Chlordiazepoxide and clidinium are a long-acting benzodiazepine and an antimuscarinic, respectively, used together in an oral preparation to control emotional and somatic factors in gastrointestinal disorders. Chlordiazepoxide; clidinium may also be used as adjunctive therapy to treat GI-related problems such as irritable bowel syndrome and peptic ulcer disease. Chlordiazepoxide; clidinium does not aid in the healing of peptic ulcers and other, clinically proven therapies should be used for active ulcer disease. The use of this combination for the treatment of acute enterocolitis is not recommended as the drug may lead to a reduction in GI motility resulting in retention of the GI toxin. Doses of each ingredient should be titrated and individualized, especially in older adults. As with all benzodiazepines, product labels carry a boxed warning about a risk of fatal respiratory depression particularly when used with opioids, as well as risks for substance abuse, misuse and addiction, and withdrawal reactions with discontinuation.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Oral Administration
-Administer orally 30 minutes to 1 hour before meals to maximize absorption.
This monograph discusses the use of the chlordiazepoxide; clidinium combination product for the management of GI disorders. Clinicians may wish to consult the individual chlordiazepoxide drug monograph for more information.
No side effects or manifestations not seen with either compound alone have been reported with the use of chlordiazepoxide; clidinium, but this possibility cannot be excluded.
Chlordiazepoxide; clidinium contains clidinium. Clidinium therapy results in adverse effects related to the pharmacological actions common to all anticholinergic agents. These include dryness of the mouth (xerostomia), blurred vision, some degree of mydriasis, urinary hesitancy and constipation. There is a risk for urinary retention. Constipation has occurred most often when the product has been combined with other spasmolytic or anticholinergic agents and/or a low residue diet. Severe constipation may occur in some patients receiving anticholinergic agents and may lead to ileus.
Drowsiness, ataxia, and confusion have been reported in some patients receiving chlordiazepoxide; clidinium, and these may occur most often in the elderly and debilitated. While these effects can be avoided in almost all instances by proper dosage adjustment, they have occasionally been observed at the lower dosage ranges. In a few instances syncope has been reported. Because chlordiazepoxide can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries.
Other adverse reactions reported during therapy with chlordiazepoxide; clidinium due to the chlordiazepoxide component include isolated instances of minor menstrual irregularity, nausea, extrapyramidal symptoms (e.g., tremor), libido increase, and libido decrease. Such side effects have been infrequent and are generally controlled with reduction of dosage. EEG changes (low-voltage fast activity) have also been observed in patients during and after chlordiazepoxide treatment.
Paradoxical reactions to chlordiazepoxide (e.g., excitability, agitation, irritability, stimulation, and acute rage) have been reported in psychiatric patients and should be watched for during chlordiazepoxide; clidinium therapy.
Allergic urticaria and anaphylactoid reactions have been reported with benzodiazepine or clidinium use. Isolated cases of skin eruptions (rash) and edema have occurred due to chlordiazepoxide.
Hematologic events (e.g., agranulocytosis), jaundice, and hepatic dysfunction of uncertain etiology have rarely been observed with chlordiazepoxide therapy. Patients receiving long-term therapy with chlordiazepoxide; clidinium should undergo periodic blood counts and liver function tests.
Chlordiazepoxide-induced purpura has been reported in one case. Thrombotic thrombocytopenic purpura (TTP) has been reported in the literature with the use of chlordiazepoxide; clidinium; in this case an immune-mediated mechanism was suspected, but whether the product caused the event was not known.
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.
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 dose or discontinuing therapy.
Tolerance to chlordiazepoxide 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 chlordiazepoxide may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.
Benzodiazepines cross the placenta and may produce sedation, hypotonia, lethargy, and neonatal respiratory depression at birth. Monitor exposed neonates 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.
Chlordiazepoxide; clidinium is contraindicated in individuals with a known or suspected hypersensitivity to chlordiazepoxide or clidinium. Use with caution in patients who report other benzodiazepine hypersensitivity as cross-reactivity is possible. Reactions consistent with anaphylaxis or angioedema (involving the tongue, glottis, or larynx), dyspnea, and throat closing have been reported with some benzodiazepines and may be fatal. Patients who develop angioedema during treatment should not be rechallenged with the drug.
Patients who present for chlordiazepoxide treatment may have an underlying psychological and/or physiological disturbance such as depression and should be thoroughly evaluated prior to initiation of the drug. Use caution when chlordiazepoxide; clidinium is used where there is any evidence of impending depression; suicidal tendencies may be present and protective measures may be necessary. Consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered.
Serious adverse reactions to chlordiazepoxide; clidinium include CNS depression and respiratory depression. Chlordiazepoxide coadministration with other CNS depressants, especially opioids, should be avoided unless no other alternatives are available as coadministration significantly increases the risk for profound sedation, respiratory depression, coma, and death. Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to the use of opioids alone. Reserve concomitant prescribing of these drugs for when alternative treatment options are inadequate. Limit dosages and durations to the minimum required and follow patients for signs and symptoms of respiratory depression and sedation. As with other benzodiazepines, chlordiazepoxide should be avoided in patients with significant pulmonary disease if possible; if use of the drug is necessary, close monitoring of pulmonary function is recommended. Chlordiazepoxide should be avoided if possible in patients with pre-existing respiratory insufficiency, such as severe chronic obstructive pulmonary disease (COPD) or sleep apnea because the drug can exacerbate respiratory depression.
Due to CNS depressive effects, caution patients against driving or operating machinery until they know how chlordiazepoxide; clidinium may affect them. Some patients may experience excessive sedation and impaired ability to perform tasks. Because chlordiazepoxide can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the older adult, with the potential for subsequent severe injuries. Increased CNS and respiratory effects may be seen with use of chlordiazepoxide in patients taking other CNS depressants, including alcohol. Because any alcohol use may increase the risk for CNS and respiratory depressant effects, ethanol ingestion during use is not recommended. Ethanol intoxication may increase the risk of serious CNS or respiratory depressant effects.
Use chlordiazepoxide; clidinium with caution in patients with a history of alcoholism or substance abuse. 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. Generally, benzodiazepines should be prescribed for short periods (2 to 4 weeks) with continued reevaluation of the need for treatment. 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 history of a seizure disorder should not be withdrawn abruptly from benzodiazepines due to the risk of precipitating seizures; status epilepticus has also been reported. Clinicians should be aware that the use of flumazenil may increase the risk of seizures, particularly in long-term users of benzodiazepines.
