Lonafarnib is a farnesyltransferase inhibitor approved for reducing the risk of mortality in patients 1 year and older with Hutchinson-Gilford progeria syndrome and for the treatment of processing-deficient progeroid laminopathies with either heterozygous LMNA mutation with progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations. Hutchinson-Gilford progeria syndrome and progeroid laminopathies are rare, fatal, genetic diseases that cause premature aging due to a mutation in LMNA, which produces the farnesylated aberrant protein, progerin. Without treatment, death from heart failure, heart attack, or stroke occurs at an average age of 14.6 years. Lonafarnib helps prevent the buildup of defective progerin or progerin-like protein. In clinical trials (n = 62) lonafarnib increased the lifespan of Hutchinson-Gildford progeria syndrome patients by an average of 3 months through the first 2 years of treatment and by an average of 2.5 years through the maximum follow-up time of 11 years. The most common side effects reported in trials included nausea, vomiting, diarrhea, infection, decreased appetite, and fatigue. Because toxicity of the eyes and kidneys occurred in animals, renal monitoring and ophthalmologic examinations are recommended periodically during treatment and when there are new visual changes. Additionally, some patients treated with lonafarnib developed laboratory test abnormalities so routine blood laboratory testing (i.e., serum electrolytes, CBC, and LFTs) should be obtained periodically.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Solid Formulations
-Administer lonafarnib twice daily with morning and evening meals; capsules should be taken with an adequate amount of water. Do NOT chew the capsules.
-If a dose is missed, take the dose as soon as possible with food, up to 8 hours prior to the next scheduled dose. If less than 8 hours remains before the next schedule dose, skip the missed dose.
-For patients with difficulty swallowing, the capsules may be opened and the entire contents mixed with 5 to 10 mL of Ora Blend SF, Ora-Plus, or orange juice. Do NOT mix with juice containing grapefruit or Seville oranges. Mix thoroughly with a spoon. Prepare each mixture fresh for each dose and take within 10 minutes of mixing. Consume the entire serving. Alternatively, empty capsule contents into a container containing 1 to 2 teaspoonfuls of applesauce. Mix thoroughly with a spoon and consume the entire serving.
During lonafarnib clinical trials, the most commonly reported adverse reactions to lonafarnib were gastrointestinal (GI) reactions. Vomiting (total, 90%; mild, 53%, moderate, 46%; severe, 2%) and nausea (total, 56%; mild, 97%, moderate, 3%) were frequently reported. During the first 4 months of treatment, 68% of patients had vomiting and 36% of patients had nausea. By the end of therapy (up to 36 months), 14% of patients who were still on lonafarnib required antiemetics or anti-nausea medications. A total of 4 patients discontinued lonafarnib, most commonly due to nausea or vomiting. Diarrhea (total, 81%; mild, 75%, moderate, 18%; severe, 8%) was commonly reported. During the first four months of treatment, 82% of patients had diarrhea. By the end of therapy (up to 36 months), 11% of patients who were still on lonafarnib had diarrhea; 43% of patients were treated with loperamide. Anorexia (53%), abdominal pain (48%), weight loss (37%), constipation (22%), and flatulence (6%) were also reported.
Infection, including abdominal infection, candidiasis, chicken pox, Clostridium difficile colitis, colitis, croup, dengue fever, influenza syndrome, influenza-like symptoms, fungal infection, gastroenteritis, gastrointestinal infection, Helicobacter pylori infection, infection, infection viral, influenza, nail infection, otitis media, parotitis, perirectal abscess, pneumonia, small intestine infection, submandibular lymphadenitis, tonsillitis, and viral infection, was reported in 78% of patients during lonafarnib clinical trials. Upper respiratory tract infection, including bronchial infection, bronchitis, sinus infection, and upper respiratory infection was reported in 51% of patients in clinical trials. Rhinitis (19%) and pyrexia/fever (14%) were also reported.
During lonafarnib clinical trials, electrolyte abnormalities, including hypermagnesemia, hypokalemia, hyperkalemia, hyponatremia, hypercalcemia, hyperphosphatemia, hypocalcemia, and hypernatremia, were reported in 43% of patients.
Myelosuppression, including decreased absolute neutrophil count (neutropenia), low total white blood cells (leukopenia), lymphopenia, and low hemoglobin/hematocrit (anemia), was reported in 35% of patients during clinical trials.
Elevated hepatic enzymes have been observed during lonafarnib clinical trials. Increased aspartate aminotransferase (total increases 35%; mild increases, 95%; severe increase, 5%) and increased alanine aminotransferase (total increases 27%; mild increases, 82%; moderate increases, 6%; severe increase, 12%) were reported in patients receiving lonafarnib. One patient with elevated hepatic enzymes also experienced hypertriglyceridemia and hyperglycemia resulting in lonafarnib discontinuation.
Hypertension (29%) has been reported during lonafarnib clinical trials. At baseline, 35% of patients had either a systolic blood pressure or a diastolic blood pressure or both above the 95th percentile. Over the course of the trials, 29% of patients had hypertension based on systolic blood pressure or diastolic blood pressure measurements above the 95th percentile on 3 or more occasions; 8% of patients who were normotensive at baseline had either systolic blood pressure or diastolic blood pressure above the 95th percentile at the end of treatment.
Fatigue (51%), dehydration (5%), headache (37%), and depressed mood (depression) (5%) have been reported in patients during clinical trials with lonafarnib. Musculoskeletal pain, including arthritis, back pain, bone pain, foot pain, intercostal pain, joint pain, knee pain, leg pain, musculoskeletal pain, pain in ankle/extremity/fingers/hip/leg/limb/lower limbs/left arm, shoulder pain, unilateral leg pain, occurred in 48% of patients receiving lonafarnib. Cerebral ischemia, including central nervous system hemorrhage, and ischemia cerebrovascular, was reported in 11% of patients receiving lonafarnib.
Ocular changes, including visual acuity change (visual impairment), corneal clouding, conjunctivitis, watering eyes, and keratitis, have been reported in 24% of patients during lonafarnib clinical trials.
During lonafarnib clinical trials, decreased blood bicarbonate (33%), cough (33%), epistaxis (21%), rash (11%), pruritus (8%), and mucositis (8%) were reported.
Administer lonafarnib with caution in patients with electrolyte imbalance. When possible, correct any electrolyte imbalance including hypokalemia, hypomagnesemia, or hypocalcemia prior to initiation of lonafarnib. During clinical trials, 43% of patients receiving lonafarnib developed electrolyte imbalances including hyperkalemia, hypokalemia, hyponatremia, or hypercalcemia. Laboratory abnormalities often improve while continuing lonafarnib, but it is not possible to exclude lonafarnib as the cause of the abnormalities. Periodically measure electrolytes and manage abnormalities accordingly.
Patients with preexisting bone marrow suppression especially neutropenia, leukopenia, or anemia should receive lonafarnib therapy with caution. During clinical trials, 35% of patients developed myelosuppression, such as reductions in absolute neutrophil count, white blood cell counts, lymphocytes, hemoglobin, or hematocrit. Laboratory abnormalities often improve while continuing lonafarnib, but it is not possible to exclude lonafarnib as the cause of the abnormalities. Periodically measure complete blood counts and manage abnormalities accordingly.
Administer lonafarnib with caution in patients with hepatic disease. During clinical trials, patients receiving lonafarnib developed increased liver enzymes such as aspartate aminotransferase (35%) or alanine aminotransferase (27%). Laboratory abnormalities often improve while continuing lonafarnib, but it is not possible to exclude lonafarnib as the cause of the abnormalities. Periodically measure liver enzymes and manage abnormalities accordingly.
Use lonafarnib with caution in patients with pre-existing cardiac arrhythmias if coadministered with CYP3A4 or CYP2C9 inhibitors. Monitor patients for signs and symptoms of arrhythmias (e.g., palpitation, dizziness, syncope, or dyspnea) because the effect of increased lonafarnib exposures on the QT interval is unknown.
Measure renal function at regular intervals during lonafarnib therapy. Based on animal data, lonafarnib may cause nephrotoxicity. Lonafarnib caused nephrotoxicity during a 6-month oral toxicity study in rats at systemic exposures approximately equal to the AUC in humans at the recommended dose of lonafarnib 150 mg/m2 twice daily. Kidney lesions (interstitial necrosis and mineralization in the inner medulla) and correlating changes in electrolytes (e.g., hyperphosphatemia and hyperkalemia) and urinalysis parameters were observed in the rats. No renal toxicity was observed at systemic exposures lower than the human AUC at 150 mg/m2 twice daily.
Perform regular eye exams in patients receiving lonafarnib. Based on animal data, lonafarnib may cause visual disturbance. Ocular (retinal) toxicity occurred in a 1-year oral toxicity study in monkeys receiving 40 mg/kg/day (3.7 times the human AUC at the recommended dose of 150 mg/m2 twice daily). The retinal injury caused rod-dependent, low-light vision decline. No retinal toxicity was observed at 20 mg/kg/day (2.1 times the human AUC at 150 mg/m2 twice daily). However, in a follow-up study in monkeys receiving 15 mg/kg/day PO for 13 weeks or 60 mg/kg/day PO for 6 weeks, rod-dependent, low-light vision was again observed. The changes were observed at several time-points throughout the treatment period. No histological changes in the retina were observed at the end of the study.
Counsel patients about the reproductive risk during lonafarnib treatment. Based on animal data, lonafarnib may cause female and male infertility. Lonafarnib caused impaired fertility in female rats at 1.2 times the human AUC at the recommended human dose of 150 mg/m2 twice daily. Lonafarnib caused impaired fertility and testicular toxicity in male rats at 1.5 times the human AUC at the recommended human dose of 150 mg/m2 twice daily. Toxicity was also observed in the male reproductive tract in monkeys at doses lower than the human dose based on plasma drug exposure. The impact on pubertal development and the potential for impaired fertility has not been adequately evaluated.
Lonafarnib may cause fetal harm based on animal studies; however, there are no well-controlled studies in pregnant women. Women who are pregnant or who become pregnant while receiving lonafarnib should be counseled on the potential hazard to the fetus. In rats receiving lonafarnib during pregnancy, lonafarnib produced an increase in post-implantation loss (resorptions) and decreases in fetal body weight and number of live fetuses at 1.2 times the human AUC at the recommended human dose of 150 mg/m2 twice daily. In rabbits, lonafarnib produced skeletal malformations and variations at exposures less than the human exposure at 150 mg/m2 twice daily, and maternal toxicity at 26 times the human exposure at 150 mg/m2 twice daily.
There are no data on the presence of lonafarnib in human milk, the effects on a breast-fed infant, or the effects on milk production. Lonafarnib is excreted in rat milk with a mean milk to plasma concentration ratio of 1.5 at 12 hours. 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 administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
For mortality risk reduction in Hutchinson-Gilford progeria syndrome (HGPS) and for the treatment of processing-deficient progeroid laminopathies with either heterozygous LMNA mutation and progerin-like protein accumulation or homozygous or compound heterozygous ZMPSTE24 mutations:
NOTE: Lonafarnib is not indicated for other types of progeroid syndromes or processing-proficient progeroid laminopathies.
NOTE: Lonafarnib has been designated as an orphan drug for this indication by the FDA.
Oral dosage (initial dosing for first 4 months of treatment):
Adults: Initially, give 115 mg/m2 PO twice daily with morning and evening meals. Round the total daily doses to the nearest 25 mg. For BSA of 0.39 to 0.48 m2, the dose is 100 mg/day (50 mg twice daily). For BSA of 0.49 to 0.59 m2, the dose is 125 mg/day (75 mg in the morning and 50 mg in the evening). For BSA of 0.6 to 0.7 m2, the dose is 150 mg/day (75 mg twice daily). For BSA of 0.71 to 0.81 m2, the dose is 175 mg/day (100 mg in the morning and 75 mg in the evening). For BSA of 0.82 to 0.92 m2, the dose is 200 mg/day (100 mg twice daily). For BSA of 0.93 to 1 m2, the dose is 225 mg/day (125 mg in the morning and 100 mg in the evening).
Children and Adolescents with a BSA of 0.39 m2 and higher: Initially, give 115 mg/m2 PO twice daily with morning and evening meals. Round the total daily doses to the nearest 25 mg. For BSA of 0.39 to 0.48 m2, the dose is 100 mg/day (50 mg twice daily). For BSA of 0.49 to 0.59 m2, the dose is 125 mg/day (75 mg in the morning and 50 mg in the evening). For BSA of 0.6 to 0.7 m2, the dose is 150 mg/day (75 mg twice daily). For BSA of 0.71 to 0.81 m2, the dose is 175 mg/day (100 mg in the morning and 75 mg in the evening). For BSA of 0.82 to 0.92 m2, the dose is 200 mg/day (100 mg twice daily). For BSA of 0.93 to 1 m2, the dose is 225 mg/day (125 mg in the morning and 100 mg in the evening).
Oral dosage (increased dose after 4 months):
Adults: After 4 months of treatment, increase the dosage to 150 mg/m2 PO twice daily with morning and evening meals. Round all total daily doses to the nearest 25 mg. For BSA of 0.39 to 0.45 m2, the dose is 125 mg/day (75 mg in the morning and 50 mg in the evening). For BSA of 0.46 to 0.54 m2, the dose is 150 mg/day (75 mg twice daily). For BSA of 0.55 to 0.62 m2, the dose is 175 mg/day (100 mg in the morning and 75 mg in the evening). For BSA of 0.63 to 0.7 m2, the dose is 200 mg/day (100 mg twice daily). For BSA of 0.71 to 0.79 m2, the dose is 225 mg/day (125 mg in the morning and 100 mg in the evening). For BSA of 0.8 to 0.87 m2, the dose is 250 mg/day (125 mg twice daily). For BSA of 0.88 to 0.95 m2, the dose is 275 mg/day (150 mg in the morning and 125 mg in the evening). For BSA of 0.96 to 1 m2, the dose is 300 mg/day (150 mg twice daily). For patients who cannot tolerate the increased dose due to gastrointestinal adverse reactions, return to the starting dose of 115 mg/m2 twice daily.
Children and Adolescents with a BSA of 0.39 m2 and higher: After 4 months of treatment, increase the dosage to 150 mg/m2 PO twice daily with morning and evening meals. Round all total daily doses to the nearest 25 mg. For BSA of 0.39 to 0.45 m2, the dose is 125 mg/day (75 mg in the morning and 50 mg in the evening). For BSA of 0.46 to 0.54 m2, the dose is 150 mg/day (75 mg twice daily). For BSA of 0.55 to 0.62 m2, the dose is 175 mg/day (100 mg in the morning and 75 mg in the evening). For BSA of 0.63 to 0.7 m2, the dose is 200 mg/day (100 mg twice daily). For BSA of 0.71 to 0.79 m2, the dose is 225 mg/day (125 mg in the morning and 100 mg in the evening). For BSA of 0.8 to 0.87 m2, the dose is 250 mg/day (125 mg twice daily). For BSA of 0.88 to 0.95 m2, the dose is 275 mg/day (150 mg in the morning and 125 mg in the evening). For BSA of 0.96 to 1 m2, the dose is 300 mg/day (150 mg twice daily). For patients who cannot tolerate the increased dose due to gastrointestinal adverse reactions, return to the starting dose of 115 mg/m2 twice daily.
Maximum Dosage Limits:
-Adults
150 mg/m2 PO twice daily.
-Geriatric
150 mg/m2 PO twice daily.
-Adolescents
150 mg/m2 PO twice daily.
-Children
BSA at least 0.39 m2: 150 mg/m2 PO twice daily.
BSA less than 0.39 m2: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; lonafarnib has not been studied in patients with hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; lonafarnib has not been studied in patients with renal impairment.
*non-FDA-approved indication
Abacavir; Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lonafarnib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Abemaciclib: (Major) If coadministration with lonafarnib is necessary, reduce the dose of abemaciclib to 100 mg PO twice daily in patients on either of the recommended starting doses of either 200 mg or 150 mg twice daily. In patients who have had already had a dose reduction to 100 mg twice daily due to adverse reactions, further reduce the dose of abemaciclib to 50 mg PO twice daily. Discontinue abemaciclib for patients unable to tolerate 50 mg twice daily. If lonafarnib is discontinued, increase the dose of abemaciclib to the original dose after 3 to 5 half-lives of lonafarnib. Abemaciclib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the relative potency adjusted unbound AUC of abemaciclib plus its active metabolites (M2, M18, and M20) by 2.5-fold in cancer patients.
Acalabrutinib: (Major) Avoid the concomitant use of acalabrutinib and lonafarnib; significantly increased acalabrutinib exposure may occur. If short-term lonafarnib use is unavoidable, interrupt acalabrutinib therapy. Wait at least 24 hours after lonafarnib is discontinued before resuming acalabrutinib at the previous dosage. Acalabrutinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In healthy subjects, the Cmax and AUC values of acalabrutinib were increased by 3.9-fold and 5.1-fold, respectively, when acalabrutinib was coadministered with another strong inhibitor for 5 days.
Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Consider a reduced dose of dihydrocodeine with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the dihydrocodeine dose until stable drug effects are achieved; monitor for evidence of opioid withdrawal. Concomitant use of dihydrocodeine with lonafarnib may increase dihydrocodeine plasma concentrations, resulting in greater metabolism by CYP2D6, increased dihydromorphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Dihydrocodeine is partially metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor.
Acetaminophen; Codeine: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Acetaminophen; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Acetaminophen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like lonafarnib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lonafarnib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Adagrasib: (Contraindicated) Coadministration of lonafarnib and adagrasib is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. The exposure of adagrasib may also be increased. Lonafarnib is a CYP3A and CYP2C9 substrate and strong CYP3A inhibitor; adagrasib is a CYP3A substrate and strong CYP3A and moderate CYP2C9 inhibitor. Coadministration with another strong CYP3A inhibitor increased the exposure of lonafarnib by 425%.
Ado-Trastuzumab emtansine: (Major) Avoid coadministration of lonafarnib with ado-trastuzumab emtansine if possible due to the risk of elevated exposure to the cytotoxic component of ado-trastuzumab emtansine, DM1. Delay ado-trastuzumab emtansine treatment until lonafarnib has cleared from the circulation (approximately 3 half-lives of lonafarnib) when possible. If concomitant use is unavoidable, closely monitor patients for ado-trastuzumab emtansine-related adverse reactions. The cytotoxic component of ado-trastuzumab emtansine, DM1, is metabolized mainly by CYP3A4 and to a lesser extent by CYP3A5; lonafarnib is a strong CYP3A4 inhibitor. Formal drug interaction studies with ado-trastuzumab emtansine have not been conducted.
Afatinib: (Moderate) If the concomitant use of lonafarnib and afatinib is necessary, monitor for afatinib-related adverse reactions. If the original dose of afatinib is not tolerated, consider reducing the daily dose of afatinib by 10 mg; resume the previous dose of afatinib as tolerated after discontinuation of lonafarnib. The manufacturer of afatinib recommends permanent discontinuation of therapy for severe or intolerant adverse drug reactions at a dose of 20 mg per day but does not address a minimum dose otherwise. Afatinib is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor. Administration with another P-gp inhibitor, given 1 hour before a single dose of afatinib, increased afatinib exposure by 48%; there was no change in afatinib exposure when the P-gp inhibitor was administered at the same time as afatinib or 6 hours later. In healthy subjects, the relative bioavailability for AUC and Cmax of afatinib was 119% and 104%, respectively, when coadministered with the same P-gp inhibitor, and 111% and 105% when the inhibitor was administered 6 hours after afatinib.
Albuterol; Budesonide: (Moderate) Avoid coadministration of oral budesonide and lonafarnib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Alfentanil: (Moderate) Consider a reduced dose of alfentanil with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the alfentanil dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Alfentanil is a sensitive CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase alfentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of alfentanil. If lonafarnib is discontinued, alfentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to alfentanil.
Alfuzosin: (Contraindicated) Coadministration of alfuzosin and lonafarnib is contraindicated due to increased alfuzosin exposure. Alfuzosin is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. When coadministered with another strong CYP3A4 inhibitor, the AUC of alfuzosin was increased by 2.5-fold to 3.2-fold.
Almotriptan: (Moderate) The maximum recommended starting dose of almotriptan is 6.25 mg if coadministration with lonafarnib is necessary; do not exceed 12.5 mg within a 24-hour period. Concomitant use of almotriptan and lonafarnib should be avoided in patients with renal or hepatic impairment. Almotriptan is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased almotriptan exposure by approximately 60%.
