Diazepam is an oral, nasal, parenteral, or rectal long-acting benzodiazepine indicated for anxiety, acute alcohol withdrawal, skeletal muscle spasm, and seizure disorders, including status epilepticus. Diazepam may be used adjunctively for skeletal muscle spasms and seizure disorders; it has not been proven useful as sole therapy in epilepsy. As an adjunct or premedication before procedures like surgery or endoscopy, diazepam may relieve apprehension or acute stress and diminish patient recall of the procedure. Like with other benzodiazepines, concomitant use of diazepam with opioids may result in profound sedation, respiratory depression, coma, and death.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
Oral Liquid Formulations
Concentrated oral solution (25 mg/5 mL)
-Use only the calibrated dropper provided with the product.
-Draw into the dropper the amount prescribed for a single dose.
-Squeeze the dropper contents into a liquid or semi-solid food such as water, juices, soda or soda-like beverages, applesauce, or puddings. Stir the liquid or food gently for a few seconds.
-Administer the entire amount of the mixture of drug and liquid or drug and food immediately. Do not store for future use.
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Once the acute symptomatology has been properly controlled with diazepam injection, transition the patient to oral diazepam therapy if further treatment is required.
Intravenous Administration
-Ensure facilities for respiratory assistance are readily available.
-Do not use small veins, such as those of the dorsum of the hand or wrist.
-Inject slowly, taking at least 1 minute for each 5 mg.
-If it is not feasible to administer diazepam directly intravenous, may inject slowly through the infusion tubing as close as possible to the vein insertion.
-Take extreme care to avoid extravasation or intraarterial administration.
-Do not dilute or mix diazepam with other solutions or drugs in syringe or infusion flask.
Intramuscular Administration
-Inject deeply into a large muscle mass.
Inhalation Administration
Intranasal Inhalation Administration
-No device assembly is required.
-Do not prime or attempt to use for more than 1 administration per device.
-Place the person on their side or back where they cannot fall.
-Remove the device from the blister pack.
-Hold the device with thumb on the bottom of the plunger and first and middle fingers on either side of the nozzle.
-Gently insert the nozzle tip into the nostril until the fingers on either side of the nozzle are against the bottom of the person's nose.
-Press the bottom of the plunger firmly with thumb to deliver the dose
-Remove the device from the nose and discard.
Rectal Administration
-Before dispensing to the patient, a pharmacist must dial in the dose and lock the rectal syringe. To do so, hold barrel of the syringe with the cap pointed downward. Grasp cap with the other hand and turn to adjust dose. Confirm prescribed dose appears in the window. Grasp and push the locking ring upward to lock both sides of the ring. Repeat steps for second syringe.
-Place the person on their side where they cannot fall.
-Get the medicine syringe. Confirm dose is visible and correct, if known. Ensure green "READY" band is visible.
-To remove protective cover from syringe, push up with thumb and pull. Ensure that both the cap and seal pin are removed.
-Lubricate rectal tip with lubricating jelly.
-Turn person on side facing you and bend upper leg forward to expose rectum. Separate buttocks to expose rectum.
-Gently insert syringe tip into rectum; rim should be snug against rectal opening. Slowly count to 3 while gently pushing the plunger in until it stops. Slowly count to 3 before removing the syringe from the rectum.
-Slowly count to 3 while holding the buttocks together to prevent leakage.
-Keep person on the side facing you. Note time given and continue to observe.
-After use, pull on the syringe plunger until it is completely removed from the syringe body. Point syringe tip over sink or toilet. Replace plunger into syringe body, gently pushing plunger until it stops. Flush toilet or rinse sink with water until gel is no longer visible.
Anterograde amnesia or memory impairment can occur following administration of therapeutic doses of benzodiazepines, such as diazepam. The risk for developing anterograde amnesia increases at higher doses and with concurrent ingestion of alcohol.
Most of the adverse effects associated with diazepam therapy are dose-dependent and CNS-related; drowsiness is most commonly reported. Other CNS side effects include headache, dizziness, ataxia, confusion, fatigue, tremor, and vertigo. During one placebo-controlled study comparing the effectiveness of oral diazepam to alprazolam in the treatment of panic disorder, drowsiness (84%) and fatigue (56.8%) were most common with diazepam use; similar incidences of side effects may occur with use of diazepam for other indications, such as anxiety. CNS adverse events occurring in controlled clinical trials of diazepam rectal gel at a greater frequency than placebo included drowsiness (23%), headache (2% to 5%), dizziness (2% to 5%), ataxia (2% to 5%), and incoordination (2% to 5%). CNS adverse events occurring in at least 1% of patients in clinical trials of diazepam rectal gel include nervousness, confusion, emotional lability, dysarthria (slurred speech) or speech disorder, thinking abnormal, and vertigo. Syncope is rarely reported with benzodiazepine use in general. Benzodiazepines may worsen existing depression. Because diazepam can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the geriatric adult, with the potential for subsequent severe injuries. There have been reports of falls and bone fractures in benzodiazepine users postmarketing; these risks are increased during concurrent use of sedatives and in the elderly. Grand mal convulsions were reported in less than 1% of patients receiving diazepam rectal gel during premarketing clinical trials; seizures (type unspecified) were reported in 1% or more of patients.
Muscle weakness (myasthenia) is among the most commonly reported side effects of oral and injectable diazepam, although the precise incidence of this side effect associated with dosage forms other than the rectal gel (1% or more) is unknown. Body weakness (asthenia) (at least 1%) has also been reported with diazepam use.
Paradoxical reactions including CNS stimulation have been reported with benzodiazepine use. Symptoms of these reactions may include unusual or inappropriate changes in behavior, nightmares, talkativeness, excitement, mania, tremor, insomnia or other sleep disturbances, anxiety, agitation, aggressiveness, irritability, hallucinations, delusions, restlessness, euphoria, acute rage reactions, increased muscle spasticity, and hyperactivity. Hyperkinesis has been reported. Euphoria occurred in 3% of patients in controlled clinical trials of diazepam rectal gel. Agitation (at least 1%) and hyperkinesia (less than 1%) were also reported in patients receiving diazepam rectal gel in clinical trials. Discontinue benzodiazepine therapy if signs of CNS stimulation occur.
Gastrointestinal (GI) and related system effects that have occurred during treatment with diazepam include constipation, nausea, xerostomia, hypersalivation, and other unspecified gastrointestinal-related disturbances. Diarrhea occurred in 4% of patients receiving diazepam rectal gel in controlled clinical trials. Other GI adverse events occurring in patients receiving diazepam rectal gel included abdominal pain (1% or more), anorexia (less than 1%), and vomiting (less than 1%). Dysgeusia (3%) was observed during clinical trials of diazepam nasal spray in patients with epilepsy.Elevated hepatic enzymes (e.g., transaminases, alkaline phosphatase) have been reported during diazepam use and there are rare reports of jaundice with benzodiazepine therapy. Monitor periodic liver function tests during chronic treatment.
Monitor periodic blood counts during chronic treatment with diazepam due to rare reports of neutropenia. Anemia was reported in less than 1% of patients receiving diazepam rectal gel in clinical trials.
Ocular side effects of diazepam use have included blurred vision and diplopia. Nystagmus and mydriasis have also been reported with use of some dosage forms. Diazepam has been reported to cause increased intraocular pressure (ocular hypertension) in some patients with glaucoma and some epidemiologic studies suggest an association of diazepam with a risk for acute angle closure glaucoma.
Urinary incontinence, changes in libido, and urinary retention have been reported with the use of diazepam for chronic conditions. Adverse GU/sexual effects including urinary incontinence, urinary retention, menstrual irregularity, and libido decrease have been reported as potential side effects of benzodiazepines.
In controlled clinical trials of diazepam rectal gel, rash occurred in 2% to 5% of patients and pruritus was reported in less than 1%. Urticaria, and skin reactions (unspecified) have been reported during treatment with diazepam. In rare instances serious allergic, anaphylactic and anaphylactoid reactions or angioedema may occur with benzodiazepines. Treatment should not be reinitiated in patients who experience angioedema or other serious allergic reaction. Dermatologic reactions to benzodiazepines may rarely include an increase in sweating. Increased sweating (hyperhidrosis) was reported in less than 1% of patients receiving diazepam rectal gel in clinical trials.
Injection site reaction, which may be severe, has been associated with diazepam injection. Phlebitis and venous thrombosis at the site of injection have been reported after administration of parenteral diazepam. Administer intravenous diazepam injection slowly (at least one minute for each 5 mg/1 mL) in order to reduce the possibility of these effects. Avoid injection into small veins, such as those in the dorsum of the hand or wrist, as well as intraarterial administration.
Asthma (wheezing) occurred in 2% of patients receiving diazepam rectal gel in controlled clinical trials compared to no patients receiving placebo. Rhinitis and hiccups were reported in 1% or more of patients, and infection, lymphadenopathy, increased cough, and urinary tract infection were reported in less than 1% of patients receiving diazepam rectal gel in clinical trials. Hiccups have been reported with diazepam injection as well. Nasal irritation or discomfort (6%) and epistaxis (2%) were observed during clinical trials of diazepam nasal spray in patients with epilepsy.
Hypotension has been reported after parenteral administration of benzodiazepines to the elderly, severely ill patients, or patients with compromised respiratory function. Hypotension has also been reported with other diazepam formulations and occurred in 1% or more of patients who received diazepam rectal gel in clinical trials. Cardiovascular collapse (cardiac arrest) and bradycardia have rarely been reported with parenteral diazepam use. In peroral endoscopic procedures, coughing, depressed respiration, shortness of breath, hyperventilation, laryngospasm, throat pain, and chest pain (unspecified) have been reported with diazepam injection; however, some of these effects may be related to the procedure performed instead of the drug. Peripheral vasodilation occurred in 1% to 5% of patients receiving diazepam rectal gel in controlled clinical trials compared to none of the patients receiving placebo.
Respiratory events associated with use of diazepam and other benzodiazepines have included apnea, dyspnea, hypoventilation, and rare reports of hyperventilation (during parenteral use for peroral endoscopic procedures). Respiratory depression can occur with benzodiazepine therapy, particularly with misuse, coadministration with other CNS depressants, or overdosage. Concomitant use of benzodiazepines and opioids or alcohol may result in profound sedation, respiratory depression, coma, and death.
Benzodiazepines cross the placenta and may produce sedation, hypotonia, lethargy, and neonatal respiratory depression at birth. Monitor neonates exposed during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Neonatal withdrawal or a neonatal abstinence syndrome has also been reported following the ingestion of therapeutic doses of benzodiazepines during the last weeks of pregnancy. Clinical manifestations of neonatal withdrawal may include hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties. These complications can appear shortly after delivery to 3 weeks after birth and persist from hours to several months, depending on the degree of dependence and pharmacokinetic profile of the benzodiazepine. Observe neonates who are exposed to benzodiazepines in utero during the later stages of pregnancy for symptoms of withdrawal and manage appropriately. Benzodiazepines should be withdrawn cautiously and slowly, using a very gradual dosage-tapering schedule.
Tolerance to benzodiazepines may develop from continued therapy. Tolerance is a physiological state characterized by a reduced response to a drug after repeated administration (i.e., a higher dose of a drug is required to produce the same effect that was once obtained at a lower dose). Tolerance to the therapeutic effect of diazepam may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.
Prolonged use of benzodiazepines can produce physiological dependence with or without psychological dependence. The risk of psychological dependence increases in those with a history of alcohol or substance abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Caution is advised when considering the use of benzodiazepines in patients with a known or suspected history of substance abuse. To discourage abuse, prescribe the smallest appropriate quantity of the benzodiazepine and provide proper disposal instructions for unused drug. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Clinically significant physiological dependence may occur with continued use of benzodiazepines. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. Withdrawal symptoms may range from mild dysphoria and insomnia to a major withdrawal syndrome including abdominal and muscle cramps, vomiting, sweating, tremors, and seizures. In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Use a gradual dosage taper to lower the risk of withdrawal reactions when reducing the diazepam dose or discontinuing therapy.
Diazepam is contraindicated in any patient with a known hypersensitivity to diazepam.
Use extreme care to avoid intraarterial administration or extravasation when administering diazepam intravenously. To reduce the possibility of venous thrombosis, phlebitis, local irritation, and rarely, vascular impairment, inject slowly and do not use small veins, such as those on the dorsum of the hand or wrist.
Monitor all patients beginning treatment with antiepileptic drugs (AEDs) or currently receiving diazepam closely for emerging or worsening depression or suicidal ideation. Advise patients and caregivers of the increased risk of suicidal thoughts and behaviors and to immediately report the emergence of new or worsening of depression, suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any patient may be related to the illness being treated. There is an increased risk of suicidal ideation and behavior in patients receiving AEDs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). The primary analysis consisted of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older). There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor. The increased risk of suicidal ideation and behavior was observed between 1 and 24 weeks after therapy initiation. However, a longer duration of therapy should not preclude the possibility of an association to the drug since most studies included in the analysis did not continue beyond 24 weeks. Diazepam is not recommended in the treatment of psychosis; do not use diazepam instead of appropriate treatment.
Benzodiazepines, including diazepam, may produce CNS depression. Advise patients against engaging in hazardous activities requiring mental alertness (e.g., driving or operating machinery or riding a bicycle) until the effects of the drug, such as drowsiness, have subsided, and their medical condition permits. Advise patients against simultaneous ethanol ingestion or ethanol intoxication as well as ingestion of other CNS depressant drugs during diazepam therapy. Do not administer diazepam injection to patients in coma or shock.