Chlordiazepoxide; clidinium is contraindicated in patients with acute closed-angle glaucoma. Some degree of mydriasis may occur due to the anticholinergic effects of clidinium which may precipitate angle-closure glaucoma.
Chlordiazepoxide; clidinium is contraindicated in patients with prostatic hypertrophy or benign bladder neck obstruction (bladder obstruction) as the product can exacerbate risks for urinary retention in these individuals. The anticholinergic effects of clidinium may be significant and are additive with other anticholinergic medications. Due to the anticholinergic actions, caution is advisable when used in patients with decreased gastrointestinal motility; as with other anticholinergic agents, avoid use in patients with ileus or GI obstruction.
Chlordiazepoxide; clidinium 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.
Chlordiazepoxide may have a porphyrogenic effect and should be used cautiously in patients with porphyria. There are isolated reports associating chlordiazepoxide with exacerbation of porphyria.
Chlordiazepoxide; clidinium should be administered cautiously to patients with hepatic disease due to the extensive metabolism of chlordiazepoxide in the liver; the elimination half-life of the drug can be prolonged. Chlordiazepoxide metabolites may accumulate leading to severe and prolonged stupor in patients with cirrhosis. Patients with hepatic disease should receive reduced initial dosages and be closely monitored for sedation and tolerability.
Use chlordiazepoxide; clidinium with caution in those with renal impairment. In renal failure (eGFR less than 10 mL/minute), it is suggested to reduce the dosage of chlordiazepoxide by at least 50%. Monitor these patients closely for excessive sedation or other adverse effects. The fixed dose nature of the combined product may not allow for appropriate dosage adjustment.
Due to the clidinium component, which has anticholinergic actions, caution individuals taking chlordiazepoxide; clidinium about exposure to ambient temperature increase. Use may decrease sweating and may increase risk for heat stroke.
Delayed elimination of these medications can either intensify or prolong the actions or adverse reactions of chlordiazepoxide; clidinium in the geriatric adult. In geriatric and debilitated individuals, use the smallest effective dosage; gradually increase as needed and tolerated only with close clinical monitoring. Because chlordiazepoxide can cause drowsiness and a decreased level of consciousness, there is a higher risk of falls, particularly in the elderly, with the potential for subsequent severe injuries. According to the Beers Criteria, chlordiazepoxide; clidinium is considered a potentially inappropriate medication (PIM) in geriatric adults and should be avoided due to the high anticholinergic properties of clidinium. Geriatric adults have an increased sensitivity to benzodiazepines and slower metabolism of long-acting agents such as chlordiazepoxide, which increases the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle accidents. Avoid use in those with the following conditions due to the potential for symptom exacerbation or adverse effects: dementia/cognitive impairment (drug-induced adverse CNS effects), delirium/high risk of delirium (new-onset or worsening delirium), or lower urinary tract symptoms/benign prostatic hyperplasia in men (urinary retention or hesitancy with anticholinergic agents). Avoid use in geriatric adults with a history of falls or fractures, unless safer alternatives are not available since benzodiazepines can produce ataxia, impaired psychomotor function, syncope, and additional falls. If a benzodiazepine must be used, consider reducing the use of other CNS-active medications and implement other strategies to reduce fall risk.
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. Chlordiazepoxide is not recommended for use in labor or obstetric delivery, including cesarean section. Monitor neonates exposed to benzodiazepines during pregnancy, labor, or obstetric delivery for signs of sedation, including respiratory depression, lethargy, or hypotonia and manage accordingly. When benzodiazepines are administered late in pregnancy, they are easily transferred to the fetus where they have the potential to accumulate, causing two major neonatal syndromes: a neonatal abstinence syndrome (NAS) (withdrawal) and floppy infant syndrome (FIS). Monitor neonates exposed to benzodiazepines late in pregnancy for NAS, including hyperreflexia, irritability, restlessness, tremors, inconsolable crying, or feeding difficulties and managed accordingly. Due to the long half-life of chlordiazepoxide and accumulation of chlordiazepoxide and its active metabolite in neonatal tissues, NAS may be delayed in newborns for up to 21 days and the symptoms may continue for 3 to 6 months. 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. Health care providers are encouraged to register patients exposed to chlordiazepoxide during pregnancy by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/research/pregnancyregistry/. There is a lack of published data regarding use of clidinium durin pregnancy, including an absence of reports of medication-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes.
Due to a lack of data regarding the safety of chlordiazepoxide; clidinium during lactation and the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, avoid use during breast-feeding. Based on studies with other benzodiazepines, it can be anticipated that chlordiazepoxide and its metabolites are excreted into breast milk. Monitor breastfed infants exposed to benzodiazepines through breast milk for sedation, poor feeding, and poor weight gain. Neonates metabolize benzodiazepines more slowly than adults and, when used chronically, accumulation may occur in the infant producing sedation, nausea, poor feeding, or other adverse effects. There are no data on the presence of clidinium in human or animal milk, effects on the breastfed infant, or effects on milk production. Anticholinergic agents may reduce the production of breast milk.
The safe and effective use of chlordiazepoxide; clidinium has not been established in infants, children, and adolescents less than 18 years of age. Pediatric individuals are generally more sensitive to the CNS effects of the benzodiazepines and studies of chlordiazepoxide; clidinium for the treatment of GI disorders in pediatric patients are not available.
To control emotional and somatic factors in gastrointestinal disorders, for the adjunctive treatment of peptic ulcer disease, or for symptomatic treatment of irritable bowel syndrome (irritable colon, spastic colon, mucous colitis) and acute enterocolitis:
Oral dosage:
Adults: 1 to 2 capsules (5 mg chlordiazepoxide and 2.5 mg clidinium per capsule) PO 3 to 4 times per day, given 30 minutes to 1 hour before meals and at bedtime. Geriatric patients should be initiated at the lower dosage. Individualize to the response and tolerance of the patient. LIMITATION OF USE: This drug does not aid in the healing of peptic ulcers; clinically-proven therapies should be used for healing active peptic ulcer disease.
Maximum Dosage Limits:
-Adults
40 mg/day PO chlordiazepoxide and 20 mg/day PO clidinium.
-Elderly
40 mg/day PO chlordiazepoxide and 20 mg/day PO clidinium.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments are not available; use lower initial dosages and monitor closely for oversedation or other adverse effects. Use chlordiazepoxide in patients with significant hepatic disease with extreme caution; there is a high risk of drug accumulation with repeated dosing.