Alosetron: (Moderate) Concomitant use of alosetron with lonafarnib may result in increased serum concentrations of alosetron and increase the risk for adverse reactions. Caution and close monitoring are advised if these drugs are used together. Alosetron is a substrate of hepatic isoenzyme CYP3A4; lonafarnib is a strong inhibitor of this enzyme. In a study of healthy female subjects, another strong CYP3A4 inhibitor increased mean alosetron AUC by 29%.
Alprazolam: (Contraindicated) Coadministration of lonafamib and alprazolam is contraindicated due to the potential for elevated alprazolam concentrations, which may cause prolonged sedation and respiratory depression. Lorazepam, oxazepam, or temazepam may be safer alternatives if a benzodiazepine must be administered in combination with lonafamib, as these benzodiazepines are not oxidatively metabolized. Alprazolam is a CYP3A4 substrate and lonafamib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased alprazolam exposure by 2.7- to 3.98-fold.
Amiodarone: (Contraindicated) Coadministration of lonafarnib and amiodarone is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, a CYP2C9 substrate and strong CYP3A4 inhibitor; amiodarone is a CYP3A4 substrate, a moderate CYP2C9 inhibitor, and moderate CYP3A4 inhibitor.
Amlodipine: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Amlodipine; Atorvastatin: (Contraindicated) Coadministration of atorvastatin and lonafarnib is contraindicated according to the manufacturer of lonafarnib. The manufacturer of atorvastatin recommends that if concomitant use of these drugs is required, a lower starting and maintenance dose of atorvastatin should be considered; monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 and P-gp substrate and lonafarnib is a strong CYP3A4 inhibitor and P-gp inhibitor. (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Amlodipine; Benazepril: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Amlodipine; Celecoxib: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Amlodipine; Olmesartan: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Amlodipine; Valsartan: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Amobarbital: (Contraindicated) Coadministration of lonafarnib and amobarbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and amobarbital is a moderate CYP3A4 inducer.
Amoxicillin; Clarithromycin; Omeprazole: (Contraindicated) Coadministration of lonafarnib and clarithromycin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Apalutamide: (Contraindicated) Coadministration of lonafarnib and apalutamide is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. The exposure of apalutamide may also be increased, increasing the risk for apalutamide-related adverse reactions. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; apalutamide is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Apixaban: (Major) Reduce the apixaban dose by 50% when administered with lonafarnib. If patients are already receiving the reduced dose of 2.5 mg twice daily, avoid coadministration. Concomitant administration of apixaban and lonafarnib may result in increased exposure to apixaban and an increase in the risk of bleeding. Apixaban is a P-gp and CYP3A4 substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. In a drug interaction study, administration of another combined P-gp/strong CYP3A4 inhibitor increased the apixaban AUC by 2-fold.
Aprepitant, Fosaprepitant: (Contraindicated) Coadministration of lonafarnib and aprepitant, fosaprepitant is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; aprepitant, fosaprepitant is a sensitive CYP3A4 substrate and moderate CYP3A4 inhibitor. Administration of a strong CYP3A4 inhibitor increased the aprepitant AUC and mean terminal half-life by approximately 5-fold and 3-fold, respectively.
Aripiprazole: (Major) Recommendations for managing aripiprazole and lonafarnib vary by aripiprazole dosage form and CYP2D6 metabolizer status. For aripiprazole oral dosage forms, administer half of the usual dose; administer a quarter of the usual dose to patients known to be poor metabolizers of CYP2D6. For monthly extended-release aripiprazole injections (Abilify Maintena), reduce the dosage from 400 mg to 300 mg/month or from 300 mg to 200 mg/month; administer 200 mg/month to patients known to be poor metabolizers of CYP2D6. For extended-release aripiprazole injections given once every 2 months (Abilify Asimtufii), reduce the dosage from 960 mg to 720 mg; avoid use in patients known to be poor metabolizers of CYP2D6. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; lonafarnib is a strong CYP3A inhibitor. (Major) Recommendations for managing aripiprazole and lonafarnib vary by aripiprazole dosage form and CYP2D6 metabolizer status. For extended-release aripiprazole lauroxil injections (Aristada), reduce the dose to the next lowest strength; no dosage adjustment is required for patients tolerating 441 mg. For extended-release aripiprazole lauroxil injections (Aristada) in patients who are known to be poor metabolizers of CYP2D6, reduce the dose to 441 mg; no dosage adjustment is necessary for patients already tolerating 441 mg. For fixed dose extended-release aripiprazole lauroxil injections (Aristada Initio), avoid concomitant use because the dose cannot be modified. Further dosage reductions may be required in patients who are also receiving a CYP2D6 inhibitor; see individual product prescribing information for details. Concomitant use may increase aripiprazole exposure and risk for side effects. Aripiprazole is CYP3A and CYP2D6 substrate; lonafarnib is a strong CYP3A inhibitor.
Artemether; Lumefantrine: (Moderate) Due to the potential for increased concentrations of lumefantrine which could lead to QT prolongation, lonafarnib should be used cautiously with artemether; lumefantrine. No dosage adjustment of artemether; lumefantrine is necessary. Lonafarnib is a strong inhibitor of CYP3A4 and artemether is a substrate of this isoenzyme. In a drug interaction study, administration of a strong CYP3A4 inhibitor, resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine.
Asciminib: (Major) Avoid coadministration of lonafarnib and asciminib; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing asciminib. Additionally, closely monitor for asciminib-related adverse reactions if using asciminib 200 mg twice daily with lonafarnib as asciminib exposure may increase. Lonafarnib is a CYP2C9 and CYP3A substrate and strong CYP3A inhibitor; asciminib is a CYP3A substrate and CYP2C9 and CYP3A inhibitor.
Aspirin, ASA; Butalbital; Caffeine: (Contraindicated) Coadministration of lonafarnib and butalbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer.
Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4. (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with lonafarnib is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate; lonafarnib is a moderate CYP2C19 inhibitor. Coadministration could increase exposure to carisoprodol and decrease exposure to meprobamate. The full pharmacological impact of these potential alterations of exposure in terms of either efficacy or safety of carisoprodol is unknown.
Aspirin, ASA; Omeprazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Aspirin, ASA; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like lonafarnib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lonafarnib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Atazanavir: (Contraindicated) Coadministration of lonafarnib and atazanavir is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Atazanavir; Cobicistat: (Contraindicated) Coadministration of lonafarnib and atazanavir is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and atazanavir is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Contraindicated) Coadministration of lonafarnib and cobicistat is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Atogepant: (Major) Avoid use of atogepant and lonafarnib when atogepant is used for chronic migraine. Limit the dose of atogepant to 10 mg PO once daily for episodic migraine if coadministered with lonafarnib. Concurrent use may increase atogepant exposure and the risk of adverse effects. Atogepant is a substrate of CYP3A and lonafarnib is a strong CYP3A inhibitor. Coadministration with a strong CYP3A inhibitor resulted in a 5.5-fold increase in atogepant overall exposure and a 2.15-fold increase in atogepant peak concentration.
Atorvastatin: (Contraindicated) Coadministration of atorvastatin and lonafarnib is contraindicated according to the manufacturer of lonafarnib. The manufacturer of atorvastatin recommends that if concomitant use of these drugs is required, a lower starting and maintenance dose of atorvastatin should be considered; monitor patients carefully for signs and symptoms of myopathy/rhabdomyolysis (e.g., muscle pain, tenderness, or weakness), particularly during the initial months of therapy and during any periods of upward dosage titration of either drug. Atorvastatin is a CYP3A4 and P-gp substrate and lonafarnib is a strong CYP3A4 inhibitor and P-gp inhibitor.
Avacopan: (Major) Avoid coadministration of lonafarnib and avacopan; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and reduce the dose of avacopan to 30 mg once daily. Closely monitor patients for adverse reactions. Lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor; avacopan is a CYP3A substrate and weak CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increase avacopan overall exposure 2.19-fold.
Avanafil: (Major) Do not use avanafil in patients receiving lonafarnib due to the risk for increased avanafil serum concentrations and serious adverse reactions. Avanafil is a sensitive CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the avanafil AUC by 13-fold.
Avapritinib: (Major) Avoid coadministration of avapritinib with lonafarnib due to the risk of increased avapritinib-related adverse reactions. Avapritinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor is predicted to increase the AUC of avapritinib by 600% at steady-state.
Axitinib: (Major) Avoid coadministration of axitinib with lonafarnib due to the risk of increased axitinib-related adverse reactions. If coadministration is unavoidable, decrease the dose of axitinib by approximately half; subsequent doses can be increased or decreased based on individual safety and tolerability. Resume the original dose of axitinib approximately 3 to 5 half-lives after lonafarnib is discontinued. Axitinib is a CYP3A4/5 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4/5 inhibitor significantly increased the plasma exposure of axitinib in healthy volunteers.
Azelastine; Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and lonafarnib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Bedaquiline: (Major) Concurrent use of bedaquiline and lonafarnib should be avoided due to the potential risk of adverse reactions to bedaquiline because of increased systemic exposure. Bedaquiline is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased bedaquiline exposure by 22%.
Belumosudil: (Major) Avoid coadministration of lonafarnib and belumosudil; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing belumosudil. Lonafarnib is a sensitive CYP3A substrate and belumosudil is a weak CYP3A inhibitor.
Belzutifan: (Moderate) Monitor for anemia and hypoxia if concomitant use of lonafarnib with belzutifan is necessary due to increased plasma exposure of belzutifan which may increase the incidence and severity of adverse reactions. Reduce the dose of belzutifan as recommended if anemia or hypoxia occur. Belzutifan is a CYP2C19 substrate and lonafarnib is a CYP2C19 inhibitor.
Benzhydrocodone; Acetaminophen: (Moderate) Consider a reduced dose of benzhydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. Benzhydrocodone is a prodrug for hydrocodone. Hydrocodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of benzhydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to benzhydrocodone.
Berotralstat: (Contraindicated) Coadministration of lonafarnib and berotralstat is contraindicated; concurrent use may increase lonafarnib exposure and the risk for lonafarnib-related adverse effects. Lonafarnib is a CYP2C9 and sensitive CYP3A substrate and berotralstat is a weak CYP2C9 and moderate CYP3A inhibitor.
Betrixaban: (Major) Avoid betrixaban use in patients with severe renal impairment receiving lonafarnib. Reduce betrixaban dosage to 80 mg PO once followed by 40 mg PO once daily in all other patients receiving lonafarnib. Concurrent use may increase betrixaban exposure resulting in an increased bleeding risk; monitor patients closely for signs and symptoms of bleeding. Betrixaban is a P-gp substrate; lonafarnib is a P-gp inhibitor. Coadministration of other P-gp inhibitors increased betrixaban exposure by 2 to 3 fold.
Bexarotene: (Contraindicated) Coadministration of lonafarnib and bexarotene is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and bexarotene is a moderate CYP3A4 inducer.
Bicalutamide: (Major) Avoid coadministration of lonafarnib and bicalutamide; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing bicalutamide. Lonafarnib is a sensitive CYP3A4 substrate and bicalutamide is a weak CYP3A4 inhibitor.
Bictegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with lonafarnib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Bortezomib: (Moderate) Monitor for signs of bortezomib toxicity and consider a bortezomib dose reduction if coadministration of lonafarnib is necessary. Bortezomib exposure may be increased. Bortezomib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased bortezomib exposure by 35%.
Bosentan: (Contraindicated) Coadministration of lonafarnib and bosentan is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. The exposure of bosentan may also be increased, increasing the risk for bosentan-related adverse reactions. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; bosentan is a CYP3A4 substrate and moderate CYP3A4 inducer.
Bosutinib: (Major) Avoid concomitant use of bosutinib and lonafarnib; bosutinib plasma exposure may be significantly increased resulting in an increased risk of bosutinib adverse events (e.g., myelosuppression, GI toxicity). Bosutinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. The Cmax and AUC values of bosutinib were increased 5.2-fold and 8.6-fold, respectively, when a single oral dose of bosutinib 100 mg PO was administered after 5 days of a strong CYP3A4 inhibitor.
Brentuximab vedotin: (Moderate) Closely monitor for an increase in brentuximab-related adverse reactions, including peripheral neuropathy or gastrointestinal side effects, if coadministration with lonafarnib is necessary. Monomethyl auristatin E (MMAE), one of the 3 components released from brentuximab vedotin, is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased MMAE exposure by approximately 34%.
Brexpiprazole: (Major) Reduce the brexpiprazole dose to half the usual dose if coadministered with lonafarnib. Administer one quarter of the usual brexpiprazole dose if the patient is also receiving a strong or moderate CYP2D6 inhibitor or is a known poor metabolizer of CYP2D6. If lonafarnib is discontinued, adjust the brexpiprazole dosage to its original level. Brexpiprazole is a CYP3A4 and CYP2D6 substrate; lonafarnib is a strong CYP3A4 inhibitor. Concomitant use of strong CYP3A4 inhibitors increased the exposure of brexpiprazole compared to use of brexpiprazole alone.
Brigatinib: (Major) Avoid coadministration of brigatinib with lonafarnib if possible due to increased plasma exposure of brigatinib; an increase in brigatinib-related adverse reactions may occur. If concomitant use is unavoidable, reduce the dose of brigatinib by approximately 50% without breaking tablets (i.e., from 180 mg to 90 mg; from 90 mg to 60 mg); after discontinuation of lonafarnib, resume the brigatinib dose that was tolerated prior to initiation of lonafarnib. Brigatinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC and Cmax of brigatinib by 101% and 21%, respectively.
Bromocriptine: (Major) When bromocriptine is used for diabetes, avoid coadministration with lonafarnib ensuring adequate washout before initiating bromocriptine. Use this combination with caution in patients receiving bromocriptine for other indications. Concurrent use may significantly increase bromocriptine concentrations. Bromocriptine is extensively metabolized in the liver via CYP3A4; lonafarnib is a strong inhibitor of CYP3A4.
Budesonide: (Moderate) Avoid coadministration of oral budesonide and lonafarnib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Formoterol: (Moderate) Avoid coadministration of oral budesonide and lonafarnib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Budesonide; Glycopyrrolate; Formoterol: (Moderate) Avoid coadministration of oral budesonide and lonafarnib due to the potential for increased budesonide exposure. Use caution with inhaled forms of budesonide as systemic exposure to the corticosteroid may also increase. Budesonide is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In the presence of another strong CYP3A4 inhibitor, the systemic exposure to oral budesonide was increased by 8-fold.
Bupivacaine; Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with lonafarnib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Buprenorphine: (Moderate) Concomitant use of buprenorphine and lonafarnib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when lonafarnib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping lonafarnib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If lonafarnib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and lonafarnib is a CYP3A4 inhibitor.
Buprenorphine; Naloxone: (Moderate) Concomitant use of buprenorphine and lonafarnib can increase the plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects, particularly when lonafarnib is added after a stable buprenorphine dose is achieved. If concurrent use is necessary, consider dosage reduction of buprenorphine until stable drug effects are achieved. Monitor patient for respiratory depression and sedation at frequent intervals. When stopping lonafarnib, the buprenorphine concentration may decrease, potentially resulting in decreased opioid efficacy or a withdrawal syndrome in patients who had developed physical dependency. If lonafarnib is discontinued, consider increasing buprenorphine dosage until stable drug effects are achieved. Monitor for signs of opioid withdrawal. Buprenorphine is a substrate of CYP3A4 and lonafarnib is a CYP3A4 inhibitor.
Buspirone: (Moderate) A low dose of buspirone used cautiously is recommended when coadministered with lonafarnib. If a patient has been titrated to a stable dosage of buspirone, a dose adjustment of buspirone may be necessary to avoid adverse events attributable to buspirone. Administering lonafarnib with buspirone may increase buspirone concentration and risk for adverse events. Buspirone is a sensitive substrate of CYP3A4; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the buspirone AUC by 19-fold with an increased incidence of buspirone-related adverse effects.
Butalbital; Acetaminophen: (Contraindicated) Coadministration of lonafarnib and butalbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine: (Contraindicated) Coadministration of lonafarnib and butalbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer.
Butalbital; Acetaminophen; Caffeine; Codeine: (Contraindicated) Coadministration of lonafarnib and butalbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Butalbital; Aspirin; Caffeine; Codeine: (Contraindicated) Coadministration of lonafarnib and butalbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and butalbital is a moderate CYP3A4 inducer. (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Cabazitaxel: (Major) Avoid coadministration of cabazitaxel with lonafarnib if possible due to increased cabazitaxel exposure. If concomitant use is unavoidable, consider reducing the dose of cabazitaxel by 25%. Cabazitaxel is primarily metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. In a drug interaction study, coadministration with another strong CYP3A4 inhibitor increased cabazitaxel exposure by 25%.
Cabotegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Cabozantinib: (Major) Avoid concomitant use of cabozantinib and lonafarnib due to the risk of increased cabozantinib exposure which may increase the incidence and severity of adverse reactions. If concomitant use is unavoidable, reduce the dose of cabozantinib. For patients taking cabozantinib tablets, reduce the dose of cabozantinib by 20 mg; for patients taking cabozantinib capsules, reduce the dose of cabozantinib by 40 mg. Resume the cabozantinib dose that was used prior to initiating treatment with lonafarnib 2 to 3 days after discontinuation of lonafarnib. Cabozantinib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased cabozantinib exposure by 38%.
Cannabidiol: (Major) Avoid coadministration of lonafarnib and cannabidiol; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and cannabidiol is a CYP2C9 inhibitor.
Capecitabine: (Major) Avoid coadministration of lonafarnib and capecitabine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and capecitabine is a CYP2C9 inhibitor.
Capivasertib: (Major) Avoid coadministration of capivasertib with lonafarnib. Concomitant use may increase the exposure of both medications and the risk for adverse effects. If concomitant use is necessary, both medications may require a dosage reduction. Reduce the dose of capivasertib to 320 mg PO twice daily for 4 days followed by 3 days off. Reduce to or continue lonafarnib at a dosage of 115 mg/m2. Capivasertib is a CYP3A substrate and weak CYP3A inhibitor; lonafarnib is a CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor is predicted to increase the overall exposure of capivasertib by up to 1.7-fold.
Capmatinib: (Moderate) Monitor for an increase in capmatinib-related adverse reactions if coadministration with lonafarnib is necessary. Capmatinib is a CYP3A substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased capmatinib exposure by 42%.
Carbamazepine: (Contraindicated) Coadministration of lonafarnib and carbamazepine is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. The exposure of carbamazepine may also be increased, increasing the risk for carbamazepine-related adverse reactions. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; carbamazepine is a CYP3A4 substrate and strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Cariprazine: (Major) The dose of cariprazine should be reduced in patients also receiving lonafarnib. When lonafarnib is initiated in a patient who is on a stable dose of cariprazine, reduce the cariprazine dosage by half. For adult patients taking cariprazine 4.5 mg daily, the dosage should be reduced to 1.5 mg or 3 mg daily. For patients taking cariprazine 1.5 mg daily, the dosing frequency should be adjusted to every other day. When initiating cariprazine in a patient who is stable on lonafarnib, the patient should be administered 1.5 mg of cariprazine on Day 1 and on Day 3 with no dose administered on Day 2. From Day 4 onward, the dose should be administered at 1.5 mg daily, and then increased to a maximum dose of 3 mg daily. When lonafarnib is withdrawn, the cariprazine dosage may need to be increased. Cariprazine is metabolized by CYP3A4 to its major active metabolite; lonafarnib is a strong CYP3A4 inhibitor. Concurrent use with another strong CYP3A4 inhibitor increased the exposure of cariprazine by about 4-fold; increased the AUC of DDCAR metabolite by about 1.5-fold; and decreased DCAR metabolite AUC by about one-third.
Carisoprodol: (Moderate) Monitor for an altered clinical response to carisoprodol if coadministration with lonafarnib is necessary. Carisoprodol is metabolized by CYP2C19 to form meprobamate; lonafarnib is a moderate CYP2C19 inhibitor. Coadministration could increase exposure to carisoprodol and decrease exposure to meprobamate. The full pharmacological impact of these potential alterations of exposure in terms of either efficacy or safety of carisoprodol is unknown.
