Midazolam

b See Contraindications (4), Table 6 for orally administered midazolam. Benzodiazepines: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4) ].

Sedatives/Hypnotics: Benzodiazepines midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of triazolam or orally administered midazolam is contraindicated due to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4 [see Contraindications (4) ] . 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.

Benzodiazepines: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration of atazanavir with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with atazanavir can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4)]. parenterally administered midazolam b ↑ midazolam Coadministration with parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation.

Sedative/Hypnotics: midazolam (oral), triazolam ↑ midazolam ↑ triazolam Coadministration with triazolam or oral administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with TYBOST may cause large increases in the concentrations of these benzodiazepines.

Sedatives/hypnotics: orally administered midazolam, triazolam ↑ midazolam ↑ triazolam Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with darunavir may cause large increases in the concentrations of these benzodiazepines.

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. Triazolam and orally administered midazolam are extensively metabolized by CYP3A.

Sedatives/hypnotics: orally administered midazolam, triazolam ↑ midazolam ↑ triazolam Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Co-administration of triazolam or orally administered midazolam with PREZCOBIX may cause large increases in the concentrations of these benzodiazepines.

Sedatives/hypnotics: orally administered midazolam, triazolam ↑ midazolam ↑ triazolam Co-administration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. parenterally administered midazolam Co-administration of parenteral midazolam should be done in a setting that ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dose reduction for parenteral midazolam should be considered, especially if more than a single dose of midazolam is administered.

Sedative/hypnotic: midazolam (oral) triazolam ↑ midazolam ↑ triazolam Coadministration with triazolam or orally administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Other benzodiazepines: e.g., parenterally administered midazolam clorazepate diazepam estazolam flurazepam ↑ sedatives/hypnotics Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with GENVOYA may cause large increases in the concentrations of these benzodiazepines.

Use of PDE-5 inhibitors for erectile dysfunction: The below PDE-5 inhibitors can be used along with increased monitoring for PDE-5-inhibitor associated adverse events: Sildenafil at a single dose not exceeding 25 mg in 48 hours, or Tadalafil at a single dose not exceeding 10 mg in 72 hours, or Vardenafil at a single dose not exceeding 2.5 mg in 72 hours Sedative/hypnotics: midazolam (oral), triazolam ↑ midazolam ↑ triazolam Coadministration with triazolam or orally administered midazolam is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Triazolam and orally administered midazolam are extensively metabolized by CYP3A. Coadministration of triazolam or orally administered midazolam with STRIBILD may cause large increases in the concentrations of these benzodiazepines.

Fosamprenavir calcium/ritonavir: ↔ Amprenavir ↔ Esomeprazole Sedative/hypnotics: Midazolam, triazolam ↑Midazolam ↑Triazolam Coadministration is contraindicated due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression [see Contraindications (4)].

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. Lurasidone Midazolam (oral) a Pimozide Triazolam a Contraindicated during and 2 weeks after itraconazole treatment.

(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.

Coadministration of ZOKINVY with a CYP3A substrate increases the AUC and C max of the CYP3A substrate [see Clinical Pharmacology ( 12.3 )] which may increase the risk of the CYP3A substrate's adverse reactions, including myopathy or rhabdomyolysis (with statins), or extreme sedation or respiratory depression (with midazolam). Midazolam Coadministration of ZOKINVY with midazolam is contraindicated [see Contraindications ( 4 )] . Temporarily discontinue ZOKINVY for 10-14 days before and 2 days after administration of midazolam [see Dosage and Administration ( 2.3 )] .

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4)]. Sedative/Hypnotics: parenterally administered midazolam ↑ midazolam If lopinavir and ritonavir is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered.

Sedative/hypnotics triazolam, oral midazolam ↑ triazolam ↑ midazolam Co-administration contraindicated due to potential for extreme sedation and respiratory depression [see Contraindications (4) ] . midazolam (administered parenterally) ↑ midazolam Co-administration of midazolam (parenteral) should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications (4) ] . Sedative/hypnotics: Parenteral midazolam ↑ midazolam Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

Sedative/Hypnotics: triazolam, orally administered midazolam ↑ triazolam ↑ midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications ( 4 )] . Sedative/hypnotics: Parenteral midazolam ↑ midazolam Co-administration should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered.