Patients with Renal Impairment Dosing
eGFR 10 mL/minute or more: Use with caution. It is advisable to start with low initial dosage and adjust to response and tolerance in patients with renal impairment.
eGFR less than 10 mL/minute or end-stage renal disease (ESRD): Reduce chlordiazepoxide dosage by 50%. Monitor closely for excessive sedation and other adverse effects. Use the fixed dose combination of chlordiazepoxide; clidinium product with caution.
*non-FDA-approved indication
AbobotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
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 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) Monitor patients for signs of urinary retention or reduced gastric motility when dihydrocodeine is used concomitantly with an anticholinergic drug. The concomitant use of dihydrocodeine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. (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 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. 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. 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.
Acetylcholine Chloride: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Aclidinium: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufacturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
Aclidinium; Formoterol: (Moderate) Although aclidinium is minimally absorbed into the systemic circulation after inhalation, there is the potential for aclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufacturer, avoid concomitant administration of aclidinium with other anticholinergic medications, when possible.
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 chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with adagrasib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A substrate; adagrasib is a strong 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 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when alfentanil is used concomitantly with an anticholinergic drug. The concomitant use of alfentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Aliskiren; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Alosetron: (Major) Concomitant use of alosetron and anticholinergics, which can decrease GI motility, may seriously worsen constipation, leading to events such as GI obstuction, impaction, or paralytic ileus. Although specific recommendations are not available from the manufacturer, it would be prudent to avoid anticholinergics in patients taking alosetron.
Alprazolam: (Moderate) Concomitant administration of alprazolam with CNS-depressant drugs can potentiate the CNS effects of either agent.
Aluminum Hydroxide: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Carbonate: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Hydroxide; Simethicone: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Aluminum Hydroxide; Magnesium Trisilicate: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Amantadine: (Major) Amantadine may exhibit anticholinergic activity. Antimuscarinics, such as clidinium, may potentiate the anticholinergic effects of amantadine.
Amiloride; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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.
Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Amobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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. (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when amoxapine is used concomitantly with other anticholinergic agents. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when these drugs are combined with amoxapine.
Amoxicillin; Clarithromycin; Omeprazole: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Antacids: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
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: (Moderate) Use caution if chlordiazepoxide and aprepitant, fosaprepitant are used concurrently and monitor for an increase in chlordiazepoxide-related adverse effects for several days after administration of a multi-day aprepitant regimen. Chlordiazepoxide 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 chlordiazepoxide. 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 125mg 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.
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.
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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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) Additive anticholinergic effects may be seen when orphenadrine is used concomitantly with other antimuscarinics. (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 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; Omeprazole: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
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. Educate patients about the risks and symptoms of respiratory depression and sedation.
Atazanavir: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Atazanavir; Cobicistat: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Atenolol; Chlorthalidone: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Atropine; Difenoxin: (Moderate) Concomitant administration of benzodiazepines with CNS-depressant drugs, such as diphenoxylate/difenoxin, can potentiate the CNS effects of either agent. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth mucle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to antimuscarinic agents, such as clidinium. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
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.
Azilsartan; Chlorthalidone: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when opium is used concomitantly with an anticholinergic drug. The concomitant use of opium and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Benazepril; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when benzhydrocodone is used concomitantly with an anticholinergic drug. The concomitant use of benzhydrocodone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Benztropine: (Moderate) CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase the sedative effects of benztropine.
Bethanechol: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Botulinum Toxins: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
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.
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 mixed opiate agonist/antagonist 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 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 mixed opiate agonist/antagonist 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 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.
Bupropion: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should consider this when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
Bupropion; Naltrexone: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should consider this when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
Buspirone: (Moderate) It is common for patients to overlap anxiety treatment when switching from benzodiazepines to buspirone. Buspirone has a slow onset of action and the drug will not block the withdrawal syndrome often seen with cessation of benzodiazepine therapy in those with benzodiazepine dependence. Therefore, before starting therapy with buspirone, withdraw patients gradually from the benzodiazepine. Alternatively, conversion to buspirone therapy may require treatment overlap to allow for the downward titration of the benzodiazepine while buspirone takes effect. It should be noted that the combination of buspirone and benzodiazepines can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Butalbital; Acetaminophen: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Butalbital; Acetaminophen; Caffeine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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 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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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 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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when butorphanol is used concomitantly with an anticholinergic drug. The concomitant use of butorphanol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
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: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Famotidine; Magnesium Hydroxide: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Magnesium Hydroxide: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Magnesium Hydroxide; Simethicone: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Calcium Carbonate; Simethicone: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
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: (Major) Avoid concomitant use of calcium carbonate and anticholinergics. Antacids may interfere with the absorption of anticholinergics.
Candesartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and chlordiazepoxide. CNS depressants can potentiate the effects of cannabidiol.
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.
Captopril; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Carbamazepine: (Moderate) Hepatic inducers, such as carbamazepine, can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
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 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 chlordiazepoxide with ceritinib is necessary. Chlordiazepoxide is a CYP3A4 substrate and 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.
Cevimeline: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
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.
Chlorothiazide: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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 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. 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. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including chlorpromazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Chlorthalidone: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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.
Cholinergic agonists: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Cimetidine: (Moderate) Cimetidine can inhibit the hepatic clearance of some benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide.
Ciprofloxacin: (Major) Ciprofloxacin is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
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. (Moderate) The use of drugs that decrease GI motility, such as drugs that exert antimuscarinic properties may pharmacodynamically oppose the effects of cisapride.
Clarithromycin: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
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: (Major) Avoid co-prescribing clozapine with other anticholinergic medicines that can cause gastrointestinal hypomotility, due to a potential to increase serious constipation, ileus, and other potentially serious bowel conditions that may result in hospitalization. Clozapine exhibits potent anticholinergic effects. Additive anticholinergic effects may be seen when clozapine is used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (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 chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
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 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 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 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 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 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.
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.
Crofelemer: (Moderate) Pharmacodynamic interactions between crofelemer and antimuscarinics are theoretically possible. Crofelemer does not affect GI motility mechanisms, but does have antidiarrheal effects. Patients taking medications that decrease GI motility, such as antimuscarinics, may be at greater risk for serious complications from crofelemer, such as constipation with chronic use. Use caution and monitor GI symptoms during coadministration.
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.