Celecoxib; Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lonafarnib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lonafarnib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Cenobamate: (Contraindicated) Coadministration of lonafarnib and cenobamate is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer.
Ceritinib: (Contraindicated) Concomitant use of lonafarnib and ceritinib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, decrease the dose of ceritinib by approximately one-third, rounded to the nearest multiple of 150 mg. Lonafarnib is a CYP3A and CYP2C9 substrate and strong CYP3A4 inhibitor; ceritinib is a CYP3A4 substrate and strong CYP3A4 and weak CYP2C9 inhibitor. Strong CYP3A4 inhibitors are expected to increase lonafarnib exposure by 425% and ceritinib exposure by 190%.
Chloramphenicol: (Contraindicated) Coadministration of lonafarnib and chloramphenicol is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and chloramphenicol is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Chlordiazepoxide: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with lonafarnib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Chlordiazepoxide; Amitriptyline: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with lonafarnib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Chlordiazepoxide; Clidinium: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with lonafarnib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Chlorpheniramine; Codeine: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Chlorpheniramine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Cilostazol: (Major) Reduce the dose of cilostazol to 50 mg twice daily when coadministered with lonafarnib and monitor for an increase in cilostazol-related adverse reactions. Concurrent use may increase cilostazol exposure. Cilostazol is a CYP3A4 and CYP2C19 substrate; lonafarnib is a strong CYP3A4 inhibitor and moderate CYP2C19 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the cilostazol AUC by 117%. Coadministration with another CYP2C19 inhibitor increased the exposure of 3,4-dehydro-cilostazol by 69%.
Cimetidine: (Major) Avoid coadministration of lonafarnib and cimetidine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing cimetidine. Lonafarnib is a sensitive CYP3A4 substrate and cimetidine is a weak CYP3A4 inhibitor.
Cinacalcet: (Moderate) Monitor for cinacalcet-related adverse effects during concomitant use of lonafarnib and adjust dosage as appropriate based on response. Concomitant use may increase cinacalcet exposure. Cinacalcet is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased cinacalcet overall exposure by 127%.
Ciprofloxacin: (Contraindicated) Coadministration of lonafarnib and ciprofloxacin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and ciprofloxacin is a moderate CYP3A4 inhibitor.
Citalopram: (Moderate) Limit the dose of citalopram to 20 mg/day if coadministered with lonafarnib. Concurrent use may increase citalopram exposure increasing the risk of QT prolongation. Citalopram is a sensitive CYP2C19 substrate; lonafarnib is a moderate inhibitor of CYP2C19.
Clarithromycin: (Contraindicated) Coadministration of lonafarnib and clarithromycin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Clindamycin: (Moderate) Monitor for an increase in clindamycin-related adverse reactions with coadministration of lonafarnib as concurrent use may increase clindamycin exposure. Clindamycin is a CYP3A4 substrate; lonafarnib is a strong inhibitor of CYP3A4.
Clonazepam: (Moderate) Monitor for increased sedation and respiratory depression if clonazepam is coadministered with lonafarnib; adjust the dose of clonazepam if necessary. The systemic exposure of clonazepam may be increased resulting in an increase in treatment-related adverse reactions. Clonazepam is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Clorazepate: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of clorazepate with lonafarnib is necessary. Concurrent use may increase clorazepate exposure. Clorazepate is a prodrug whose active metabolite (N-desmethyldiazepam) is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor.
Clozapine: (Moderate) Consider a clozapine dose reduction if coadministered with lonafarnib and monitor for adverse reactions. If lonafarnib is discontinued, monitor for lack of clozapine effect, and increase dose if necessary. A clinically relevant increase in the plasma concentration of clozapine may occur during concurrent use. Clozapine is partially metabolized by CYP3A4; lonafarnib is a strong CYP3A4 inhibitor.
Cobicistat: (Contraindicated) Coadministration of lonafarnib and cobicistat is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Cobimetinib: (Major) Avoid coadministration of lonafarnib with cobimetinib due to the increased risk of cobimetinib-related adverse reactions. Cobimetinib is a sensitive CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased cobimetinib exposure by 6.7-fold.
Codeine: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Codeine; Phenylephrine; Promethazine: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Codeine; Promethazine: (Moderate) Concomitant use of codeine with lonafarnib may increase codeine plasma concentrations, resulting in greater metabolism by CYP2D6 and, increased morphine concentrations, and prolonged opioid adverse reactions, including hypotension, respiratory depression, profound sedation, coma, and death. It is recommended to avoid this combination when codeine is being used for cough. If coadministration is necessary, monitor patients closely at frequent intervals and consider a dosage reduction of codeine until stable drug effects are achieved. Discontinuation of lonafarnib could decrease codeine plasma concentrations, decrease opioid efficacy, and potentially lead to a withdrawal syndrome in those with physical dependence to codeine. If lonafarnib is discontinued, monitor the patient carefully and consider increasing the opioid dosage if appropriate. Codeine is primarily metabolized by CYP2D6 to morphine, and by CYP3A4 to norcodeine; norcodeine does not have analgesic properties; lonafarnib is a strong inhibitor of CYP3A4.
Colchicine: (Major) Avoid concomitant use of colchicine and lonafarnib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and lonafarnib is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Conivaptan: (Contraindicated) Coadministration of conivaptan and lonafarnib is contraindicated due to the potential for increased conivaptan and lonafarnib exposure. Conivaptan is a CYP3A substrate and moderate CYP3A inhibitor; lonafarnib is a CYP3A substrate and strong CYP3A inhibitor. In a drug interaction study, coadministration of a strong CYP3A inhibitor increased the exposure of oral conivaptan by 11-fold.
Conjugated Estrogens; Medroxyprogesterone: (Moderate) Use caution if coadministration of lonafarnib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4; lonafarnib is a strong CYP3A4 inhibitor.
Copanlisib: (Major) Avoid the concomitant use of copanlisib and lonafarnib if possible; increased copanlisib exposure may occur. If coadministration cannot be avoided, reduce the copanlisib dose to 45 mg and monitor patients for copanlisib-related adverse events (e.g., hypertension, infection, and skin rash). Copanlisib is a CYP3A substrate; lonafarnib is a strong CYP3A inhibitor.
Crizotinib: (Contraindicated) Concomitant use of lonafarnib and crizotinib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. While coadministration is not recommended, if use is necessary, a crizotinib dosage reduction is required; specific dosage adjustment recommendations are dependent on age, indication, and body surface area (BSA). For adult patients with non-small cell lung cancer (NSCLC) or inflammatory myofibroblastic tumor (IMT), decrease the crizotinib dose to 250 mg once daily. For pediatric patients or young adults with anaplastic large cell lymphoma (ALCL) or IMT, BSA-based dosage adjustments are recommended; consult product labeling for specific recommendations. Lonafarnib is a CYP3A substrate and strong CYP3A inhibitor; crizotinib is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors has been observed to increase crizotinib overall exposure by 57% to 216%.
Cyclosporine: (Contraindicated) Coadministration of lonafarnib and cyclosporine is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp inhibitor; cyclosporine is a CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor.
Dabigatran: (Moderate) Monitor for an increase in dabigatran-related adverse reactions if coadministration with lonafarnib is necessary in patients with CrCl greater than 50 mL/minute. Avoid coadministration in patients with CrCl less than 50 mL/minute when dabigatran is administered for treatment or reduction in risk of recurrence of deep venous thrombosis (DVT) or pulmonary embolism (PE) or prophylaxis of DVT or PE following hip replacement surgery. Avoid coadministration in patients with CrCl less than 30 mL/minute in patients with non-valvular atrial fibrillation. Serum concentrations of dabigatran are expected to be higher in patients with renal impairment compared to patients with normal renal function. Dabigatran is a P-glycoprotein substrate and lonafarnib is a P-gp inhibitor.
Dabrafenib: (Contraindicated) Coadministration of lonafarnib and dabrafenib is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. The exposure of dabrafenib may also be increased, increasing the risk for dabrafenib-related adverse reactions including skin toxicity, ocular toxicity, and cardiotoxicity. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; dabrafenib is a CYP3A4 substrate and moderate CYP3A4 inducer.
Daclatasvir: (Major) Reduce the daclatasvir dose to 30 mg PO once daily if coadministered with lonafarnib due to increased daclatasvir exposure. Daclatasvir is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the daclatasvir AUC by 3-fold.
Dalfopristin; Quinupristin: (Major) Avoid coadministration of lonafarnib and dalfopristin; quinupristin; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing dalfopristin; quinupristin. Lonafarnib is a sensitive CYP3A4 substrate and dalfopristin; quinupristin is a weak CYP3A4 inhibitor.
Danazol: (Contraindicated) Coadministration of lonafarnib and danazol is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and danazol is a moderate CYP3A4 inhibitor.
Dapagliflozin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with lonafarnib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Daridorexant: (Major) Avoid concomitant use of daridorexant and lonafarnib. Concomitant use may increase the exposure of both drugs and the risk for adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Daridorexant is a CYP3A substrate and weak CYP3A inhibitor and lonafarnib is a CYP3A substrate and strong CYP3A inhibitor. Concomitant use of another strong CYP3A inhibitor increased daridorexant overall exposure by over 400%.
Darifenacin: (Moderate) The daily dose of darifenacin should not exceed 7.5 mg PO when administered with lonafarnib due to increased darifenacin exposure. Darifenacin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor.
Darunavir: (Contraindicated) Coadministration of lonafarnib and darunavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both drugs are sensitive CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Darunavir; Cobicistat: (Contraindicated) Coadministration of lonafarnib and cobicistat is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Contraindicated) Coadministration of lonafarnib and darunavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both drugs are sensitive CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Contraindicated) Coadministration of lonafarnib and cobicistat is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Contraindicated) Coadministration of lonafarnib and darunavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both drugs are sensitive CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Coadministration of tenofovir alafenamide with lonafarnib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Dasatinib: (Major) Avoid coadministration of dasatinib and lonafarnib due to the potential for increased dasatinib exposure and subsequent toxicity including QT prolongation and torsade de pointes (TdP). If coadministration cannot be avoided, consider a dasatinib dose reduction to 40 mg PO daily if original dose was 140 mg daily, 20 mg PO daily if original dose was 100 mg daily, or 20 mg PO daily if original dose was 70 mg daily. Stop dasatinib during use of lonafarnib in patients receiving dasatinib 60 mg or 40 mg PO daily. If dasatinib is not tolerated after dose reduction, either discontinue lonafarnib or stop dasatinib until lonafarnib is discontinued. Allow a washout of approximately 1 week after lonafarnib is stopped before increasing the dasatinib dose or reinitiating dasatinib. Dasatinib is a CYP3A4 substrate that has the potential to prolong the QT interval; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of dasatinib by 5-fold.
Deflazacort: (Major) Decrease deflazacort dose to one third of the recommended dosage when coadministered with lonafarnib. Concurrent use may significantly increase concentrations of 21-desDFZ, the active metabolite of deflazacort, resulting in an increased risk of toxicity. Deflazacort is a CYP3A4 substrate; lonafarnib is a strong inhibitor of CYP3A4. Administration of deflazacort with another strong CYP3A4 inhibitor increased total exposure to 21-desDFZ by about 3-fold.
Delavirdine: (Contraindicated) Coadministration of lonafarnib and delavirdine is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; delavirdine is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Dexamethasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of lonafarnib with dexamethasone is necessary, due to increased dexamethasone exposure; Cushing's syndrome and adrenal suppression could potentially occur with long-term use. Consider the use of corticosteroids such as beclomethasone and prednisolone, whose concentrations are less affected by strong CYP3A inhibitors, especially for long-term use. Dexamethasone is primarily metabolized by CYP3A and lonafarnib is a strong CYP3A inhibitor. Another strong CYP3A inhibitor has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.
Dexlansoprazole: (Moderate) The plasma concentrations of dexlansoprazole may be elevated when administered concurrently with lonafarnib. Clinical monitoring for adverse effects, such as GI effects, is recommended during coadministration. Dexlansoprazole is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor.
Dextromethorphan; Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with lonafarnib is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Diazepam: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with lonafarnib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 and CYP2C19 substrate and lonafarnib is a CYP2C19 and strong CYP3A4 inhibitor.
Digoxin: (Moderate) Increase monitoring of serum digoxin concentrations and watch for potential signs and symptoms of clinical toxicity when starting, adjusting, or discontinuing lonafarnib. Concurrent use may increase digoxin exposure. Digoxin is a P-glycoprotein (P-gp) substrate with a narrow therapeutic index and lonafarnib is a P-gp inhibitor.
Dihydroergotamine: (Contraindicated) Concomitant use of ergotamine with lonafarnib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor.
Diltiazem: (Contraindicated) Coadministration of lonafarnib and diltiazem is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; diltiazem is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Disopyramide: (Moderate) Monitor for an increase in disopyramide-related adverse reactions if coadministration with lonafarnib is necessary as concurrent use may increase disopyramide exposure. Disopyramide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Although specific drug interaction studies have not been done for disopyramide, cases of life-threatening interactions have been reported when disopyramide was coadministered with other strong CYP3A4 inhibitors.
Disulfiram: (Major) Avoid coadministration of lonafarnib and disulfiram; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and disulfiram is a CYP2C9 inhibitor.
Docetaxel: (Major) Avoid coadministration of docetaxel with lonafarnib if possible due to increased plasma concentrations of docetaxel. If concomitant use is unavoidable, closely monitor for docetaxel-related adverse reactions and consider a 50% dose reduction of docetaxel. Docetaxel is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased docetaxel exposure by 2.2-fold.
Dofetilide: (Moderate) Monitor for an increase in dofetilide-related adverse reactions, including QT prolongation, if coadministration with lonafarnib is necessary as concurrent use may increase dofetilide exposure. Dofetilide is a minor CYP3A4 substrate and lonarfarnib is a strong CYP3A4 inhibitor; however, because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant administration of CYP3A4 inhibitors may increase the risk of arrhythmias (torsade de pointes).
Dolutegravir: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lonafarnib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Dolutegravir; Lamivudine: (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lonafarnib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Dolutegravir; Rilpivirine: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. (Moderate) Monitor for increased toxicity of dolutegravir if coadministered with lonafarnib. Concurrent use may increase the plasma concentrations of dolutegravir. Dolutegravir is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Donepezil: (Moderate) Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is recommended during coadministration of lonafarnib. The plasma concentrations of donepezil may be elevated when administered concurrently with lonafarnib. Donepezil is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Donepezil; Memantine: (Moderate) Clinical monitoring for donepezil-related adverse effects, such as GI or cholinergic effects, is recommended during coadministration of lonafarnib. The plasma concentrations of donepezil may be elevated when administered concurrently with lonafarnib. Donepezil is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Doravirine: (Minor) Coadministration of doravirine and lonafarnib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; lonafarnib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doravirine; Lamivudine; Tenofovir disoproxil fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor. (Minor) Coadministration of doravirine and lonafarnib may result in increased doravirine plasma concentrations. Doravirine is a CYP3A4 substrate; lonafarnib is a strong inhibitor. In drug interaction studies, concurrent use of strong CYP3A4 inhibitors increased doravirine exposure by more than 3-fold; however, this increase was not considered clinically significant.
Doxorubicin Liposomal: (Major) Avoid coadministration of doxorubicin with lonafarnib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Concurrent use of CYP3A4 and P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Doxorubicin: (Major) Avoid coadministration of doxorubicin with lonafarnib due to increased systemic exposure of doxorubicin resulting in increased treatment-related adverse reactions. Doxorubicin is a CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Concurrent use of CYP3A4 and P-gp inhibitors with doxorubicin has resulted in clinically significant interactions.
Dronabinol: (Moderate) Monitor for increased toxicity (e.g., feeling high, dizziness, confusion, somnolence) of dronabinol if coadministered with lonafarnib. Coadministration may increase the exposure of dronabinol. Dronabinol is a CYP3A4 substrate; lonafarnib is a strong CYP3A inhibitor.
Dronedarone: (Contraindicated) Coadministration of lonafarnib and dronedarone is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; dronedarone is a sensitive CYP3A4 substrate and moderate CYP3A4 inhibitor.
Drospirenone: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with lonafarnib. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and lonafarnib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects which may increase serum potassium; lonafarnib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Coadministration with another strong CYP3A4 inhibitor resulted in a moderate increase of drospirenone exposure.
Drospirenone; Estetrol: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with lonafarnib. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and lonafarnib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects which may increase serum potassium; lonafarnib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Coadministration with another strong CYP3A4 inhibitor resulted in a moderate increase of drospirenone exposure.
Drospirenone; Estradiol: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with lonafarnib. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and lonafarnib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects which may increase serum potassium; lonafarnib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Coadministration with another strong CYP3A4 inhibitor resulted in a moderate increase of drospirenone exposure.
Drospirenone; Ethinyl Estradiol: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with lonafarnib. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and lonafarnib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects which may increase serum potassium; lonafarnib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Coadministration with another strong CYP3A4 inhibitor resulted in a moderate increase of drospirenone exposure.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Moderate) Monitor for an increase in drospirenone-related adverse effects if coadministered with lonafarnib. Consider monitoring serum potassium concentrations during the first month of dosing in high-risk patients who take drospirenone and lonafarnib long-term. Drospirenone is a CYP3A4 substrate that has antimineralocorticoid effects which may increase serum potassium; lonafarnib is a strong inhibitor of CYP3A4 and may increase drospirenone concentrations. Coadministration with another strong CYP3A4 inhibitor resulted in a moderate increase of drospirenone exposure.
Dutasteride: (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with lonafarnib is necessary. Dutasteride is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
Dutasteride; Tamsulosin: (Major) Avoid concurrent use of tamsulosin and lonafarnib due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4, and strong inhibitors of CYP3A4, such as lonafarnib, are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively. (Moderate) Monitor for dutasteride-related adverse reactions if coadministration with lonafarnib is necessary. Dutasteride is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Although the effect of strong CYP3A4 inhibitors on dutasteride has not been studied, dutasteride exposure may increase.
Duvelisib: (Contraindicated) Coadministration of lonafarnib and duvelisib is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If concomitant use is necessary, reduce the duvelisib dose to 15 mg PO twice daily and monitor for increased toxicity. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; duvelisib is a CYP3A4 substrate and moderate CYP3A4 inhibitor. Duvelisib exposure is estimated to increase approximately 2-fold if used concomitantly with strong CYP3A4 inhibitors.
Edoxaban: (Major) If coadministered with lonafarnib, a P-gp inhibitor, dosage reduction of edoxaban, a P-gp substrate, may be necessary for patients being treated for deep venous thrombosis (DVT) or pulmonary embolism (PE). An edoxaban dose reduction to 30 mg PO once daily is recommended by the manufacturer for use with certain P-gp inhibitors; however, because use of concomitant P-gp inhibitors was limited to only certain drugs that inhibit P-gp in DVT/PE clinical trials, clinicians should use professional judgment and guide edoxaban dose adjustments based on patient response if coadministered with lonafarnib. Based on clinical experience in patients with non-valvular atrial fibrillation, no dose reduction is recommended for concomitant use of lonafarnib. Increased concentrations of edoxaban may occur during concomitant use of lonafarnib; monitor for increased adverse effects of edoxaban.
Efavirenz: (Contraindicated) Coadministration of lonafarnib and efavirenz is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of lonafarnib and efavirenz is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of lonafarnib and efavirenz is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and efavirenz is a moderate CYP3A4 inducer. (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor.
Elacestrant: (Major) Avoid concomitant use of elacestrant and lonafarnib due to the risk of increased elacestrant exposure which may increase the risk for adverse effects. Elacestrant is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased elacestrant overall exposure by 5.3-fold.
Elagolix: (Contraindicated) Concurrent use of lonafarnib and elagolix is contraindicated as use may decrease lonafarnib exposure and efficacy. Elagolix exposure and the risk for elagolix-related adverse effects may also be increased. If concurrent use is necessary, limit elagolix therapy to a maximum duration of six months in patients receiving 150 mg daily or one month in patients receiving 200 mg twice daily. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; elagolix is a CYP3A4 substrate and moderate CYP3A4 inducer. Coadministration of elagolix with another strong CYP3A4 inhibitor increased elagolix exposure by 120%.