Oral diazepam tablets are contraindicated for use in patients with severe respiratory insufficiency or sleep apnea syndrome. Use extreme care when administering diazepam in patients with limited pulmonary reserve or compromised respiratory function related to concurrent pulmonary disease process (e.g., asthma, pneumonia) or neurologic damage due to the possibility of apnea or cardiac arrest. Additionally, avoid coadministration with other CNS depressants, especially opioids, unless no other alternatives are available as coadministration significantly increases the risk for profound sedation, respiratory depression, coma, and death.
Diazepam is contraindicated in patients with closed-angle glaucoma. Diazepam may be used in patients with open-angle glaucoma who are receiving appropriate therapy.
Oral diazepam tablets are contraindicated in patients with severe hepatic disease. In general, use diazepam with caution in patients with liver disease. Concomitant liver disease is known to decrease the clearance of diazepam. Because of isolated reports of jaundice, periodic liver function tests are advisable during long-term diazepam therapy.
Diazepam metabolites are excreted by the kidneys; to avoid their excess accumulation, use caution when administering diazepam to patients with renal disease, including renal impairment or renal failure.
Oral diazepam tablets are contraindicated in patients with myasthenia gravis. Other dosage forms of diazepam should be used with caution in patients with a neuromuscular disease, such as myasthenia gravis; these patients may be more sensitive to the CNS and respiratory effects of the benzodiazepines.
Because of isolated reports of neutropenia, periodic blood counts are advisable during long-term diazepam therapy.
Due to the potential for prolonged CNS depression, oral diazepam is contraindicated in neonates and infants younger than 6 months, and parenteral diazepam is not recommended for use in neonates younger than 1 month. The response of children to benzodiazepine therapy can be unpredictable. In general, the pediatric population is more sensitive to the effects of benzodiazepines. Initially, use the lowest dose of diazepam in children, with increases made according to response. When using parenteral diazepam, ensure age and size appropriate resuscitative equipment and trained personnel are readily available. The safety and efficacy of diazepam rectal gel have not been established in children younger than 2 years. The safety and efficacy of diazepam nasal spray have not been established in children younger than 6 years. Serious and fatal adverse reactions, including gasping syndrome, can occur in neonates and low birth weight infants treated with benzyl alcohol-preserved drugs, including diazepam nasal spray. The gasping syndrome is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known.
Use diazepam with caution in patients with a history of alcoholism or substance abuse due to the potential for psychological dependence. The use of benzodiazepines exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Assess patients for risks of addiction, abuse, or misuse before drug initiation, and monitor patients who receive benzodiazepines routinely for development of these behaviors or conditions. A potential risk of abuse should not preclude appropriate treatment in any patient, but requires more intensive counseling and monitoring. To discourage abuse, the smallest appropriate quantity of the benzodiazepine should be prescribed, and proper disposal instructions for unused drug should be given to patients. Avoid or minimize concomitant use of CNS depressants or other medications associated with addiction or abuse. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, and death. Advise patients to seek immediate medical attention if they experience symptoms such as trouble breathing. Abrupt discontinuation or rapid dosage reduction of benzodiazepines after continued use may precipitate acute withdrawal reactions, which can be life-threatening. The risks of physiological dependence and withdrawal increase with longer treatment duration and higher daily dose. Benzodiazepine dependence can occur after administration of therapeutic doses for as few as 1 to 2 weeks and withdrawal symptoms may be seen after the discontinuation of therapy. To reduce the risk of acute withdrawal reactions, use a gradual taper to reduce the dosage or to discontinue benzodiazepines. No standard benzodiazepine tapering schedule is suitable for all patients; therefore, create a patient-specific plan to gradually reduce the dosage. If a patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently, decrease the dosage more slowly. Patients with a seizure history or who are taking drugs that lower the seizure threshold (e.g., certain antidepressants, phenothiazines) should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating a seizure. During benzodiazepine withdrawal, the greatest risk of seizure appears to be during the first 24 to 72 hours. Diazepam is not recommended for chronic, daily use as an anticonvulsant. Chronic daily use of diazepam may increase the frequency and/or severity of tonic-clonic seizures, requiring an increase in the dosage of standard anticonvulsant medication. In such cases, abrupt withdrawal of chronic diazepam may also be associated with a temporary increase in the frequency and/or severity of seizures in patients with a seizure disorder. Tonic status epilepticus has been precipitated in patients treated with intravenous diazepam for petit mal status or petit mal variant status. Clinicians should be aware that the use of flumazenil may increase the risk of seizures.
There are no adequate data on the effects of diazepam use during human pregnancy. Consider diazepam use during pregnancy only when the clinical situation warrants the risk to the fetus. Measurable amounts of diazepam have been found in cord blood, indicating placental transfer of the drug. Recent case-control and cohort studies of benzodiazepine use during pregnancy have not confirmed increased risks of congenital malformations previously reported with early studies of benzodiazepines, including diazepam and chlordiazepoxide. In animal studies, administration of diazepam during the organogenesis period of pregnancy resulted in increased incidences of fetal malformations at doses greater than those used clinically. Data for diazepam and other benzodiazepines suggest the possibility of increased neuronal cell death and long-term effects on neurobehavioral and immunological function based on findings in animals following prenatal or early postnatal exposure at clinically relevant doses. Benzodiazepines are not recommended for use in labor or obstetric delivery, including cesarean section due to risks of residual pharmacological effects in the neonate. Monitor neonates exposed to benzodiazepines during pregnancy, labor, or obstetric delivery for signs of sedation, respiratory depression, or lethargy, and manage accordingly. Use of benzodiazepines late in pregnancy may result in a neonatal abstinence syndrome (NAS) or floppy infant syndrome (FIS). Monitor the neonate for hypotonia and withdrawal symptoms, including hyperreflexia, irritability, restlessness, tremors, inconsolable crying, or feeding difficulties and manage accordingly. The incidence, time to onset, and duration of NAS or FIS symptoms is multi-factorial (e.g., duration of use, drug lipophilicity, placental disposition, degree of accumulation in neonatal tissues). FIS typically occurs after chronic fetal exposure to long-acting benzodiazepines (e.g., chlordiazepoxide), or when benzodiazepines are administered shortly before delivery, resulting in newborn toxicity of variable severity and duration. FIS primarily occurs within the first few hours after labor and may last for up to 14 days. If a benzodiazepine is required during pregnancy, avoid first trimester administration if possible, consider short-acting agents, limit treatment to the shortest possible duration and lowest effective dose, and discontinue the drug well before delivery. There are pregnancy exposure registries that monitor outcomes in pregnant patients exposed to diazepam. Information about the North American Antiepileptic Drug (NAAED) Pregnancy Registry can be obtained at https://www.aedpregnancyregistry.org/ or by calling 1-888-233-2334. Information about the National Pregnancy Registry for Psychiatric Medications can be obtained at https://womensmentalhealth.org/research/pregnancyregistry/ or by calling 1-866-961-2388.
Diazepam is excreted into human breast milk. There are no data to assess the effects of diazepam or its active metabolite on milk production. There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Breast-feeding is not recommended in patients receiving oral diazepam. After acute use of rectal diazepam, advise the patient not to breastfeed for an appropriate period of time after the rectal dose is administered; diazepam and its metabolites may be present in human breast milk for prolonged periods of time after acute use. Monitor breastfed infants exposed to nasal diazepam through breast milk for sedation, poor feeding, and poor weight gain. Diazepam concentrations were assessed in 3 breast-feeding mothers receiving diazepam 30 mg daily for 6 days after delivery. The mean concentration of diazepam and its metabolite in the mothers' sera, the breast milk, and the infants' sera at 4 days were 831 ng/mL, 79 ng/mL, and 415 ng/mL and at 6 days were 1,084 ng/mL, 130 ng/mL, and 105 ng/mL, respectively. The infants' mean serum concentration decrease from days 4 to 6 may be due to decreases in the amount of milk consumed or the onset of elimination mechanisms. None of the infants showed signs of lethargy or hypoventilation. An infant exposed to diazepam 30 mg daily at 5 days postpartum experienced weight loss, lethargy, and electroencephalogram (EEG) findings consistent with sedative medication. A small series of 9 infants exposed to diazepam at unspecified doses through breast milk found the only adverse event was mild jaundice in 3 of the infants. If occasional maternal therapy with a benzodiazepine is required, lorazepam or oxazepam may be reasonable alternatives for some patients. Some experts suggest that occasional maternal treatment with usual doses of lorazepam or oxazepam would pose little risk to a breast-feeding infant.
In geriatric and debilitated adults, it is recommended that diazepam dosage be limited to the smallest effective amount to preclude the development of ataxia or oversedation; closely monitor. Use caution when administering diazepam intravenously or chronically by any route in older adults due to the risk of apnea and/or cardiac instability. Significant accumulation of diazepam and its major metabolite, desmethyldiazepam, has been noted in geriatric subjects receiving prolonged, routine therapy. Decreased elimination may also occur in some older adults due to a decline in renal function and can either intensify or prolong the adverse reactions of the drug. Because diazepam can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the geriatric adult, with the potential for subsequent severe injuries. Due to its long half-life and the availability of safer alternatives, diazepam is not a drug of choice for most indications outside of seizure disorders in the older adult. According to the Beers Criteria, benzodiazepines are considered potentially inappropriate medications (PIMs) in geriatric adults and avoidance is generally recommended, although some agents may be appropriate for seizure disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or peri-procedural anesthesia. Older adults have an increased sensitivity to benzodiazepines and slower metabolism of long-acting agents like diazepam, which increases their risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents. Avoid in those with the following conditions due to the potential for symptom exacerbation or adverse effects: delirium (new-onset or worsening delirium), dementia (adverse CNS effects), and history of falls/fractures (ataxia, impaired psychomotor function, syncope, and additional falls). If a benzodiazepine must be used, consider reducing use of other CNS-active medications and implement other strategies to reduce fall risk. The Beers Criteria are not meant to apply to patients at the end of life or receiving palliative care, when risk-benefit considerations of drug therapy can be different. The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates anxiolytic/sedative/hypnotic medication use in residents of long-term care facilities (LTCFs). When a medication is used to induce sleep, treat a sleep disorder, manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity in accordance with OBRA guidelines. Dosages and durations of treatment used in the geriatric adult should be in accordance with prescribing labels, published literature recommendations, and expert guidelines.
For the treatment of anxiety disorders or for the short-term relief of the symptoms of anxiety:
Oral dosage:
Adults: 2 to 10 mg PO 2 to 4 times daily depending on the severity of symptoms. In debilitated adults, initate with 2 to 2.5 mg PO 1 or 2 times daily, with gradual increase if needed. Max: 40 mg/day. To discontinue, taper or decrease dose gradually.
Geriatric Adults: 2 to 2.5 mg PO 1 or 2 times daily, initially. May increase the dose gradually as needed and tolerated. Use the lowest effective dosage. Adult Max: 40 mg/day. To discontinue, taper or decrease dose gradually.
Children and Adolescents 1 to 17 years: 1 to 2.5 mg PO 3 to 4 times daily, initially. May increase the dose gradually as needed and tolerated. Adult Max: 40 mg/day. Guidelines state there is insufficient information to draw conclusions about the benefits or harms of benzodiazepine use for anxiety disorders in pediatric patients.
Intravenous and Intramuscular dosage:
Adults: 2 to 5 mg IM or IV for moderate anxiety disorders and symptoms of anxiety; repeat in 3 to 4 hours if necessary. For severe anxiety disorders and symptoms of anxiety, 5 to 10 mg IM or IV; repeat in 3 to 4 hours if necessary.
For the treatment of alcohol withdrawal:
-for the treatment of non-severe alcohol withdrawal:
Oral dosage (fixed-dose):
Adults: 10 mg PO every 6 hours on day 1, then 10 mg PO every 8 hours on day 2, then 10 mg PO every 12 hours on day 3, then 10 mg PO once daily at bedtime on days 4 and 5. The FDA-approved dosage is 10 mg PO 3 or 4 times daily for 24 hours, then 5 mg PO 3 or 4 times daily as needed.
Oral dosage (symptom-triggered):
Adults: 10 mg PO every 4 hours as needed on day 1, 10 mg PO every 6 hours as needed on days 2 and 3, and then 10 mg PO every 12 hours as needed on days 4 and 5. The FDA-approved dosage is 10 mg PO 3 or 4 times daily for 24 hours, then 5 mg PO 3 or 4 times daily as needed.
Intravenous dosage:
Adults: 10 to 20 mg IV or 10 mg IM as a single dose, initially, then 5 to 10 mg IV or IM in 3 hours if needed.
-for the treatment of severe alcohol withdrawal:
Intravenous dosage:
Adults: 10 mg IV every 5 to 10 minutes for 2 doses, then 20 mg IV every 5 to 10 minutes for 2 doses, then 40 mg IV every 5 to 10 minutes for 3 doses as needed. If the patient is hyperdynamic and agitated after diazepam 200 mg within 3 hours, consider phenobarbital or propofol. Doses of 100 to 500 mg IV initially and 2,000 to 2,335 mg IV over 48 to 96 hours, respectively, have been reported.
For the treatment of benzodiazepine withdrawal*:
Oral dosage:
Adults: Because benzodiazepine withdrawal is more pronounced with shorter-acting agents, diazepam has been proposed as the benzodiazepine of choice for managing withdrawal. Diazepam-equivalent doses have been established for some other benzodiazepines. Diazepam should be tapered off in increments of 0.5 to 2 mg per week over a period of 4 to 16 weeks.