CNS depressant that increases risk of hypoventilation, airway obstruction, desaturation, apnea, and prolonged drug effect.

Increased midazolam exposure may increase risk of adverse reactions with 3-day aprepitant regimen; dose reduction may be warranted.

Strong CYP3A4 inhibitor that significantly decreases midazolam plasma clearance, resulting in prolonged sedation.

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

Concomitant use may cause enhanced CNS depressant effects. Dosage reduction of dexmedetomidine or midazolam may be required.

Enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine or midazolam may be required. No pharmacokinetic interactions demonstrated.

Diltiazem increases midazolam AUC 3-4 fold and Cmax 2-fold, with elimination half-life increased 1.5-2.5 fold, resulting in prolonged sedation and increased clinical effects.

Concomitant use depresses central nervous system and accentuates the sedative effect of intravenous midazolam.

May result in prolonged sedation due to decreased plasma clearance. Approximately doubled the half-life of midazolam.

Erythromycin has been reported to decrease clearance of midazolam and may increase its pharmacologic effect.

Concomitant use increases risk of respiratory depression and accentuates sedative effect. Monitor closely for respiratory depression and sedation.

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

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

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

Concomitant use increases risk of respiratory depression and accentuates sedative effect. Monitor closely for respiratory depression and sedation.

Concomitant use increases risk of respiratory depression and accentuates sedative effect. Monitor closely for respiratory depression and sedation.

7 DRUG INTERACTIONS Table 3: Clinically Significant Drug Interactions With NAYZILAM 7.1 CYP3A4 Inhibitors Clinical Impact: Concomitant use of CYP3A4 inhibitors may result in prolonged sedation because of a decrease in plasma clearance of midazolam. Intervention: Avoid co-administration of NAYZILAM with moderate or strong CYP3A4 inhibitors. NAYZILAM should be used with caution when co-administered with mild CYP3A4 inhibitors.

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

Causes 56% reduction in midazolam clearance and approximately doubles half-life, significantly prolonging sedation.

Concomitant use depresses central nervous system and accentuates the sedative effect of intravenous midazolam.

Probe substrate for CYP3A4/5; potent inhibition of both hepatic and intestinal CYP3A4/5 observed after first dose and steady state with APTIVUS/ritonavir.

Clearance of midazolam may be increased by armodafinil, resulting in lower systemic exposure. Dosage adjustment should be considered.

Bicalutamide co-administration increases midazolam levels 1.5-fold (Cmax) and 1.9-fold (AUC). Caution should be exercised when co-administered.

Ceritinib increased systemic exposure of this sensitive CYP3A substrate. Avoid coadministration or consider dose reduction of midazolam if unavoidable.

Inhibits P450-3A4 enzyme system, increasing midazolam steady-state concentration and prolonging sedation by decreasing plasma clearance.

Dabrafenib decreased systemic exposure of midazolam (CYP3A4 substrate), potentially reducing efficacy. Monitor for loss of effectiveness.

Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [ see Clinical Pharmacology (12.3)].

Intravenous midazolam reduces MAC of desflurane by 16-17% at doses of 25-50 µg/kg. Adjust dose accordingly.

Co-administration leads to enhancement of pharmacodynamic effects. Reduction in dosage of dexmedetomidine or midazolam may be required.

Inhibits P450-3A4 enzyme system, increasing midazolam half-life from 5 to 7 hours and prolonging sedation.

COCs Increasing the Plasma Concentrations of CYP450 Enzymes : In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase. Two additional clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4 were each performed in 24 healthy postmenopausal women.

COCs Increasing the Plasma Concentrations of CYP450 Enzymes : In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase.

COCs Increasing the Plasma Concentrations of CYP450 Enzymes: In clinical studies, administration of a hormonal contraceptive containing EE did not lead to any increase or only to a weak increase in plasma concentrations of CYP3A4 substrates (e.g., midazolam) while plasma concentrations of CYP2C19 substrates (e.g., omeprazole and voriconazole) and CYP1A2 substrates (e.g., theophylline and tizanidine) can have a weak or moderate increase.

Elagolix decreases midazolam plasma concentrations. Consider increasing midazolam dose by no more than 2-fold.

