that are inhibited in murine models include: herpes simplex 1 and 2, cytomegalovirus (CMV), hepatitis C virus, influenza virus, and poliovirus. Inhibition of bovine immunodeficiency virus via inhibition of reverse transcriptase in vitro lead to research in HIV infection; however, trials have been terminated due to lack of clinical benefit in initial human studies. A preliminary study in humans failed to show activity against hepatitis C. In vitro studies of viral-infected human blood have failed to show significant anti-viral activity. There is no evidence of efficacy of St. John's wort in any human viral illness at this time. While hyperforin appears to inhibit S. aureus in vitro, antibacterial activity in vivo is uncertain.
Other actions: Other minor pharmacologic actions of St. John's wort include mild estrogenic activity. St. John's wort has induced contractions of animal uterine muscle tissue in vitro. St. John's wort may suppress the production of arachodonic acid and leukotrienes, leading to decreased inflammation and white blood cell infiltration. In addition, there may be some stimulation of cellular and humoral immunity. These actions may explain the use of St. John's wort as a historical treatment for burns and minor skin wounds.
St. John's wort is administered orally. Most commonly, when used to lift the mood, the herb is taken orally as a tea made from the leaves, or as an extract in tablet or capsule form. Potency of St. John's wort preparations, expressed as percentage of hypericin, can vary substantially from manufacturer to manufacturer. In one analysis of commercial extracts, 50% of products tested contained less than 80% of the hypericin content stated on the label, and 30% of brands tested contained less than 50% of their stated hypericin content. Some clinicians note that only one commercial extract, known as LI 160, has been associated with clinical effectiveness in controlled trials.
Single and multiple dose pharmacokinetic studies of the LI 160 extract of St. John's wort have been performed. The different components of the herb may have different pharmacokinetic parameters, but these are not well understood. Steady state plasma concentrations are reached after 4 days of continued dosing of LI 160 300 mg three times per day. Hypericin does cross the blood-brain barrier. Elimination half-life ranges 16-36 hours in single dose studies, but the route of elimination of St. John's wort or its components has not been delineated. As with all antidepressants, several weeks of therapy are required to reach full effectiveness.
Affected cytochrome P450 isoenzymes and drug transporters: CYP3A4, P-gp
St. John's Wort can interact with several drugs. Pharmacodynamic and pharmacokinetic interactions are possible. St. John's Wort induces hepatic microsomal CYP450 enzyme CYP3A4. In addition, it appears that the herb may increase the expression of P-glycoprotein (P-gp), resulting in increased efflux and lowered serum concentrations of interacting medications that are substrates for P-gp.
-Route-Specific Pharmacokinetics
Oral Route
When St. John's wort is administered via the oral route, hypericin appears to be maximally absorbed in 2 hours, whereas pseudohypericin is absorbed in 0.5-1 hour. Both hypericin and pseudohypericin appear to have non-linear increases in AUC with increasing oral dosage; the effect is most pronounced for hypericin.