Elagolix; Estradiol; Norethindrone acetate: (Contraindicated) Concurrent use of lonafarnib and elagolix is contraindicated as use may decrease lonafarnib exposure and efficacy. Elagolix exposure and the risk for elagolix-related adverse effects may also be increased. If concurrent use is necessary, limit elagolix therapy to a maximum duration of six months in patients receiving 150 mg daily or one month in patients receiving 200 mg twice daily. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; elagolix is a CYP3A4 substrate and moderate CYP3A4 inducer. Coadministration of elagolix with another strong CYP3A4 inhibitor increased elagolix exposure by 120%.
Elbasvir; Grazoprevir: (Major) Avoid coadministration of lonafarnib and grazoprevir; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for adverse reactions from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing grazoprevir. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; grazoprevir is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased grazoprevir exposure by 3-fold. (Moderate) Monitor for an increase in elbasvir-related adverse reactions if coadministration with lonafarnib is necessary. Elbasvir is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased elbasvir exposure by 3-fold.
Eletriptan: (Contraindicated) Eletriptan is contraindicated with recent use (i.e., within 72 hours) of lonafarnib due to the potential for increased eletriptan exposure. Eletriptan is a sensitive substrate of CYP3A4; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the Cmax and AUC of eletriptan by 3-fold and 6-fold, respectively.
Elexacaftor; tezacaftor; ivacaftor: (Major) Avoid concomitant use of lonafarnib and ivacaftor due to the risk of increased exposure and adverse effects from both drugs. If coadministration is unavoidable, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly and reduce to or continue lonafarnib at a dosage or 115 mg/m2. Coadministration is not recommended in patients younger than 6 months. Lonafarnib is a CYP2C9 and CYP3A substrate and strong CYP3A inhibitor; ivacaftor is a CYP3A substrate and CYP2C9 and weak CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of elexacaftor; tezacaftor; ivacaftor to twice a week in the morning, approximately 3 to 4 days apart (i.e., Day 1 and Day 4) when coadministered with lonafarnib; omit the evening dose of ivacaftor. Coadministration may increase elexacaftor; tezacaftor; ivacaftor exposure and adverse reactions. Elexacaftor, tezacaftor, and ivacaftor are CYP3A substrates; lonafarnib is a strong CYP3A inhibitor. Coadministration of a strong CYP3A inhibitor increased elexacaftor exposure by 2.8- fold, tezacaftor exposure by 4.5-fold, and ivacaftor exposure by 15.6-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with lonafarnib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately three to four days apart (i.e., day one and day four). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Eliglustat: (Major) In intermediate or poor CYP2D6 metabolizers (IMs or PMs), coadministration of lonafarnib and eliglustat is contraindicated. In extensive CYP2D6 metabolizers (EMs), coadministration of these agents requires dosage reduction of eliglustat to 84 mg PO once daily. The coadministration of eliglustat with both lonafarnib and a moderate or strong CYP2D6 inhibitor is contraindicated in all patients. Eliglustat is a CYP3A and CYP2D6 substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration of eliglustat with CYP3A inhibitors such as lonafarnib increases eliglustat exposure and the risk of serious adverse events (e.g., QT prolongation and cardiac arrhythmias); this risk is the highest in CYP2D6 IMs and PMs because a larger portion of the eliglustat dose is metabolized via CYP3A.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Contraindicated) Coadministration of lonafarnib and cobicistat is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Coadministration of tenofovir alafenamide with lonafarnib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Contraindicated) Coadministration of lonafarnib and cobicistat is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; cobicistat is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. (Moderate) Coadministration of tenofovir alafenamide with lonafarnib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Emtricitabine; Rilpivirine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor.
Emtricitabine; Tenofovir alafenamide: (Moderate) Coadministration of tenofovir alafenamide with lonafarnib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor.
Encorafenib: (Contraindicated) Coadministration of lonafarnib and encorafenib is contraindicated due to the risk of decreased lonafarnib exposure, which may reduce its efficacy. Concomitant use may also increase encorafenib exposure which may increase the risk for adverse effects. If concomitant use is necessary, an encorafenib dosage reduction is required: reduce a daily dose of 450 mg to 150 mg, reduce the daily dose to 75 mg for all other dosages. Lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor and encorafenib is a CYP3A substrate and strong CYP3A inducer. Coadministration with another strong CYP3A inducer decreased the exposure of lonafarnib by 98%. Concomitant use with another strong CYP3A inhibitor increased encorafenib overall exposure by 3-fold.
Enfortumab vedotin: (Moderate) Closely monitor for signs of enfortumab vedotin-related adverse reactions if concurrent use with lonafarnib is necessary. Concomitant use may increase unconjugated monomethyl auristatin E (MMAE) exposure, which may increase the incidence or severity of enfortumab-vedotin toxicities. MMAE, the microtubule-disrupting component of enfortumab vedotin, is a CYP3A4 and P-gp substrate; lonafarnib is a dual P-gp/strong CYP3A4 inhibitor. Based on physiologically-based pharmacokinetic (PBPK) modeling predictions, concomitant use of enfortumab vedotin with another dual P-gp/strong CYP3A4 inhibitor is predicted to increase the exposure of unconjugated MMAE by 38%.
Entrectinib: (Major) Avoid coadministration of entrectinib with lonafarnib due to increased entrectinib exposure which may increase the risk for entrectinib-related adverse effects. If coadministration is necessary in adults and pediatric patients 2 years and older, reduce the dose of entrectinib (600 mg/day to 100 mg/day; 400 mg or 300 mg/day to 50 mg/day; 200 mg/day to 50 mg every other day) and limit coadministration to 14 days or less. For pediatric patients with a starting dose less than 200 mg, avoid coadministration. Entrectinib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased the overall exposure of entrectinib by 6-fold.
Enzalutamide: (Contraindicated) Coadministration of lonafarnib and enzalutamide is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Eplerenone: (Contraindicated) Eplerenone is contraindicated for use with lonafarnib due to increased eplerenone exposure which increases the risk of developing hyperkalemia and hypotension. Eplerenone is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Another strong CYP3A4 inhibitor increased serum eplerenone concentrations by roughly 5-fold.
Erdafitinib: (Major) Avoid coadministration of erdafitinib and lonafarnib due to the risk for increased plasma concentrations of erdafitinib. If concomitant use is necessary, closely monitor for erdafitinib-related adverse reactions and consider dose modifications as clinically appropriate. Erdafitinib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased erdafitinib overall exposure by 134%.
Ergotamine: (Contraindicated) Concomitant use of ergotamine with lonafarnib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor.
Ergotamine; Caffeine: (Contraindicated) Concomitant use of ergotamine with lonafarnib is contraindicated due to an increased risk for vasospasm which may lead to cerebral or peripheral ischemia. Concomitant use may increase ergotamine exposure. Ergotamine is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor.
Erlotinib: (Major) Avoid coadministration of erlotinib with lonafarnib if possible due to the increased risk of erlotinib-related adverse reactions. If concomitant use is unavoidable and severe reactions occur, reduce the dose of erlotinib by 50 mg decrements. Erlotinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased erlotinib exposure by 67%.
Erythromycin: (Contraindicated) Coadministration of lonafarnib and erythromycin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and erythromycin is a moderate CYP3A4 inhibitor.
Eslicarbazepine: (Contraindicated) Coadministration of lonafarnib and eslicarbazepine is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and eslicarbazepine is a moderate CYP3A4 inducer.
Estazolam: (Moderate) Monitor for estazolam-related adverse reactions, including sedation and respiratory depression, if coadministration with lonafarnib is necessary. Estazolam is primarily metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. In vivo drug-drug interaction studies were not conducted between estazolam and inhibitors of CYP3A.
Eszopiclone: (Major) The total dose of eszopiclone should not exceed 2 mg when administered with lonafarnib. Coadministration may increase eszopiclone exposure resulting in increased risk of next-day psychomotor or memory impairment and decreased ability to perform tasks requiring full mental alertness such as driving. CYP3A4 is a primary metabolic pathway for eszopiclone; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased eszopiclone exposure by 2.2-fold.
Ethosuximide: (Moderate) Monitor for an increase in ethosuximide-related adverse reactions if coadministration with lonafarnib is necessary. Concurrent use may increase the plasma concentrations of ethosuximide. Ethosuximide is a CYP3A4 substrate with a narrow therapeutic index and lonafarnib is a strong CYP3A4 inhibitor.
Etrasimod: (Major) Avoid concomitant use of etrasimod and lonafarnib in CYP2C9 poor metabolizers due to the risk for increased etrasimod exposure which may increase the risk for adverse effects. Etrasimod is a CYP2C9 and CYP3A substrate and lonafarnib is a strong CYP3A inhibitor.
Etravirine: (Contraindicated) Concurrent use of etravirine and lonafarnib is contraindicated and may produce unpredictable effects on lonafarnib including an increase in lonafarnib-related adverse effects or reduced lonafarnib efficacy. Etravirine exposure and adverse effects may also increase. Lonafarnib is a CYP3A4 and CYP2C9 substrate and a strong CYP3A4 and moderate CYP2C19 inhibitor. Etravirine is a CYP3A4 and CYP2C19 substrate, an inducer of CYP3A4, and an inhibitor of CYP2C9. Per the manufacturer, lonafarnib use is contraindicated with strong and moderate CYP3A4 inducers.
Everolimus: (Major) Avoid coadministration of lonafarnib and everolimus; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If concomitant use is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor everolimus levels and for adverse effects from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing everolimus. Lonafarnib is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp inhibitor; everolimus is a sensitive CYP3A4 substrate, P-gp substrate, and weak CYP3A4 inhibitor. Coadministration with a dual strong CYP3A4 and P-gp inhibitor increased the AUC of everolimus by 15-fold.
Ezetimibe; Simvastatin: (Contraindicated) Coadministration of simvastatin and lonafarnib is contraindicated due to the risk of elevated plasma concentrations of simvastatin leading to myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and a P-gp substrate; lonafarnib is a strong CYP3A4 and P-gp inhibitor.
Fedratinib: (Contraindicated) Concomitant use of lonafarnib and fedratinib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce the dose of fedratinib to 200 mg PO once daily. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; fedratinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased fedratinib exposure by 3-fold.
Felodipine: (Moderate) Concurrent use of felodipine and lonafarnib should be approached with caution; conservative dosing of felodipine due to the potential for significant increases in felodipine exposure is recommended. Monitor for evidence of increased felodipine effects including decreased blood pressure and increased heart rate. Felodipine is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Concurrent use of another strong CYP3A4 inhibitor increased felodipine AUC and half-life by approximately 8-fold and 2-fold, respectively.
Fentanyl: (Moderate) Consider a reduced dose of fentanyl with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the fentanyl dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Fentanyl is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase fentanyl exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of fentanyl. If lonafarnib is discontinued, fentanyl plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to fentanyl.
Fesoterodine: (Major) Limit the dose of fesoterodine to 4 mg once daily in adults and pediatric patients weighing more than 35 kg if coadministered with lonafarnib. Avoid use of fesoterodine and lonafarnib in pediatric patients weighing 25 to 35 kg. Concurrent use may increase fesoterodine exposure. Fesoterodine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor led to approximately a doubling of the overall exposure of 5-hydroxymethyl tolterodine (5-HMT), the active metabolite of fesoterodine.
Fexinidazole: (Major) Avoid coadministration of lonafarnib and fexinidazole. Concomitant use may increase lonafarnib exposure and increase the risk for lonafarnib-related adverse effects. Use may also limit the conversion of fexinidazole to its active metabolites reducing its efficacy. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and reduced fexinidazole efficacy. Resume previous lonafarnib dosage 14 days after discontinuing fexinidazole. Lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor; fexinidazole is a CYP3A substrate and weak CYP3A inhibitor. Fexinidazole is converted to its active metabolites via CYP3A.
Finasteride; Tadalafil: (Major) Avoid coadministration of tadalafil and lonafarnib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of lonafarnib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as lonafarnib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Finerenone: (Contraindicated) Concomitant use of finerenone and lonafarnib is contraindicated. Concomitant use may increase finerenone exposure and the risk for finerenone-related adverse reactions. Finerenone is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased overall exposure to finerenone by more than 400%.
Flibanserin: (Contraindicated) The concomitant use of flibanserin and strong CYP3A4 inhibitors such as lonafarnib is contraindicated due to increased flibanserin concentrations, which can cause severe hypotension and syncope. If initiating flibanserin following the use of lonafarnib, start flibanserin at least 2 weeks after the last dose of lonafarnib. If initiating lonafarnib following flibanserin use, begin therapy at least 2 days after the last dose of flibanserin. In cases where the benefit of initiating lonafarnib therapy within 2 days of stopping flibanserin clearly outweighs the risk of flibanserin-related hypotension and syncope, monitor the patient for signs of hypotension and syncope.
Fluconazole: (Contraindicated) Coadministration of lonafarnib and fluconazole is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and a CYP2C9 substrate; fluconazole is a moderate CYP3A4 inhibitor and moderate CYP2C9 inhibitor.
Fluorouracil, 5-FU: (Major) Avoid coadministration of lonafarnib and fluorouracil; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and fluorouracil is a CYP2C9 inhibitor.
Fluoxetine: (Major) Avoid coadministration of lonafarnib and fluoxetine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing fluoxetine. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate and fluoxetine is a weak CYP3A4 and CYP2C9 inhibitor.
Flurazepam: (Moderate) Monitor for an increase in flurazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with lonafarnib is necessary. Concurrent use may increase flurazepam exposure. Flurazepam is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Fluticasone: (Major) Coadministration of inhaled fluticasone propionate and lonafarnib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Salmeterol: (Major) Avoid concomitant use of salmeterol with lonafarnib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose. (Major) Coadministration of inhaled fluticasone propionate and lonafarnib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate.
Fluticasone; Umeclidinium; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and lonafarnib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Monitor for an increase in vilanterol-related adverse effects if coadministered with lonafarnib. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor significantly increased systemic exposure to vilanterol.
Fluticasone; Vilanterol: (Major) Coadministration of inhaled fluticasone propionate and lonafarnib is not recommended; use caution with inhaled fluticasone furoate. Increased systemic corticosteroid effects, including Cushing's syndrome and adrenal suppression, may occur. Fluticasone is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with strong inhibitors increased plasma fluticasone propionate exposure resulting in 45% to 86% decreases in serum cortisol AUC. A strong inhibitor increased fluticasone furoate exposure by 1.33-fold with a 27% reduction in weighted mean serum cortisol; this change does not necessitate dose adjustment of fluticasone furoate. (Moderate) Monitor for an increase in vilanterol-related adverse effects if coadministered with lonafarnib. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor significantly increased systemic exposure to vilanterol.
Fluvastatin: (Major) Avoid coadministration of lonafarnib and fluvastatin; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and fluvastatin is a CYP2C9 inhibitor.
Fluvoxamine: (Contraindicated) Coadministration of lonafarnib and fluvoxamine is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and CYP2C9 substrate; fluvoxamine is a moderate CYP3A4 inhibitor and a weak CYP2C9 inhibitor.
Food: (Major) Advise patients to avoid cannabis use during lonafarnib treatment. Concomitant use may alter the exposure of some cannabinoids and increase the risk for adverse reactions. The cannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are CYP3A substrates and lonafarnib is a strong CYP3A inhibitor. Concomitant use of a cannabinoid product containing THC and CBD at an approximate 1:1 ratio with another strong CYP3A inhibitor increased THC, 11-OH-THC, and CBD peak exposures by 1.3-, 3-, and 1.9-fold respectively.
Formoterol; Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with lonafarnib is necessary, due to increased mometasone exposure; Cushing syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Fosamprenavir: (Contraindicated) Coadministration of lonafarnib and fosamprenavir is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. The exposure of fosamprenavir may also be increased. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; fosamprenavir is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Fosphenytoin: (Contraindicated) Coadministration of lonafarnib and fosphenytoin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and fosphenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Fostamatinib: (Major) Avoid coadministration of lonafarnib and fostamatinib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for adverse reactions from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing fostamatinib. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; fostamatinib is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure to R406 (the major active metabolite of fostamatinib) by 102%.
Futibatinib: (Major) Avoid concurrent use of futibatinib and lonafarnib. Concomitant use may increase futibatinib exposure and the risk of adverse effects (e.g., ocular toxicity, hyperphosphatemia). Futibatinib is a substrate of CYP3A and P-gp; lonafarnib is a dual P-gp and strong CYP3A inhibitor. Coadministration with another dual P-gp and strong CYP3A inhibitor increased futibatinib exposure by 41%.
Gefitinib: (Moderate) Monitor for an increase in gefitinib-related adverse reactions if coadministration with lonafarnib is necessary. Gefitinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased gefitinib exposure by 80%.
Gemfibrozil: (Major) Avoid coadministration of lonafarnib and gemfibrozil; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and gemfibrozil is a CYP2C9 inhibitor.
Gilteritinib: (Major) Consider an alternative to lonafarnib during treatment with gilteritinib. Concurrent use may increase gilteritinib exposure resulting in treatment-related adverse events. If coadministration is required, frequently monitor for gilteritinib adverse reactions. Interrupt therapy and reduce the gilteritinib dose if serious or life-threatening toxicity occurs. Gilteritinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the gilteritinib AUC by 120% in a drug interaction study.
Glasdegib: (Major) Consider an alternative to lonafarnib during treatment with glasdegib. Concurrent use may increase glasdegib exposure resulting in treatment-related adverse events including QT prolongation. If coadministration cannot be avoided, monitor for increased adverse events; more frequent ECG monitoring is recommended. Glasdegib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of a strong CYP3A4 inhibitor increased the glasdegib AUC by 2.4-fold in a drug interaction study.
Glecaprevir; Pibrentasvir: (Moderate) Caution is advised with coadministration of glecaprevir and lonafarnib as increased plasma concentrations of glecaprevir may occur resulting in increased risk of glecaprevir-related adverse events. Glecaprevir is a P-gp substrate and lonafarnib is a P-gp inhibitor. (Moderate) Caution is advised with coadministration of pibrentasvir and lonafarnib as increased plasma concentrations of pibrentasvir may occur resulting in increased risk of pibrentasvir-related adverse events. Pibrentasvir is a substrate of P-glycoprotein (P-gp) and lonafarnib is a P-gp inhibitor.
Granisetron: (Moderate) Monitor for increased granisetron-related adverse effects, such as gastrointestinal or CNS effects, if coadministration with lonafarnib is necessary. Concurrent use may increase granisetron exposure. Granisetron is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Grapefruit juice: (Contraindicated) Advise patients to avoid grapefruit juice or grapefruit-containing foods during treatment with lonafarnib; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and grapefruit juice is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Guaifenesin; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Guanfacine: (Major) If coadministration of lonafarnib with extended-release (ER) guanfacine is necessary, reduce the guanfacine dosage to half of the recommended dose. Specific recommendations for immediate-release (IR) guanfacine are not available. Monitor patients closely for adverse effects including hypotension, drowsiness, lethargy, and bradycardia. If lonafarnib is discontinued, the guanfacine ER dosage should be increased back to the recommended dose. Guanfacine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor; lonafarnib may significantly increase guanfacine plasma concentrations.
Haloperidol: (Moderate) Monitor for an increase in haloperidol-related side effects, such as QT prolongation and extrapyramidal symptoms, if coadministered with lonafarnib. Coadministration may increase the exposure of haloperidol. Haloperidol is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Homatropine; Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Ibuprofen: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Hydrocodone; Pseudoephedrine: (Moderate) Consider a reduced dose of hydrocodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. It is recommended to avoid this combination when hydrocodone is being used for cough. Hydrocodone is a CYP3A4 substrate, and coadministration with CYP3A4 inhibitors like lonafarnib can increase hydrocodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of hydrocodone. These effects could be more pronounced in patients also receiving a CYP2D6 inhibitor. If lonafarnib is discontinued, hydrocodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to hydrocodone.
Ibrexafungerp: (Major) Decrease the ibrexafungerp dose to 150 mg PO every 12 hours for 1 day if administered concurrently with lonafarnib. Coadministration may result in increased ibrexafungerp exposure and toxicity. Ibrexafungerp is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the AUC and Cmax of ibrexafungerp by 5.8-fold and 2.5-fold, respectively.
Ibrutinib: (Major) Avoid concomitant use of ibrutinib and lonafarnib; ibrutinib plasma concentrations may increase resulting in severe ibrutinib toxicity (e.g., hematologic toxicity, bleeding, infection). Ibrutinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased ibrutinib exposure by 5.7-fold to 24-fold.