ORIAHNN may decrease midazolam plasma concentrations. Consider increasing midazolam dose by no more than 2-fold and individualize therapy based on patient response.

Erythromycin decreases clearance and may increase pharmacological effect of midazolam.

7.2 Pharmacokinetic Drug Interactions Table 3: Effect of Fexinidazole on other Drugs Drugs Metabolized by Cytochrome P450 (CYP) 3A4/5 Examples (not fully inclusive): Lovastatin, simvastatin, nisoldipine, saquinavir, midazolam, certain hormonal contraceptives (e.g., birth control pills, skin patches, implant) Clinical Impact Fexinidazole is considered a moderate CYP3A4/5 inducer [see Clinical Pharmacology (12.3) ] .

( 7.3 ) Midazolam : Decreased exposure; monitor for suboptimal effect of midazolam. Midazolam Concomitant use of glycerol phenylbutyrate decreased the systemic exposure of midazolam. Monitor for suboptimal effect of midazolam in patients who are being treated with glycerol phenylbutyrate.

Midazolam Use with Caution Concomitant administration of CRESEMBA and midazolam results in increase in midazolam exposure. Consider dose reduction of midazolam when isavuconazole is coadministered [see Clinical Pharmacology ( 12.3 )] .

Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Use With Caution Midazolam : When oral midazolam is coadministered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated (see WARNINGS ). In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.

Lapatinib increases midazolam exposure by 45% (oral) and 22% (IV) as a CYP3A4 substrate. Monitor and consider dose reduction.

Sedatives/Hypnotics: midazolam (oral) triazolam ↑ midazolam (oral) ↑ triazolam Use with caution when midazolam or triazolam is concomitantly administered with SUNLENCA 7.4 Drugs without Clinically Significant Interactions with SUNLENCA Based on drug interaction studies conducted with SUNLENCA, no clinically significant drug interactions have been observed with: darunavir/cobicistat, cobicistat, famotidine, pitavastatin, rosuvastatin, tenofovir alafenamide, and voriconazole.

7.2 Potential for PREVYMIS to Affect Other Drugs Co-administration of PREVYMIS with midazolam results in increased midazolam plasma concentrations, indicating that letermovir is a moderate inhibitor of CYP3A [see Clinical Pharmacology (12.3) ] . CYP3A Substrates Examples: alfentanil, fentanyl, midazolam, and quinidine ↑ CYP3A substrate When PREVYMIS is co-administered with a CYP3A substrate, refer to the prescribing information for dosing of the CYP3A substrate with a moderate CYP3A inhibitor .

Other CNS Depressants The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication, which depresses the central nervous system, particularly narcotics (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response (see DOSAGE AND ADMINISTRATION ). Other Drug Interactions Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole.

Other CNS Depressants and Alcohol The sedative effect of Midazolam Injection is accentuated by concomitantly administered medication that depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), secobarbital, and droperidol, and also by alcohol [see Warnings and Precautions (5.1, 5.4, 5.6)]. Cytochrome P450-3A4 Inhibitors Caution is advised when Midazolam Injection is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system (e.g., cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole). These drug interactions may result in prolonged sedation caused by a decrease in plasma clearance of midazolam [see Clinical Pharmacology (12.3)].

Clearance may be increased by modafinil resulting in lower systemic exposure. Dosage adjustment should be considered when used concomitantly.

Netupitant significantly increases systemic exposure to midazolam; consider potential effects of increased plasma concentrations.

Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4.

Palbociclib increases midazolam plasma exposure by 61%. Monitor and consider dose reduction of midazolam.

Benzodiazepines that are CYP3A4 Substrates Mechanism and Clinical Effect(s) Concomitant use of posaconazole with midazolam increased midazolam plasma concentrations which could potentiate and prolong hypnotic and sedative effects [see Clinical Pharmacology (12.3) ] . 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) ].

Oral midazolam exposure increased up to 65% with 150 mg ranitidine twice daily. Monitor for excessive or prolonged sedation.

Oral midazolam exposure increased up to 65% with ranitidine 150 mg twice daily. Monitor for excessive or prolonged sedation.

Stiripentol is an inhibitor and inducer of CYP3A4; consider dose adjustment of midazolam when administered concomitantly with DIACOMIT.