For the treatment of muscle spasm due to local pathology such as muscle or joint inflammation or trauma; athetosis; stiff-man syndrome; tetanus; or spasticity due to upper motor neuron diseases such as cerebral palsy:
-for the treatment of muscle spasm due to local pathology such as muscle or joint inflammation or trauma; athetosis; stiff-man syndrome; or spasticity due to upper motor neuron diseases such as cerebral palsy:
Intravenous or Intramuscular dosage:
Adults: 5 to 10 mg IV or IM every 3 to 4 hours as needed.
Children and Adolescents 5 to 17 years: 5 to 10 mg IV or IM every 3 to 4 hours as needed.
Infants and Children 1 month to 4 years: 1 to 2 mg IV or IM every 3 to 4 hours as needed.
Oral dosage:
Adults: 2 to 10 mg PO 2 to 4 times per day depending upon the severity of the symptoms. Use lower initial adult doses for the debilitated adult patient.
Older Adults: 2 to 2.5 mg PO 1 to 2 times daily, increasing the dose according to response and patient tolerability.
Infants, Children, and Adolescents 6 months to 17 years: 1 to 2.5 mg PO 3 to 4 times daily. The dose may be increased as needed and tolerated.
-for the treatment of muscle spasm due to tetanus:
Intravenous dosage:
Adults: 0.1 to 0.3 mg/kg/dose (Usual Max: 10 mg/dose) IV every 1 to 6 hours as needed. May require larger doses; titrate up if needed. If insufficient response, consider continuous infusion.
Children and Adolescents 5 to 17 years: 0.1 to 0.3 mg/kg/dose (Usual Max: 10 mg/dose) IV every 1 to 6 hours as needed. May require larger doses; titrate up if needed. If insufficient response, consider continuous infusion.
Infants and Children 1 month to 4 years: 0.1 to 0.3 mg/kg/dose (Usual Max: 2 mg/dose) IV every 1 to 6 hours as needed. May require larger doses; titrate up if needed. If insufficient response, consider continuous infusion.
Neonates*: 0.1 to 0.3 mg/kg IV every 1 to 4 hours as needed. If insufficient response, consider continuous infusion.
Continuous Intravenous Infusion dosage:
Adults: 0.1 mg/kg/hour continuous IV infusion, initially. Titrate by 0.1 mg/kg/hour if symptoms persist as long as respiratory rate is maintained at 12 breaths/minute or more. Max: 0.8 mg/kg/hour. Gradually decrease the infusion and convert to scheduled oral diazepam when spasm severity and frequency have decreased.
Infants, Children, and Adolescents: 0.1 mg/kg/hour continuous IV infusion, initially. Titrate by 0.1 mg/kg/hour if symptoms persist as long as respiratory rate is maintained at an adequate rate based on age. Max: 0.8 mg/kg/hour. Gradually decrease the infusion and convert to scheduled oral diazepam when spasm severity and frequency have decreased.
Neonates*: 0.1 mg/kg/hour continuous IV infusion, initially. Titrate by 0.1 mg/kg/hour if symptoms persist as long as respiratory rate is 30 breaths/minute or more. Max: 0.8 mg/kg/hour. Gradually decrease the infusion and convert to scheduled oral diazepam when spasm severity and frequency have decreased.
Oral dosage*:
Adults: Calculate the total daily dose of IV diazepam and divide PO every 6 hours. Reduce dose by 5% to 20% daily until at 0.05 mg/kg/dose PO every 6 hours. Then extend the interval daily as tolerated to every 8 hours, then every 12 hours, then every 24 hours, and then discontinue. Wean more slowly if withdrawal symptoms occur.
Infants, Children, and Adolescents: Calculate the total daily dose of IV diazepam and divide PO every 6 hours. Reduce dose by 5% to 20% daily until at 0.05 mg/kg/dose PO every 6 hours. Then extend the interval daily as tolerated to every 8 hours, then every 12 hours, then every 24 hours, and then discontinue. Wean more slowly if withdrawal symptoms occur.
Neonates: Calculate the total daily dose of IV diazepam and divide PO every 6 hours. Reduce dose by 5% to 20% daily until at 0.05 mg/kg/dose PO every 6 hours. Then extend the interval daily as tolerated to every 8 hours, then every 12 hours, then every 24 hours, and then discontinue. Wean more slowly if withdrawal symptoms occur.
For the treatment of status epilepticus:
Intravenous dosage:
Adults : 0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV as a single dose; may repeat dose once in 5 minutes if needed. Alternatively, 5 to 10 mg IV every 10 to 15 minutes as needed up to a maximum of 30 mg. May repeat in 2 to 4 hours if needed.
Children and Adolescents 5 to 17 years: 0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV as a single dose; may repeat dose once in 5 minutes if needed. Alternatively, 1 mg IV every 2 to 5 minutes as needed up to a maximum of 10 mg. May repeat in 2 to 4 hours if needed.
Infants and Children 1 month to 4 years: 0.15 to 0.2 mg/kg/dose (Max: 10 mg/dose) IV as a single dose; may repeat dose once in 5 minutes if needed. Alternatively, 0.2 to 0.5 mg IV every 2 to 5 minutes as needed up to a maximum of 5 mg. May repeat in 2 to 4 hours if needed.
Neonates*: 0.1 to 0.15 mg/kg/dose IV every 10 minutes as needed. Mean total dose: 0.38 mg/kg IV (range: 0.09 to 0.71 mg/kg). NOTE: Not recommended as a first-line agent due to sodium benzoate and benzoic acid in the injection.
Rectal dosage*:
Adults: 0.2 to 0.5 mg/kg/dose (Max: 20 mg/dose) rectally as a single dose.
Children and Adolescents 12 to 17 years: 0.2 mg/kg/dose (Max: 20 mg/dose) rectally as a single dose.
Children 6 to 11 years: 0.3 mg/kg/dose (Max: 20 mg/dose) rectally as a single dose.
Children 2 to 5 years: 0.5 mg/kg/dose (Max: 20 mg/dose) rectally as a single dose.
For the treatment of intermittent, stereotypic, episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from usual seizure pattern:
Intravenous dosage:
Adults: 5 to 10 mg IV every 10 to 15 minutes as needed up to a maximum of 30 mg. May repeat in 2 to 4 hours if needed.
Children and Adolescents 5 to 17 years: 1 mg IV every 2 to 5 minutes as needed up to a maximum of 10 mg. May repeat in 2 to 4 hours if needed.
Infants and Children 1 month to 4 years: 0.2 to 0.5 mg IV every 2 to 5 minutes as needed up to a maximum of 5 mg. May repeat in 2 to 4 hours if needed.
Rectal dosage:
NOTE: It is recommended that rectal diazepam be used to treat no more than 5 episodes per month and no more than 1 episode every 5 days.
NOTE: The 2.5 mg dose may also be used as a partial replacement dose for patients who expel a portion of the first dose.
Adults: 0.2 mg/kg/dose rectally once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.
Older and/or Debilitated Adults: 0.2 mg/kg/dose rectally once; round dose downward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.
Children and Adolescents 12 to 17 years: 0.2 mg/kg/dose rectally once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.
Children 6 to 11 years: 0.3 mg/kg/dose rectally once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.
Children 2 to 5 years: 0.5 mg/kg/dose rectally once; round dose upward to the next available dosage strength. May give a second dose 4 to 12 hours after the first dose if needed.
Intranasal dosage:
NOTE: The recommended weight-based dosages of diazepam nasal spray are 0.2 mg/kg for adults, adolescents, and children 12 years and 0.3 mg/kg for children 6 to 11 years. Specific dosage recommendations provide acceptable weight ranges for each dose and age category, such that patients will receive between 90% and 180% of the calculated recommended dose.
Adults weighing 76 kg or more: 10 mg in each nostril once, for a total dose of 20 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Adults weighing 51 to 75 kg: 7.5 mg in each nostril once, for a total dose of 15 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Adults weighing 35 to 50 kg: 10 mg in 1 nostril once, for a total dose of 10 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Adolescents weighing 76 kg or more: 10 mg in each nostril once, for a total dose of 20 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Children and Adolescents 12 to 17 years weighing 51 to 75 kg: 7.5 mg in each nostril once, for a total dose of 15 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Children and Adolescents 12 to 17 years weighing 28 to 50 kg: 10 mg in 1 nostril once, for a total dose of 10 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Children 12 years weighing 14 to 27 kg: 5 mg in 1 nostril once, for a total dose of 5 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Children 6 to 11 years weighing 56 to 74 kg: 10 mg in each nostril once, for a total dose of 20 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Children 6 to 11 years weighing 38 to 55 kg: 7.5 mg in each nostril once, for a total dose of 15 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Children 6 to 11 years weighing 19 to 37 kg: 10 mg in 1 nostril once, for a total dose of 10 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
Children 6 to 11 years weighing 10 to 18 kg: 5 mg in 1 nostril once, for a total dose of 5 mg. May give a second dose after at least 4 hours after the initial dose, if required. Do not use more than 2 doses to treat a single episode. Do not treat more than 1 episode every 5 days and more than 5 episodes/month.
For adjunctive treatment of convulsive disorders, such as partial seizures or generalized tonic-clonic seizures:
Oral dosage (oral solution or regular tablets):
Adults : 2 to 10 mg PO 2 to 4 times daily.
Geriatric: 2 to 2.5 mg PO 1 to 2 times daily; increase dose gradually as needed and tolerated.
Infants, Children, and Adolescents 6 months to 17 years: 1 to 2.5 mg PO 3 to 4 times daily; increase dose gradually as needed and tolerated.
For amnesia induction or for procedural sedation:
Intravenous dosage:
Adults (prior to cardioversion): 5 to 15 mg IV 5 to 10 minutes before the procedure.
Adults (prior to endoscopy): Dose may be titrated up to 20 mg IV, depending on response and patient tolerability.
Infants*, Children*, and Adolescents*: 0.05 to 0.1 mg/kg/dose IV initially, titrate slowly to a maximum dose of 0.25 mg/kg IV.
Oral dosage:
Adults: 10 mg PO 45 to 60 minutes before the procedure.
Infants*, Children*, and Adolescents* (for procedures or conscious sedation): 0.2 to 0.4 mg/kg/dose (Max: 20 mg/dose) PO 45 to 60 minutes before the procedure.
For the treatment of acute chloroquine overdose* in combination with epinephrine:
Intravenous dosage:
Adults: Eleven cases of acute chloroquine overdose (total ingested dose ranged 5 to 12 g) were treated with diazepam 2 mg/kg IV over 30 minutes in combination with IV epinephrine, general anesthesia with thiopental, and FiO2 40%. Diazepam was continued at a dose of 1 to 2 mg/kg/day IV for 2 to 4 additional days. Other vasopressors and/or inotropic agents were used as necessary. Ten of 11 patients were discharged alive from the hospital. The one patient who died had ingested the largest total dose (15 g) of chloroquine.
For the treatment of insomnia*:
Oral dosage:
Adults: 2 to 10 mg PO at bedtime; individualize and titrate dosage according to patient response.
Geriatric Adults: 2 to 10 mg PO at bedtime is the usual adult dosage range; individualize and titrate according to patient response. Use is not recommended due to the long half-life of diazepam, the availability of safer sleep agents, and the increased sensitivity to benzodiazepines (e.g., ataxia, psychomotor impairment, syncope, falls) within the geriatric population.
For the treatment of cocaine-associated acute coronary syndromes*, including acute myocardial infarction, NSTEMI* and unstable angina*:
Intravenous dosage:
Adults: 5 mg IV every 5 minutes as needed until chest pain resolution. Max: 15 mg.
For sedation induction* or the treatment of agitation*:
Intravenous dosage:
Adults: 5 to 10 mg IV every 3 to 5 minutes as needed until sedation occurs.
Maximum Dosage Limits:
-Adults
Dosage must be individualized. Suggested maximum doses: 40 mg/day PO in divided doses for chronic ambulatory uses. A maximum dose has not been specifically defined by the manufacturer for emergent conditions.
-Geriatric
Dosage must be individualized. Suggested maximum dose: 40 mg/day PO in divided doses for many chronic ambulatory uses. A maximum dose has not been specifically defined by the manufacturer for emergent conditions.
-Adolescents
Dosage must be individualized. Suggested maximum dose: 0.6 mg/kg IV in 8 hour period for acute anxiety.
-Children
Dosage must be individualized. Suggested maximum dose: 0.6 mg/kg IV in 8 hour period for acute anxiety.
-Infants
Maximum dosage not established.
-Neonates
Maximum dosage not established.
Patients with Hepatic Impairment Dosing
Dosage should be modified depending on clinical response and degree of hepatic impairment, but no quantitative recommendations are available.
Patients with Renal Impairment Dosing
Dosage should be modified depending on clinical response and degree of renal impairment, but no quantitative recommendations are available; active and inactive diazepam metabolites are excreted by the kidney.
*non-FDA-approved indication
Acetaminophen; Aspirin, ASA; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Caffeine; Dihydrocodeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Caffeine; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Acetaminophen; Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Dextromethorphan; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acetaminophen; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Acetaminophen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Acetaminophen; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Acrivastine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Adagrasib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with adagrasib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and adagrasib is a CYP3A inhibitor.
Alfentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs, such as diazepam, can potentiate the CNS effects of either agent.