Ibuprofen; Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like lonafarnib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lonafarnib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Idelalisib: (Contraindicated) Coadministration of lonafarnib and idelalisib is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; idelalisib is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425% and increased idelalisib exposure by 1.8-fold.
Ifosfamide: (Moderate) Monitor for a decrease in the efficacy of ifosfamide if coadministration with lonafarnib is necessary. Ifosfamide is metabolized by CYP3A4 to its active alkylating metabolites. Lonafarnib is a strong CYP3A4 inhibitor. Coadministration may decrease plasma concentrations of these active metabolites, decreasing the effectiveness of ifosfamide treatment.
Iloperidone: (Major) Reduce the iloperidone dose by one-half if coadministered with lonafarnib. If lonafarnib is discontinued, increase the iloperidone dose to the previous level. Increased iloperidone exposure may occur with concurrent use. Iloperidone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of iloperidone and its metabolites P88 and P95 by 57%, 55% and 35%, respectively.
Imatinib: (Contraindicated) Coadministration of lonafarnib and imatinib is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; imatinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Indacaterol; Glycopyrrolate: (Moderate) Monitor for beta-agonist side effects like tremor, nervousness, or fast, irregular heart rate, if indacaterol is coadministered with lonafarnib. Concurrent use may increase indacaterol exposure, although such increases in indacaterol exposure are unlikely to require any dose adjustment. Indacaterol is a CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. In drug interaction studies, coadministration of indacaterol inhalation powder 300 mcg (single dose) with another dual strong CYP3A4 and P-gp inhibitor caused an approximately 2-fold increase in indacaterol exposure.
Indinavir: (Contraindicated) Concomitant use of lonafarnib and indinavir is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, consider reducing the dose of indinavir to 600 mg PO every 8 hours. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; indinavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Infigratinib: (Major) Avoid concomitant use of infigratinib and lonafarnib. Coadministration may increase infigratinib exposure, increasing the risk for adverse effects. Infigratinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of infigratinib by 622%.
Irinotecan Liposomal: (Major) Avoid administration of lonafarnib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; lonafarnib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Irinotecan: (Major) Avoid administration of lonafarnib during treatment with irinotecan and for at least 1 week prior to starting therapy unless there are no therapeutic alternatives. Irinotecan and its active metabolite, SN-38, are CYP3A4 substrates; lonafarnib is a strong CYP3A4 inhibitor. Concomitant use may increase systemic exposure to both irinotecan and SN-38.
Isavuconazonium: (Contraindicated) Coadministration of lonafarnib and isavuconazonium is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitors; isavuconazonium is a sensitive CYP3A4 substrate and moderate CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased isavuconazole exposure by 422%.
Isoniazid, INH: (Major) Avoid coadministration of lonafarnib and isoniazid; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing isoniazid. Lonafarnib is a sensitive CYP3A4 substrate and isoniazid is a weak CYP3A4 inhibitor.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Contraindicated) Coadministration of lonafarnib and rifampin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the exposure of lonafarnib by 98%. (Major) Avoid coadministration of lonafarnib and isoniazid; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing isoniazid. Lonafarnib is a sensitive CYP3A4 substrate and isoniazid is a weak CYP3A4 inhibitor.
Isoniazid, INH; Rifampin: (Contraindicated) Coadministration of lonafarnib and rifampin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the exposure of lonafarnib by 98%. (Major) Avoid coadministration of lonafarnib and isoniazid; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing isoniazid. Lonafarnib is a sensitive CYP3A4 substrate and isoniazid is a weak CYP3A4 inhibitor.
Isradipine: (Moderate) Monitor for an increase in isradipine-related adverse reactions including hypotension if coadministration with lonafarnib is necessary. Concomitant use may increase isradipine exposure. Lonafarnib is a strong CYP3A4 inhibitor and isradipine is metabolized by CYP3A4.
Istradefylline: (Major) Avoid coadministration of lonafarnib and istradefylline; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, do not exceed 20 mg once daily of istradefylline and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing istradefylline. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; istradefylline is a CYP3A4 substrate and weak CYP3A4 inhibitor. Istradefylline exposure was increased by 2.5-fold when administered with a strong inhibitor in a drug interaction study.
Itraconazole: (Contraindicated) Coadministration of lonafarnib and itraconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both drugs are CYP3A4 substrates and strong CYP3A4 inhibitors. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Ivabradine: (Contraindicated) Coadministration of lonafarnib with ivabradine is contraindicated due to an increase in plasma concentrations of ivabradine, which may exacerbate bradycardia and conduction disturbances. Ivabradine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivabradine exposure by 7.7-fold.
Ivacaftor: (Major) Avoid concomitant use of lonafarnib and ivacaftor due to the risk of increased exposure and adverse effects from both drugs. If coadministration is unavoidable, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly and reduce to or continue lonafarnib at a dosage or 115 mg/m2. Coadministration is not recommended in patients younger than 6 months. Lonafarnib is a CYP2C9 and CYP3A substrate and strong CYP3A inhibitor; ivacaftor is a CYP3A substrate and CYP2C9 and weak CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold.
Ivosidenib: (Major) Avoid coadministration of ivosidenib with lonafarnib due to increased plasma concentrations of ivosidenib, which increases the risk of QT prolongation. If concomitant use is unavoidable, reduce the dose of ivosidenib to 250 mg PO once daily. Monitor ECGs for QTc prolongation and monitor electrolytes, correcting any electrolyte abnormalities as clinically appropriate. If lonafarnib is discontinued, wait at least 5 half-lives of lonafarnib before increasing the dose of ivosidenib to the recommended dose of 500 mg PO once daily. Ivosidenib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ivosidenib single-dose AUC to 269% of control, with no change in Cmax.
Ixabepilone: (Major) Avoid concurrent use of ixabepilone and lonafarnib due to increased ixabepilone exposure, which may increase the risk of adverse reactions. If concomitant use is unavoidable, reduce the dose of ixabepilone to 20 mg/m2. Ixabepilone is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ixabepilone exposure by 79%.
Ketoconazole: (Contraindicated) Coadministration of lonafarnib and ketoconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both lonafarnib and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with ketoconazole increased the exposure of lonafarnib by 425%.
Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor.
Lansoprazole: (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Contraindicated) Coadministration of lonafarnib and clarithromycin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Monitor for lansoprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase lansoprazole exposure. Lansoprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Lapatinib: (Major) Avoid coadministration of lonafarnib and lapatinib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, decrease the dose of lapatinib to 500 mg PO once daily and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. If lonafarnib is discontinued, increase lapatinib to the indicated dose after a washout period of approximately 1 week. Resume previous lonafarnib dosage 14 days after discontinuing lapatinib. Lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor; lapatinib is a CYP3A4 and P-gp substrate and weak CYP3A4 inhibitor. Concomitant use with another strong CYP3A4 inhibitor increased lapatinib exposure by 3.6-fold and increased the half-life of lapatinib by 1.7-fold.
Larotrectinib: (Major) Avoid coadministration of lonafarnib and larotrectinib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce the dose of larotrectinib by 50% and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. After lonafarnib has been discontinued for 3 to 5 elimination half-lives, resume the larotrectinib dose taken prior to initiating lonafarnib. Resume previous lonafarnib dosage 14 days after discontinuing larotrectinib. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; larotrectinib is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the larotrectinib AUC by 4.3-fold.
Lefamulin: (Contraindicated) Coadministration of lonafarnib and oral lefamulin is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. An interaction is not expected with intravenous lefamulin. Lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor; oral lefamulin is a CYP3A4 and P-gp substrate and moderate CYP3A4 inhibitor.
Lemborexant: (Major) Avoid coadministration of lemborexant and lonafarnib as concurrent use may increase lemborexant exposure and the risk of adverse effects. Lemborexant is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the lemborexant AUC by up to 4.5-fold.
Lenacapavir: (Contraindicated) Coadministration of lonafarnib and lenacapavir is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A substrate and lenacapavir is a moderate CYP3A inhibitor.
Leniolisib: (Major) Avoid concomitant use of leniolisib and lonafarnib due to the risk for increased leniolisib exposure which may increase the risk for adverse effects. Leniolisib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased leniolisib overall exposure by 2-fold.
Letermovir: (Contraindicated) Coadministration of lonafarnib and letermovir is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and letermovir is a moderate CYP3A4 inhibitor.
Levamlodipine: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Levoketoconazole: (Contraindicated) Coadministration of lonafarnib and ketoconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Both lonafarnib and ketoconazole are CYP3A substrates and strong CYP3A inhibitors. Coadministration with ketoconazole increased the exposure of lonafarnib by 425%.
Levomilnacipran: (Major) Do not exceed a levomilnacipran dose of 80 mg once daily if coadministration with lonafarnib is necessary. Concomitant use may increase levomilnacipran exposure. Levomilnacipran is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased levomilnacipran exposure by about 50%.
Lidocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with lonafarnib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Lidocaine; Epinephrine: (Moderate) Monitor for lidocaine toxicity if coadministration with lonafarnib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Lidocaine; Prilocaine: (Moderate) Monitor for lidocaine toxicity if coadministration with lonafarnib is necessary as concurrent use may increase lidocaine exposure. Lidocaine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Lomitapide: (Contraindicated) Concomitant use of lonafarnib and lomitapide is contraindicated; if treatment with lonafarnib is unavoidable, lomitapide should be stopped during treatment. Lomitapide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lomitapide exposure by approximately 27-fold.
Loperamide: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with lonafarnib. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and lonafarnib is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Loperamide; Simethicone: (Moderate) Monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest), if coadministered with lonafarnib. Concurrent use may increase loperamide exposure. Loperamide is a CYP3A4 and P-gp substrate and lonafarnib is a strong CYP3A4 and P-gp inhibitor. Coadministration with another strong CYP3A4 and P-gp inhibitor increased loperamide exposure by 3.8-fold.
Lopinavir; Ritonavir: (Contraindicated) Coadministration of lonafarnib and ritonavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Moderate) Monitor for an increase in lopinavir-related adverse reactions if coadministration with lonafarnib is necessary. Concurrent use may increase the plasma concentrations of lopinavir. Lopinavir is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Lorlatinib: (Contraindicated) Concurrent use of lonafarnib and lorlatinib is contraindicated as use may decrease lonafarnib exposure and efficacy. Lorlatinib exposure and the risk for lorlatinib-related adverse effects may also be increased. If concomitant use is necessary, reduce the starting dose of lorlatinib from 100 mg to 75 mg once daily, or from 75 mg to 50 mg once daily. Lorlatinib is a CYP3A4 substrate and moderate CYP3A4 inducer and lonafarnib is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lorlatinib exposure by 42%.
Lovastatin: (Contraindicated) Coadministration of lovastatin and lonafarnib is contraindicated due to the risk of elevated plasma concentrations of lovastatin leading to myopathy and rhabdomyolysis. Lovastatin is a P-gp substrate and sensitive CYP3A4 substrate; lonafarnib is a P-gp inhibitor and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lovastatin exposure by 11 to 36-fold.
Lumacaftor; Ivacaftor: (Major) Avoid concomitant use of lonafarnib and ivacaftor due to the risk of increased exposure and adverse effects from both drugs. If coadministration is unavoidable, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly and reduce to or continue lonafarnib at a dosage or 115 mg/m2. Coadministration is not recommended in patients younger than 6 months. Lonafarnib is a CYP2C9 and CYP3A substrate and strong CYP3A inhibitor; ivacaftor is a CYP3A substrate and CYP2C9 and weak CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Lumacaftor; ivacaftor dosage adjustment is not required when lonafarnib is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking lonafarnib, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking lonafarnib. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A4 to reach steady state. Ivacaftor is a CYP3A4 substrate, and lumacaftor is a strong CYP3A4 inducer. Although lonafarnib is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy because of lumacaftor's CYP3A4 induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor dosage adjustment is not required when lonafarnib is started in a patient already taking lumacaftor; ivacaftor. However, if lumacaftor; ivacaftor is initiated in a patient already taking lonafarnib, reduce the dose of lumacaftor; ivacaftor to 1 tablet PO daily or 1 packet of oral granules every other day for the first week of treatment, and then increase to the usual recommended daily dose. This dosage adjustment is also necessary if lumacaftor; ivacaftor therapy has been interrupted for more than 1 week and re-initiated while the patient is taking lonafarnib. The 1-week lead-in period at the lower lumacaftor; ivacaftor dosage allows for lumacaftor's induction of CYP3A4 to reach steady state. Ivacaftor is a CYP3A4 substrate, and lumacaftor is a strong CYP3A4 inducer. Although lonafarnib is a strong CYP3A4 inhibitor, net ivacaftor exposure at steady state is not expected to exceed that achieved with ivacaftor monotherapy because of lumacaftor's CYP3A4 induction. In pharmacokinetic studies, coadministration of lumacaftor; ivacaftor with another strong CYP3A4 inhibitor increased ivacaftor exposure by 4.3-fold.
Lumateperone: (Major) Reduce the dose of lumateperone to 10.5 mg once daily if concomitant use of lonafarnib is necessary. Concurrent use may increase lumateperone exposure and the risk of adverse effects. Lumateperone is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with a strong CYP3A4 inhibitor increased lumateperone exposure by approximately 4-fold.
Lurasidone: (Contraindicated) Coadministration of lurasidone with lonafarnib is contraindicated due to increased plasma concentrations of lurasidone. Lurasidone is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased lurasidone exposure by 9-fold.
Lurbinectedin: (Major) Avoid concomitant use of lurbinectedin and lonafarnib due to the risk of increased lurbinectedin exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of lurbinectedin by 50%. Lurbinectedin is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of lurbinectedin by 2.7-fold.
Macitentan: (Major) Avoid coadministration of macitentan with lonafarnib due to the risk of increased macitentan exposure and adverse effects. Consider alternative treatment options for pulmonary hypertension if treatment with lonafarnib is necessary. Macitentan is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased macitentan exposure by approximately 2-fold.
Maraviroc: (Major) Reduce the dose of maraviroc when coadministration with lonafarnib is necessary, regardless of whether the patient is receiving a concomitant strong CYP3A inducer. The effect of lonafarnib on maraviroc exposure is expected to exceed that of the inducer and overall, increased maraviroc concentrations are expected. Coadministration of maraviroc with lonafarnib is contraindicated in patients with CrCl less than 30 mL/min. Recommendations for reducing the maraviroc dose when administered with lonafarnib (with or without a concomitant CYP3A inducer) are: adults and children weighing 40 kg or more: 150 mg PO twice daily; children weighing 30 to 39 kg: 100 mg PO twice daily; children weighing 20 to 29 kg: 75 mg PO twice daily (or 80 mg PO twice daily for solution); children weighing 10 to 19 kg: 50 mg PO twice daily. Maraviroc is a sensitive CYP3A and P-gp substrate and lonafarnib is a strong CYP3A and P-gp inhibitor.
Maribavir: (Major) Avoid coadministration of lonafarnib and maribavir; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing maribavir. Lonafarnib is a sensitive CYP3A4 substrate and maribavir is a weak CYP3A4 inhibitor.
Mavacamten: (Contraindicated) Mavacamten is contraindicated for use with lonafarnib due to risk of heart failure due to systolic dysfunction and risk for reduced lonafarnib efficacy. Concomitant use increases mavacamten exposure and may decrease lonafarnib exposure. Mavacamten is a CYP2C19 substrate and substrate and moderate inducer of CYP3A and lonafarnib is a moderate CYP2C19 inhibitor and sensitive substrate and strong inhibitor of CYP3A. Concomitant use with a strong CYP3A inhibitor is predicted to increase mavacamten overall exposure up to 130%.
Medroxyprogesterone: (Moderate) Use caution if coadministration of lonafarnib with medroxyprogesterone is necessary, as the systemic exposure of medroxyprogesterone may be increased resulting in an increase in treatment-related adverse reactions. Medroxyprogesterone is metabolized primarily by hydroxylation via a CYP3A4; lonafarnib is a strong CYP3A4 inhibitor.
Mefloquine: (Moderate) Use mefloquine with caution if coadministration with lonafarnib is necessary as concurrent use may increase mefloquine exposure and mefloquine-related adverse reactions. Mefloquine is a substrate of CYP3A4 and P-gp and lonafarnib is a P-gp inhibitor and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of mefloquine by 79%.
Meperidine: (Moderate) Consider a reduced dose of meperidine with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, meperidine plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to meperidine. Meperidine is a substrate of CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. Concomitant use with lonafarnib can increase meperidine exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of meperidine.
Metformin; Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with lonafarnib is necessary. Repaglinide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
Metformin; Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with lonafarnib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Methadone: (Moderate) Consider a reduced dose of methadone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, methadone plasma concentrations can decrease resulting in reduced efficacy and potential withdrawal syndrome in a patient who has developed physical dependence to methadone. Methadone is a substrate of CYP3A4, CYP2B6, CYP2C19, CYP2C9, and CYP2D6; lonafarnib is a strong CYP3A4 and moderate CYP2C19 inhibitor. Concomitant use with lonafarnib can increase methadone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of methadone.
Methohexital: (Contraindicated) Coadministration of lonafarnib and methohexital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and methohexital is a moderate CYP3A4 inducer.
Methylergonovine: (Major) Avoid concomitant use of methylergonovine with lonafarnib. Concomitant use may increase methylergonovine exposure and the risk for vasospasm which may lead to cerebral or peripheral ischemia. Methylergonovine is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor.
Methylprednisolone: (Moderate) Monitor for corticosteroid-related adverse events if methylprednisolone is used with lonafarnib. Concurrent use may increase the exposure of methylprednisolone. Methylprednisolone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Other strong CYP3A4 inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Midazolam: (Contraindicated) Coadministration of midazolam and lonafarnib is contraindicated; concurrent use may significantly increase the exposure of midazolam and the risk of adverse effects. Discontinue lonafarnib for 10 to 14 days before and 2 days after administration of midazolam. Midazolam is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with lonafarnib increased the exposure of midazolam by 639%.
Midostaurin: (Major) Avoid the concomitant use of midostaurin and lonafarnib due to the risk of increased midostaurin exposure which may increase the incidence and severity of adverse reactions. If concomitant use cannot be avoided, monitor patients for signs and symptoms of midostaurin toxicity, particularly during the first week of midostaurin therapy for those with systemic mastocytosis/mast cell leukemia and during the first week of each cycle for those with acute myeloid leukemia. Midostaurin is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of one strong CYP3A4 inhibitor with a single dose of midostaurin increased the exposure of midostaurin and its active metabolites CGP62221 and CGP52421 by 10.4-fold, 3.5-fold, and 1.2-fold, respectively. Coadministration of another strong CYP3A4 inhibitor with twice daily doses of midostaurin increased Day 28 trough concentrations of midostaurin, CGP62221, and CGP52421 by 2.1-fold, 1.2-fold, and 1.3-fold respectively compared with day 21 trough levels with midostaurin alone.
Mifepristone: (Contraindicated) Concomitant use of lonafarnib and mifepristone is contraindicated as use together increases the exposure and risk of adverse effects from both drugs. Consider alternatives. If concomitant use of mifepristone is absolutely necessary for the treatment of Cushing's syndrome in a patient already receiving lonafarnib, initiate mifepristone at a dose of 300 mg and titrate to a maximum of 900 mg/day if clinically indicated. Monitor closely for lonafarnib and mifepristone toxicity. If a patient is taking mifepristone daily and lonafarnib is necessary, consult the product literature for recommended dose adjustments. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate and strong CYP3A4 inhibitor; mifepristone is a CYP3A4 substrate and strong CYP3A4 and moderate CYP2C9 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Mirtazapine: (Moderate) Monitor for an increase in mirtazapine-related adverse reactions if coadministration with lonafarnib is necessary. Mirtazapine is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the Cmax and AUC of a single dose of mirtazapine by approximately 40% and 50%, respectively.
Mirvetuximab Soravtansine: (Moderate) Closely monitor for mirvetuximab soravtansine-related adverse reactions if concomitant use of lonafarnib is necessary. DM4, the cytotoxic component of mirvetuximab soravtansine, is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use may increase unconjugated DM4 exposure.
Mitapivat: (Major) Avoid coadministration of mitapivat with lonafarnib due to increased risk of adverse reactions from mitapivat. Coadministration increases mitapivat concentrations. Mitapivat is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors increased mitapivat overall exposure by 3.6 to 4.9-fold.
