Diazepam

Sedatives/hypnotics: orally administered midazolam, triazolam metabolized by CYP3A e.g., buspirone, diazepam, estazolam, zolpidem parenterally administered midazolam ↑ midazolam ↑ triazolam ↑ sedatives/hypnotics Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

buspirone, diazepam, estazolam, zolpidem parenterally administered midazolam ↑ midazolam ↑ triazolam ↑ sedatives/hypnotics Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

Monoamine Oxidase Inhibitors (MAOIs): (2.9 , 2.10 , 4.1 , 5.2 ) Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued (5.2 , 7.7) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) Benzodiazepines: Diazepam - increased t½, alprazolam – further psychomotor performance decrement due to increased levels (7.7) Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.7) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.7) Serotonergic Drugs: (2.9 , 2.10 , 4.1 , 5.2) Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.4) Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.6 , 7.7) Olanzapine: When used in combination with fluoxetine, also refer to the Drug Interactions section of the package insert for Symbyax (7.7) Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3) ] .

Monoamine Oxidase Inhibitors (MAOIs): (2.9 , 2.10 , 4.1 , 5.2 ) Drugs Metabolized by CYP2D6: Fluoxetine is a potent inhibitor of CYP2D6 enzyme pathway (7.7) Tricyclic Antidepressants (TCAs): Monitor TCA levels during coadministration with fluoxetine or when fluoxetine has been recently discontinued (5.2 , 7.7) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs (7.2) Benzodiazepines: Diazepam - increased t½, alprazolam – further psychomotor performance decrement due to increased levels (7.7) Antipsychotics: Potential for elevation of haloperidol and clozapine levels (7.7) Anticonvulsants: Potential for elevated phenytoin and carbamazepine levels and clinical anticonvulsant toxicity (7.7) Serotonergic Drugs: (2.9 , 2.10 , 4.1 , 5.2) Drugs that Interfere with Hemostasis (e.g., NSAIDs, Aspirin, Warfarin): May potentiate the risk of bleeding (7.4) Drugs Tightly Bound to Plasma Proteins: May cause a shift in plasma concentrations (7.6 , 7.7) Olanzapine: When used in combination with fluoxetine, also refer to the Drug Interactions section of the package insert for Symbyax (7.7) Drugs that Prolong the QT Interval: Do not use fluoxetine with thioridazine or pimozide. Benzodiazepines — The half-life of concurrently administered diazepam may be prolonged in some patients [see Clinical Pharmacology (12.3) ] .

Telaprevir Decrease AUC by 92% Systemic Hormonal Contraceptives Prevention or Management Advise patients to change to non-hormonal methods of birth control during rifampin therapy Estrogens Decrease exposure Progestins Anticonvulsants Phenytoin § Decrease exposure § Antiarrhythmics Disopyramide Decrease exposure Mexiletine Decrease exposure Quinidine Decrease exposure Propafenone Decrease AUC by 50% to 67% Tocainide Decrease exposure Antiestrogens Tamoxifen Decrease AUC by 86% Toremifene Decrease steady state concentrations of toremifene in serum Antithrombotic Agents Clopidogrel Prevention or Management Concomitant use of clopidogrel and rifampin should be discouraged Increase active metabolite exposure and risk of bleeding Ticagrelor Prevention or Management Avoid use Decrease exposure Antipsychotics Haloperidol Decrease plasma concentrations by 70% Lurasidone Prevention or Management: Concomitant use is contraindicated (See CONTRADICTIONS ) Decrease exposure Oral Anticoagulants Prevention or Management Perform prothrombin time daily or as frequently as necessary to establish and maintain the required dose of anticoagulant Warfarin Decrease exposure Antifungals Fluconazole Decrease AUC by 23% Itraconazole Prevention or Management Not recommended 2 weeks before and during itraconazole treatment Decrease exposure Ketoconazole Decrease exposure Beta-blockers Metoprolol Decrease exposure Propranolol Decrease exposure Benzodiazepines Diazepam *,¶ Decrease exposure Benzodiazepine-Related Drugs Zopiclone Decrease AUC by 82% Zolpidem Decrease AUC by 73% Calcium Channel Blockers ¶ Diltiazem Decrease exposure Nifedipine # Decrease exposure Verapamil Decrease exposure Corticosteroids Þ Prednisolone Decrease exposure Cardiac Glycosides Digoxin Prevention or Management Measure serum digoxin concentrations before initiating rifampin.