Danazol: (Moderate) Danazol is a CYP3A4 inhibitor and can theoretically reduce the metabolism of CYP3A4 substrates, including chlordiazepoxide.
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: (Major) Monitor for excessive sedation and somnolence during use of daridorexant with chlordiazepoxide. 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 daridorexant, a reduction in dose of one or both agents may be needed. The risk of next-day impairment, including impaired driving, is increased if daridorexant is taken with other CNS depressants.
Darunavir: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Darunavir; Cobicistat: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed. (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Dasiglucagon: (Major) The concomitant use of intravenous glucagon and anticholinergics increases the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Concomitant use is not recommended.
DaxibotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Delavirdine: (Moderate) Delavirdine is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
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 chlordiazepoxide, may have additive effects and worsen drowsiness or sedation.
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; Bupropion: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should consider this when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
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.
Dextromethorphan; Quinidine: (Moderate) The anticholinergic effects of quinidine may be significant and may be enhanced when combined with antimuscarinics. Anticholinergic agents administered concurrently with quinidine may produce additive antivagal effects on AV nodal conduction.
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.
Digoxin: (Moderate) Anticholinergics, because of their ability to cause tachycardia, can antagonize the beneficial actions of digoxin in atrial fibrillation/flutter. Routine therapeutic monitoring should be continued when an antimuscarinic agent is prescribed with digoxin until the effects of combined use are known.
Diltiazem: (Moderate) Diltiazem could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide.
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. (Moderate) Diphenoxylate is a synthetic opiate derivative that appears to exert its effect locally and centrally on the smooth mucle cells of the GI tract to inhibit GI motility and slow excess GI propulsion. The effects can be additive to antimuscarinic agents, such as clidinium. In some cases, constipation might occur, and effects on the CNS or bladder function may also be additive.
Disopyramide: (Moderate) In addition to its electrophysiologic effects, disopyramide exhibits clinically significant anticholinergic properties. These can be additive with other anticholinergics. Clinicians should be aware that urinary retention, particularly in males, and aggravation of glaucoma are realistic possibilities of using disopyramide with other anticholinergic agents.
Disulfiram: (Moderate) Disulfiram competes for the binding sites on hepatic cytochrome P-450 with benzodiazepines that undergo oxidative metabolism, including chlordiazepoxide, thereby slowing the metabolism of benzodiazepines and increasing their steady-state plasma concentrations.
Donepezil: (Moderate) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
Donepezil; Memantine: (Moderate) The adverse effects of anticholinergics, such as dry mouth, urinary hesitancy or blurred vision may be enhanced with use of memantine; dosage adjustments of the anticholinergic drug may be required when memantine is coadministered. In addition, preliminary evidence indicates that chronic anticholinergic use in patients with Alzheimer's Disease may possibly have an adverse effect on cognitive function. Therefore, the effectiveness of drugs used in the treatment of Alzheimer's such as memantine, may be adversely affected by chronic antimuscarinic therapy. (Moderate) The therapeutic benefits of donepezil, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
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 coadministration of dronabinol with anticholinergics is necessary. Concurrent use of dronabinol, THC with anticholinergics may result in additive drowsiness, hypertension, tachycardia, and possibly cardiotoxicity. (Moderate) Use caution if the use of benzodiazepines are necessary with dronabinol, and monitor for additive dizziness, confusion, somnolence, and other CNS effects.
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 chlordiazepoxide. 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 chlordiazepoxide. 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 chlordiazepoxide. Monitor patients closely for excessive side effects.
Elbasvir; Grazoprevir: (Moderate) Administering chlordiazepoxide with elbasvir; grazoprevir may result in elevated chlordiazepoxide plasma concentrations. Chlordiazepoxide is a substrate of CYP3A; grazoprevir is a weak CYP3A inhibitor. If these drugs are used together, closely monitor for signs of adverse events.
Eluxadoline: (Major) Avoid use of eluxadoline with medications that may cause constipation, such as anticholinergics. Discontinue use of eluxadoline in patients who develop severe constipation lasting more than 4 days.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) The plasma concentrations of chlordiazepoxide may be elevated when administered concurrently with cobicistat. Clinical monitoring for adverse effects is recommended during coadministration. Cobicistat is a strong CYP3A4 inhibitor, while chlordiazepoxide is a CYP3A4 substrate.
Enalapril; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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.
Eprosartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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.
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.
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) Hydantoin anticonvulsants can theoretically increase the clearance of chlordiazepoxide, leading to lower benzodiazepine concentrations. Chlordiazepoxide may also have an unpredictable effect on phenytoin serum concentrations.
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.
Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and benzodiazepines. Concurrent use may result in additive CNS depression.
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 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.
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) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
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. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including fluphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
Fluticasone; Umeclidinium; Vilanterol: (Moderate) There is the potential for umeclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of umeclidinium with other anticholinergic medications when possible.
Fluvoxamine: (Moderate) Fluvoxamine may inhibit the metabolism of benzodiazepines that undergo hepatic oxidation, including chlordiazepoxide.
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: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Fosinopril; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Fosphenytoin: (Moderate) Hydantoin anticonvulsants can theoretically increase the clearance of benzodiazepines metabolized by oxidative metabolism, such as chlordiazepoxide, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide has been reported to have an unpredictable effect on 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 chlordiazepoxide is added or discontinued.
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.
Galantamine: (Moderate) The therapeutic benefits of galantamine, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
General anesthetics: (Moderate) Concomitant administration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent.
Glucagon: (Major) The concomitant use of intravenous glucagon and anticholinergics increases the risk of gastrointestinal adverse reactions due to additive effects on inhibition of gastrointestinal motility. Concomitant use is not recommended.
Glycopyrronium: (Moderate) Although glycopyrronium is minimally absorbed into the systemic circulation after topical application, there is the potential for glycopyrronium to have additive anticholinergic effects when administered with other antimuscarinics. Per the manufaturer, avoid concomitant administration of glycopyrronium with other anticholinergic medications.
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.
Guanidine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
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. Educate patients about the risks and symptoms of respiratory depression and sedation. Avoid opiate cough medications in patients taking benzodiazepines.
Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Hydrochlorothiazide, HCTZ; Moexipril: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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. 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. 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. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when hydromorphone is used concomitantly with an anticholinergic drug. The concomitant use of hydromorphone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Hydroxyzine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
Ibritumomab Tiuxetan: (Moderate) Use anticholinergics, such as clidinium bromide, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
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. Educate patients about the risks and symptoms of respiratory depression and sedation.
Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with chlordiazepoxide, a CYP3A substrate, as chlordiazepoxide 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) CYP3A4 inhibitors, such as imatinib, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
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.
IncobotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
Indinavir: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Ipratropium: (Moderate) Although ipratropium is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinic or anticholinergic medications. Per the manufacturer, avoid coadministration.
Ipratropium; Albuterol: (Moderate) Although ipratropium is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinic or anticholinergic medications. Per the manufacturer, avoid coadministration.
Irbesartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with chlordiazepoxide may result in increased serum concentrations of chlordiazepoxide. Chlordiazepoxide 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; Pyrazinamide, PZA; Rifampin: (Moderate) Several hepatic inducers, such as rifampin, can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Isoniazid, INH; Rifampin: (Moderate) Several hepatic inducers, such as rifampin, can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
Itraconazole: (Moderate) Antimuscarinics can raise intragastric pH. This effect may decrease the oral bioavailability of itraconazole; antimuscarinics should be used cautiously in patients receiving itraconazole. (Moderate) CYP3A4 inhibitors, such as itraconazole, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
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 chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ketoconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and ketoconazole is a strong CYP3A4 inhibitor.
Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
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.
Letermovir: (Moderate) Closely monitor for chlordiazepoxide-related adverse events if given with letermovir. In patients who are also receiving treatment with cyclosporine, the magnitude of this interaction may be amplified. A clinically relevant increase in the plasma concentration of chlordiazepoxide, a CYP3A4 substrate, may occur during concurrent administration with letermovir, a moderate CYP3A4 inhibitor. 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 chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ketoconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide 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. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when levorphanol is used concomitantly with an anticholinergic drug. The concomitant use of levorphanol and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Linaclotide: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as linaclotide.
Lisinopril; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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 chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with lonafarnib is necessary; adjust the dose of chlordiazepoxide if necessary. Chlordiazepoxide is a CYP3A4 substrate and lonafarnib is a strong CYP3A4 inhibitor.
Lopinavir; Ritonavir: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Losartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Loxapine: (Moderate) Loxapine has anticholinergic activity. The concomitant use of loxapine and other anticholinergic drugs can increase the risk of anticholinergic adverse reactions including exacerbation of glaucoma, constipation, and urinary retention. Depending on the agent used, additive drowsiness/dizziness may also occur.
Lubiprostone: (Moderate) Antimuscarinic drugs can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation, such as lubiprostone. The clinical significance of these potential interactions is uncertain.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of chlordiazepoxide by decreasing its systemic exposure; a dosage increase of chlordiazepoxide may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Chlordiazepoxide is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of chlordiazepoxide by decreasing its systemic exposure; a dosage increase of chlordiazepoxide may be necessary during co-administration of lumacaftor; ivacaftor. Do not exceed the maximum recommended dose. Chlordiazepoxide is a CYP3A4 substrate. Lumacaftor is a strong CYP3A inducer.
Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and benzodiazepines. Concurrent use may result in additive CNS depression.
Lurasidone: (Moderate) Antipsychotic agents may disrupt core temperature regulation; therefore, caution is recommended during concurrent use of lurasidone and medications with anticholinergic activity such as antimuscarinics. Concurrent use of lurasidone and medications with anticholinergic activity may contribute to heat-related disorders. Monitor patients for heat intolerance, decreased sweating, or increased body temperature if lurasidone is used with antimuscarinics. (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.
Macimorelin: (Major) Avoid use of macimorelin with drugs that may blunt the growth hormone response to macimorelin, such as antimuscarinic anticholinergic agents. Healthcare providers are advised to discontinue anticholinergics at least 1 week before administering macimorelin. Use of these medications together may impact the accuracy of the macimorelin growth hormone test.
Magnesium Hydroxide: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Magnesium Salts: (Moderate) Antacids may inhibit the oral absorption of anticholinergics. Simultaneous oral administration should be avoided when feasible; separate dosing by at least 2 hours to limit an interaction.
Maprotiline: (Moderate) Additive anticholinergic and CNS effects may be seen when maprotiline is used concomitantly with clidinium. (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.
Meclizine: (Moderate) Coadministration can potentiate the CNS effects (e.g., increased sedation or respiratory depression) of either agent. Use caution with this combination.
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.
Memantine: (Moderate) The adverse effects of anticholinergics, such as dry mouth, urinary hesitancy or blurred vision may be enhanced with use of memantine; dosage adjustments of the anticholinergic drug may be required when memantine is coadministered. In addition, preliminary evidence indicates that chronic anticholinergic use in patients with Alzheimer's Disease may possibly have an adverse effect on cognitive function. Therefore, the effectiveness of drugs used in the treatment of Alzheimer's such as memantine, may be adversely affected by chronic antimuscarinic therapy.
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 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when meperidine is used concomitantly with an anticholinergic drug. The concomitant use of meperidine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
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.
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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when methadone is used concomitantly with an anticholinergic drug. The concomitant use of methadone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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: (Moderate) Drugs with significant antimuscarinic activity, such as anticholinergics and antimuscarinics, may slow GI motility and thus may reduce the prokinetic actions of metoclopramide. Monitor patients for an increase in gastrointestinal complaints, such as reflux or constipation. Additive drowsiness may occur as well. The clinical significance is uncertain. (Minor) Combined use of metoclopramide and other CNS depressants, such as anxiolytics, sedatives, and hypnotics, can increase possible sedation.
Metolazone: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Metoprolol; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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.
Mitotane: (Major) Use caution if mitotane and chlordiazepoxide are used concomitantly, and monitor for decreased efficacy of chlordiazepoxide and a possible change in dosage requirements. Mitotane is a strong CYP3A4 inducer and chlordiazepoxide is a CYP3A4 substrate in vitro; coadministration may result in decreased plasma concentrations of chlordiazepoxide. Additionally, mitotane can cause sedation, lethargy, vertigo, and other CNS adverse reactions; additive CNS effects may occur initially when mitotane is given concurrently with chlordiazepoxide.
Molindone: (Moderate) Antipsychotics are associated with anticholinergic effects; therefore, additive effects may be seen during concurrent use of molindone and other drugs having anticholinergic activity such as antimuscarinics. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other CNS effects may also occur.
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. 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. 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. (Moderate) Concurrent use of nabilone with anticholinergics may result in pronounced tachycardia and drowsiness.