Mitotane: (Contraindicated) Coadministration of lonafarnib and mitotane is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and mitotane is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Mobocertinib: (Major) Avoid concomitant use of mobocertinib and lonafarnib. Concomitant use may increase mobocertinib exposure and the risk for adverse reactions such as QT prolongation. Mobocertinib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Use of a strong CYP3A inhibitor is predicted to increase the overall exposure of mobocertinib and its active metabolites by 374% to 419%.
Modafinil: (Major) Avoid coadministration of lonafarnib and modafinil; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. The exposure of modafinil may also be increased. If coadministration is unavoidable, closely monitor patients for adverse reactions from both drugs. Lonafarnib is a CYP2C9 substrate and strong CYP3A4 inhibitor; modafinil is a CYP3A4 substrate and CYP2C9 inhibitor.
Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with lonafarnib is necessary, due to increased mometasone exposure; Cushing syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Morphine: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with lonafarnib is necessary; decrease the dose of either drug as necessary. Morphine is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Morphine; Naltrexone: (Moderate) Monitor for an increase in morphine-related adverse reactions, including hypotension, sedation, and respiratory depression, if coadministration with lonafarnib is necessary; decrease the dose of either drug as necessary. Morphine is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor. Coadministration with P-gp inhibitors can increase morphine exposure by about 2-fold.
Nafcillin: (Contraindicated) Coadministration of lonafarnib and nafcillin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and nafcillin is a moderate CYP3A4 inducer.
Naldemedine: (Moderate) Monitor for potential naldemedine-related adverse reactions if coadministered with lonafarnib. The plasma concentrations of naldemedine may be increased during concurrent use. Naldemedine is a CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Naloxegol: (Contraindicated) Concomitant use of naloxegol with lonafarnib is contraindicated. Naloxegol is metabolized primarily by CYP3A4. Strong CYP3A4 inhibitors, such as lonafarnib, can significantly increase exposure to naloxegol which may precipitate opioid withdrawal symptoms such as hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, irritability, and yawning.
Nanoparticle Albumin-Bound Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of nab-paclitaxel with lonafarnib is necessary due to the risk of increased plasma concentrations of paclitaxel. Nab-paclitaxel is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Nanoparticle Albumin-Bound Sirolimus: (Major) Avoid concomitant use of sirolimus and lonafarnib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and lonafarnib is a strong CYP3A and P-gp inhibitor.
Nefazodone: (Contraindicated) Coadministration of lonafarnib and nefazodone is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and nefazodone is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Nelfinavir: (Contraindicated) Coadministration of lonafarnib and nelfinavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, moderate 2C19 inhibitor, and strong CYP3A4 inhibitor. Nelfinavir is a CYP3A4 substrate, CYP2C19 substrate, and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Neratinib: (Major) Avoid concomitant use of lonafarnib with neratinib due to an increased risk of neratinib-related toxicity. Neratinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased neratinib exposure by 381%; concomitant use with other strong inhibitors of CYP3A4 may also increase neratinib concentrations.
Netupitant, Fosnetupitant; Palonosetron: (Contraindicated) Coadministration of lonafarnib and netupitant is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; netupitant is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Nevirapine: (Moderate) Monitor for an increase in nevirapine-related adverse reactions if coadministration with lonafarnib is necessary. Nevirapine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP3A4 inhibitor increased nevirapine exposure by 100%; concomitant use with a strong CYP3A4 inhibitor may also increase nevirapine exposure.
Nicardipine: (Major) Avoid coadministration of lonafarnib and nicardipine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing nicardipine. Lonafarnib is a sensitive CYP3A4 substrate and nicardipine is a weak CYP3A4 inhibitor.
NIFEdipine: (Moderate) Careful monitoring and dose adjustment of nifedipine may be necessary if administered with lonafarnib as nifedipine exposure and adverse effects may be increased. Consider initiating nifedipine at the lowest dose. Nifedipine is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor.
Nilotinib: (Contraindicated) Concomitant use of lonafarnib and nilotinib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce the nilotinib dose to 300 mg once daily in patients with resistant or intolerant Ph+ CML or to 200 mg once daily in patients with newly diagnosed Ph+ CML and monitor closely for QT prolongation. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; nilotinib is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Nimodipine: (Major) Avoid coadministration of nimodipine with lonafarnib due to the risk of significant hypotension. If concomitant use is unavoidable, monitor blood pressure and reduce the dose of nimodipine as clinically appropriate. Nimodipine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Nirmatrelvir; Ritonavir: (Contraindicated) Coadministration of lonafarnib and ritonavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Nirogacestat: (Contraindicated) Coadministration of lonafarnib and nirogacestat is contraindicated as concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Concomitant use may also increase nirogacestat exposure. Lonafarnib is a CYP3A substrate and strong CYP3A inhibitor; nirogacestat is a CYP3A substrate and moderate CYP3A inhibitor. Concomitant use with other strong CYP3A inhibitors is predicted to increase nirogacestat overall exposure by 3.46- to 8.2-fold.
Nisoldipine: (Major) Avoid coadministration of nisoldipine with lonafarnib due to increased plasma concentrations of nisoldipine. If coadministration is unavoidable, monitor blood pressure closely during concurrent use of these medications. Nisoldipine is a CYP3A4 substrate and lonafarnib is a CYP3A4 inhibitor. Coadministration with another CYP3A4 inhibitor increased the AUC of nisoldipine by 30% to 45%.
Nitisinone: (Major) Avoid coadministration of lonafarnib and nitisinone; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and nitisinone is a CYP2C9 inhibitor.
Olanzapine; Fluoxetine: (Major) Avoid coadministration of lonafarnib and fluoxetine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing fluoxetine. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate and fluoxetine is a weak CYP3A4 and CYP2C9 inhibitor.
Olaparib: (Major) Avoid coadministration of olaparib with lonafarnib due to the risk of increased olaparib-related adverse reactions. If concomitant use is unavoidable, reduce the dose of olaparib to 100 mg twice daily; the original dose may be resumed 3 to 5 elimination half-lives after lonafarnib is discontinued. Olaparib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor; concomitant use may increase olaparib exposure. Coadministration with another strong CYP3A4 inhibitor increased the olaparib Cmax by 42% and the AUC by 170%.
Oliceridine: (Moderate) Monitor patients closely for respiratory depression and sedation at frequent intervals and base subsequent doses on the patient's severity of pain and response to treatment if concomitant administration of oliceridine and lonafarnib is necessary; less frequent dosing of oliceridine may be required. Concomitant use of oliceridine and lonafarnib may increase the plasma concentration of oliceridine, resulting in increased or prolonged opioid effects. If lonafarnib is discontinued, consider increasing the oliceridine dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oliceridine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Olopatadine; Mometasone: (Moderate) Monitor for steroid-related adverse reactions if coadministration of mometasone with lonafarnib is necessary, due to increased mometasone exposure; Cushing syndrome and adrenal suppression could potentially occur with long-term use. Mometasone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Omaveloxolone: (Major) Avoid concomitant use of omaveloxolone and lonafarnib. If concomitant use is necessary, decrease omaveloxolone dose to 50 mg once daily. Concomitant use may increase omaveloxolone exposure and the risk for omaveloxolone-related adverse effects. Omaveloxolone is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased omaveloxolone overall exposure by 4-fold.
Omeprazole: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Contraindicated) Coadministration of lonafarnib and rifabutin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Rifabutin exposure and the risk for rifabutin-related adverse effects may also be increased; rifabutin dosage adjustments may be required if concomitant use is necessary. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor and rifabutin is a CYP3A4 substrate and moderate CYP3A4 inducer. (Moderate) Monitor for omeprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for omeprazole-related adverse effects during coadministration with lonafarnib. Concurrent use may increase omeprazole exposure. Omeprazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Oritavancin: (Major) Avoid coadministration of lonafarnib and oritavancin; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and oritavancin is a CYP2C9 inhibitor.
Osilodrostat: (Major) Avoid coadministration of lonafarnib and osilodrostat; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce the dose of osilodrostat by half and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing osilodrostat. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; osilodrostat is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Ospemifene: (Moderate) Monitor for an increase in ospemifene-related adverse reactions if coadministration with lonafarnib is necessary. Ospemifene is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong inhibitor increased ospemifene systemic exposure by 1.4-fold.
Oxybutynin: (Moderate) Monitor for an increase in oxybutynin-related adverse reactions if coadministration with lonafarnib is necessary. Oxybutynin is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased mean oxybutynin plasma concentrations by approximately 2-fold.
Oxycodone: (Moderate) Consider a reduced dose of oxycodone with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the oxycodone dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Oxycodone is a CYP3A4 substrate, and coadministration with strong CYP3A4 inhibitors like lonafarnib can increase oxycodone exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of oxycodone. If lonafarnib is discontinued, oxycodone plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to oxycodone.
Paclitaxel: (Moderate) Monitor for an increase in paclitaxel-related adverse reactions if coadministration of paclitaxel with lonafarnib is necessary due to the risk of increased plasma concentrations of paclitaxel. Paclitaxel is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. In vitro, coadministration with both strong and moderate CYP3A4 inhibitors increased paclitaxel exposure; however, the concentrations used exceeded those found in vivo following normal therapeutic doses. The pharmacokinetics of paclitaxel may also be altered in vivo as a result of interactions with CYP3A4 inhibitors.
Pacritinib: (Contraindicated) Concurrent use of pacritinib with lonafarnib is contraindicated due to increased pacritinib exposure which increases the risk of adverse reactions. Lonafarnib exposure may also increase, increasing the risk for adverse reactions. Pacritinib is a CYP3A substrate and a weak CYP3A4 inhibitor. Lonafarnib is a sensitive CYP3A4 substrate and a strong CYP3A inhibitor. The manufacturer of lonafarnib recommends a dose reduction when given concurrently with weak CYP3A4 inhibitors.
Palbociclib: (Major) Avoid coadministration of lonafarnib and palbociclib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce the dose of palbociclib to 75 mg PO once daily and reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. If lonafarnib is discontinued, increase the palbociclib dose (after 3 to 5 half-lives of lonafarnib) to the dose used before initiation of lonafarnib. Resume previous lonafarnib dosage 14 days after discontinuing palbociclib. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; palbociclib is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of palbociclib by 87%.
Palovarotene: (Major) Avoid concomitant use of palovarotene and lonafarnib due to the risk for increased palovarotene exposure which may increase the risk for adverse effects. Palovarotene is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased palovarotene overall exposure by 3-fold.
Panobinostat: (Major) Reduce the starting dose of panobinostat to 10 mg when coadministered with lonafarnib. Concurrent use may increase systemic exposure of panobinostat. Panobinostat is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the AUC of panobinostat by 73%.
Paricalcitol: (Moderate) Monitor plasma PTH and serum calcium and phosphorous concentrations if a patient initiates or discontinues therapy with both paricalcitol and lonafarnib, or during periods of dose titration. If hypercalcemia occurs, the dose of paricalcitol should be reduced or withheld until these parameters are normalized. Paricalcitol is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor approximately doubled the exposure of paricalcitol.
Pazopanib: (Major) Avoid coadministration of lonafarnib and pazopanib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If concomitant use is necessary, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and reduce the pazopanib dose to 400 mg PO once daily. Additional pazopanib dosage adjustments may be necessary. Lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor; pazopanib is a CYP3A4 and P-gp substrate and weak CYP3A4 inhibitor. Another strong CYP3A4 inhibitor increased the Cmax and AUC of pazopanib by 1.5-fold and 1.7-fold, respectively.
Pemigatinib: (Major) Avoid coadministration of pemigatinib and lonafarnib due to the risk of increased pemigatinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of pemigatinib to 9 mg PO once daily if original dose was 13.5 mg per day and to 4.5 mg PO once daily if original dose was 9 mg per day. If lonafarnib is discontinued, resume the original pemigatinib dose after 3 elimination half-lives of lonafarnib. Pemigatinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased pemigatinib exposure by 88%.
Perindopril; Amlodipine: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Pexidartinib: (Contraindicated) Concurrent use of lonafarnib and pexidartinib is contraindicated due to the risk of decreased lonafarnib exposure which may reduce its efficacy. Concomitant use may also increase pexidartinib exposure and the risk for pexidartinib-related adverse effects. If concomitant use is necessary, reduce the pexidartinib dosage as follows: 500 mg/day or 375 mg/day of pexidartinib, reduce to 125 mg twice daily; 250 mg/day of pexidartinib, reduce to 125 mg once daily. If lonafarnib is discontinued, increase the pexidartinib dose to the original dose after 3 plasma half-lives of lonafarnib. Pexidartinib is a CYP3A substrate and moderate CYP3A inducer; lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor. Coadministration of another strong CYP3A inhibitor increased pexidartinib exposure by 70%.
Phenobarbital: (Contraindicated) Coadministration of lonafarnib and phenobarbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Contraindicated) Coadministration of lonafarnib and phenobarbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and phenobarbital is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Phenytoin: (Contraindicated) Coadministration of lonafarnib and phenytoin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and phenytoin is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Pimavanserin: (Major) Reduce the dose of pimavanserin to 10 mg PO once daily and monitor for pimavanserin-related adverse reactions, including nausea, vomiting, confusion, loss of balance or coordination, and QT prolongation if coadministration with lonafarnib is necessary. Concurrent use may increase pimavanserin exposure. Pimavanserin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In drug interaction studies, coadministration with a strong CYP3A4 inhibitor increased exposure to pimavanserin by 3-fold.
Pimozide: (Contraindicated) Concurrent use of pimozide and lonafarnib is contraindicated. Coadministration may result in elevated pimozide concentrations resulting in QT prolongation, ventricular arrhythmias, and sudden death. Pimozide is metabolized primarily through CYP3A4, and lonafarnib is a strong CYP3A4 inhibitor.
Pirtobrutinib: (Major) Avoid concomitant use of pirtobrutinib and lonafarnib due to the risk of increased exposure of both drugs which may increase the risk for adverse effects. If concomitant use is necessary, decrease the dosage of both drugs and closely monitor patients for adverse reactions. Reduce the pirtobrutinib dose by 50 mg. If the current pirtobrutinib dosage is 50 mg once daily, interrupt pirtobrutinib treatment for the duration of lonafarnib use. Resume the previous dose of pirtobrutinib after lonafarnib is discontinued for 5 half-lives. Reduce to or continue lonafarnib at a dosage of 115 mg/m2 and resume previous lonafarnib dosage 14 days after discontinuing pirtobrutinib. Pirtobrutinib is a CYP3A substrate and weak CYP3A inhibitor and lonafarnib is a sensitive CYP3A substrate and strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased pirtobrutinib overall exposure by 49%.
Ponatinib: (Major) Avoid coadministration of ponatinib and lonafarnib due to the potential for increased ponatinib exposure. If concurrent use cannot be avoided, reduce the ponatinib dose to the next lower dose level (45 mg to 30 mg; 30 mg to 15 mg; 15 mg to 10 mg). If the patient is taking ponatinib 10 mg once daily prior to concurrent use, avoid the use of lonafarnib and consider alternative therapy. After lonafarnib has been discontinued for 3 to 5 half-lives, resume the dose of ponatinib that was tolerated prior to starting lonafarnib. Ponatinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the ponatinib AUC by 78%.
Posaconazole: (Contraindicated) Coadministration of lonafarnib and posaconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and P-gp inhibitor. Posaconazole strong CYP3A4 inhibitor and P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Pralsetinib: (Major) Avoid concomitant use of lonafarnib and pralsetinib due to the risk of increased pralsetinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of pralsetinib to 200 mg once daily for patients taking a daily dose of 400 mg or 300 mg, and to 100 mg once daily for patients taking a daily dose of 200 mg. Pralsetinib is a CYP3A and P-gp substrate and lonafarnib is a combined strong CYP3A and P-gp inhibitor. Coadministration with a combined strong CYP3A and P-gp inhibitor is predicted to increase the overall exposure of pralsetinib by 251%.
Prednisolone: (Moderate) Monitor for corticosteroid-related adverse events if prednisolone is used with lonafarnib. Concurrent use may increase the exposure of prednisolone. Prednisolone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Other strong CYP3A4 inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Prednisone: (Moderate) Monitor for corticosteroid-related adverse events if prednisone is used with lonafarnib. Concurrent use may increase the exposure of prednisone. Prednisone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Other strong CYP3A4 inhibitors have been reported to decrease the metabolism of certain corticosteroids by up to 60%.
Primidone: (Contraindicated) Coadministration of lonafarnib and primidone is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and primidone is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Probenecid; Colchicine: (Major) Avoid concomitant use of colchicine and lonafarnib due to the risk for increased colchicine exposure which may increase the risk for adverse effects. Concomitant use is contraindicated in patients with renal or hepatic impairment. Additionally, this combination is contraindicated if colchicine is being used for cardiovascular risk reduction. If concomitant use is necessary outside of these scenarios, consider a colchicine dosage reduction. Specific dosage reduction recommendations are available for colchicine tablets for some indications; it is unclear if these dosage recommendations are appropriate for other products or indications. For colchicine tablets being used for gout prophylaxis, reduce the dose from 0.6 mg twice daily to 0.3 mg once daily or from 0.6 mg once daily to 0.3 mg once every other day. For colchicine tablets being used for gout treatment, reduce the dose from 1.2 mg followed by 0.6 mg to 0.6 mg without an additional dose. For colchicine tablets being used for Familial Mediterranean Fever, the maximum daily dose is 0.6 mg. Colchicine is a CYP3A and P-gp substrate and lonafarnib is a dual strong CYP3A and P-gp inhibitor. Concomitant use with other dual strong CYP3A and P-gp inhibitors has been observed to increase colchicine overall exposure by 3- to 4-fold.
Propafenone: (Moderate) Monitor for increased propafenone toxicity if coadministered with lonafarnib; concurrent use may increase propafenone exposure and therefore increase the risk of proarrhythmias. Avoid simultaneous use of propafenone and lonafarnib with a CYP2D6 inhibitor or in patients with CYP2D6 deficiency. Propafenone is a CYP3A4 and CYP2D6 substrate; lonafarnib is a strong CYP3A4 inhibitor.
Propranolol: (Moderate) Monitor for increased propranolol adverse reactions, including bradycardia and hypotension, during coadministration of lonafarnib as concurrent use may increase propranolol exposure. Propranolol is a CYP2C19 substrate and lonafarnib is a moderate CYP2C19 inhibitor.
Quetiapine: (Major) Reduce quetiapine dose to one sixth when coadministered with lonafarnib. Coadministration may significantly increase quetiapine exposure and related side effects. If lonafarnib is discontinued, increase the quetiapine dose by 6-fold. Quetiapine is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of quetiapine by approximately 6-fold.
Quinidine: (Moderate) Monitor ECG and for quinidine-related adverse reactions if coadministration with lonafarnib is necessary. Concomitant use may result in increased plasma concentrations of quinidine. Quinidine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Quinine: (Major) Avoid coadministration of lonafarnib and quinine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2; closely monitor patients for adverse reactions from both drugs. Resume previous lonafarnib dosage 14 days after discontinuing quinine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; quinine is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of quinine by 45% and decreased the clearance by 31%.
Quizartinib: (Major) Avoid concomitant use of lonafarnib with quizartinib due to the risk of increased quizartinib exposure which may increase the risk of adverse reactions. If concomitant use is necessary, reduce the dose of quizartinib to 26.5 mg for patients taking a daily dose of 53 mg, and to 17.7 mg for patients taking a daily dose of 35.4 mg or 26.5 mg; interrupt quizartinib therapy for the duration of the strong CYP3A inhibitor use for patients already taking a daily dose of 17.7 mg. Quizartinib is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased the overall exposure of quizartinib by 94%.
Ramelteon: (Moderate) Monitor for an increase in ramelteon-related adverse reactions if coadministration with lonafarnib is necessary. Ramelteon is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ramelteon exposure by 84%.
Ranolazine: (Contraindicated) Concomitant use of lonafarnib and ranolazine is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce to or continue lonafarnib at a dosage of 115 mg/m2. Ranolazine is a CYP3A4 and P-gp substrate and weak CYP3A4 inhibitor; lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased ranolazine exposure by 220%.
Regorafenib: (Major) Avoid coadministration of lonafarnib and regorafenib; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a CYP2C9 substrate and strong CYP3A4 inhibitor; regorafenib is a CYP3A4 substrate and CYP2C9 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased regorafenib exposure by 33% and decreased exposure of the active metabolites, M-2 and M-5, by 93% each.