Aluminum Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Amiodarone: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with amiodarone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and amiodarone is a CYP3A inhibitor.
Amitriptyline: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Amobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Amoxapine: (Moderate) Amoxapine may enhance the response to the effects of benzodiazepines and other CNS depressants. Patients should be warned of the possibility of drowsiness that may impair performance of potentially hazardous tasks such as driving an automobile or operating machinery.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam. (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with omeprazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Antacids: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Apalutamide: (Moderate) Monitor for diazepam withdrawal symptoms or lack of efficacy if coadministration of diazepam with apalutamide is necessary. Diazepam is a CYP3A4, CYP2C9, and CYP2C19 substrate. Apalutamide is a strong CYP3A4 and CYP2C19 inducer, as well as a weak CYP2C9 inducer.
Apomorphine: (Moderate) Apomorphine causes significant somnolence. Concomitant administration of apomorphine and benzodiazepines could result in additive depressant effects.
Apraclonidine: (Minor) No specific drug interactions were identified with systemic agents and apraclonidine during clinical trials. Theoretically, apraclonidine might potentiate the effects of CNS depressant drugs such as the anxiolytics, sedatives, and hypnotics, including barbiturates or benzodiazepines.
Aprepitant, Fosaprepitant: (Major) Use caution if diazepam and aprepitant, fosaprepitant are used concurrently and monitor for an increase in diazepam-related adverse effects for several days after administration of a multi-day aprepitant regimen. If a benzodiazepine is necessary, a dosage adjustment of the multi-day regimen may be necessary depending on the clinical situation (e.g., elderly patients) and degree of monitoring available; no dosage adjustment is needed for a single 40-mg dose of aprepitant or 150-mg dose of fosaprepitant. Consider selection of an agent that is not metabolized via CYP3A4 isoenzymes (e.g., lorazepam, oxazepam, temazepam). Diazepam is a CYP3A4 substrate. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of diazepam. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Aprepitant is also a CYP2C9 inducer and diazepam is a CYP2C9 substrate. Administration of a CYP2C9 substrate, tolbutamide, on days 1, 4, 8, and 15 with a 3-day regimen of oral aprepitant (125 mg/80 mg/80 mg) decreased the tolbutamide AUC by 23% on day 4, 28% on day 8, and 15% on day 15. The AUC of tolbutamide was decreased by 8% on day 2, 16% on day 4, 15% on day 8, and 10% on day 15 when given prior to oral administration of aprepitant 40 mg on day 1, and on days 2, 4, 8, and 15. The effects of aprepitant on tolbutamide were not considered significant.
Aripiprazole: (Moderate) Monitor blood pressure and for unusual drowsiness and sedation during coadministration of aripiprazole and benzodiazepines. Intensity of sedation and orthostatic hypotension were greater with the combination of oral aripiprazole and lorazepam compared to aripiprazole alone.
Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inhibitor of CYP2C19. In theory, dosage reductions may be required for drugs that are largely eliminated via CYP2C19 metabolism such as diazepam during coadministration with armodafinil.
Asciminib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with asciminib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and asciminib is a CYP3A inhibitor.
Asenapine: (Moderate) Drugs that can cause CNS depression, if used concomitantly with asenapine, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when asenapine is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics (including barbiturates), buprenorphine, buprenorphine; naloxone, butorphanol, dronabinol, THC, nabilone, nalbuphine, opiate agonists, pentazocine, acetaminophen; pentazocine, aspirin, ASA; pentazocine, and pentazocine; naloxone.
Aspirin, ASA; Butalbital; Caffeine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Aspirin, ASA; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Aspirin, ASA; Caffeine; Orphenadrine: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Aspirin, ASA; Carisoprodol; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Aspirin, ASA; Citric Acid; Sodium Bicarbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Aspirin, ASA; Omeprazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with omeprazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Aspirin, ASA; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Atazanavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Atazanavir; Cobicistat: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors. (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Atropine; Difenoxin: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
Avacopan: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with avacopan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and avacopan is a CYP3A inhibitor.
Azelastine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and benzodiazepines. Concurrent use may result in additive CNS depression.
Azelastine; Fluticasone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of azelastine and benzodiazepines. Concurrent use may result in additive CNS depression.
Baclofen: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Barbiturates: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Belladonna; Opium: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Belumosudil: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with belumosudil is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and belumosudil is a CYP3A inhibitor.
Belzutifan: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with belzutifan is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and belzutifan is a CYP3A inducer.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
Berotralstat: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with berotralstat is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and berotralstat is a CYP2C19 and CYP3A inhibitor.
Bicalutamide: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with bicalutamide is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and bicalutamide is a CYP3A4 inhibitor.
Bosentan: (Moderate) Bosentan is an inducer of cytochrome P450 enzymes, specifically the CYP2C9 and CYP3A4 isoenzymes, and may decrease concentrations of drugs metabolized by these enzymes, including diazepam.
Brexanolone: (Moderate) Concomitant use of brexanolone with CNS depressants like the benzodiazepines may increase the likelihood or severity of adverse reactions related to sedation and additive CNS depression. Monitor for excessive sedation, dizziness, and a potential for loss of consciousness during brexanolone use.
Brigatinib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with brigatinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and brigatinib is a CYP3A4 inducer.
Brimonidine: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
Brimonidine; Brinzolamide: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
Brimonidine; Timolol: (Moderate) Based on the sedative effects of brimonidine in individual patients, brimonidine administration has potential to enhance the CNS depressants effects of the anxiolytics, sedatives, and hypnotics including benzodiazepines.
Brompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Brompheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Brompheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Buprenorphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If parental diazepam is used with an opiate agonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Buprenorphine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated for pain in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. Reduce injectable buprenorphine dose by 1/2, and for the buprenorphine transdermal patch, start therapy with the 5 mcg/hour patch. If parental diazepam is used with an opiate agonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. In patients treated with buprenorphine for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia in patients receiving buprenorphine maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation.
Butalbital; Acetaminophen: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Butalbital; Acetaminophen; Caffeine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Butalbital; Acetaminophen; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Butalbital; Aspirin; Caffeine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Butorphanol: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Caffeine; Sodium Benzoate: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Calcium Carbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Calcium Carbonate; Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Calcium Carbonate; Simethicone: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Calcium, Magnesium, Potassium, Sodium Oxybates: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
Calcium; Vitamin D: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Cannabidiol: (Moderate) Consider a dose reduction of diazepam as clinically appropriate, if adverse reactions occur when administered with cannabidiol. Additive sedation and somnolence may occur. Increased diazepam exposure is possible. Diazepam is a CYP2C19 substrate. In vitro data predicts inhibition of CYP2C19 by cannabidiol potentially resulting in clinically significant interactions.
Capivasertib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with capivasertib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and capivasertib is a CYP3A inhibitor.
Capsaicin; Metaxalone: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Carbamazepine: (Moderate) Carbamazepine is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Monitor closely for signs of reduced diazepam effects.
Carbidopa; Levodopa; Entacapone: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Carbinoxamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Cariprazine: (Moderate) Due to the CNS effects of cariprazine, caution should be used when cariprazine is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.
Carisoprodol: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Celecoxib; Tramadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and benzodiazepines. Concurrent use may result in additive CNS depression.
Ceritinib: (Moderate) Monitor for an increase in sedation and respiratory depression if coadministration of diazepam with ceritinib is necessary. At low concentrations, diazepam is a CYP2C19 substrate but at high concentrations, CYP3A4 is also involved. Ceritinib is a strong CYP3A4 inhibitor.
Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Chlophedianol; Dexbrompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorcyclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlordiazepoxide; Amitriptyline: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Chlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Dextromethorphan: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines. (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpheniramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Chlorpheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Chlorpromazine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Chlorzoxazone: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Cimetidine: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with cimetidine is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and cimetidine is a CYP2C19 and CYP3A inhibitor.
Ciprofloxacin: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ciprofloxacin is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and ciprofloxacin is a CYP3A inhibitor.
Cisapride: (Moderate) Cisapride may enhance the sedative effects of benzodiazepines. Patients should not drive or operate heavy machinery until they know how the combination affects them. Patient counseling is important, as cisapride alone does not cause drowsiness or affect psychomotor function.
Clarithromycin: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam.
Clemastine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Clobazam: (Major) Use clobazam with other benzodiazepines with caution due to the risk for additive CNS depression.
Clomipramine: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Clonidine: (Moderate) Clonidine has CNS depressive effects and can potentiate the actions of other CNS depressants including benzodiazepines.
Clozapine: (Moderate) If concurrent therapy with clozapine and a benzodiazepine is necessary, it is advisable to begin with the lowest possible benzodiazepine dose and closely monitor the patient, particularly at initiation of treatment and following dose increases. Although the combination has been used safely, adverse reactions such as confusion, ataxia, somnolence, delirium, collapse, cardiac arrest, respiratory arrest, and death have occurred rarely in patients receiving clozapine concurrently or following benzodiazepine therapy. Several benzodiazepines, including clonazepam, oxazepam, flurazepam, diazepam, clobazam, flunitrazepam, and lorazepam have been implicated in these reactions. At least one case of sudden death was reported following intravenous administration of lorazepam to a patient receiving clozapine.
Cobicistat: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Codeine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Codeine; Guaifenesin: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Codeine; Guaifenesin; Pseudoephedrine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines.
Codeine; Phenylephrine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Codeine; Promethazine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid prescribing opiate cough medications in patients taking benzodiazepines. (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Colesevelam: (Moderate) Colesevelam may decrease the absorption of anticonvulsants. To minimize potential for interactions, consider administering oral anticonvulsants at least 1 hour before or at least 4 hours after colesevelam.
COMT inhibitors: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Conivaptan: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with conivaptan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and conivaptan is a CYP3A inhibitor.
Crizotinib: (Moderate) Monitor for increased diazepam-related adverse reactions including sedation and respiratory depression if coadministration with crizotinib is necessary. Diazepam is a CYP3A4 substrate and crizotinib is a moderate CYP3A inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
Cyclobenzaprine: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Cyproheptadine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dalfopristin; Quinupristin: (Moderate) Monitor for diazepam-related adverse reactions including sedation and respiratory depression if coadministration with dalfopristin; quinupristin is necessary due to increased diazepam exposure. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor and diazepam is metabolized by CYP3A4.
Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and can decrease the hepatic metabolism of diazepam.
Dantrolene: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Daridorexant: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with daridorexant is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and daridorexant is a CYP3A inhibitor.
Darunavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Darunavir; Cobicistat: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors. (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors. (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Delavirdine: (Moderate) Delavirdine is a potent inhibitor of the CYP3A4 and increased plasma concentrations of drugs extensively metabolized by this enzyme, such as diazepam, should be expected with concurrent use of delavirdine.
Desflurane: (Moderate) Concurrent use with benzodiazepines can decrease the minimum alveolar concentration (MAC) of desflurane needed to produce anesthesia.
Desipramine: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Desogestrel; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Deutetrabenazine: (Moderate) Advise patients that concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as diazepam, may have additive effects and worsen drowsiness or sedation.
Dexamethasone: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with dexamethasone is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and dexamethasone is a CYP3A inducer.
Dexbrompheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexbrompheniramine; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexchlorpheniramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dexmedetomidine: (Moderate) Concurrent use of dexmedetomidine and benzodiazepines may result in additive CNS depression. A reduction in dosage of dexmedetomidine or the benzodiazepine may be required.
Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Dextromethorphan; Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Dicyclomine: (Moderate) Dicyclomine can cause drowsiness, so it should be used cautiously in patients receiving CNS depressants like benzodiazepines.
Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
Diltiazem: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with diltiazem is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and diltiazem is a CYP3A inhibitor.
Dimenhydrinate: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine; Ibuprofen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine; Naproxen: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Diphenhydramine; Phenylephrine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Diphenoxylate; Atropine: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent.
Disulfiram: (Moderate) Disulfiram may compete for the binding sites on hepatic cytochrome P-450 (CYP) with benzodiazepines that undergo oxidative metabolism such as diazepam, thereby slowing the metabolism of diazepam and increasing its steady-state plasma concentrations.
Doxepin: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Doxylamine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Doxylamine; Pyridoxine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Dronabinol: (Moderate) Use caution if the use of benzodiazepines are necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
Dronedarone: (Moderate) Dronedarone is metabolized by and is an inhibitor of CYP3A. Diazepam is a substrate for CYP3A4. The concomitant administration of dronedarone and CYP3A substrates may result in increased exposure of the substrate and should, therefore, be undertaken with caution.
Droperidol: (Major) Droperidol administration is associated with an established risk for QT prolongation and torsades de pointes. In December 2001, the FDA issued a black box warning regarding the use of droperidol and its association with QT prolongation and potential for cardiac arrhythmias based on post-marketing surveillance data. Risk factors for the development of prolonged QT syndrome may include the use of benzodiazepines. Also, droperidol and benzodiazepines can both cause CNS depression. If used with a benzodiazepine, droperidol should be initiated at a low dose and adjusted upward, with caution, as needed to achieve the desired effect.
Drospirenone; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Drospirenone; Ethinyl Estradiol; Levomefolate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Efavirenz: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) In vivo, efavirenz has been shown to induce hepatic enzymes CYP3A4 and CYP2B6. Patients receiving benzodiazepines that are metabolized by these isoenzymes may experience decreased benzodiazepine serum concentrations if administered concurrently with efavirenz. Efavirenz should be used with caution with oxidized benzodiazepines including diazepam. In addition, efavirenz inhibits CYP2C9 in vitro; diazepam is also metabolized via this isoenzyme. Monitor patients closely for excessive side effects.