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 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when nalbuphine is used concomitantly with an anticholinergic drug. The concomitant use of nalbuphine and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Nelfinavir: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Nicardipine: (Moderate) CYP3A4 inhibitors, such as nicardipine, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. Monitor patients closely who receive concurrent therapy.
Nirmatrelvir; Ritonavir: (Major) Consider withholding chlordiazepoxide, if clinically appropriate, during receipt of ritonavir-boosted nirmatrelvir. If this is not feasible, consider using an alternative COVID-19 therapy or reducing the chlordiazepoxide dose. However, do not stop chlordiazepoxide abruptly or rapidly reduce the dose as this may precipitate an acute withdrawal reaction, especially in patients who have been receiving high doses over an extended period. Coadministration may increase chlordiazepoxide exposure resulting in increased toxicity and excessive sedation. Chlordiazepoxide is a CYP3A substrate and nirmatrelvir is a CYP3A inhibitor. (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
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.
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 cardiopulmonary 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 severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
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 cardiopulmonary 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 severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used. (Moderate) Fluoxetine could theoretically inhibit CYP3A4 metabolism of oxidized benzodiazepines, including chlordiazepoxide. Patients should be monitored for clinical response, and adjust benzodiazepine dosage if needed.
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 cardiopulmonary 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 severity of adverse effects such as drowsiness, sedation, dizziness, and orthostatic hypotension. (Moderate) Additive anticholinergic effects may be seen when olanzapine and anticholinergics are used concomitantly; use with caution. Use of olanzapine and other drugs with anticholinergic activity can increase the risk for severe gastrointestinal adverse reactions related to hypomotility. Olanzapine exhibits anticholinergic activity. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the anticholinergic agent used.
Oliceridine: (Major) Concomitant use of oliceridine with chlordiazepoxide may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medication with chlordiazepoxide 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oliceridine is used with clidinium. Use of anticholinergics may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.
Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Olmesartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Omeprazole: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
Omeprazole; Amoxicillin; Rifabutin: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole. (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
Omeprazole; Sodium Bicarbonate: (Moderate) Omeprazole inhibits CYP2C19. There have been some case reports describing an interaction between omeprazole and benzodiazepines metabolized via the cytochrome P450 system, such as chlordiazepoxide. Patients should be monitored to determine if it is necessary to adjust the dosage of the benzodiazepine when taken concomitantly with omeprazole.
OnabotulinumtoxinA: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
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) Chlordiazepoxide is metabolized by CYP3A4; oritavancin is a weak CYP3A4 inducer. Plasma concentrations and efficacy of chlordiazepoxide may be reduced if these drugs are administered concurrently.
Orphenadrine: (Moderate) Additive anticholinergic effects may be seen when orphenadrine is used concomitantly with other antimuscarinics. (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. 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. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when oxymorphone is used concomitantly with an anticholinergic drug. The concomitant use of oxymorphone and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
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.
Paroxetine: (Moderate) Monitor for signs or symptoms of anticholinergic toxicity during concomitant anticholinergic medication and paroxetine use. Concomitant use may result in additive anticholinergic adverse effects.
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 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when pentazocine is used concomitantly with an anticholinergic drug. The concomitant use of pentazocine and anticholinergic medications may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Pentobarbital: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including perphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
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. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including perphenazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Additive CNS and/or respiratory depression may occur. Additionally, barbiturates may increase the metabolism of chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are 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) Monitor for decreased sweating and increased body temperature, especially in hot weather, during concomitant use of topiramate and other drugs that predispose persons to heat-related disorders, such as anticholinergic medications. Concomitant use increases the risk for oligohidrosis and hyperthermia. (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) Phenytoin is a hepatic inducer and can theoretically increase the clearance of chlordiazepoxide oxidative metabolism, leading to lower benzodiazepine concentrations. In addition, chlordiazepoxide 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 chlordiazepoxide is added or discontinued.
Pilocarpine: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Pimozide: (Moderate) Due to the effects of pimozide on cognition, it should be used cautiously with other CNS depressants including benzodiazepines.
Posaconazole: (Moderate) Posaconazole inhibits CYP3A4 and may increase serum concentrations of benzodiazepines metabolized by this enzyme, including chlordiazepoxide.
Potassium Bicarbonate: (Moderate) Use anticholinergics, such as clidinium bromide, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
Potassium Chloride: (Moderate) Use anticholinergics, such as clidinium bromide, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
Pralidoxime: (Major) The muscarinic actions of drugs known as parasympathomimetics, including both direct cholinergic receptor agonists and cholinesterase inhibitors, can antagonize the antimuscarinic actions of anticholinergic drugs, and vice versa.
Pramipexole: (Major) Concomitant administration of benzodiazepines with CNS-depressant drugs, including pramipexole, can potentiate the CNS effects.
Pramlintide: (Major) Pramlintide therapy should not be considered in patients taking medications that alter gastric motility, such as anticholinergics. Pramlintide slows gastric emptying and the rate of nutrient delivery to the small intestine. Medications that have depressive effects on GI could potentiate the actions of pramlintide.
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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Procainamide: (Moderate) The anticholinergic effects of procainamide may be significant and may be enhanced when combined with anticholinergics. Anticholinergic agents administered concurrently with procainamide may produce additive antivagal effects on AV nodal conduction, although this is not as well documented for procainamide as for quinidine.
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. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including prochlorperazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
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: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
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) Somnolence is a commonly reported adverse effect of quetiapine; coadministration of quetiapine with anxiolytics, sedatives, and hypnotics, or other CNS depressants may result in additive sedative effects.
Quinapril; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Quinidine: (Moderate) The anticholinergic effects of quinidine may be significant and may be enhanced when combined with antimuscarinics. Anticholinergic agents administered concurrently with quinidine may produce additive antivagal effects on AV nodal conduction.
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 chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Rasagiline: (Moderate) MAOIs exhibit secondary anticholinergic actions. Additive anticholinergic effects may be seen when MAOIs are used concomitantly with antimuscarinics. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive CNS effects are also possible when many of these drugs are combined with MAOIs. (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. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when remifentanil is used concomitantly with an anticholinergic drug. The concomitant use of remifentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
Remimazolam: (Major) The sedative effect of remimazolam can be accentuated by chlordiazepoxide. Titrate the dose of remimazolam to the desired clinical response and continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation.