Concomitant use not recommended due to enhancement of sedative effect.

Diazepam injection has produced hypotension or muscular weakness when used with barbiturates. May potentiate diazepam action.

Inhibits hepatic enzymes (CYP3A and 2C19), leading to increased and prolonged sedation.

CNS depressant that with fentanyl can cause decreased pulmonary artery pressure, hypotension, respiratory depression, profound sedation, coma, and death.

Inhibits hepatic enzymes (CYP3A and 2C19), leading to increased and prolonged sedation.

Inhibits hepatic enzymes (CYP3A and 2C19), leading to increased and prolonged sedation.

May potentiate the action of diazepam. Careful consideration of pharmacology needed when combined.

Diazepam Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, the impairment of motor skills produced by mirtazapine has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking mirtazapine.

Inhibits hepatic enzymes (CYP3A and 2C19), leading to increased and prolonged sedation.

May potentiate or be potentiated by diazepam action, increasing respiratory depression risk. Careful consideration required.

May potentiate the action of diazepam. Careful consideration of pharmacology needed when combined.

CNS depressant that may cause cardiovascular depression, hypotension, respiratory depression, profound sedation, coma, and death when combined with sufentanil.

May potentiate or be potentiated by diazepam action. Careful consideration should be given when combining.

Elimination of diazepam may be prolonged by armodafinil via inhibition of metabolic enzymes, resulting in higher systemic exposure. Dose reduction may be required.

Increases in nordiazepam levels (~15%) with minor adverse effects including dizziness, headache, and nausea observed.

Minor adverse clinical effects (dizziness, headache, nausea) observed; about 15% increases in nordiazepam concentrations.

CYP3A4 inducer that increases diazepam elimination, potentially decreasing efficacy.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

Cimetidine reduces hepatic metabolism of diazepam, delaying elimination and increasing blood levels.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted.

Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. Nursing Mothers Risk Summary Clorazepate and its active metabolite, nordiazepam, are present in breast milk.

CYP3A4 inhibitor that decreases diazepam elimination, potentially increasing adverse reactions.

CYP3A4 substrate; diazepam may interfere with its metabolism, leading to potential drug-drug interaction.

Benzodiazepine with additive sedative effects when combined with desipramine; careful consideration of pharmacology required.

CYP3A4 inducer that increases diazepam elimination, potentially decreasing efficacy.

Valproate can affect the pharmacokinetics of diazepam by inhibiting its metabolism or protein binding displacement.

CYP2C19 substrate that may have altered exposure when used concomitantly with esomeprazole.

Drugs Metabolized by CYP1A2 or CYP2C19 Examples (not fully inclusive): CYP1A2: duloxetine, tacrine, tizanidine, theophylline CYP2C19: lansoprazole, mephenytoin, diazepam Clinical Impact Increased risk for adverse reactions associated with increased concentrations of the drug due to inhibition of either CYP1A2 or CYP2C19 by fexinidazole [see Clinical Pharmacology (12.3) ] .

May decrease phenytoin serum levels; dose adjustment may be required.

CYP2C19 substrate; diazepam may interfere with its metabolism, leading to potential drug-drug interaction.

Antipsychotics, Anxiolytics and Hypnotics Alprazolam a Aripiprazole a Buspirone a Cariprazine Diazepam a Haloperidol a Midazolam (IV) a Quetiapine Ramelteon Risperidone a Suvorexant Monitor for adverse reactions.

Elimination may be prolonged by modafinil with resultant higher systemic exposure. Dose adjustment may be necessary when used concomitantly.

Additive CNS depressant effects; psychomotor function particularly impaired with concurrent use. Caution must be used when administering nabilone in combination.

Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology (12.3) ] . Intervention: Monitor patients for increased sedation and adjust the dose of diazepam as needed.