Elagolix: (Minor) Coadministration of elagolix with diazepam may theoretically increase plasma concentrations of diazepam. Elagolix is a weak CYP2C19 inhibitor and diazepam is a CYP2C19 sensitive substrate. Monitor for diazepam-related adverse effects during coadministration with elagolix.
Elagolix; Estradiol; Norethindrone acetate: (Minor) Coadministration of elagolix with diazepam may theoretically increase plasma concentrations of diazepam. Elagolix is a weak CYP2C19 inhibitor and diazepam is a CYP2C19 sensitive substrate. Monitor for diazepam-related adverse effects during coadministration with elagolix.
Elbasvir; Grazoprevir: (Moderate) Administering diazepam with elbasvir; grazoprevir may result in elevated diazepam plasma concentrations. At high concentrations, diazepam is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Elexacaftor; tezacaftor; ivacaftor: (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of diazepam may be elevated when administered concurrently with cobicistat. Close clinical monitoring is recommended during coadministration; diazepam dose reductions may be required. Predictions regarding this interaction can be made based on the metabolic pathways of these drugs. Cobicistat is a strong inhibitor of CYP3A4, an isoenzyme partially responsible for the metabolism of diazepam. These drugs used in combination may result in elevated diazepam plasma concentrations, causing an increased risk for diazepam-related adverse events.
Enasidenib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, and decreased efficacy if coadministration with enasidenib is necessary. Concurrent use may alter diazepam exposure although the net effect is unknown. Diazepam is a CYP2C19 and CYP3A substrate and enasidenib is a CYP2C19 inhibitor and weak CYP3A inducer.
Encorafenib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with encorafenib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and encorafenib is a CYP3A inducer.
Entacapone: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Enzalutamide: (Moderate) Monitor for withdrawal symptoms or lack of efficacy if coadministration of diazepam with enzalutamide is necessary. Diazepam is a CYP3A4, CYP2C9, and CYP2C19 substrate; enzalutamide is a strong CYP3A4 inducer, as well as a moderate CYP2C9 and CYP2C19 inducer.
Ergotamine; Caffeine: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Erythromycin: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with erythromycin is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and erythromycin is a CYP3A inhibitor.
Esketamine: (Major) Closely monitor patients receiving esketamine and benzodiazepines for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
Esomeprazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with esomeprazole is necessary. Administration of esomeprazole with diazepam resulted in a 45% decrease in clearance of diazepam. Diazepam is a CYP2C19 substrate and esomeprazole is a CYP2C19 inhibitor.
Eszopiclone: (Moderate) Concomitant administration of benzodiazepines with eszopiclone can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. The concurrent use of eszopiclone with other anxiolytics, sedatives, and hypnotics at bedtime or in the middle of the night is not recommended. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. If used together, a reduction in the dose of one or both drugs may be needed.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethinyl Estradiol; Norelgestromin: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Ethinyl Estradiol; Norethindrone Acetate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Ethinyl Estradiol; Norgestrel: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Ethotoin: (Moderate) Ethotoin is a hepatic enzyme inducer and thus may accelerate the metabolism of several other anticonvulsants, and can theoretically add to the CNS-depressant effects of other CNS depressants, including the anxiolytics, sedatives, and hypnotics which may be used concomitantly for seizure control or as psychotropics. Ethotoin should be used cautiously with diazepam, as decreased diazepam serum concentrations may be seen when coadministered with phenytoin. In addition, diazepam has been reported to have an unpredictable effect on phenytoin serum concentrations (e.g., to increase, decrease, or cause no change in phenytoin serum concentrations). Conflicting results may have been observed due to saturable phenytoin metabolism and/or other conditions associated with the reported data. Since definitive controlled trial data are lacking, phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.
Ethynodiol Diacetate; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Etomidate: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Etonogestrel; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Etravirine: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with etravirine is necessary. Concurrent use may increase diazepam exposure.
Everolimus: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with everolimus is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and everolimus is a CYP3A4 inhibitor.
Fedratinib: (Moderate) Monitor for increased diazepam-related adverse reactions including sedation and respiratory depression if coadministration with fedratinib is necessary. Diazepam is a CYP3A4 and CYP2C19 substrate and fedratinib is a moderate CYP3A and CYP2C19 inhibitor. Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and benzodiazepines. Concurrent use may result in additive CNS depression.
Fenofibric Acid: (Minor) At therapeutic concentrations, fenofibric acid is a weak inhibitor of CYP2C19. Concomitant use of fenofibric acid with CYP2C19 substrates, such as diazepam, has not been formally studied. Fenofibric acid may theoretically increase plasma concentrations of CYP2C19 substrates and could lead to toxicity for drugs that have a narrow therapeutic range. Monitor the therapeutic effect of diazepam during coadministration with fenofibric acid.
Fentanyl: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Fexinidazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with fexinidazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and fexinidazole is a CYP2C19 and CYP3A inhibitor.
Fluconazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with fluconazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and fluconazole is a CYP2C19 and CYP3A inhibitor.
Flumazenil: (Major) Flumazenil competes with benzodiazepines for binding at the GABA/benzodiazepine-receptor complex, the specific binding site of benzodiazepines. Because binding at the receptor is competitive and flumazenil has a much shorter duration of action than do most benzodiazepines, it is possible for the effects of flumazenil to dissipate sooner than the effects of the benzodiazepine. Flumazenil does not affect the pharmacokinetics of the benzodiazepines. Abrupt awakening can cause dysphoria, agitation, and possibly increased adverse effects. If administered to patients who have received a benzodiazepine chronically, abrupt interruption of benzodiazepine agonism by flumazenil can induce benzodiazepine withdrawal including seizures. Flumazenil has minimal effects on benzodiazepine-induced respiratory depression; suitable ventilatory support should be available, especially in treating acute benzodiazepine overdose. Flumazenil does not reverse the actions of barbiturates, opiate agonists, or tricyclic antidepressants.
Fluoxetine: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with fluoxetine is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and fluoxetine is a CYP2C19 inhibitor.
Fluphenazine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Fluvoxamine: (Major) Fluvoxamine decreases the oxidative hepatic metabolism of diazepam. Diazepam is metabolized by CYP2C19 and CYP3A4 and fluvoxamine inhibits these CYP isoenzymes and appears to have a significant effect on diazepam exposure, clearance, and elimination half-life. Monitor the patient closely for sedation, CNS depression, and prolonged benzodiazepine effects. Dose reduction may be necessary. In a study with healthy volunteers, concurrent fluvoxamine intake was associated with increased mean peak plasma diazepam concentrations (from 108 to 143 ng/mL, geometric means, difference not significant), with a marked reduction in apparent oral diazepam clearance (significant difference, p less than 0.01) and with a prolongation in diazepam half-life (from 51 to 118 hours; p less than 0.01). N-Desmethyldiazepam AUC values were also significantly increased. These data suggest the interaction is likely to have clinical significance.
Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
Fosamprenavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Fosphenytoin: (Moderate) Monitor for decreased efficacy of diazepam and/or fosphenytoin and phenytoin toxicity if coadministration is necessary; dosage adjustments may be required. Concurrent use may decrease diazepam exposure and decrease or increase phenytoin exposure. Diazepam is a CYP3A substrate and phenytoin is a CYP3A inducer. There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.
Gabapentin: (Major) Concomitant use of benzodiazepines with gabapentin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate gabapentin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
General anesthetics: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Glycerol Phenylbutyrate: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with glycerol phenylbutyrate is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and glycerol phenylbutyrate is a CYP3A inducer.
Grapefruit juice: (Major) Orally-administered diazepam may interact with grapefruit juice. Grapefruit juice has been shown to increase diazepam peak serum concentrations (Cmax) and exposure (AUC) by 1.5-fold and 3.2-fold, respectively, when diazepam was administered orally. Grapefruit juice contains furano-coumarins and certain flavonoids which may inhibit the CYP3A4 isozyme. Increased sedation or other CNS effects may be possible. To prevent this interaction, it would be prudent to avoid taking oral diazepam with grapefruit juice.
Green Tea: (Minor) Patients taking benzodiazepines for insomnia should not use caffeine-containing products, such as green tea, prior to going to bed as these products may antagonize the sedative effects of the benzodiazepine.
Guaifenesin; Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Guanfacine: (Moderate) Guanfacine has been associated with sedative effects and can potentiate the actions of other CNS depressants including benzodiazepines.
Haloperidol: (Moderate) Haloperidol can potentiate the actions of other CNS depressants, such as benzodiazepines, Caution should be exercised with simultaneous use of these agents due to potential excessive CNS effects.
Homatropine; Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydrocodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydrocodone; Ibuprofen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydrocodone is initiated in a patient taking a benzodiazepine, reduce initial dosage and titrate to clinical response; for hydrocodone extended-release products, initiate hydrocodone at 20% to 30% of the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydromorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If hydromorphone is initiated in a patient taking a benzodiazepine, reduce the initial dosage of hydromorphone and titrate to clinical response; for hydromorphone extended-release tablets, use 1/3 to 1/2 of the estimated hydromorphone starting dose. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Hydroxychloroquine: (Moderate) Monitor persons with epilepsy for seizure activity during concomitant diazepam and hydroxychloroquine use. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Hydroxyzine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Ibuprofen; Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with diazepam, a CYP3A substrate, as diazepam toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
Iloperidone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with iloperidone, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when iloperidone is given in combination with other centrally-acting medications including anxiolytics, sedatives, and hypnotics.
Imatinib: (Moderate) Imatinib is a potent inhibitor of cytochrome P450 3A4 and may increase concentrations of other drugs metabolized by this enzyme including diazepam.
Imipramine: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Indinavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with diazepam may result in increased serum concentrations of diazepam. Diazepam is a substrate of the hepatic isoenzyme CYP3A4; isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are used together.
Isocarboxazid: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
Isoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Isoniazid, INH: (Moderate) Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifampin may require higher doses of diazepam to achieve the desired clinical effect. (Moderate) Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
Isoniazid, INH; Rifampin: (Major) Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifampin may require higher doses of diazepam to achieve the desired clinical effect. (Moderate) Concurrent use of isoniazid, INH and diazepam can increase serum concentrations of diazepam due to alterations in the half-life and clearance of diazepam. Patients should be observed for signs of altered diazepam effects if isoniazid therapy is initiated or discontinued.
Itraconazole: (Moderate) Monitor for increased and prolonged sedation if coadministration of itraconazole and diazepam is necessary. A dose reduction of diazepam may be necessary. Diazepam is a CYP3A4 substrate; itraconazole is a strong CYP3A4 inhibitor.
Ivacaftor: (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
Ketamine: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Ketoconazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ketoconazole is necessary. Concurrent use increases diazepam exposure. Diazepam is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam.
Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and benzodiazepines. Concurrent use may result in additive CNS depression.
Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during use of lemborexant with benzodiazepines. Dosage adjustments may be necessary when administered together because of potentially additive CNS effects. Use of more than 2 hypnotics should be avoided due to the additive CNS depressant and complex sleep-related behaviors that may occur. While anxiolytic medications may be used concurrently with lemborexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
Lenacapavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with lenacapavir is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and lenacapavir is a CYP3A inhibitor.
Letermovir: (Moderate) Plasma concentrations of diazepam could be increased when administered concurrently with letermovir. The magnitude of this interaction may be elevated in patients who are also receiving cyclosporine. If these drugs are given together, closely monitor for reduced diazepam efficacy and diazepam-related adverse events. Diazepam is a substrate of CYP3A4. Letermovir is a moderate inhibitor of CYP3A4. When given with cyclosporine, the combined effect of letermovir and cyclosporine on CYP3A4 substrates may be similar to a strong CYP3A4 inhibitor.
Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with benzodiazepines should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
Levoketoconazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ketoconazole is necessary. Concurrent use increases diazepam exposure. Diazepam is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Levomilnacipran: (Moderate) Concurrent use of many CNS active drugs, including benzodiazepines, with levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with levomilnacipran.
Levonorgestrel; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Levonorgestrel; Ethinyl Estradiol; Ferrous Fumarate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Levorphanol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If levorphanol is initiated in a patient taking a benzodiazepine, reduce the initial dose of levorphanol by approximately 50% or more. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Lofexidine: (Moderate) Monitor for excessive hypotension and sedation during coadministration of lofexidine and benzodiazepines. Lofexidine can potentiate the effects of CNS depressants such as benzodiazepines.
Lonafarnib: (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.
Lopinavir; Ritonavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Lorlatinib: (Moderate) Monitor for diazepam withdrawal symptoms or lack of efficacy if coadministration with lorlatinib is necessary. Lorlatinib is a moderate CYP3A4 inducer and diazepam is a primarily metabolized by CYP2C19 at low concentrations, but at higher concentrations CYP3A4 is also involved. Coadministration may result in decreased plasma concentrations of diazepam.