Relugolix: (Major) Avoid concomitant use of relugolix and oral lonafarnib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer lonafarnib at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and lonafarnib is a weak P-gp inhibitor.
Relugolix; Estradiol; Norethindrone acetate: (Major) Avoid concomitant use of relugolix and oral lonafarnib. Concomitant use may increase relugolix exposure and the risk of relugolix-related adverse effects. If concomitant use is unavoidable, administer lonafarnib at least six hours after relugolix and monitor for adverse reactions. Relugolix is a P-glycoprotein (P-gp) substrate and lonafarnib is a weak P-gp inhibitor.
Repaglinide: (Moderate) A dose reduction of repaglinide and increased frequency of blood glucose monitoring may be required if coadministration with lonafarnib is necessary. Repaglinide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased repaglinide exposure by up to 1.5-fold.
Repotrectinib: (Contraindicated) Coadministration of lonafarnib and repotrectinib is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Concomitant use may also increase repotrectinib exposure and the risk for repotrectinib-related adverse effects. Lonafarnib is a sensitive CYP3A substrate and dual strong CYP3A and P-gp inhibitor; repotrectinib is a CYP3A and P-gp substrate and moderate CYP3A inducer. Coadministration with another strong CYP3A and P-gp inhibitor increased repotrectinib exposure by 5.9-fold.
Retapamulin: (Moderate) Coadministration of retapamulin with strong CYP3A4 inhibitors, such as lonafarnib, in patients younger than 24 months is not recommended. Systemic exposure of topically administered retapamulin may be higher in patients younger than 24 months than in patients 2 years and older. Retapamulin is a CYP3A4 substrate.
Ribociclib: (Contraindicated) Concomitant use of lonafarnib and ribociclib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce the dose of ribociclib to 400 mg once daily. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ribociclib is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425% and increased the ribociclib exposure by 220%.
Ribociclib; Letrozole: (Contraindicated) Concomitant use of lonafarnib and ribociclib is contraindicated and may increase the exposure and risk of adverse effects from both drugs. If concomitant use is necessary, reduce the dose of ribociclib to 400 mg once daily. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ribociclib is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425% and increased the ribociclib exposure by 220%.
Rifabutin: (Contraindicated) Coadministration of lonafarnib and rifabutin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Rifabutin exposure and the risk for rifabutin-related adverse effects may also be increased; rifabutin dosage adjustments may be required if concomitant use is necessary. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor and rifabutin is a CYP3A4 substrate and moderate CYP3A4 inducer.
Rifampin: (Contraindicated) Coadministration of lonafarnib and rifampin is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and rifampin is a strong CYP3A4 inducer. Coadministration with rifampin decreased the exposure of lonafarnib by 98%.
Rifapentine: (Contraindicated) Coadministration of lonafarnib and rifapentine is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with another strong CYP3A4 inducer decreased the exposure of lonafarnib by 98%.
Rifaximin: (Moderate) Monitor for an increase in rifaximin-related adverse reactions if coadministration with lonafarnib is necessary. Concomitant use may increase rifaximin exposure. In patients with hepatic impairment, a potential additive effect of reduced metabolism may further increase systemic rifaximin exposure. Rifaximin is a P-gp substrate and lonafarnib is a P-gp inhibitor. Coadministration with another P-gp inhibitor increased rifaximin overall exposure by 124-fold.
Rilpivirine: (Moderate) Coadministration of rilpivirine with lonafarnib may result in increased plasma concentrations of rilpivirine, leading to an increase in rilpivirine-related adverse effects. Rilpivirine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Rimegepant: (Major) Avoid coadministration of rimegepant with lonafarnib; concurrent use may increase rimegepant exposure. Rimegepant is a substrate of CYP3A4 and P-gp; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration of rimegepant with another strong CYP3A4 inhibitor increased rimegepant exposure by 4-fold.
Riociguat: (Major) Consider a starting dose of 0.5 mg PO three times daily when initiating riociguat in patients receiving lonafarnib; concurrent use may increase riociguat exposure. Monitor for signs and symptoms of hypotension on initiation and during treatment with lonafarnib. Consider a dose reduction in patients who may not tolerate the hypotensive effect of riociguat. Riociguat is a substrate of CYP3A4, P-gp, and BCRP; lonafarnib is a strong CYP3A4 and P-gp inhibitor.
Ripretinib: (Moderate) Monitor patients more frequently for ripretinib-related adverse reactions if coadministered with lonafarnib. Coadministration may increase the exposure of ripretinib and its active metabolite (DP-5439), which may increase the risk of adverse reactions. Ripretinib and DP-5439 are metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ripretinib and DP-5439 exposure by 99%.
Ritlecitinib: (Contraindicated) Coadministration of lonafarnib and ritlecitinib is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A substrate and ritlecitinib is a moderate CYP3A inhibitor.
Ritonavir: (Contraindicated) Coadministration of lonafarnib and ritonavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; ritonavir is a CYP3A4 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Rivaroxaban: (Major) Avoid coadministration of rivaroxaban and lonafarnib; significant increases in rivaroxaban exposure may occur which may increase the bleeding risk. Rivaroxaban is a substrate of CYP3A4/5 and the P-glycoprotein (P-gp) transporter; lonafarnib is a combined P-gp and strong CYP3A4 inhibitor. Concurrent use of a single dose of rivaroxaban and another combined P-gp and strong CYP3A4 inhibitor increased the steady-state rivaroxaban AUC and Cmax by 150% and 60%, respectively. Similar increases in pharmacodynamic effects such as factor Xa inhibition and PT prolongation were also observed.
Roflumilast: (Moderate) Monitor for an increase in roflumilast-related adverse reactions if concomitant use with lonafarnib is necessary. Concurrent use may increase roflumilast exposure. Roflumilast is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of roflumilast by 99%.
Romidepsin: (Moderate) Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity during initial administration of romidepsin with lonafarnib. Romidepsin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. In a pharmacokinetic drug interaction trial, a strong CYP3A4 inhibitor increased romidepsin AUC by approximately 25%.
Rucaparib: (Major) Avoid coadministration of lonafarnib and rucaparib; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing rucaparib. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate; rucaparib is a weak CYP3A4 and CYP2C9 inhibitor.
Ruxolitinib: (Major) Reduce the ruxolitinib dosage when coadministered with lonafarnib in patients with myelofibrosis (MF) or polycythemia vera (PV) as increased ruxolitinib exposure and toxicity may occur. No dose adjustments are necessary for patients with graft-versus-host disease; however, monitor blood counts more frequently for toxicity and adjust ruxolitinib dosage for adverse reactions. In MF patients, reduce the initial dose to 10 mg PO twice daily for platelet count of 100,000 cells/mm3 or more and 5 mg PO once daily for platelet count of 50,000 to 99,999 cells/mm3. In PV patients, reduce the initial dose to 5 mg PO twice daily. In MF or PV patients stable on ruxolitinib dose of 10 mg PO twice daily or more, reduce dose by 50%; in patients stable on ruxolitinib dose of 5 mg PO twice daily, reduce ruxolitinib to 5 mg PO once daily. Avoid the use of lonafarnib in MF or PV patients who are stable on a ruxolitinib dose of 5 mg PO once daily. Ruxolitinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Salmeterol: (Major) Avoid concomitant use of salmeterol with lonafarnib. Concomitant use increases salmeterol exposure and may increase the incidence and severity of salmeterol-related adverse effects. Signs and symptoms of excessive beta-adrenergic stimulation commonly include tachyarrhythmias, hypertension, and tremor. Salmeterol is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased salmeterol overall exposure 16-fold mainly due to increased bioavailability of the swallowed portion of the dose.
Saquinavir: (Contraindicated) Coadministration of lonafarnib and saquinavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, a P-gp inhibitor, and a strong CYP3A4 inhibitor. Saquinavir is a sensitive CYP3A4 substrate, a P-gp substrate, and a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Saxagliptin: (Major) Limit the dose of saxagliptin to 2.5 mg PO once daily when administered with lonafarnib due to significantly increased saxagliptin exposure. Saxagliptin is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased the saxagliptin AUC up to 3.7-fold.
Secobarbital: (Contraindicated) Coadministration of lonafarnib and secobarbital is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and secobarbital is a moderate CYP3A4 inducer.
Selpercatinib: (Major) Avoid coadministration of selpercatinib and lonafarnib; concurrent use may increase the exposure of both drugs which may increase the risk of adverse reactions, including QT prolongation. If coadministration is unavoidable, reduce the dose of selpercatinib to 40 mg PO twice daily if original dose was 120 mg twice daily, and to 80 mg PO twice daily if original dose was 160 mg twice daily. Reduce to or continue lonafarnib at a dosage of 115 mg/m2. Monitor ECGs for QT prolongation more frequently. If lonafarnib is discontinued, resume the original selpercatinib dose after 3 to 5 elimination half-lives of lonafarnib. Resume previous lonafarnib dosage 14 days after discontinuing selpercatinib. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; selpercatinib is a CYP3A4 substrate and weak CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selpercatinib exposure by 133%.
Selumetinib: (Major) Avoid coadministration of selumetinib and lonafarnib due to the risk of increased selumetinib exposure which may increase the risk of adverse reactions. If coadministration is unavoidable, reduce the dose of selumetinib to 20 mg/m2 PO twice daily if original dose was 25 mg/m2 twice daily and 15 mg/m2 PO twice daily if original dose was 20 mg/m2 twice daily. If lonafarnib is discontinued, resume the original selumetinib dose after 3 elimination half-lives of lonafarnib. Selumetinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased selumetinib exposure by 49%.
Sildenafil: (Major) Coadministration with lonafarnib is not recommended in patients receiving sildenafil for pulmonary arterial hypertension (PAH). When sildenafil is used for erectile dysfunction, consider a starting dose of 25 mg for patients receiving lonafarnib. Concurrent use may increase sildenafil plasma concentrations resulting in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection. Sildenafil is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the sildenafil AUC between 3- and 11-fold.
Silodosin: (Contraindicated) Concurrent use of silodosin and lonafarnib is contraindicated due to increased plasma concentrations of silodosin resulting in an increase of treatment-related adverse reactions. Silodosin is extensively metabolized by CYP3A4 and is a P-gp substrate; lonafarnib is a strong CYP3A4 inhibitor and a P-gp inhibitor. Coadministration with another strong CYP3A4 inhibitor increased silodosin exposure by 2.9-fold to 3.2-fold.
Simvastatin: (Contraindicated) Coadministration of simvastatin and lonafarnib is contraindicated due to the risk of elevated plasma concentrations of simvastatin leading to myopathy, rhabdomyolysis, and acute renal failure. Simvastatin is a sensitive CYP3A4 substrate and a P-gp substrate; lonafarnib is a strong CYP3A4 and P-gp inhibitor.
Siponimod: (Moderate) Concomitant use of siponimod and lonafarnib may increase siponimod exposure. If the patient is also receiving a drug regimen containing a moderate CYP2C9 inhibitor, use of siponimod is not recommended due to a significant increase in siponimod exposure. Siponimod is a CYP2C9 and CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with a moderate CYP2C9/CYP3A4 dual inhibitor led to a 2-fold increase in the AUC of siponimod.
Sirolimus: (Major) Avoid concomitant use of sirolimus and lonafarnib. Coadministration may increase sirolimus concentrations and increase the risk for sirolimus-related adverse effects. Sirolimus is a CYP3A and P-gp substrate and lonafarnib is a strong CYP3A and P-gp inhibitor. Concomitant use of another strong CYP3A and P-gp inhibitor increased sirolimus overall exposure by 10.9-fold.
Solifenacin: (Major) Do not exceed a dose of 5 mg per day of solifenacin in patients receiving lonafarnib as concurrent use may increase solifenacin exposure. Solifenacin is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased solifenacin exposure by 2.7-fold.
Sonidegib: (Major) Avoid coadministration of sonidegib with lonafarnib due to increased plasma concentrations of sonidegib which may increase the risk of treatment-related adverse reactions. Sonidegib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased sonidegib exposure by 2.2-fold.
Sotorasib: (Contraindicated) Coadministration of lonafarnib and sotorasib is contraindicated; concurrent use may decrease lonafarnib exposure, which may reduce its efficacy. Lonafarnib is a sensitive CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
Sparsentan: (Major) Avoid concomitant use of sparsentan and lonafarnib. Concomitant use may increase sparsentan exposure and the risk for sparsentan-related adverse effects. Sparsentan is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased sparsentan overall exposure by 174%.
Spironolactone: (Major) Avoid coadministration of lonafarnib and spironolactone; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing spironolactone. Lonafarnib is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Major) Avoid coadministration of lonafarnib and spironolactone; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing spironolactone. Lonafarnib is a sensitive CYP3A4 substrate and spironolactone is a weak CYP3A4 inhibitor.
St. John's Wort, Hypericum perforatum: (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%.
Stiripentol: (Major) Avoid coadministration of lonafarnib and stiripentol; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing stiripentol. Lonafarnib is a sensitive CYP3A4 substrate and stiripentol is a weak CYP3A4 inhibitor.
Streptogramins: (Major) Avoid coadministration of lonafarnib and dalfopristin; quinupristin; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing dalfopristin; quinupristin. Lonafarnib is a sensitive CYP3A4 substrate and dalfopristin; quinupristin is a weak CYP3A4 inhibitor.
Sufentanil: (Moderate) Because the dose of the sufentanil sublingual tablets cannot be titrated, consider an alternate opiate if lonafarnib must be administered. Consider a reduced dose of sufentanil injection with frequent monitoring for respiratory depression and sedation if concurrent use of lonafarnib is necessary. If lonafarnib is discontinued, consider increasing the sufentanil injection dose until stable drug effects are achieved and monitor for evidence of opioid withdrawal. Sufentanil is a CYP3A4 substrate, and coadministration with a strong CYP3A4 inhibitor like lonafarnib can increase sufentanil exposure resulting in increased or prolonged opioid effects including fatal respiratory depression, particularly when an inhibitor is added to a stable dose of sufentanil. If lonafarnib is discontinued, sufentanil plasma concentrations will decrease resulting in reduced efficacy of the opioid and potential withdrawal syndrome in a patient who has developed physical dependence to sufentanil.
Sulfamethoxazole; Trimethoprim, SMX-TMP, Cotrimoxazole: (Major) Avoid coadministration of lonafarnib and sulfamethoxazole; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, closely monitor patients for lonafarnib-related adverse reactions. Lonafarnib is a CYP2C9 substrate and sulfamethoxazole is a CYP2C9 inhibitor.
Sunitinib: (Major) Avoid coadministration of lonafarnib with sunitinib if possible due to increased sunitinib exposure, which may increase the risk of QT prolongation. If concomitant use is unavoidable, monitor the QT interval more frequently and consider reducing the daily dose of sunitinib to a minimum of 37.5 mg for patients with GIST or RCC, and to a minimum of 25 mg for patients with pNET. Sunitinib is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased exposure of sunitinib and its primary active metabolite by 51%.
Suvorexant: (Major) Avoid coadministration of suvorexant and lonafarnib due to the potential for significantly increased suvorexant exposure. Suvorexant is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the suvorexant AUC by 2.8-fold.
Tacrolimus: (Major) Decrease tacrolimus dose and closely monitor tacrolimus serum concentrations if coadministration with lonafarnib is necessary; additional dosage reductions may be required. Concurrent use may increase tacrolimus serum concentrations and increase the risk of toxicity. Tacrolimus is a sensitive CYP3A4 substrate with a narrow therapeutic range; lonafarnib is a strong CYP3A4 inhibitor.
Tadalafil: (Major) Avoid coadministration of tadalafil and lonafarnib for the treatment of pulmonary hypertension. For the treatment of erectile dysfunction, do not exceed 10 mg tadalafil within 72 hours of lonafarnib for the 'as needed' dose or 2.5 mg daily for the 'once-daily' dose. Tadalafil is metabolized predominantly by CYP3A4. Potent inhibitors of CYP3A4, such as lonafarnib, may reduce tadalafil clearance. Increased systemic exposure to tadalafil may result in increased associated adverse events including hypotension, syncope, visual changes, and prolonged erection.
Talazoparib: (Moderate) Monitor for an increase in talazoparib-related adverse reactions if coadministration with lonafarnib is necessary. Talazoparib is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Tamsulosin: (Major) Avoid concurrent use of tamsulosin and lonafarnib due to the potential for elevated tamsulosin concentrations. Such increases in tamsulosin concentrations may produce clinically significant and potentially serious side effects, such as hypotension, dizziness, and vertigo. Tamsulosin is extensively metabolized by CYP3A4, and strong inhibitors of CYP3A4, such as lonafarnib, are expected to significantly raise tamsulosin concentrations. Concomitant treatment with another strong CYP3A4 inhibitor increased the Cmax and AUC of tamsulosin by a factor of 2.2 and 2.8, respectively.
Tazemetostat: (Major) Avoid coadministration of tazemetostat with lonafarnib as concurrent use may increase tazemetostat exposure and the frequency and severity of adverse reactions. Tazemetostat is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration of a moderate CYP3A4 inhibitor increased tazemetostat exposure by 3.1-fold.
Telmisartan; Amlodipine: (Major) Avoid coadministration of lonafarnib and amlodipine; concurrent use may increase the exposure of both drugs and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions and/or symptoms of hypotension and edema; adjust the dose of amlodipine as clinically appropriate. Resume previous lonafarnib dosage 14 days after discontinuing amlodipine. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; amlodipine is a CYP3A4 substrate and weak CYP3A4 inhibitor.
Temsirolimus: (Major) Avoid coadministration of temsirolimus and lonafarnib due to the risk of increased temsirolimus exposure resulting in an increased risk of adverse reactions. If concomitant use is unavoidable, consider reducing the dose of temsirolimus to 12.5 mg per week. If lonafarnib is discontinued, resume the original temsirolimus dose after a washout period of approximately 1 week. Temsirolimus is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor did not have a significant effect on temsirolimus exposure but increased the exposure of sirolimus (the primary and active metabolite) by 3.1-fold.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with lonafarnib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Tenofovir Alafenamide: (Moderate) Coadministration of tenofovir alafenamide with lonafarnib may result in increased plasma concentrations of tenofovir leading to an increase in tenofovir-related adverse effects. Tenofovir alafenamide is a P-gp substrate and lonafarnib is a P-gp inhibitor.
Tenofovir Disoproxil Fumarate: (Moderate) Coadministration of tenofovir disoproxil fumarate with lonafarnib may result in increased plasma concentrations of tenofovir, leading to an increase in tenofovir-related adverse effects. Tenofovir disoproxil fumarate is a P-glycoprotein (P-gp) substrate and lonafarnib is a P-gp inhibitor.
Tezacaftor; Ivacaftor: (Major) Avoid concomitant use of lonafarnib and ivacaftor due to the risk of increased exposure and adverse effects from both drugs. If coadministration is unavoidable, administer ivacaftor at the usual recommended dose but reduce the frequency to twice weekly and reduce to or continue lonafarnib at a dosage or 115 mg/m2. Coadministration is not recommended in patients younger than 6 months. Lonafarnib is a CYP2C9 and CYP3A substrate and strong CYP3A inhibitor; ivacaftor is a CYP3A substrate and CYP2C9 and weak CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ivacaftor exposure by 8.5-fold. (Major) Reduce the dosing frequency of tezacaftor; ivacaftor when coadministered with lonafarnib; coadministration may increase tezacaftor; ivacaftor exposure and adverse reactions. When combined, give one tezacaftor/ivacaftor combination tablet twice a week, approximately three to four days apart (i.e., day one and day four). The evening dose of ivacaftor should not be taken. Both tezacaftor and ivacaftor are CYP3A substrates (ivacaftor is a sensitive substrate); lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased tezacaftor and ivacaftor exposure 4- and 15.6-fold, respectively.
Thiotepa: (Major) Avoid the concomitant use of thiotepa and lonafarnib if possible; reduced metabolism to the active thiotepa metabolite may result in decreased thiotepa efficacy. Consider an alternative agent with no or minimal potential to inhibit CYP3A4. If coadministration is necessary, monitor patients for signs of reduced thiotepa efficacy. In vitro, thiotepa is metabolized via CYP3A4 to the active metabolite, TEPA; lonafarnib is a strong CYP3A4 inhibitor.
