Alprazolam

Strong CYP3A inhibitor is contraindicated with alprazolam due to profound effect on clearance, resulting in increased concentrations.

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. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

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. Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Strong CYP3A inhibitor is contraindicated with alprazolam due to profound effect on clearance, resulting in increased concentrations.

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. (See PRECAUTIONS: DRUG INTERACTIONS .) Enhanced Sedation Coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. Concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam or alprazolam is contraindicated.

Listed in CONTRAINDICATIONS and WARNINGS sections, indicating contraindicated use with nefazodone.

( 7.1 ) Use with CYP3A Inhibitors (except ritonavir): Increase the risk of adverse reactions of alprazolam. Strong Inhibitors of CYP3A (except ritonavir) Clinical implication Concomitant use of alprazolam with strong CYP3A inhibitors has a profound effect on the clearance of alprazolam, resulting in increased concentrations of alprazolam and increased risk of adverse reactions [see Clinical Pharmacology (12.3) ]. Prevention or management Concomitant use of alprazolam with a strong CYP3A4 inhibitor (except ritonavir) is contraindicated [see Contraindications (4) , Warnings and Precautions (5.5) ].

Produces additive CNS depressant effects when co-administered with alprazolam.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Increased alprazolam exposure may increase risk of adverse reactions with 3-day aprepitant regimen; monitor for benzodiazepine-related adverse reactions.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of digoxin toxicity.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Erythromycin may increase the pharmacologic effects of alprazolam through decreased clearance.

Related benzodiazepine whose effect may be increased by erythromycin.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Increased alprazolam exposure may increase the risk of adverse reactions. Monitor for benzodiazepine-related adverse reactions.

Increased alprazolam exposure may increase risk of adverse reactions. Monitor for benzodiazepine-related adverse reactions.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

Concomitant use increases risk of respiratory depression due to actions at different CNS receptor sites.

CYP3A4 inhibitor that increases warfarin effect and INR; requires close monitoring.

7.1 Drugs Having Clinically Important Interactions with Alprazolam Table 4 includes clinically significant drug interactions with alprazolam [see CLINICAL PHARMACOLOGY (12.3)]. Table 4: Clinically Significant Drug Interactions with Alprazolam Opioids Clinical implication The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Prevention or management Limit dosage and duration of concomitant use of alprazolam and opioids, and monitor patients closely for respiratory depression and sedation [see WARNINGS AND PRECAUTIONS (5.1)].

CYP3A inducer. Can increase alprazolam metabolism and decrease plasma levels. Caution recommended during coadministration.

Weak CYP3A inhibitor may increase alprazolam concentrations; avoid use or consider dose reduction.

Steady state plasma concentrations of desipramine can increase by approximately 20% when coadministered with alprazolam up to 4 mg/day. Clinical significance unknown.

Possible drug interaction with alprazolam based on clinical studies in other benzodiazepines. Caution recommended during coadministration.

Moderate CYP3A inhibitor may increase alprazolam concentrations; avoid use or consider dose reduction.

Potential interaction due to fluvoxamine inhibition of CYP3A4, which is involved in alprazolam metabolism.

Possible drug interaction with alprazolam based on clinical studies in other benzodiazepines. Caution recommended.

CYP3A4 inhibitor that increases haloperidol plasma concentrations; monitor for increased adverse effects including QTc prolongation.

CYP3A4 inhibitor that increases haloperidol plasma concentrations, raising risk of adverse events including QTc prolongation.

Steady state plasma concentrations of imipramine can increase by approximately 30% when coadministered with alprazolam up to 4 mg/day. Clinical significance unknown.

Possible drug interaction with alprazolam based on clinical studies in other benzodiazepines. Caution recommended during coadministration.

Alprazolam Triazolam Triazolam, Alprazolam : Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is coadministered with clarithromycin.

Benzodiazepine increases impairment of cognitive and motor skills. Avoid concomitant use.

Moderate CYP3A inhibitor may increase alprazolam concentrations; avoid use or consider dose reduction.

Benzodiazepine metabolized via CYP3A4; increased plasma concentrations possible when administered with AKYNZEO.