Luliconazole: (Moderate) Theoretically, luliconazole may increase the side effects of diazepam, which is a CYP2C19 and CYP3A4 substrate. Monitor patients for adverse effects of diazepam, such as CNS effects and respiratory depression. In vitro, therapeutic doses of luliconazole inhibit the activity of CYP2C19 and CYP3A4 and small systemic concentrations may be noted with topical application, particularly when applied to patients with moderate to severe tinea cruris. No in vivo drug interaction trials were conducted prior to the approval of luliconazole.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of diazepam by decreasing its systemic exposure. If used together, monitor patients closely for loss of diazepam efficacy; a diazepam dosage adjustment may be required to obtain the desired therapeutic effect. Diazepam is primarily metabolized by CYP2C19 and CYP3A4, and to a lesser extent by CYP2B6 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9. (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of diazepam by decreasing its systemic exposure. If used together, monitor patients closely for loss of diazepam efficacy; a diazepam dosage adjustment may be required to obtain the desired therapeutic effect. Diazepam is primarily metabolized by CYP2C19 and CYP3A4, and to a lesser extent by CYP2B6 and CYP2C9. Lumacaftor is a strong CYP3A inducer; in vitro data also suggest that lumacaftor; ivacaftor may induce CYP2B6 and CYP2C19, and induce and/or inhibit CYP2C9.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and benzodiazepines. Concurrent use may result in additive CNS depression.
Lurasidone: (Moderate) Due to the CNS effects of lurasidone, caution should be used when lurasidone is given in combination with other centrally acting medications such as anxiolytics, sedatives, and hypnotics, including benzodiazepines. In one study, co-administration of lurasidone and midazolam increased the Cmax and AUC of midazolam by about 21% and 44%, respectively, compared to midazolam alone; however, dosage adjustment of midazolam based upon pharmacokinetic parameters is not required during concurrent use of lurasidone.
Magnesium Hydroxide: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Magnesium Salts: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Maprotiline: (Moderate) Benzodiazepines or other CNS depressants should be combined cautiously with maprotiline because they could cause additive depressant effects and possible respiratory depression or hypotension. The combination of benzodiazepines and maprotiline is commonly used clinically and is considered to be safe as long as patients are monitored for excessive adverse effects from either agent. Maprotiline may lower the seizure threshold, so when benzodiazepines are used for anticonvulsant effects the patient should be monitored for desired clinical outcomes.
Maribavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with maribavir is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and maribavir is a weak CYP3A inhibitor.
Mavacamten: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with mavacamten is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and mavacamten is a CYP2C19 and CYP3A inducer.
Meclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Mefloquine: (Moderate) Coadministration of mefloquine and anticonvulsants may result in lower than expected anticonvulsant concentrations and loss of seizure control. Monitoring of the anticonvulsant serum concentration is recommended. Dosage adjustments may be required during and after therapy with mefloquine.
Melatonin: (Major) Use caution when combining melatonin with the benzodiazepines; when the benzodiazepine is used for sleep, co-use of melatonin should be avoided. Use of more than 1 agent for hypnotic purposes may increase the risk for over-sedation, CNS effects, or sleep-related behaviors. Be alert for unusual changes in moods or behaviors. Use caution when combining melatonin with benzodiazepines for other uses. Patients reporting unusual sleep-related behaviors should likely discontinue melatonin use. In animal studies, melatonin has been shown to increase benzodiazepine binding to receptor sites. In one case report, a benzodiazepine-dependent woman with an 11 year history of insomnia weaned and discontinued her benzodiazepine prescription within a few days without rebound insomnia or apparent benzodiazepine withdrawal when melatonin was given. In another case report, the ingestion of excessive melatonin along with normal doses of chlordiazepoxide and an antidepressant resulted in lethargy and short-term amnestic responses. Both cases suggest additive pharmacodynamic effects. In a clinical trial, there was clear evidence for a transitory pharmacodynamic interaction between melatonin and another hypnotic agent one hour following co-dosing. Concomitant administration resulted in increased impairment of attention, memory and coordination compared to the hypnotic agent alone.
Meperidine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Meprobamate: (Moderate) Concomitant administration of benzodiazepines with meprobamate can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed.
Meropenem: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with meropenem is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and meropenem is a CYP2C19 and CYP3A inducer.
Meropenem; Vaborbactam: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with meropenem is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP2C19 and CYP3A substrate and meropenem is a CYP2C19 and CYP3A inducer.
Metaxalone: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Methadone: (Major) Concurrent use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective dose and minimum duration possible. If methadone is initiated for pain in an opioid-naive patient taking a benzodiazepine, use an initial methadone dose of 2.5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial benzodiazepine dose and titrate to response. In patients treated with methadone for opioid use disorder, cessation of benzodiazepines or other CNS depressants is preferred in most cases. Consider alternatives to benzodiazepines for conditions such as anxiety or insomnia during methadone maintenance treatment. Educate patients about the risks and symptoms of respiratory depression and sedation. If parenteral diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Methocarbamol: (Moderate) Concurrent use of benzodiazepines and other CNS active medications including skeletal muscle relaxants, can potentiate the CNS effects of either agent. Lower doses of one or both agents may be required. The severity of this interaction may be increased when additional CNS depressants are given.
Methohexital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Methscopolamine: (Moderate) CNS depression can be increased when methscopolamine is combined with other CNS depressants such as any anxiolytics, sedatives, and hypnotics.
Methyldopa: (Moderate) Methyldopa is associated with sedative effects. Methyldopa can potentiate the effects of CNS depressants such as barbiturates, benzodiazepines, opiate agonists, or phenothiazines when administered concomitantly.
Metoclopramide: (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
Metyrapone: (Moderate) Metyrapone may cause dizziness and/or drowsiness. Other drugs that may also cause drowsiness, such as benzodiazepines, should be used with caution. Additive drowsiness and/or dizziness is possible.
Metyrosine: (Moderate) The concomitant administration of metyrosine with benzodiazepines can result in additive sedative effects.
Milnacipran: (Moderate) Concurrent use of many CNS-active drugs with milnacipran or levomilnacipran has not been evaluated by the manufacturer. Therefore, caution is advisable when combining anxiolytics, sedatives, and hypnotics or other psychoactive medications with these medications.
Minocycline: (Minor) Injectable minocycline contains magnesium sulfate heptahydrate. Because of the CNS-depressant effects of magnesium sulfate, additive central-depressant effects can occur following concurrent administration with CNS depressants such as benzodiazepines. Caution should be exercised when using these agents concurrently.
Mirtazapine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and mirtazapine due to the risk for additive CNS depression.
Mitapivat: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with mitapivat is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and mitapivat is a weak CYP3A inducer.
Mitotane: (Major) Use caution if mitotane and diazepam are used concomitantly, and monitor for decreased efficacy of diazepam and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer; diazepam is predominantly metabolized by CYP2C19, but at high concentrations, CYP3A4 is also involved. Coadministration may result in decreased plasma concentrations of diazepam. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with diazepam.
Mobocertinib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with mobocertinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and mobocertinib is a CYP3A inducer.
Modafinil: (Moderate) Modafinil has demonstrated an inhibition of the CYP2C19 hepatic microsomal isoenzyme at pharmacologically relevant concentrations. Drugs that are largely eliminated via CYP2C19 metabolism, such as diazepam, may have prolonged elimination upon co-administration of modafinil.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Monoamine oxidase inhibitors: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
Morphine: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Morphine; Naltrexone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If morphine is initiated in a patient taking a benzodiazepine, reduce initial dosages and titrate to clinical response. For extended-release tablets, start with morphine 15 mg PO every 12 hours, and for extended-release capsules, start with 30 mg PO every 24 hours or less. Use an initial morphine; naltrexone dose of 20 mg/0.8 mg PO every 24 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Nabilone: (Major) Nabilone should not be taken with benzodiazepines or other sedative/hypnotic agents because these substances can potentiate the central nervous system effects of nabilone. Additive drowsiness and CNS depression can occur.
Nalbuphine: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Naproxen; Esomeprazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with esomeprazole is necessary. Administration of esomeprazole with diazepam resulted in a 45% decrease in clearance of diazepam. Diazepam is a CYP2C19 substrate and esomeprazole is a CYP2C19 inhibitor.
Nefazodone: (Moderate) Diazepam is metabolized by oxidative metabolism, specifically, the hepatic isozymes CYP2C19 and CYP3A4. As a result, diazepam is susceptible to interactions with drugs that inhibit these hepatic enzymes including nefazodone.
Nelfinavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Nevirapine: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with nevirapine is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and nevirapine is a CYP3A inducer.
Nicardipine: (Moderate) Nicardipine is an inhibitor of CYP3A4 isoenzymes. Co-administration with nicardipine may lead to an increase in serum levels of drugs that are CYP3A4 substrates including diazepam.
Nirmatrelvir; Ritonavir: (Major) Consider withholding diazepam, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the diazepam dose. However, do not stop diazepam abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients have been receiving high doses over an extended period. Coadministration may increase diazepam exposure resulting in increased toxicity and excessive sedation. Diazepam is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Nirogacestat: (Moderate) Monitor for changes in diazepam response if concomitant use with nirogacestat is necessary. Nirogacestat may have an unpredictable effect on diazepam overall exposure which may increase the risk for diazepam-related adverse reactions, including sedation and respiratory depression, or decrease diazepam efficacy. Diazepam is a CYP2C19 and CYP3A substrate and nirogacestat is a CYP2C19 inducer and CYP3A inhibitor.
Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as benzodiazepines. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with benzodiazepines.
Norethindrone Acetate; Ethinyl Estradiol; Ferrous fumarate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Norethindrone; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Norethindrone; Ethinyl Estradiol; Ferrous fumarate: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Norgestimate; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Nortriptyline: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Odevixibat: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with odevixibat is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and odevixibat is a weak CYP3A inducer.
Olanzapine: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Olanzapine; Fluoxetine: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine. (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with fluoxetine is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and fluoxetine is a CYP2C19 inhibitor.
Olanzapine; Samidorphan: (Major) Concurrent use of intramuscular olanzapine and parenteral benzodiazepines is not recommended due to the potential for adverse effects from the combination including excess sedation and/or cardiorespiratory depression. Although oral formulations of olanzapine and benzodiazepines may be used together, additive effects on respiratory depression and/or CNS depression are possible. Drugs that can cause CNS depression, if used concomitantly with olanzapine, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. Besides ethanol, clinicians should use other anxiolytics, sedatives, and hypnotics cautiously with olanzapine.
Oliceridine: (Major) Concomitant use of oliceridine with diazepam may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with diazepam to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If injectable diazepam is used with oliceridine, reduce the oliceridine dosage by at least one-third.
Olutasidenib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with olutasidenib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and olutasidenib is a CYP3A inducer.
Omaveloxolone: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with omaveloxolone is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and omaveloxolone is a CYP3A inducer.
Omeprazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with omeprazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with omeprazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor. (Moderate) Rifabutin induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as diazepam, may require dosage adjustments when administered concurrently with rifabutin.
Omeprazole; Sodium Bicarbonate: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with omeprazole is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP2C19 substrate and omeprazole is a CYP2C19 inhibitor. (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Opicapone: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Oritavancin: (Moderate) Coadministration of oritavancin and diazepam may result in increases or decreases in diazepam exposure and may increase side effects or decrease efficacy of diazepam. Diazepam is metabolized by CYP3A4, CYP2C9, and CYP2C19. Oritavancin weakly induces CYP3A4, while weakly inhibiting CYP2C9 and CYP2C19. If these drugs are administered concurrently, monitor the patient for signs of toxicity or lack of efficacy.
Orphenadrine: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Oxycodone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxycodone is initiated in a patient taking a benzodiazepine, reduce dosages and titrate to clinical response. For acetaminophen; oxycodone extended-release tablets, start with 1 tablet PO every 12 hours, and for other oxycodone products, use an initial dose of oxycodone at 1/3 to 1/2 the usual dosage. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Oxymorphone: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If oxymorphone is initiated in a patient taking a benzodiazepine, use an initial dose of oxymorphone at 1/3 to 1/2 the usual dosage and titrate to clinical response. If the extended-release oxymorphone tablets are used concurrently with a CNS depressant, use an initial dosage of 5 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Pacritinib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with pacritinib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and pacritinib is a CYP3A inhibitor.
Paliperidone: (Moderate) Drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness when coadministered with paliperidone. Monitor for signs and symptoms of CNS depression and advise patients to avoid driving or engaging in other activities requiring mental alertness until they know how this combination affects them.
Papaverine: (Moderate) Concurrent use of papaverine with potent CNS depressants such as benzodiazepines could lead to enhanced sedation.
Pazopanib: (Moderate) Pazopanib is a weak inhibitor of CYP3A4. Coadministration of pazopanib and diazepam, a CYP3A4 substrate, may cause an increase in systemic concentrations of diazepam. Use caution when administering these drugs concomitantly.
Pentazocine; Naloxone: (Major) Concomitant use of mixed opiate agonists/antagonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of mixed opiate agonists/antagonists with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If a mixed opiate agonist/antagonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the mixed opiate agonist/antagonist and titrate to clinical response. If parental diazepam is used with a mixed opiate agonist/antagonist, reduce the mixed opiate agonist/antagonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking a mixed opiate agonist/antagonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Pentobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Perampanel: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
Perphenazine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Perphenazine; Amitriptyline: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression. (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Pexidartinib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with pexidartinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and pexidartinib is a CYP3A4 inducer.
Phenelzine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
Phenobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers. (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
Phenothiazines: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Phentermine; Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
Phenylephrine: (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Phenytoin: (Moderate) Monitor for decreased efficacy of diazepam and/or phenytoin and phenytoin toxicity if coadministration is necessary; dosage adjustments may be required. Concurrent use may decrease diazepam exposure and decrease or increase phenytoin exposure. Diazepam is a CYP3A substrate and phenytoin is a CYP3A inducer. There have also been reports that the metabolic elimination of phenytoin is decreased by diazepam.
Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including benzodiazepines.
Pirtobrutinib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with pirtobrutinib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and pirtobrutinib is a CYP3A and CYP2C19 inhibitor.
Posaconazole: (Moderate) Diazepam is a substrate of CYP2C19 and CYP3A4, and inhibition of metabolism by posaconazole could lead to elevated diazepam blood levels.
Pramipexole: (Major) Concomitant administration of benzodiazepines with CNS-depressant drugs, including pramipexole, can potentiate the CNS effects.
Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Major) Prasterone, dehydroepiandrosterone, DHEA may inhibit the metabolism of benzodiazepines (e.g., alprazolam, estazolam, midazolam) which undergo CYP3A4-mediated metabolism. In one study of elderly volunteers, half of the patients received DHEA 200 mg/day PO for 2 weeks, followed by a single dose of triazolam 0.25 mg. Triazolam clearance was reduced by close to 30% in the DHEA-pretreated patients vs. the control group; however, the effect of DHEA on CYP3A4 metabolism appeared to vary widely among subjects. While more study is needed, benzodiazepine-induced CNS sedation and other adverse effects might be increased in some individuals if DHEA is co-administered.
Pregabalin: (Major) Concomitant use of benzodiazepines with pregabalin may cause excessive sedation, somnolence, and respiratory depression. If concurrent use is necessary, initiate pregabalin at the lowest recommended dose and monitor patients for symptoms of respiratory depression and sedation. Educate patients about the risks and symptoms of excessive CNS depression and respiratory depression.
Primidone: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Procarbazine: (Minor) CNS depressants benzodiazepines can potentiate the CNS depression caused by procarbazine therapy, so these drugs should be used together cautiously.
Prochlorperazine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Promethazine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Promethazine; Dextromethorphan: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Promethazine; Phenylephrine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression. (Moderate) The therapeutic effect of phenylephrine may be decreased in patients receiving benzodiazepines. Monitor patients for decreased pressor effect if these agents are administered concomitantly.
Propofol: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Protease inhibitors: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Protriptyline: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Pseudoephedrine; Triprolidine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Quetiapine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of diazepam and quetiapine. Concurrent use may result in additive CNS depression.
Ramelteon: (Moderate) Ramelteon is a sleep-promoting agent; therefore, additive pharmacodynamic effects are possible when combining ramelteon with benzodiazepines or other miscellaneous anxiolytics, sedatives, and hypnotics. Pharmacokinetic interactions have been observed with the use of zolpidem. Use of ramelteon 8 mg/day for 11 days and a single dose of zolpidem 10 mg resulted in an increase in the median Tmax of zolpidem of about 20 minutes; exposure to zolpidem was unchanged. Ramelteon use with hypnotics of any kind is considered duplicative therapy and these drugs are generally not co-administered.
Ranolazine: (Moderate) CYP3A4 inhibitors, like ranolazine, may reduce the metabolism of diazepam and increase the potential for benzodiazepine toxicity.
Rasagiline: (Moderate) The CNS-depressant effects of MAOIs can be potentiated with concomitant administration of other drugs known to cause CNS depression including buprenorphine, butorphanol, dronabinol, THC, nabilone, nalbuphine, and anxiolytics, sedatives, and hypnotics. Use these drugs cautiously with MAOIs; warn patients to not drive or perform other hazardous activities until they know how a particular drug combination affects them. In some cases, the dosages of the CNS depressants may need to be reduced.
Remifentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Benzodiazepine doses may need to be reduced up to 75% during coadministration with remifentanil. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Remimazolam: (Major) The sedative effect of remimazolam can be accentuated by diazepam. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
Repotrectinib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with repotrectinib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and repotrectinib is a CYP3A inducer.
Ribociclib: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with ribociclib is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Ribociclib is a strong CYP3A4 inhibitor.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with ribociclib is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Ribociclib is a strong CYP3A4 inhibitor.
Rifabutin: (Moderate) Rifabutin induces hepatic isoenzymes CYP3A4 and CYP2C8/9. Drugs metabolized by CYP3A4 and CYP2C8/9, such as diazepam, may require dosage adjustments when administered concurrently with rifabutin.
Rifampin: (Major) Rifampin is a potent inducer of the hepatic isoenzyme CYP3A4, one of the pathways responsible for the hepatic metabolism of diazepam. Patients receiving rifampin may require higher doses of diazepam to achieve the desired clinical effect.
Rifapentine: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with rifapentine is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and rifapentine is a CYP3A4 inducer.
Risperidone: (Moderate) Due to the primary CNS effects of risperidone, caution should be used when risperidone is given in combination with other centrally acting medications including anxiolytics, sedatives, and hypnotics.
Ritlecitinib: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with ritlecitinib is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and ritlecitinib is a CYP3A inhibitor.
Ritonavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Ropinirole: (Moderate) Concomitant use of ropinirole with other CNS depressants can potentiate the sedation effects of ropinirole.
Rotigotine: (Major) Concomitant use of rotigotine with other CNS depressants, such as benzodiazepines, can potentiate the sedative effects of rotigotine.
Rucaparib: (Moderate) Monitor for an increase in diazepam-related adverse reactions including sedation and respiratory depression if coadministration with rucaparib is necessary. Diazepam is a CYP2C19 substrate and rucaparib is a weak CYP2C19 inhibitor. Concomitant use may increase plasma concentrations of diazepam.
Safinamide: (Moderate) Dopaminergic medications, including safinamide, may cause a sudden onset of somnolence which sometimes has resulted in motor vehicle accidents. Patients may not perceive warning signs, such as excessive drowsiness, or they may report feeling alert immediately prior to the event. Because of possible additive effects, advise patients about the potential for increased somnolence during concurrent use of safinamide with other sedating medications, such as benzodiazepines.
Saquinavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Scopolamine: (Moderate) Scopolamine may cause dizziness and drowsiness. Concurrent use of scopolamine and CNS depressants can adversely increase the risk of CNS depression.
Secobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of diazepam. Diazepam is a CYP2C9, CYP2C19, and CYP3A4 substrate. Barbiturates are CYP2C9, CYP2C19, and CYP3A4 inducers.
Sedating H1-blockers: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Segesterone Acetate; Ethinyl Estradiol: (Minor) Ethinyl estradiol may inhibit the clearance of benzodiazepines that undergo oxidation, thereby increasing serum concentrations of concomitantly administered benzodiazepines.
Selegiline: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and selegiline due to the risk for additive CNS depression.
Selpercatinib: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with selpercatinib is necessary; decrease the dose of diazepam if necessary. Concurrent use may increase exposure of diazepam. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Selpercatinib is a weak CYP3A4 inhibitor.
Sevoflurane: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Sincalide: (Moderate) Sincalide-induced gallbladder ejection fraction may be affected by benzodiazepines. False study results are possible in patients with drug-induced hyper- or hypo-responsiveness; thorough patient history is important in the interpretation of procedure results.
Skeletal Muscle Relaxants: (Moderate) Concomitant use of skeletal muscle relaxants with benzodiazepines can result in additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given. Monitor patients who take benzodiazepines with another CNS depressant for symptoms of excess sedation.
Sodium Bicarbonate: (Moderate) The coadministration of diazepam with antacids results in delayed diazepam absorption due to the fact that antacids delay gastric emptying. It may be prudent to separate dosing by 2 hours to limit any potential interaction.
Sodium Oxybate: (Contraindicated) Sodium oxybate should not be used in combination with CNS depressant anxiolytics, sedatives, and hypnotics or other sedative CNS depressant drugs. Specifically, sodium oxybate use is contraindicated in patients being treated with sedative hypnotic drugs. Sodium oxybate (GHB) has the potential to impair cognitive and motor skills. For example, the concomitant use of barbiturates and benzodiazepines increases sleep duration and may contribute to rapid onset, pronounced CNS depression, respiratory depression, or coma when combined with sodium oxybate.
Sodium Phenylbutyrate; Taurursodiol: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with taurursodiol is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A substrate and taurursodiol is a CYP3A inducer.
Sotorasib: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with sotorasib is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and sotorasib is a CYP3A4 inducer.
Sparsentan: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with sparsentan is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP2C19 substrate and sparsentan is a CYP2C19 inducer.
Spironolactone: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with spironolactone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and spironolactone is a CYP3A inhibitor.
Spironolactone; Hydrochlorothiazide, HCTZ: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with spironolactone is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and spironolactone is a CYP3A inhibitor.
St. John's Wort, Hypericum perforatum: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with St. John's Wort is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 substrate and St. John's Wort is a CYP3A4 inducer.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and diazepam. CNS depressants can potentiate the effects of stiripentol. Consider a dose adjustment of diazepam when coadministered with stiripentol. Coadministration may alter plasma concentrations of diazepam resulting in an increased risk of adverse reactions and/or decreased efficacy. Diazepam is a substrate of CYP3A4, CYP2B6, and CYP2C19. In vitro data predicts inhibition or induction of CYP3A4 and CYP2B6 and inhibition of CYP2C19 by stiripentol potentially resulting in clinically significant interactions.
Streptogramins: (Moderate) Monitor for diazepam-related adverse reactions including sedation and respiratory depression if coadministration with dalfopristin; quinupristin is necessary due to increased diazepam exposure. Dalfopristin; quinupristin is a weak CYP3A4 inhibitor and diazepam is metabolized by CYP3A4.
Sufentanil: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Suvorexant: (Moderate) CNS depressant drugs may have cumulative effects when administered concurrently and they should be used cautiously with suvorexant. A reduction in dose of the CNS depressant may be needed in some cases. These agents include the benzodiazepines.
Tapentadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If tapentadol is initiated in a patient taking a benzodiazepine, a reduced initial dosage of tapentadol is recommended. If the extended-release tapentadol tablets are used concurrently with a benzodiazepine, use an initial tapentadol dose of 50 mg PO every 12 hours. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. Educate patients about the risks and symptoms of respiratory depression and sedation.
Teduglutide: (Moderate) Altered mental status has been observed in patients taking teduglutide and benzodiazepines in the adult clinical studies for teduglutide. Careful monitoring and possible dose adjustment of the benzodiazepine agent may be required. Teduglutide has direct effects on the gut that may increase benzodiazepine exposure by improving oral absorption.
Telotristat Ethyl: (Moderate) Monitor patients for decreased efficacy of diazepam if coadministration with telotristat is necessary. Concurrent use may decrease diazepam exposure. Diazepam is a CYP3A4 and CYP2B6 substrate. Telotristat is a weak CYP3A4 inducer and based on in vitro studies, Potential induction of CYP2B6 in vivo by telotristat cannot be ruled out.
Tetrabenazine: (Moderate) Concurrent use of tetrabenazine and drugs that can cause CNS depression, such as benzodiazepines, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension.
Tezacaftor; Ivacaftor: (Moderate) Use caution when administering ivacaftor and diazepam concurrently because patients may be at increased risk for adverse effects from diazepam. Ivacaftor is a CYP3A inhibitor, and diazepam is a CYP3A substrate. Diazepam is also metabolized by CYP2C19, which is not affected by ivacaftor. Co-administration of ivacaftor with midazolam, another CYP3A substrate, increased midazolam exposure by 1.5-fold.
Thalidomide: (Major) The use of benzodiazepine anxiolytics, sedatives, or hypnotics with thalidomide may cause an additive sedative effect and should be avoided. Thalidomide frequently causes drowsiness and somnolence. Dose reductions may be required. Patients should be instructed to avoid situations where drowsiness may be a problem and not to take other medications that may cause drowsiness without adequate medical advice. Advise patients as to the possible impairment of mental and/or physical abilities required for the performance of hazardous tasks, such as driving a car or operating other complex or dangerous machinery.
Theophylline, Aminophylline: (Minor) Aminophylline or Theophylline have been reported to counteract the pharmacodynamic effects of diazepam and possibly other benzodiazepines. The clinical significance of this interaction is not certain. A proposed mechanism is competitive binding of these methylxanthines to adenosine receptors in the brain. If such therapy is initiated or discontinued, monitor the clinical response to the benzodiazepine.
Thioridazine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Thiothixene: (Moderate) Thiothixene can potentiate the CNS-depressant action of other drugs such as benzodiazepines. Caution should be exercised during simultaneous use of these agents due to potential excessive CNS effects or additive hypotension.
Tiagabine: (Moderate) Because of the possible additive effects of drugs that depress the central nervous system, benzodiazepines should be used with caution in patients receiving tiagabine.
Tipranavir: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with protease inhibitors is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and protease inhibitors are moderate to strong CYP3A4 inhibitors.
Tizanidine: (Moderate) Concurrent use of tizanidine and CNS depressants like the benzodiazepines can cause additive CNS depression. The severity of this interaction may be increased when additional CNS depressants are given.
Tolcapone: (Major) Concomitant administration of benzodiazepines with other drugs have CNS depressant properties, including COMT inhibitors, can potentiate the CNS effects of either agent. COMT inhibitors have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
Topiramate: (Moderate) Topiramate has the potential to cause CNS depression as well as other cognitive and/or neuropsychiatric adverse reactions. The CNS depressant effects of topiramate can be potentiated pharmacodynamically by concurrent use of CNS depressant agents such as the benzodiazepines.