Revefenacin: (Moderate) Although revefenacin is minimally absorbed into the systemic circulation after inhalation, there is the potential for additive anticholinergic effects when administered with other antimuscarinics. Avoid concomitant administration with other anticholinergic and antimucarinic medications.
Ribociclib: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ribociclib is necessary; adjust the dose of chlordiazepoxide if necessary. Ribociclib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Ribociclib; Letrozole: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with ribociclib is necessary; adjust the dose of chlordiazepoxide if necessary. Ribociclib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Rifabutin: (Moderate) Rifabutin is a hepatic inducer and can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, including chlordiazepoxide, leading to lower benzodiazepine concentrations.
Rifampin: (Moderate) Several hepatic inducers, such as rifampin, can theoretically increase the clearance of benzodiazpines metabolized by oxidative metabolism, leading to lower benzodiazepine concentrations.
RimabotulinumtoxinB: (Moderate) The use of systemic antimuscarinic/anticholinergic agents following the administration of botulinum toxins may result in a potentiation of systemic anticholinergic effects (e.g., blurred vision, dry mouth, constipation, or urinary retention).
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.
Ritonavir: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
Rivastigmine: (Moderate) The therapeutic benefits of rivastigmine, a cholinesterase inhibitor, may be diminished during chronic co-administration with antimuscarinics or medications with potent anticholinergic activity. When concurrent use is not avoidable, the patient should be monitored for cognitive decline and anticholinergic side effects. Clinicians should generally avoid multiple medications with anticholinergic activity in the patient with dementia. Some of the common selective antimuscarinic drugs for bladder problems, (such as oxybutynin, darifenacin, trospium, fesoterodine, tolerodine, or solifenacin), do not routinely cause problems with medications used for dementia, but may cause anticholinergic side effects in some patients. Atropine may be used to offset bradycardia in cholinesterase inhibitor overdose.
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.
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: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
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 chlordiazepoxide. Chlordiazepoxide is a CYP3A4 substrate. Barbiturates are CYP3A4 inducers.
Secretin: (Major) Discontinue anticholinergic medications at least 5 half-lives before administering secretin. Patients who are receiving anticholinergics at the time of stimulation testing may be hyporesponsive to secretin stimulation and produce a false result. Consider additional testing and clinical assessments for aid in diagnosis.
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.
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 anticholinergics. 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. (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 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 Sulfate; Magnesium Sulfate; Potassium Chloride: (Moderate) Use anticholinergics, such as clidinium bromide, and concomitant solid oral dosage forms of potassium chloride with caution due to risk for gastrointestinal mucosal injury. Anticholinergics may decrease gastric motility and increase the transit time of solid oral dosage forms of potassium chloride leading to prolonged contact with the gastrointestinal mucosa.
Solifenacin: (Moderate) Additive anticholinergic effects may be seen when drugs with antimuscarinic properties like solifenacin are used concomitantly with other antimuscarinics. Blurred vision and dry mouth would be common effects. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur.
Spironolactone; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
St. John's Wort, Hypericum perforatum: (Major) St. John's Wort may induce the hepatic CYP3A4 metabolism of chlordiazepoxide which is metabolized by oxidation. It would be prudent to avoid co-administration of St. John's Wort with chlordiazepoxide. Benzodiazepines that are not metabolized by CYP3A4 such as oxazepam or lorazepam may be alternatives if a benzodiazepine is required in combination with St. John's Wort.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and chlordiazepoxide. CNS depressants can potentiate the effects of stiripentol.
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 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. (Moderate) Monitor patients for signs of urinary retention or reduced gastric motility when sufentanil is used concomitantly with an anticholinergic drug. The concomitant use of sufentanil and anticholinergic drugs may increase risk of urinary retention and/or severe constipation, which may lead to paralytic ileus. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect.
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. Educate patients about the risks and symptoms of respiratory depression and sedation. (Moderate) Tapentadol should be used cautiously with anticholinergic medications since additive depressive effects on GI motility or bladder function may occur. Monitor patients for signs of urinary retention or reduced gastric motility. Opiates increase the tone and decrease the propulsive contractions of the smooth muscle of the gastrointestinal tract. Prolongation of the gastrointestinal transit time may be the mechanism of the constipating effect. Opiate analgesics combined with antimuscarinics can cause severe constipation or paralytic ileus, especially with chronic use. Additive CNS effects like drowsiness or dizziness may also occur.
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.
Tegaserod: (Major) Drugs that exert significant anticholinergic properties such as antimuscarinics may pharmacodynamically oppose the effects of prokinetic agents such as tegaserod. Avoid administering antimuscarinics along with tegaserod under most circumstances. Inhaled respiratory antimuscarinics, such as ipratropium, are unlikely to interact with tegaserod. Ophthalmic anticholinergics may interact if sufficient systemic absorption of the eye medication occurs.
Telmisartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Tenapanor: (Moderate) Anticholinergics can promote constipation and pharmacodynamically oppose the action of drugs used for the treatment of constipation or constipation-associated irritable bowel syndrome, such as tenapanor.
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.
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.
Thiazide diuretics: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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. (Moderate) Additive anticholinergic effects may be seen when drugs with anticholinergic properties like thioridazine are used concomitantly with anticholinergic agents. Adverse effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Additive drowsiness may also occur, depending on the interacting agent.
Thiothixene: (Moderate) Anticholinergics may have additive effects with thiothixene, an antipsychotic with the potential for anticholinergic activity. Monitor for anticholinergic-related adverse effects such as xerostomia, blurred vision, constipation, and urinary retention during concurrent use. (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.
Tiotropium: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Tiotropium; Olodaterol: (Major) Avoid concomitant use of anticholinergic medications and tiotropium due to increased risk for anticholinergic adverse effects.
Tipranavir: (Major) CYP3A4 inhibitors, such as protease inhibitors, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity. A decrease in the chlordiazepoxide dose may be needed.
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.
Tolterodine: (Moderate) Additive anticholinergic effects may be seen when tolterodine is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined.
Topiramate: (Moderate) Monitor for decreased sweating and increased body temperature, especially in hot weather, during concomitant use of topiramate and other drugs that predispose persons to heat-related disorders, such as anticholinergic medications. Concomitant use increases the risk for oligohidrosis and hyperthermia. (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 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 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) Verapamil is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
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.
Triamterene; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
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. (Moderate) Additive anticholinergic effects may be seen when anticholinergics are used concomitantly with phenothiazines, including trifluoperazine. Clinicians should note that antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness or other additive CNS effects may also occur.