Diazepam: May potentiate orthostatic hypotension ( 7.1, 7.2 ) Alcohol: May potentiate orthostatic hypotension ( 7.1 ) Carbamazepine: Increased clearance of olanzapine ( 7.1) Fluvoxamine: May increase olanzapine levels ( 7.1 ) Olanzapine and Fluoxetine in Combination: Also refer to the DrugInteractions section of the package insert for Symbyax. (7.1) CNS Acting Drugs: Caution should be used when taken in combination with other centrally acting drugs and alcohol ( 7.2 ) Antihypertensive Agents: Enhanced antihypertensive effect ( 7.2 ) Levodopa and Dopamine Agonists: May antagonize levodopa/dopamine agonists (7.2 ) Other Concomitant Drug Therapy: When using olanzapine in combination with lithium or valproate, refer to the Drug Interactions sections of the package insert for those products ( 7.2 ) 7.1 Potential for Other Drugs to Affect Olanzapine Diazepam — The co-administration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [see Drug Interactions (7.2) ]. Diazepam — Olanzapine did not influence the pharmacokinetics of diazepam or its active metabolite N-desmethyldiazepam.

Diazepam, Alcohol, and Other CNS Acting Drugs Clinical Implication: Concomitant use of diazepam, alcohol, or other CNS acting drugs with LYBALVI may potentiate the orthostatic hypotension observed with olanzapine [see Warnings and Precautions ( 5.9 )] . Prevention or Management: LYBALVI should be used with caution in patients receiving concomitantly diazepam or other CNS acting drugs, or using alcohol.

Co-administration with olanzapine potentiates orthostatic hypotension.

CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clopidogrel Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3 )]. Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology ( 12.3 )] . Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.

CYP2C19 Substrates (e.g., clopidogrel, citalopram, cilostazol, phenytoin, diazepam) Clopidogrel Clinical Impact: Concomitant use of omeprazole 80 mg results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition [see Clinical Pharmacology ( 12.3 )]. Diazepam Clinical Impact: Increased exposure of diazepam [see Clinical Pharmacology ( 12.3 )] . Intervention: Monitor patients for increased sedation and reduce the dose of diazepam as needed.

CYP2C19 substrate with increased plasma concentrations when combined with omeprazole.

May potentiate or be potentiated by diazepam action. Careful consideration should be given when combining.

CYP3A4 substrate; diazepam may interfere with its metabolism, leading to potential drug-drug interaction.

CYP3A4 inducer that increases diazepam elimination, potentially decreasing efficacy.

CYP3A4 inducer that increases diazepam elimination, potentially decreasing efficacy.

May decrease phenytoin serum levels; monitoring of phenytoin levels recommended.

CYP2C19 substrate; diazepam may interfere with its metabolism, leading to potential drug-drug interaction.

CYP2C19 inhibitor that decreases diazepam elimination, potentially increasing adverse reactions.

Highly protein-bound drugs include diazepam, diazoxide, and lidocaine. 7.3 Other Highly Protein-Bound Drugs Raloxifene hydrochloride tablets should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine.

Highly protein-bound drugs include diazepam, diazoxide, and lidocaine. 7.3 Other Highly Protein-Bound Drugs Raloxifene hydrochloride should be used with caution with certain other highly protein-bound drugs such as diazepam, diazoxide, and lidocaine.

May potentiate or be potentiated by diazepam action. Careful consideration should be given when combining.

Sertraline decreases diazepam clearance by 32% and increases desmethyldiazepam Tmax. Clinical significance is unknown but monitoring may be warranted.

Sertraline decreases diazepam clearance by 32% and increases desmethyldiazepam Tmax by 23%. Clinical significance unknown.

DIACOMIT may inhibit CYP2C19 metabolism of diazepam; consider dose reduction if adverse reactions occur.

CYP3A4 substrate; diazepam may interfere with its metabolism, leading to potential drug-drug interaction.

May potentiate or be potentiated by diazepam action. Careful consideration should be given when combining.

CYP2C19 inhibitor that decreases diazepam elimination, potentially increasing adverse reactions.

CYP3A4 inhibitor that decreases diazepam elimination, potentially increasing adverse reactions.

CNS depressant that may potentiate CNS-depressant effects of diazepam.

Valproate can inhibit diazepam metabolism and displace it from protein binding, potentially increasing diazepam concentrations.

Valproate can affect pharmacokinetics by inhibiting metabolism or protein binding displacement. Dosage adjustment may be necessary.

CYP3A4 substrate; diazepam may interfere with its metabolism, leading to potential drug-drug interaction.