Effects of Other Drugs/Substances on ENVARSUS XR a, d a ENVARSUS XR dosage adjustment recommendation based on observed effect of co-administered drug on tacrolimus exposures [see Clinical Pharmacology (12.3) ] , literature reports of altered tacrolimus exposures, or the other drug’s known CYP3A inhibitor/inducer status b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to immediate-release tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate) d A drug interaction study with voriconazole was conducted for ENVARSUS XR [see Clinical Pharmacology (12.3) ] .

CNS Depressant: Midazolam b ↓ midazolam Monitor for effectiveness of midazolam.

7 DRUG INTERACTIONS CYP3A4 Substrates (e.g., midazolam): Efficacy of concomitant drugs may be decreased; monitor for suboptimal efficacy and consider increasing the dose of the concomitant drug. ( 7.1 ) 7.1 CYP3A4 Substrates Concomitant use of Xermelo may decrease the efficacy of drugs that are CYP3A4 substrates (e.g., midazolam) by decreasing their systemic exposure.

Moderate reduction in induction dosage requirements of thiopental (about 15%).

Inhibits P450-3A4 enzyme system, increasing midazolam half-life from 5 to 7 hours and prolonging sedation.

Prevention or Management Midazolam Closely monitor patients for signs or symptoms of increased or prolonged central nervous system effects (e.g., somnolence and confusion) and refer to the CYP3A substrate prescribing information for dosage adjustments when used concomitantly with VOQUEZNA TRIPLE PAK.

Voxelotor increased systemic exposure of midazolam. Avoid coadministration or consider dose reduction of midazolam.

CYP3A4 substrate; atomoxetine did not cause clinically important interaction with CYP3A-metabolized drugs.

CYP3A substrate; atomoxetine did not cause clinically important inhibition or induction of CYP3A metabolism.

Azithromycin had a modest effect on midazolam pharmacokinetics. No dosage adjustment recommended.

CYP3A4 substrate. Darifenacin did not have significant impact on midazolam pharmacokinetics.

CYP3A4 substrate. Istradefylline 20 mg did not affect midazolam exposure.

Concomitant administration of moxidectin 8 mg oral dose did not have an effect on midazolam pharmacokinetics in healthy subjects.

No significant interaction observed with midazolam in healthy subjects.

In drug interaction trials, dolutegravir did not have a clinically relevant effect on the pharmacokinetics of the following drugs: tenofovir, methadone, midazolam, rilpivirine, and oral contraceptives containing norgestimate and ethinyl estradiol.

John's wort (Hypericum perforatum) 7.4 Drugs without Clinically Significant Interactions with VEMLIDY Based on drug interaction studies conducted with VEMLIDY, no clinically significant drug interactions have been observed with: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

80% increase Midazolam Similar to diazepam.

Concomitant use of REZUROCK with sensitive CYP3A substrates (e.g., midazolam) is predicted to increase CYP3A substrate exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions related to these substrates.

7.6 Drugs without Clinically Significant Interactions with BIKTARVY Based on drug interaction studies conducted with BIKTARVY or the components of BIKTARVY, no clinically significant drug interactions have been observed when BIKTARVY is combined with the following drugs: ethinyl estradiol, ledipasvir/sofosbuvir, midazolam, norgestimate, sertraline, sofosbuvir, sofosbuvir/velpatasvir, and sofosbuvir/velpatasvir/voxilaprevir.

7.4 Drugs without Clinically Significant Interactions with Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine [see Clinical Pharmacology ( 12.3 )] .

7.5 Drugs without Clinically Significant Interactions Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine [see Clinical Pharmacology ( 12.3 )] .

7.4 Drugs without Clinically Significant Interactions with Cabotegravir Based on drug interaction study results, the following drugs can be coadministered with cabotegravir without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, rifabutin, and rilpivirine [see Clinical Pharmacology ( 12.3 )] .