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. (Moderate) Trimethobenzamide has CNS depressant effects and may cause drowsiness. The concurrent use of trimethobenzamide with other medications that cause CNS depression, like the anticholinergics, may potentiate the effects of either trimethobenzamide or the anticholinergic.
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.
Trospium: (Moderate) Additive anticholinergic effects may be seen when trospium is used concomitantly with other antimuscarinics. When possible, avoid concurrent use, especially in the elderly, who are more susceptible to the anticholinergic effects. Consider alternatives to these other medications, if available. Clinicians should note that antimuscarinic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Blurred vision, constipation, and dry mouth may be more prominent additive effects. With many of the listed agents, additive drowsiness may also occur when combined with trospium.
Tucatinib: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with tucatinib is necessary; adjust the dose of chlordiazepoxide if necessary. Tucatinib is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Umeclidinium: (Moderate) There is the potential for umeclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of umeclidinium with other anticholinergic medications when possible.
Umeclidinium; Vilanterol: (Moderate) There is the potential for umeclidinium to have additive anticholinergic effects when administered with other anticholinergics or antimuscarinics. Per the manufaturer, avoid concomitant administration of umeclidinium with other anticholinergic medications when possible.
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.
Valsartan; Hydrochlorothiazide, HCTZ: (Minor) Coadministration of thiazides and antimuscarinics (e.g., atropine and biperiden) may result in increased bioavailability of the thiazide. This is apparently a result of a decrease in gastrointestinal motility and rate of stomach emptying by the antimuscarinic agent. In addition, diuretics can increase urinary frequency, which may aggravate bladder symptoms.
Verapamil: (Moderate) Verapamil is a CYP3A4 inhibitor and may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Vibegron: (Moderate) Vibegron should be administered with caution in patients taking anticholinergics because of potential for an increased risk of urinary retention. Monitor for symptoms of urinary difficulties or urinary retention. Patients may note constipation or dry mouth with use of these drugs together.
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.
Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) CYP3A4 inhibitors, such as clarithromycin, may reduce the metabolism of chlordiazepoxide and increase the potential for benzodiazepine toxicity.
Voriconazole: (Moderate) Monitor for an increase in chlordiazepoxide-related adverse reactions including sedation and respiratory depression if coadministration with voriconazole is necessary; adjust the dose of chlordiazepoxide if necessary. Voriconazole is a strong CYP3A4 inhibitor and chlordiazepoxide is a CYP3A4 substrate.
Warfarin: (Moderate) Chlordiazepoxide has been associated with a decreased anticoagulation response to warfarin. Monitor coagulation parameters and adjust warfarin dosage as needed.
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 chlordiazepoxide.
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.
Zonisamide: (Moderate) Zonisamide use is associated with case reports of decreased sweating, hyperthermia, heat intolerance, or heat stroke and should be used with caution in combination with other drugs that may also predispose patients to heat-related disorders like anticholinergics.
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.
Chlordiazepoxide and clidinium are combined in a single formulation for antianxiety effects (chlordiazepoxide) and anticholinergic/antispasmolytic effects (clidinium). The additive effects of these two drugs may help to control the emotional and somatic factors that appear to be important in functional gastrointestinal disorders.
-Chlordiazepoxide: Benzodiazepines act at the level of the limbic, thalamic, and hypothalamic regions of the CNS to produce CNS depression. 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.
-Clidinium: Clidinium is an anticholinergic and antisecretory agent used to decrease motility in the GI, urinary, and biliary tracts. Clidinium, a quaternary compound, is structurally related to belladonna alkaloids. Clidinium is a competitive inhibitor at autonomic postganglionic cholinergic receptors, located in many tissues including the GI tract. The principal clinical effects of antimuscarinics such as clidinium are a reduction in salivary, bronchial, and sweat gland secretions; mydriasis; cycloplegia; changes in heart rate; contraction of the bladder detrusor muscle and of the GI smooth muscle; decreased gastric secretion; and decreased GI motility. The early spike increase in rectosigmoid activity following a meal (also known as the gastrocolic response) is inhibited by clidinium; this reduction in rectosigmoid activity may be useful in irritable bowel syndrome. At lower doses, a paradoxical decrease in heart rate occurs. At higher doses, effects are seen at nicotinic receptors in autonomic ganglia, causing restlessness, hallucinations, disorientation, and/or delirium.
Chlordiazepoxide; clidinium combination products are administered orally.
-Chlordiazepoxide: Chlordiazepoxide distributes throughout the body and is about 96% protein-bound. It crosses the CSF, placenta and is distributed into breast milk. Chlordiazepoxide undergoes oxidative metabolism in the liver, producing several active metabolites. Chlordiazepoxide and its metabolites have a half-life ranging anywhere from 5-100 hours. The main active metabolite, desmethyldiazepam, has a half-life of several days. Repeated dosing may lead to drug accumulation, particularly in liver disease. Elimination occurs primarily as active metabolites in the urine.
-Clidinium: Clidinium does not cross the blood-brain barrier, placenta or eye due to poor lipid solubility. It is not known if clidinium crosses into breast milk, but its use may decrease production of milk due to anticholinergic effects. Clidinium is metabolized in the liver to its 3-hydroxy alcohol. The elimination half-life is biphasic with an initial half-life of 2.4 hours and a terminal half-life of 20 hours. Roughly one-third of the dose is excreted renally within the first 24 hours after dosing. Twenty to 40% of the dose is excreted in the feces.
-Route-Specific Pharmacokinetics
Oral Route
-Chlordiazepoxide: Oral chlordiazepoxide is rapidly absorbed across the GI with 100% bioavailability. A reduction in anxiety is usually evident within 45 minutes following an oral dose, but this response correlates with the steady-state plasma levels of the active metabolites rather than of the parent drug.
-Clidinium: Clidinium is poorly absorbed from the intestine. The onset of action is roughly 1 hour with a duration of 3 hours.
-Special Populations
Hepatic Impairment
The half-lives of chlordiazepoxide and clidinium may be significantly prolonged in patients with hepatic disease due to reduced metabolism of the parent drugs.
-Chlordiazepoxide: Repeated dosing may lead to drug accumulation, particularly in patients with liver disease.
Elderly
Chlordiazepoxide; clidinium contains chlordiazepoxide. Volume of distribution and elimination half-life of chlordiazepoxide may increase in the elderly who may be prone to accumulation of chlordiazepoxide and its active metabolites.