Diazepam does not affect the pharmacokinetics of acamprosate; no clinically important interaction.

The pharmacokinetics of acamprosate are not affected by diazepam.

Reduce diazepam peak concentrations by 30% and slow rate of absorption with 20-25 minute delay in peak achievement, but no effect on extent of absorption.

Prazosin has been administered without adverse drug interaction with diazepam in limited clinical experience.

Administered without adverse drug interaction in limited clinical experience.

Terazosin has been used concomitantly with diazepam in at least 50 patients with no interactions observed.

Used concomitantly with terazosin in at least 50 patients with no interactions observed.

No significant pharmacokinetic interaction observed. Diazepam did not affect venlafaxine or ODV pharmacokinetics, and venlafaxine did not affect diazepam psychomotor effects.

Diazepam did not affect venlafaxine or ODV pharmacokinetics, and venlafaxine did not affect diazepam pharmacokinetics or psychomotor effects.

25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

Other Benzodiazepines : clorazepate diazepam estazolam flurazepam parenterally administered midazolam ↑ sedatives/hypnotics Parenterally administered midazolam: Coadministration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin.

Atomoxetine did not affect the binding of warfarin, acetylsalicylic acid, phenytoin, or diazepam to human albumin.

Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam ↑ sedatives/hypnotics Coadministration with parenteral midazolam may increase plasma concentrations of midazolam.

However, neither phenobarbital nor diazepam appears to affect dantrolene sodium metabolism. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone.

However, neither phenobarbital nor diazepam appears to affect Dantrium metabolism. Binding to plasma protein is not significantly altered by diazepam, diphenylhydantoin, or phenylbutazone.

buspirone, diazepam, estazolam, zolpidem ↑ sedatives/hypnotics With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions.

metabolized by CYP3A: e.g., buspirone, diazepam, estazolam, zolpidem ↑ sedatives/hypnotics With concomitant use, titration is recommended with sedatives/hypnotics metabolized by CYP3A and a lower dose of the sedatives/hypnotics should be considered with monitoring for increased and prolonged effects or adverse reactions.

In healthy subjects, no significant drug-drug interaction was observed when disopyramide phosphate was coadministered with either propranolol or diazepam.

Diazepam: Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate.

Doxazosin tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and flu remedies.

Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Coadministration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate.

Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam ↑ sedatives/hypnotics Triazolam and orally administered midazolam are extensively metabolized by CYP3A.

Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam buspirone zolpidem ↑ sedatives/hypnotics Coadministration of parenteral midazolam with STRIBILD should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

In vitro studies have shown no binding displacement between entacapone and other highly bound drugs, such as warfarin, salicylic acid, phenylbutazone, and diazepam.

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Co-administration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Coadministration of esomeprazole 30 mg and diazepam, a CYP2C19 substrate, resulted in a 45% decrease in clearance of diazepam.

Benzodiazepine: diazepam ↑ diazepam Concomitant use of etravirine tablets with diazepam may increase plasma concentrations of diazepam. A decrease in diazepam dose may be needed. Benzodiazepine: diazepam ↑ diazepam Concomitant use of etravirine tablets with diazepam may increase plasma concentrations of diazepam.

Compounds tested in man include warfarin, theophylline, phenytoin, diazepam, aminopyrine and antipyrine.

Diazepam: See WARNINGS AND PRECAUTIONS ( 5.9 ).

Benzodiazepines: Alprazolam, clorazepate, diazepam, flurazepam ↑ Benzodiazepines Clinical significance is unknown.

Chloral Hydrate Diazepam Ethionamide Lovastatin Metoclopramide 6-Mercaptopurine Nitroprusside Para-aminosalicylate sodium Perphenazine Resorcinol (excessive topical use) Thiazide Diuretics These agents have been associated with thyroid hormone and/or TSH level alterations by various mechanisms.

No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine, and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients.

No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients.

7.7 Other Drugs Used in the Surgical Setting No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients.

Drug Interactions No untoward clinical manifestations have been observed in limited experience with patients in whom milrinone was used concurrently with the following drugs: digitalis glycosides; lidocaine, quinidine; hydralazine, prazosin; isosorbide dinitrate, nitroglycerin; chlorthalidone, furosemide, hydrochlorothiazide, spironolactone; captopril; heparin, warfarin, diazepam, insulin; and potassium supplements.