In addition, carbamazepine causes, or would be expected to cause, decreased levels of the following drugs, for which monitoring of concentrations or dosage adjustment may be necessary: acetaminophen, albendazole, alprazolam, aprepitant, buprenorphone, bupropion, citalopram, clonazepam, clozapine, corticosteroids (e.g., prednisolone, dexamethasone), cyclosporine, dicumarol, dihydropyridine calcium channel blockers (e.g., felodipine), doxycycline, ethosuximide, everolimus, haloperidol, imatinib, itraconazole, lamotrigine, levothyroxine, methadone, methsuximide, mianserin, midazolam, olanzapine, oral and other hormonal contraceptives, oxcarbazepine, paliperidone, phensuximide, phenytoin, praziquantel, protease inhibitors, risperidone, sertraline, sirolimus, tadalafil, theophylline, tiagabine, topiramate, tramadol, trazodone, tricyclic antidepressants (e.g., imipramine, amitriptyline, nortriptyline), valproate, warfarin, ziprasidone, zonisamide.

Dosage adjustments of the drugs metabolized by CYP2C8 (e.g., repaglinide) and CYP3A4/5 (e.g., midazolam, sirolimus and tacrolimus) may be necessary if they are given concurrently with spironolactone.

7.4 CYP3A4 Substrates Darifenacin (30 mg daily) did not have a significant impact on midazolam (7.5 mg) pharmacokinetics [ see Clinical Pharmacology (12.3)] .

Examples desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine 7.2 Drugs Having No Clinically Important Interactions with Desvenlafaxine Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with desvenlafaxine [see Clinical Pharmacology ( 12.3 )] .

Examples desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine 7.2 Drugs Having No Clinically Important Interactions with desvenlafaxine Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with desvenlafaxine [see CLINICAL PHARMACOLOGY (12.3)].

Examples desipramine, atomoxetine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine 7.2 Drugs Having No Clinically Important Interactions with PRISTIQ Based on pharmacokinetic studies, no dosage adjustment is required for drugs that are mainly metabolized by CYP3A4 (e.g., midazolam), or for drugs that are metabolized by both CYP2D6 and CYP3A4 (e.g., tamoxifen, aripiprazole), when administered concomitantly with PRISTIQ [see Clinical Pharmacology (12.3) ].

midazolam, pimozide, simvastatin) is necessary when XELSTRYM is co-administered [see CLINICAL PHARMACOLOGY (12.3) ].

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.

b 7.4 Drugs without Clinically Significant Interactions with Dolutegravir Based on drug interaction trial results, the following drugs can be coadministered with dolutegravir without a dose adjustment: atazanavir/ritonavir, darunavir/ritonavir, elbasvir/grazoprevir, methadone, midazolam, omeprazole, oral contraceptives containing norgestimate and ethinyl estradiol, prednisone, rifabutin, rilpivirine, sofosbuvir/velpatasvir, and tenofovir [see Clinical Pharmacology ( 12.3 )] .

7.2 Effect of PIFELTRO on Other Drugs No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: dolutegravir, lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, and midazolam [see Clinical Pharmacology (12.3) ] .

7.3 Effect of DELSTRIGO on Other Drugs No clinically significant changes in concentration were observed for the following agents when co-administered with doravirine: lamivudine, TDF, elbasvir and grazoprevir, ledipasvir and sofosbuvir, atorvastatin, an oral contraceptive containing ethinyl estradiol and levonorgestrel, metformin, methadone, or midazolam.

7.2 Influence of SLYND on other Medicinal Products Based on in vitro studies and in vivo interaction studies in female volunteers using omeprazole, simvastatin and midazolam as marker substrate, an interaction of drospirenone with the metabolism of other active substances is unlikely.

Two further clinical drug-drug interaction studies using simvastatin and midazolam as marker substrates for CYP3A4, respectively, were performed and the results of these studies demonstrated that pharmacokinetics of the CYP3A4 substrates were not influenced by steady-state DRSP concentrations.

No clinically significant drug interactions have been either observed or are expected when DESCOVY is combined with the following drugs: buprenorphine, itraconazole, ketoconazole, lorazepam, methadone, midazolam, naloxone, norbuprenorphine, norgestimate/ethinyl estradiol, and sertraline.

7.8 Drugs Without Clinically Significant Interactions with ODEFSEY Based on drug interaction studies conducted with the fixed dose combination or components of ODEFSEY, no clinically significant drug interactions have been observed when ODEFSEY is combined with the following drugs: acetaminophen, atorvastatin, chlorzoxazone, digoxin, ethinyl estradiol, ledipasvir, metformin, midazolam, norethindrone, norgestimate, sildenafil, simeprevir, sofosbuvir, velpatasvir, and voxilaprevir.