Moderate and weak CYP3A4 inhibitors include alprozalam, ameprenavir, amiodarone, aprepitant, atazanavir, cimetidine, cyclosporine, diltiazem, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, quinuprestin/dalfopristin, valproic acid, and verapamil.

Increased alprazolam maximum plasma concentration by 18%, decreased clearance by 22%, and increased half-life by 29%.

In vitro studies suggest possible drug interaction with alprazolam based on CYP3A inhibition. Caution recommended during coadministration.

CYP3A inducer. Can increase alprazolam metabolism and decrease plasma levels. Caution recommended during coadministration.

Prevention or Management Midazolam, Alprazolam, Triazolam Closely monitor for adverse reactions associated with high plasma concentrations of benzodiazepines that are CYP3A4 substrates during concomitant use, and a benzodiazepine receptor antagonist should be available to reverse effects [see Warnings and Precautions (5.7) ].

Decreased alprazolam maximum plasma concentration by 6%, decreased clearance by 38%, and increased half-life by 58%.

In vitro studies suggest possible CYP3A inhibition, but in vivo study with steady state sertraline 50-150 mg/day did not reveal clinically significant pharmacokinetic changes.

If alprazolam orally disintegrating tablets are coadministered with other psychotropic agents or anticonvulsant drugs, carefully consider the pharmacology of the agents to be employed, particularly with compounds which might potentiate the action of benzodiazepines. The benzodiazepines, including alprazolam, produce additive CNS depressant effects when coadministered with other psychotropic medications, anticonvulsants, antihistaminics, alcohol and other drugs which themselves produce CNS depression. 7.2 Drugs Effecting Salivary Flow and Stomach pH Because alprazolam orally disintegrating tablets disintegrate in the presence of saliva, and the formulation requires an acidic environment to dissolve, concomitant drugs or diseases that cause dry mouth or raise stomach pH might slow disintegration or dissolution, resulting in slowed or decreased absorption.

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

Psychoactive Drugs Hallucinations have been reported when ketorolac tromethamine was used in patients taking psychoactive drugs (fluoxetine, thiothixene, alprazolam).

7.2 Weak CYP3A4 Inhibitors Weak CYP3A4 inhibitors (such as alprazolam, amiodarone, amlodipine, atorvastatin, bicalutamide, cilostazol, cimetidine, cyclosporine, fluoxetine, fluvoxamine, ginkgo, goldenseal, isoniazid, lapatinib, nilotinib, pazopanib, ranitidine, ranolazine, ticagrelor, zileuton) can increase lomitapide exposure approximately 2-fold [see Clinical Pharmacology (12.3) ] .

Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine.

Data from in vitro studies of benzodiazepines other than alprazolam suggest a possible drug interaction for the following: ergotamine, cyclosporine, amiodarone, nicardipine, and nifedipine.

Coadministration of alprazolam and fluoxetine has resulted in increased alprazolam plasma concentrations and in further psychomotor performance decrement due to increased alprazolam levels.

Concomitant use of posaconazole and other benzodiazepines metabolized by CYP3A4 (e.g., alprazolam, triazolam) could result in increased plasma concentrations of these benzodiazepines.

The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol. The pharmacokinetics of oxazepam, triazolam, lorazepam, and alprazolam are not affected by co-administration of propranolol.

No dose adjustment for EMSAM is needed when EMSAM is used concomitantly with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and CYP3A4 inhibitors (e.g., ketoconazole). No clinically meaningful change in selegiline exposure was seen when EMSAM was co-administered with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and ketoconazole [see Clinical Pharmacology (12.3) ] . No dose adjustment of alprazolam, ibuprofen, levothyroxine, olanzapine, risperidone, warfarin, or strong CYP3A4 inhibitors (e.g., ketoconazole) is necessary when these drugs are used in combination with EMSAM.

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.

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.

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.

Alprazolam Triazolam Calcium Channel Blockers Clinical Effect Clarithromycin is a strong CYP3A inhibitor.

Other benzodiazepines including triazolam and alprazolam (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) HMG-CoA Reductase Inhibitors (Statins) (CYP3A4 Inhibition) In Vitro Studies Demonstrated Potential for Voriconazole to Inhibit Metabolism (Increased Plasma Exposure) Frequent monitoring for adverse reactions and toxicity related to statins.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3.