Ticagrelor: (Major) Avoid coadministration of ticagrelor with lonafarnib due to increased plasma concentrations of ticagrelor resulting in an increased risk of dyspnea, bleeding, and other treatment-related adverse reactions; lonafarnib exposure may also be increased. Ticagrelor is a sensitive CYP3A4 and P-gp substrate and weak CYP3A4 inhibitor; lonafarnib is a sensitive CYP3A4 substrate and P-gp and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased ticagrelor exposure by approximately 7-fold.
Tinidazole: (Moderate) Monitor for an increase in tinidazole-related adverse reactions if coadministration with lonafarnib is necessary. Concurrent use may increase the exposure of tinidazole. Tinidazole is a CYP3A4 substrate and lonafarnib is a strong CYP3A inhibitor.
Tipranavir: (Contraindicated) Coadministration of lonafarnib and tipranavir is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp inhibitor. Tipranavir is a sensitive CYP3A4 substrate, strong CYP3A4 inhibitor, and P-gp substrate. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Tisotumab Vedotin: (Moderate) Monitor for tisotumab vedotin-related adverse reactions if concomitant use with lonafarnib is necessary due to increased monomethyl auristatin E (MMAE) exposure which may increase the incidence and severity of adverse reactions. MMAE, the active component of tisotumab vedotin, is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Clinical drug interaction studies have not been conducted for tisotumab vedotin. However, coadministration of another antibody-drug conjugate that contains MMAE with a strong CYP3A inhibitor increased unconjugated MMAE exposure by 34%.
Tofacitinib: (Major) A dosage reduction of tofacitinib is necessary if coadministered with lonafarnib. In patients receiving tofacitinib 5 mg twice daily, reduce to 5 mg once daily; in patients receiving tofacitinib 10 mg twice daily, reduce to 5 mg twice daily; in patients receiving tofacitinib extended-release 11 mg once daily, switch to the immediate-release formulation at a dose of 5 mg once daily. Tofacitinib is a CYP3A4 and CYP2C19 substrate and lonafarnib is a strong CYP3A4 and moderate CYP2C19 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased tofacitinib exposure by 2-fold.
Tolterodine: (Major) Reduce the dose of immediate-release tolterodine to 1 mg twice daily and extended-release tolterodine to 2 mg once daily if coadministered with lonafarnib. Concurrent use may increase tolterodine exposure as lonafarnib is a strong CYP3A4 inhibitor. In CYP2D6 poor metabolizers, the CYP3A4 pathway becomes important in tolterodine elimination. Because it is difficult to assess which patients will be poor CYP2D6 metabolizers, reduced doses of tolterodine are advised when administered with strong CYP3A4 inhibitors. In a drug interaction study, coadministration of a strong CYP3A4 inhibitor increased the tolterodine AUC by 2.5-fold in CYP2D6 poor metabolizers.
Tolvaptan: (Contraindicated) The concomitant use of tolvaptan and lonafarnib is contraindicated. Concurrent use is expected to increase tolvaptan exposure. Tolvaptan is a sensitive CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of another strong CYP3A4 inhibitor increased tolvaptan exposure 5-fold. No data exists regarding the appropriate dose adjustment needed to allow safe administration of tolvaptan with strong CYP3A4 inhibitors.
Topotecan: (Major) Avoid coadministration of lonafarnib with oral topotecan due to increased topotecan exposure; lonafarnib may be administered with intravenous topotecan. Oral topotecan is a substrate of P-glycoprotein (P-gp) and lonafarnib is a P-gp inhibitor. Coadministration increases the risk of topotecan-related adverse reactions. Oral administration within 4 hours of another P-gp inhibitor increased the dose-normalized AUC of topotecan lactone and total topotecan 2-fold to 3-fold compared to oral topotecan alone.
Toremifene: (Major) Avoid coadministration of lonafarnib with toremifene if possible due to increased plasma concentrations of toremifene which may result in QT prolongation; increased lonafarnib exposure may also occur. If concomitant use is unavoidable, closely monitor ECGs, electrolytes, and for lonafarnib-related adverse reactions; correct hypokalemia or hypomagnesemia prior to administration of toremifene. Toremifene is a CYP3A4 substrate that has been shown to prolong the QTc interval in a dose- and concentration-related manner and a CYP2C9 inhibitor; lonafarnib is a CYP2C9 substrate and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased toremifene exposure by 2.9-fold; exposure to N-demethyltoremifene was reduced by 20%.
Trabectedin: (Major) Avoid the concomitant use of trabectedin with lonafarnib due to the risk of increased trabectedin exposure. Trabectedin is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the systemic exposure of a single dose of trabectedin (0.58 mg/m2 IV) by 66% compared to a single dose of trabectedin (1.3 mg/m2) given alone.
Tramadol: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lonafarnib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lonafarnib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Tramadol; Acetaminophen: (Moderate) Consider a tramadol dosage reduction until stable drug effects are achieved if coadministration with lonafarnib is necessary. Closely monitor for seizures, serotonin syndrome, and signs of sedation and respiratory depression. Respiratory depression from increased tramadol exposure may be fatal. Concurrent use of lonafarnib, a strong CYP3A4 inhibitor, may increase tramadol exposure and result in greater CYP2D6 metabolism thereby increasing exposure to the active metabolite M1, which is a more potent mu-opioid agonist.
Trandolapril; Verapamil: (Contraindicated) Coadministration of lonafarnib and verapamil is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; verapamil is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Trazodone: (Major) Avoid coadministration of trazodone with lonafarnib due to the potential for increased trazodone exposure and associated adverse effects including QT prolongation. If concurrent use cannot be avoided, consider a reduced dose of trazodone based on tolerability. Trazodone is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration of other strong CYP3A4 inhibitors increased the exposure of trazodone compared to the use of trazodone alone.
Triamcinolone: (Moderate) Monitor for an increase in triamcinolone-related adverse effects, such as fluid retention, electrolyte disturbances, and adrenal suppression, if concomitant use of lonafarnib is necessary. Concomitant use may increase triamcinolone exposure. Triamcinolone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Other strong CYP3A4 inhibitors have decreased corticosteroid metabolism by up to 60%.
Triazolam: (Contraindicated) Concomitant use of lonafarnib with triazolam is contraindicated due to the risk of serious adverse events, such as prolonged hypnotic and/or sedative effects. Triazolam is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Consider safer alternatives if a benzodiazepine must be administered in combination with lonafarnib. Benzodiazepines not metabolized by the CYP3A4 enzyme (e.g., lorazepam, oxazepam) are less likely to be affected by strong CYP3A4 inhibitors.
Trofinetide: (Major) Avoid coadministration of lonafarnib and trofinetide; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing trofinetide. Lonafarnib is a sensitive CYP3A substrate and trofinetide is a weak CYP3A inhibitor.
Tucatinib: (Contraindicated) Coadministration of lonafarnib and tucatinib is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and tucatinib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Ubrogepant: (Contraindicated) Coadministration of ubrogepant and lonafarnib is contraindicated as concurrent use may increase ubrogepant exposure and the risk of adverse effects. Ubrogepant is a CYP3A4 and P-gp substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor resulted in a 9.7-fold increase in the exposure of ubrogepant.
Ulipristal: (Minor) Concomitant use of ulipristal and lonafarnib may increase the plasma concentration of ulipristal resulting in an increased risk for ulipristal-related adverse events; however, this is not likely to be significant for single-dose emergency contraceptive use. Ulipristal is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Coadministration with another strong CYP3A inhibitor increased ulipristal overall exposure by 5.9-fold and increased the overall exposure if ulipristal's active metabolite, monodemethyl-ulipristal acetate, by 2.4-fold.
Umeclidinium; Vilanterol: (Moderate) Monitor for an increase in vilanterol-related adverse effects if coadministered with lonafarnib. Coadministration may increase vilanterol exposure. Vilanterol is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor significantly increased systemic exposure to vilanterol.
Upadacitinib: (Major) During concomitant use of upadacitinib and lonafarnib reduce the upadacitinib dosage to 15 mg once daily. During induction for ulcerative colitis and Crohn's disease reduce the upadacitinib dosage to 30 mg once daily. Concomitant use may increase upadacitinib exposure and risk for adverse effects. Concomitant use with another strong CYP3A inhibitor increased upadacitinib overall exposure 1.75-fold.
Valbenazine: (Major) Reduce the dose of valbenazine to 40 mg once daily if coadministration with lonafarnib is necessary. Prolongation of the QT interval is not clinically significant at valbenazine concentrations expected with recommended dosing; however, valbenazine concentrations may be higher in patients taking a strong CYP3A4 inhibitor and QT prolongation may become clinically significant. Valbenazine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased both valbenazine and NBI-98782 exposure by approximately 2-fold.
Valproic Acid, Divalproex Sodium: (Major) Avoid coadministration of lonafarnib and valproic acid; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing valproic acid. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate; valproic acid is a weak CYP3A4 inhibitor and moderate CYP2C9 inhibitor.
Vamorolone: (Major) Decrease the vamorolone dose to 4 mg/kg once daily (max: 200 mg) and monitor for adverse effects if concomitant use with lonafarnib is necessary. Concomitant use may increase vamorolone exposure and the risk for vamorolone-related adverse effects. Vamorolone is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased vamorolone overall exposure by 44%.
Vardenafil: (Major) Do not use vardenafil orally disintegrating tablets with lonafarnib due to increased vardenafil exposure; do not exceed a single dose of 2.5 mg per 24-hour period of vardenafil oral tablets. Vardenafil is primarily metabolized by CYP3A4/5; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of vardenafil by 10- to 16-fold.
Vemurafenib: (Major) Avoid the concomitant use of vemurafenib and lonafarnib; vemurafenib exposure may be increased resulting in an increased risk of adverse events, including QT prolongation. If use with lonafarnib cannot be avoided, consider a vemurafenib dose reduction; monitor patients closely for the development of adverse events and dose reduce or discontinue therapy based on manufacturer guidance. Vemurafenib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of vemurafenib by 40%.
Venetoclax: (Major) Coadministration of lonafarnib with venetoclax is contraindicated during the initiation and ramp-up phase in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL); consider an alternative medication or adjust the venetoclax dose with close monitoring for toxicity (e.g., hematologic toxicity, GI toxicity, and tumor lysis syndrome) in patients receiving a steady daily dose of venetoclax if concurrent use is necessary. In patients with acute myeloid leukemia (AML), reduce the venetoclax dose and monitor for toxicity during concurrent use. Resume the original venetoclax dose two to three days after discontinuation of lonafarnib. Specific venetoclax dosage adjustments are as follows: CLL/SLL patients at steady daily dose: 100 mg/day. AML patients: 10 mg on day one, 20 mg on day two, 50 mg on day three, then 100 mg/day starting on day four. Venetoclax is a P-gp and CYP3A4 substrate; lonafarnib is a P-gp and strong CYP3A4 inhibitor. Coadministration of strong CYP3A4 inhibitors increased the venetoclax AUC by 90% to 690% in drug interaction studies while coadministration with a single dose of another P-gp inhibitor increased venetoclax exposure by 78%.
Verapamil: (Contraindicated) Coadministration of lonafarnib and verapamil is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and strong CYP3A4 inhibitor; verapamil is a CYP3A4 substrate and moderate CYP3A4 inhibitor.
Vilazodone: (Major) Do not exceed a vilazodone dose of 20 mg once daily if coadministration with lonafarnib is necessary; the original dose of vilazodone can be resumed if lonafarnib is discontinued. Vilazodone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vilazodone exposure by 50%.
Viloxazine: (Major) Avoid coadministration of lonafarnib and viloxazine; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing viloxazine. Lonafarnib is a sensitive CYP3A4 substrate and viloxazine is a weak CYP3A4 inhibitor.
Vinblastine: (Moderate) Monitor for an earlier onset and/or increased severity of vinblastine-related adverse reactions, including myelosuppression, constipation, and peripheral neuropathy, if coadministration with lonafarnib is necessary. Vinblastine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Vincristine Liposomal: (Major) Avoid coadministration of vincristine with lonafarnib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Vincristine: (Major) Avoid coadministration of vincristine with lonafarnib due to increased plasma concentrations of vincristine, resulting in an earlier onset and/or increased severity of neuromuscular side effects. Vincristine is a CYP3A4 and P-gp substrate and lonafarnib is a P-gp and strong CYP3A4 inhibitor.
Vinorelbine: (Moderate) Monitor for an earlier onset and/or increased severity of vinorelbine-related adverse reactions, including constipation and peripheral neuropathy, if coadministration with lonafarnib is necessary. Vinorelbine is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Voclosporin: (Contraindicated) Concomitant use of voclosporin and lonafarnib is contraindicated; concomitant use may increase the exposure of voclosporin and the risk of voclosporin-related adverse effects such as nephrotoxicity, hypertension, and QT prolongation. Voclosporin is a sensitive CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased voclosporin exposure by approximately 19-fold.
Vonoprazan: (Major) Avoid coadministration of lonafarnib and vonoprazan; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing vonoprazan. Lonafarnib is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin: (Major) Avoid coadministration of lonafarnib and vonoprazan; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing vonoprazan. Lonafarnib is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Contraindicated) Coadministration of lonafarnib and clarithromycin is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate and clarithromycin is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%. (Major) Avoid coadministration of lonafarnib and vonoprazan; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing vonoprazan. Lonafarnib is a sensitive CYP3A substrate and vonoprazan is a weak CYP3A inhibitor.
Vorapaxar: (Major) Avoid coadministration of vorapaxar with lonafarnib due to increased plasma concentrations of vorapaxar and the risk of treatment-related adverse reactions. Vorapaxar is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased vorapaxar exposure by 2-fold; the bleeding risk for a change in exposure of this magnitude is not known.
Voriconazole: (Contraindicated) Coadministration of lonafarnib and voriconazole is contraindicated; concurrent use may increase the exposure of both drugs and the risk of adverse effects. Lonafarnib is a sensitive CYP3A4 substrate, CYP2C9 substrate, and strong CYP3A4 inhibitor; voriconazole is a CYP3A4 substrate, moderate CYP2C9 inhibitor, and strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the exposure of lonafarnib by 425%.
Voxelotor: (Contraindicated) Coadministration of lonafarnib and voxelotor is contraindicated; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Lonafarnib is a sensitive CYP3A substrate and voxelotor is a moderate CYP3A inhibitor.
Warfarin: (Major) Avoid coadministration of lonafarnib and warfarin; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. Concurrent use may also increase warfarin exposure leading to increased bleeding risk. If coadministration is unavoidable, closely monitor INR and for adverse reactions of both drugs. Lonafarnib is a CYP2C9 substrate and strong CYP3A4 inhibitor; warfarin is a CYP3A4 substrate and CYP2C9 inhibitor.
Zafirlukast: (Major) Avoid coadministration of lonafarnib and zafirlukast; concurrent use may increase the exposure of lonafarnib and the risk of adverse effects. If coadministration is unavoidable, reduce to or continue lonafarnib at a dosage of 115 mg/m2 and closely monitor patients for lonafarnib-related adverse reactions. Resume previous lonafarnib dosage 14 days after discontinuing zafirlukast. Lonafarnib is a sensitive CYP3A4 and CYP2C9 substrate and zafirlukast is a weak CYP3A4 and CYP2C9 inhibitor.
Zaleplon: (Moderate) Monitor for an increase in zaleplon-related adverse reactions, including excessive sedation and confusion, if coadministered with lonafarnib. Routine dosage adjustments of zaleplon are not required. Zaleplon is partially metabolized by CYP3A4 and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with a single dose of another strong CYP3A4 inhibitor increased the AUC of zaleplon by 20%.
Zanubrutinib: (Major) Decrease the zanubrutinib dose to 80 mg PO once daily if coadministered with lonafarnib. Coadministration may result in increased zanubrutinib exposure and toxicity (e.g., infection, bleeding, and atrial arrhythmias). Interrupt zanubrutinib therapy as recommended for adverse reactions. After discontinuation of lonafarnib, resume the previous dose of zanubrutinib. Zanubrutinib is a CYP3A4 substrate; lonafarnib is a strong CYP3A4 inhibitor. The AUC of zanubrutinib was increased by 278% when coadministered with another strong CYP3A4 inhibitor.
Ziprasidone: (Moderate) Monitor for an increase in ziprasidone-related adverse effects, including QT prolongation, CNS effects, and extrapyramidal symptoms, if coadministered with lonafarnib. Coadministration use may increase ziprasidone exposure. Ziprasidone is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with another strong CYP3A4 inhibitor increased the AUC of ziprasidone by approximately 35% to 40%.
Zolpidem: (Moderate) Consider decreasing the dose of zolpidem if coadministration with lonafarnib is necessary. Concurrent use may increase zolpidem exposure. Zolpidem is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor. Coadministration with other strong CYP3A4 inhibitors increased the AUC of zolpidem by 34% to 70%.
Zuranolone: (Major) Decrease the zuranolone dose to 30 mg once daily and monitor for zuranolone-related adverse effects if concomitant use with lonafarnib is necessary. Concomitant use may increase zuranolone exposure and the risk for zuranolone-related adverse effects. Zuranolone is a CYP3A substrate and lonafarnib is a strong CYP3A inhibitor. Concomitant use with another strong CYP3A inhibitor increased zuranolone overall exposure by 1.62-fold.
Lonafarnib inhibits farnesyltransferase by reversibly binding to the farnesyltransferase CAAX binding site, inhibiting farnesylation and subsequent accumulation of progerin and progerin-like proteins in the inner nuclear membrane.
Lonafarnib is administered orally. Protein binding is greater than or equal to 99% for lonafarnib. At steady state, the volume of distribution ranges between 87.8 and 97.4 L, respectively, after 100 mg and 75 mg PO twice daily. Lonafarnib is primarily (62%) excreted by the kidneys; less than 1% of a dose is excreted in the feces. The active metabolites HM17 and HM21 are the 2 most prominent metabolites. The mean half-life is approximately 4 to 6 hours in healthy patients.
Affected cytochrome P450 isoenzymes: CYP3A, CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, P-gp, OATP1B1, OATP1B3, and BCRP.
Lonafarnib is primarily metabolized by CYP3A and to a lesser extent by CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1 in vitro. Lonafarnib is a CYP3A substrate and strong CYP3A inhibitor. Lonafarnib is an inhibitor of CYP2C8 and CYP2C19. Lonafarnib is likely a marginal substrate of P-gp. Lonafarnib is an inhibitor of P-gp, OATP1B1, OATP1B3, and BCRP.
-Route-Specific Pharmacokinetics
Oral Route
The absolute bioavailability of lonafarnib after oral administration is not known. The maximum peak plasma concentration of lonafarnib were 834 (32%) ng/mL and 964 (32%) ng/mL, respectively after administration of lonafarnib 75 mg and 100 mg twice daily in healthy patients under fasted conditions. After twice daily administration, Cmax occurs about 2 hours for doses of 115 mg/m2 and 4 hours for doses of 150 mg/m2. The Cmax is approximately 1,777 +/- 1,083 ng/mL for a dose of 115 mg/m2 and 2,695 +/- 1,090 ng/mL for a dose of 150 mg/m2. The AUC is 9,869 +/- 6,327 ng x hour/mL for a dose of 115 mg/m2 and 16,020 +/- 4,978 ng x hour/mL for a dose of 150 mg/m2. When a single oral dose of lonafarnib 75 mg was given with a high-fat meal, the Cmax decreased 55% and AUC decreased 29% when compared to fasted conditions. When a single oral dose of lonafarnib 75 mg was given with a low-fat meal, the Cmax decreased 25% and AUC decreased 21% when compared to fasted conditions.
-Special Populations
Hepatic Impairment
The pharmacokinetics of lonafarnib have not been studied in patients with hepatic impairment.
Renal Impairment
The pharmacokinetics of lonafarnib have not been studied in patients with renal impairment.
Geriatric
After a single dose of lonafarnib 100 mg PO in healthy patients, the lonafarnib AUC and Cmax were 59% and 27% higher in patients 65 years and older, respectively, compared to patients 18 to 45 years of age. The exposure difference was not considered clinically meaningful.
Gender Differences
After a single dose of lonafarnib 100 mg PO in healthy patients, the lonafarnib AUC and Cmax were 44% and 26% higher in female patients, respectively, compared to male patients. The exposure difference was not considered clinically meaningful.