7.9 Midazolam (CYP3A4/5 Substrate) Single-dose administration of midazolam to healthy volunteers following administration of multiple-dose everolimus indicated that everolimus is a weak inhibitor of CYP3A4/5. Dose adjustment of midazolam or other CYP3A4/5 substrates is not necessary when everolimus is coadministered with midazolam or other CYP3A4/5 substrates [see Clinical Pharmacology ( 12.5 )] .

7.9 Midazolam (CYP3A4/5 Substrate) Single-dose administration of midazolam to healthy volunteers following administration of multiple-dose everolimus indicated that everolimus is a weak inhibitor of CYP3A4/5. Dose adjustment of midazolam or other CYP3A4/5 substrates is not necessary when everolimus is coadministered with midazolam or other CYP3A4/5 substrates [see Clinical Pharmacology (12.5) ] .

(See PRECAUTIONS .) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%.

Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.

Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.

7.5 Drugs with No Observed Clinically Significant Interactions with MAVYRET No dose adjustment is required when MAVYRET is coadministered with the following medications: abacavir, amlodipine, caffeine, dextromethorphan, dolutegravir, elvitegravir/ cobicistat, emtricitabine, ethinyl estradiol of 20 mcg or less, felodipine, lamivudine, lamotrigine, losartan, midazolam, norethindrone or other progestin-only contraceptives, omeprazole, raltegravir, rilpivirine, sofosbuvir, tacrolimus, tenofovir alafenamide, tenofovir disoproxil fumarate, tolbutamide, and valsartan.

Co-administration with oral midazolam, a sensitive CYP3A substrate, increased midazolam exposure 1.5-fold, consistent with weak inhibition of CYP3A by ivacaftor.

o Midazolam Midazolam is a 3A4 substrate. There was no effect of lacosamide (200 mg single dose or repeat doses of 400 mg/day given as 200 mg BID) on the pharmacokinetics of midazolam (single dose, 7.5 mg), indicating no inhibitory or inducing effects on CYP3A4.

7.3 Drugs without Clinically Significant Interactions with HARVONI Based on drug interaction studies conducted with the components of HARVONI (ledipasvir or sofosbuvir) or HARVONI, no clinically significant drug interactions have been either observed or are expected when HARVONI is used with the following drugs [see Clinical Pharmacology (12.3) ]: abacavir, atazanavir/ritonavir, cyclosporine, darunavir/ritonavir, dolutegravir, efavirenz, elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide, emtricitabine, lamivudine, methadone, midazolam, oral contraceptives, pravastatin, raltegravir, rilpivirine, tacrolimus, or verapamil.

Examples Alfentanil, avanafil, buspirone, conivaptan b , dabigatran etexilate, darifenacin, darunavir, digoxin, ebastine, everolimus, fexofenadine, ibrutinib, lomitapide, lovastatin, lurasidone, midazolam, naloxegol, nisoldipine, saquinavir, simvastatin, sirolimus, tacrolimus, tipranavir b , triazolam, and vardenafil.

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when lisdexamfetamine dimesylate is co-administered [see Clinical Pharmacology (12.3) ] .

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when VYVANSE is co-administered [see Clinical Pharmacology (12.3) ] .

From a pharmacokinetic perspective, no dose adjustment for drugs that are substrates of CYP1A2 (e.g., theophylline, duloxetine, melatonin), CYP2D6 (e.g., atomoxetine, desipramine, venlafaxine), CYP2C19 (e.g., omeprazole, lansoprazole, clobazam), and CYP3A4 (e.g., midazolam, pimozide, simvastatin) is necessary when lisdexamfetamine dimesylate capsules are co-administered [see Clinical Pharmacology ( 12.3 )] .

Co-administration of ORKAMBI is not recommended with sensitive CYP3A substrates or CYP3A substrates with a narrow therapeutic index [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ] such as: Benzodiazepines : midazolam, triazolam (consider an alternative to these benzodiazepines).

7.4 Drugs without Clinically Significant Interactions with LIVTENCITY No clinically significant interactions were observed in clinical drug-drug interaction studies of LIVTENCITY and ketoconazole, antacid, caffeine, warfarin, voriconazole, dextromethorphan, or midazolam [see Clinical Pharmacology (12.3) ] .