Tramadol: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Tramadol; Acetaminophen: (Major) Concomitant use of opiate agonists with benzodiazepines may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opiate pain medications with benzodiazepines to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If an opiate agonist is initiated in a patient taking a benzodiazepine, use a lower initial dose of the opiate and titrate to clinical response. If parental diazepam is used with an opiate agonist, reduce the opiate agonist dosage by at least 1/3. If a benzodiazepine is prescribed for an indication other than epilepsy in a patient taking an opiate agonist, use a lower initial dose of the benzodiazepine and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Trandolapril; Verapamil: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with verapamil is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and verapamil is a CYP3A4 inhibitor.
Tranylcypromine: (Moderate) Monitor for unusual drowsiness and sedation during coadministration of benzodiazepines and monoamine oxidase inhibitors (MAOIs) due to the risk for additive CNS depression.
Trazodone: (Major) Monitor for excessive sedation and somnolence during coadministration of trazodone and benzodiazepines. Concurrent use may result in additive CNS depression.
Tricyclic antidepressants: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Trifluoperazine: (Major) Limit dosage and duration of benzodiazepines during concomitant phenothiazine use and monitor for unusual drowsiness and sedation due to the risk for additive CNS depression.
Trihexyphenidyl: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of trihexyphenidyl.
Trimethobenzamide: (Moderate) The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the benzodiazepines, may potentiate the effects of either trimethobenzamide or the benzodiazepine.
Trimipramine: (Major) Limit dosage and duration of benzodiazepines during concomitant use with tricyclic antidepressants, and monitor patients closely for respiratory depression and sedation. Additive CNS depression may occur.
Triprolidine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Trofinetide: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with trofinetide is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A substrate and trofinetide is a CYP3A inhibitor.
Tucatinib: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with tucatinib is necessary; decrease the dose of diazepam if necessary. Concurrent use may increase exposure of diazepam. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Tucatinib is a strong CYP3A4 inhibitor.
Valerian, Valeriana officinalis: (Major) Any substances that act on the CNS, including psychoactive drugs and drugs used as anesthetic adjuvants (e.g., barbiturates, benzodiazepines), may theoretically interact with valerian, Valeriana officinalis. The valerian derivative, dihydrovaltrate, binds at barbiturate binding sites; valerenic acid has been shown to inhibit enzyme-induced breakdown of GABA in the brain; the non-volatile monoterpenes (valepotriates) have sedative activity. These interactions are probably pharmacodynamic in nature. There is a possibility of interaction with valerian at normal prescription dosages of anxiolytics, sedatives, and hypnotics (including barbiturates and benzodiazepines). Patients who are taking barbiturates or other sedative/hypnotic drugs should avoid concomitant administration of valerian. Patients taking medications such as tricyclic antidepressants, lithium, MAOIs, skeletal muscle relaxants, SSRIs and serotonin norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine) should discuss the use of herbal supplements with their health care professional prior to consuming valerian; combinations should be approached with caution in the absence of clinical data. Patients should not abruptly stop taking their prescribed psychoactive medications.
Valproic Acid, Divalproex Sodium: (Minor) The administration of valproic acid to patients receiving diazepam can cause an increase in diazepam serum concentrations. If therapeutic effect is altered in patients receiving these medications, an alternative anticonvulsant should be instituted.
Vemurafenib: (Moderate) Vemurafenib is an inducer of CYP3A4 and decreased plasma concentrations of drugs metabolized by this enzyme, such as diazepam, could be expected with concurrent use. Use caution, and monitor therapeutic effects of diazepam when coadministered with vemurafenib.
Verapamil: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with verapamil is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and verapamil is a CYP3A4 inhibitor.
Vigabatrin: (Moderate) Vigabatrin may cause somnolence and fatigue. Drugs that can cause CNS depression, if used concomitantly with vigabatrin, may increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness. Caution should be used when vigabatrin is given in combination with benzodiazepines.
Vilazodone: (Moderate) Due to the CNS effects of vilazodone, caution should be used when vilazodone is given in combination with other centrally acting medications such as the benzodiazepines.
Viloxazine: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with viloxazine is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and viloxazine is a CYP3A4 inhibitor.
Vonoprazan: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with vonoprazan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and vonoprazan is a CYP3A and CYP2C19 inhibitor.
Vonoprazan; Amoxicillin: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with vonoprazan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and vonoprazan is a CYP3A and CYP2C19 inhibitor.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Clarithromycin is a significant inhibitor of CYP3A4 isoenzymes. Clarithromycin could theoretically inhibit the CYP3A4-mediated metabolism of oxidized benzodiazepines, such as diazepam. (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with vonoprazan is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A and CYP2C19 substrate and vonoprazan is a CYP3A and CYP2C19 inhibitor.
Voriconazole: (Moderate) Monitor for an increase in diazepam-related adverse reactions if coadministration with voriconazole is necessary; decrease the dose of diazepam if necessary. At low concentrations, diazepam is primarily metabolized by CYP2C19; however, CYP3A4 is also involved at higher concentrations. Voriconazole is a strong CYP3A4.
Voxelotor: (Moderate) Monitor for an increase in diazepam-related adverse reactions, including sedation and respiratory depression, if coadministration with voxelotor is necessary. Concurrent use may increase diazepam exposure. Diazepam is a CYP3A4 substrate and voxelotor is a CYP3A4 inhibitor.
Zafirlukast: (Moderate) In vitro data indicate that zafirlukast inhibits the CYP2C9 and CYP3A4 isoenzymes at concentrations close to the clinically achieved total plasma concentrations. Until more clinical data are available, zafirlukast should be used cautiously in patients stabilized on drugs metabolized by CYP3A4, such as diazepam.
Zaleplon: (Major) Monitor for excessive sedation and somnolence during coadministration of zaleplon and benzodiazepines. Concurrent use may result in additive CNS depression. If used together, a reduction in the dose of one or both drugs may be needed.
Ziprasidone: (Moderate) Ziprasidone has the potential to impair cognitive and motor skills. Additive CNS depressant effects are possible when ziprasidone is used concurrently with any CNS depressant.
Zolpidem: (Major) Concomitant administration of benzodiazepines with zolpidem can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. If used together, a reduction in the dose of one or both drugs may be needed. For Intermezzo brand of sublingual zolpidem tablets, reduce the dose to 1.75 mg/night. Concurrent use of zolpidem with other sedative-hypnotics, including other zolpidem products, at bedtime or the middle of the night is not recommended. In addition, sleep-related behaviors, such as sleep-driving, are more likely to occur during concurrent use of zolpidem and other CNS depressants than with zolpidem alone.
Zuranolone: (Major) Avoid the use of multiple sedating agents due to the risk for additive CNS depression. If use is necessary, consider a downward dosage adjustment of either or both medications, especially in patients with additional risk factors for sedation-related harm.
Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS and can produce any level of CNS depression required including sedation, hypnosis, skeletal muscle relaxation, and anticonvulsant activity. Recent evidence indicates that benzodiazepines exert their effects through enhancement of the gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex. GABA is an inhibitory neurotransmitter that exerts its effects at specific receptor subtypes designated GABA-A and GABA-B. GABA-A is the primary receptor subtype in the CNS and is thought to be involved in the actions of anxiolytics and sedatives.
Specific benzodiazepine receptor subtypes are thought to be coupled to GABA-A receptors. Three types of BNZ receptors are located in the CNS and other tissues; the BNZ1 receptors are located in the cerebellum and cerebral cortex, the BNZ2 receptors in the cerebral cortex and spinal cord, and the BNZ3 receptors in peripheral tissues. Activation of the BNZ1 receptor is thought to mediate sleep while the BNZ2 receptor affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. Benzodiazepines bind nonspecifically to BNZ1 and BNZ2 which ultimately enhances the effects of GABA. Unlike barbiturates which augment GABA responses by increasing the length of time that chloride channels are open, benzodiazepines enhance the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
The antianxiety action of benzodiazepines may be a result of their ability to block cortical and limbic arousal following stimulation of the reticular pathways while muscle relaxation properties are mediated by inhibiting both mono- and polysynaptic pathways. Benzodiazepine can also depress muscle and motor nerve function directly. Animal studies of the anticonvulsant actions suggest that benzodiazepines augment presynaptic inhibition of neurons, thereby limiting the spread of electrical activity, although they do not actually inhibit the abnormally discharging focus. Benzodiazepines alleviate insomnia by decreasing the latency to sleep and increasing sleep continuity and total sleep time through their effects on GABA.
Benzodiazepines may also have other actions. For example, diazepam has been shown to counteract the cardiovascular toxicity of chloroquine. It is thought that diazepam increases the urinary clearance of chloroquine by improving electrocardiographic and hemodynamic function.
Diazepam is administered orally, nasally, parenterally, and rectally. Both diazepam and its major active metabolite, desmethyldiazepam, bind extensively to plasma proteins (95% to 98%). Diazepam and its metabolite cross the blood-brain barrier. In young healthy males, the volume of distribution at steady-state is 0.8 to 1 L/kg. Metabolism of diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. Diazepam is extensively metabolized to 1 major active metabolite, desmethyldiazepam, and 2 minor active metabolites, temazepam (3-hydroxydiazepam) and oxazepam (3-hydroxy-N-diazepam). At therapeutic doses, desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam while oxazepam and temazepam are usually undetectable. The initial distribution phase is followed by a prolonged terminal elimination phase (half-life up to 48 hours). The terminal elimination half-life of N-desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates. The clearance of diazepam is 20 to 30 mL/minute in young adults. Diazepam accumulates upon multiple dosing, and there is some evidence that the terminal elimination half-life is slightly prolonged. The marked interindividual variability in the clearance of diazepam is probably attributable to variability of CYP2C19, which is known to exhibit genetic polymorphism, and CYP3A4.
Affected cytochrome P450 isoenzymes and drug transporters: CYP2C19, CYP3A4
Diazepam is metabolized by the hepatic isozymes CYP2C19 and CYP3A4.
-Route-Specific Pharmacokinetics
Oral Route
After oral administration, more than 90% of diazepam is absorbed. Tmax is 1 to 1.5 hours, with a range of 0.25 to 2.5 hours. The decline in the plasma-concentration time profile after oral administration is biphasic. The initial distribution phase has a half-life of approximately 1 hour, although it may range up to more than 3 hours. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food, mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in Tmax to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. An average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) occurs when diazepam is administered with food.
Inhalation Route
After administration of diazepam nasal spray in healthy adult subjects, Tmax was 1.5 hours. The estimated volume of distribution at steady-state is 0.8 to 1 L/kg. The absolute bioavailability of diazepam nasal spray relative to intravenous diazepam was 97%. The mean elimination half-life of diazepam after administration of a 10 mg dose of nasal spray was about 49.2 hours. Diazepam plasma exposures (Cmax and AUC) increased approximately proportional to dose from 5 to 20 mg. In a relative bioavailability study of diazepam nasal spray and rectal gel 15 and 20 mg in healthy adult subjects, diazepam Cmax and AUC were 2- to 4-fold less variable for nasal spray and within the range of those seen with rectal gel. Pharmacokinetic parameters were similar between seizure and non-seizure states in patients with epilepsy.
Other Route(s)
Rectal Route
Diazepam is well absorbed after rectal administration. Tmax after administration of diazepam rectal gel is 1.5 hours. The absolute bioavailability of diazepam rectal gel relative to intravenous diazepam is 90%. The volume of distribution of diazepam rectal gel is approximately 1 L/kg. The mean elimination half-lives of diazepam and desmethyldiazepam after administration of a 15 mg dose of diazepam rectal gel are approximately 46 hours and 71 hours, respectively.
-Special Populations
Hepatic Impairment
After administration of 0.1 to 0.15 mg/kg of diazepam intravenously, the half-life of diazepam was prolonged by 2- to 5-fold in subjects with alcoholic cirrhosis (n = 24) compared to age-matched control subjects (n = 37) with a corresponding 50% decrease in clearance. Individual half-lives over 500 hours have been reported in mild to moderate cirrhosis. There is also an increase in volume of distribution. Mean half-life is also prolonged with hepatic fibrosis to 90 hours (range 66 to 104 hours), with chronic active hepatitis to 60 hours (range 26 to 76 hours), and with acute viral hepatitis to 74 hours (range 49 to 129 hours). In chronic active hepatitis, clearance is decreased by almost half.
Renal Impairment
The pharmacokinetics of diazepam have not been studied in patients with renal impairment.
Pediatrics
In full-term infants, elimination half-lives of approximately 30 hours have been reported, with a longer average half-life of 54 hours reported in premature infants of 28 to 34 weeks gestational age and 8 to 81 days postpartum. In both premature and full-term infants, the active metabolite desmethyldiazepam shows evidence of continued accumulation compared to children. Longer half-lives in infants may be due to incomplete maturation of metabolic pathways. After IV administration (0.33 mg/kg), diazepam has a longer half-life in neonates (birth up to 1 month; approximately 50 to 95 hours) and infants (1 month up to 2 years; approximately 40 to 50 hours), whereas it has a shorter half-life in children (2 to 12 years; approximately 15 to 21 hours) and adolescents (12 to 16 years; approximately 18 to 20 hours).
Geriatric
A study of single-dose IV administration of diazepam (0.1 mg/kg) indicates that the elimination half-life of diazepam increases linearly with age, ranging from about 15 hours at 18 years (healthy young adults) to about 100 hours at 95 years (healthy elderly) with a corresponding decrease in clearance of free diazepam.
Gender Differences
Gender does not have any effect on the pharmacokinetics of diazepam.
Other
Cigarette Smoking
Cigarette smoking does not have any effect on the pharmacokinetics of diazepam.