Sedative/hypnotics buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotic A dose decrease may be needed for these drugs when co-administered with PAXLOVID and monitoring for adverse events.

7.6 Potential for Other Drugs to Affect Olanzapine and Fluoxetine Capsules Benzodiazepines — Coadministration of diazepam with olanzapine potentiated the orthostatic hypotension observed with olanzapine [ see Drug Interactions ( 7.7 ) ]. Benzodiazepines — Multiple doses of olanzapine did not influence the pharmacokinetics of diazepam and its active metabolite N-desmethyldiazepam. When concurrently administered with fluoxetine, the half-life of diazepam may be prolonged in some patients [ see Clinical Pharmacology ( 12.3 ) ].

Diazepam Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.

Diazepam Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.

Diazepam Under steady-state conditions, diazepam does not appear to affect paroxetine kinetics. The effects of paroxetine on diazepam were not evaluated.

Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites. Diazepam does not alter the pharmacokinetics of propranolol. Benzodiazepines Propranolol can inhibit the metabolism of diazepam, resulting in increased concentrations of diazepam and its metabolites.

Studies in healthy subjects have shown that rabeprazole does not have clinically significant interactions with other drugs metabolized by the CYP450 system, such as warfarin and theophylline given as single oral doses, diazepam as a single intravenous dose, and phenytoin given as a single intravenous dose (with supplemental oral dosing).

Table 4: Drug Interactions with PRIFTIN: Dosage Adjustment May be Necessary Drug Class Examples of Drugs Within Class Antiarrhythmics Disopyramide, mexiletine, quinidine, tocainide Antibiotics Chloramphenicol, clarithromycin, dapsone, doxycycline; Fluoroquinolones (such as ciprofloxacin) Oral Anticoagulants Warfarin Anticonvulsants Phenytoin Antimalarials Quinine Azole Antifungals Fluconazole, itraconazole, ketoconazole Antipsychotics Haloperidol Barbiturates Phenobarbital Benzodiazepines Diazepam Beta-Blockers Propranolol Calcium Channel Blockers Diltiazem, nifedipine, verapamil Cardiac Glycoside Preparations Digoxin Corticosteroids Prednisone Fibrates Clofibrate Oral Hypoglycemics Sulfonylureas (e.g., glyburide, glipizide) Hormonal Contraceptives/Progestins Ethinyl estradiol, levonorgestrel Immunosuppressants Cyclosporine, tacrolimus Methylxanthines Theophylline Narcotic analgesics Methadone Phosphodiesterase-5 (PDE-5) Inhibitors Sildenafil Thyroid preparations Levothyroxine Tricyclic antidepressants Amitriptyline, nortriptyline 7.5 Other Interactions The conversion of PRIFTIN to 25-desacetyl rifapentine is mediated by an esterase enzyme.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

Sedative/hypnotics: buspirone, clorazepate, diazepam, estazolam, flurazepam, zolpidem ↑ sedative/hypnotics A dose decrease may be needed for these drugs when co-administered with ritonavir.

Diazepam may interfere with metabolism of terfenadine, a CYP3A4 substrate, leading to potential drug-drug interaction.

25% increase Diazepam Benzodiazepines increase CNS concentrations of adenosine, a potent CNS depressant, while theophylline blocks adenosine receptors. Larger diazepam doses may be required to produce desired level of sedation. Discontinuation of theophylline without reduction of diazepam dose may result in respiratory depression.

7.3 Diazepam Under steady-state conditions for venlafaxine administered at 150 mg/day, a single 10 mg dose of diazepam did not appear to affect the pharmacokinetics of either venlafaxine or ODV in 18 healthy male subjects. Venlafaxine also did not have any effect on the pharmacokinetics of diazepam or its active metabolite, desmethyldiazepam, or affect the psychomotor and psychometric effects induced by diazepam. This finding was confirmed in vivo by clinical drug interaction studies in which venlafaxine did not inhibit the metabolism of several CYP3A4 substrates, including alprazolam, diazepam, and terfenadine.

Multiple doses of TRINTELLIX did not affect the pharmacokinetics or pharmacodynamics (composite cognitive score) of diazepam [see Clinical Pharmacology (12.3) ] .