7 DRUG INTERACTIONS Opioid Analgesics and Other Sedative Hypnotics : Risk of respiratory depression is increased ( 7.1 ) Cytochrome P450-3A4 Inhibitors : May result in prolonged sedation due to decreased plasma clearance of midazolam. The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see Dosage and Administration (2) ].

In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.

7.5 Benzodiazepines Metabolized by CYP3A4 Concomitant administration of posaconazole with midazolam increases the midazolam plasma concentrations by approximately 5-fold. Increased plasma midazolam concentrations could potentiate and prolong hypnotic and sedative effects.

Therefore, an increase in the metabolism of coadministered CYP1A2 substrates (e.g., theophylline, caffeine) or CYP3A4 substrates (e.g., midazolam, testosterone) is not anticipated.

7.2 Effect of Pretomanid on Other Drugs Midazolam Co-administration of pretomanid with the CYP3A4 substrate, midazolam, resulted in no clinically significant effect on the pharmacokinetics of midazolam or its major metabolite, 1-hydroxy-midazolam [see Clinical Pharmacology (12.3) ] .

Midazolam (CYP3A4 Substrate) In 23 healthy subjects who received multiple doses of quinine sulfate capsules, 324 mg three times daily x 7 days with a single oral 2 mg dose of midazolam, the mean AUC and C max of midazolam and 1-hydroxymidazolam were not significantly affected. This finding indicates that 7-day dosing with quinine sulfate capsules,324 mg every 8 hours did not induce the metabolism of midazolam.

7.2 Drugs without Clinically Significant Interactions with ISENTRESS or ISENTRESS HD ISENTRESS In drug interaction studies performed using ISENTRESS film-coated tablets 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: ethinyl estradiol/norgestimate, methadone, midazolam, lamivudine, tenofovir disoproxil fumarate, etravirine, darunavir/ritonavir, or boceprevir.

Concomitant administration of ramelteon with omeprazole (CYP2C19 substrate), dextromethorphan (CYP2D6 substrate), midazolam (CYP3A4 substrate), theophylline (CYP1A2 substrate), digoxin (p-glycoprotein substrate), warfarin (CYP2C9 [S]/CYP1A2 [R] substrate), venlafaxine, fluvoxamine, donepezil, doxepin, sertraline, escitalopram, and gabapentin did not produce clinically meaningful changes in peak and total exposures to these drugs.

Dosage adjustments of the drugs metabolized by CYP2C8 (e.g., repaglinide) and CYP3A4/5 (e.g., midazolam, sirolimus and tacrolimus) may be necessary if they are given concurrently with spironolactone.

Strong CYP3A Inducers Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate).

Midazolam or Lovastatin) — Tadalafil had no significant effect on exposure (AUC) to midazolam or lovastatin.

Potential for tezacaftor/ivacaftor to affect other drugs 7.4 CYP3A Substrates Co-administration of SYMDEKO with midazolam (oral), a sensitive CYP3A substrate, did not affect midazolam exposure.

80% increase Midazolam Similar to diazepam.

80% increase Midazolam Similar to diazepam.

No relevant interactions with substrates for CYP 2A6 (warfarin), CYP 1A2 (caffeine), CYP 3A4 (midazolam, terfenadine, cyclosporine), CYP 2C19 (S-mephenytoin) and CYP 2D6 (desipramine) were observed in vitro.

7.5 Effect of Toremifene on CYP3A4 Substrates In a study of 20 healthy subjects, 2 mg midazolam once daily (days 6 and 18) coadministered with toremifene as a 480 mg loading dose followed by 80 mg once daily for 16 days. Following coadministration on days 6 and 18 relevant increases in midazolam and α-hydroxymidazolam Cmax and AUC were not observed. Following coadministration on day 18 midazolam and α-hydroxymidazolam Cmax and AUC were reduced by less than 20%.

Tranquilizers/Anti-Depressants Due to metabolism via the CYP enzyme system, there have been reports that verapamil may increase the concentrations of buspirone, midazolam, almotriptan and imipramine.

Midazolam (CYP3A4 Inhibition) Significantly Increased Increased plasma exposures may increase the risk of adverse reactions and toxicities related to benzodiazepines.