Efavirenz (Page 3 of 10)

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of efavirenz tablets. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.13)]Central and Peripheral Nervous System: abnormal coordination, ataxia, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo
Endocrine: gynecomastia
Gastrointestinal: constipation, malabsorption
Cardiovascular: flushing, palpitations
Liver and Biliary System: hepatic enzyme increase, hepatic failure, hepatitis.
Metabolic and Nutritional: hypercholesterolemia, hypertriglyceridemia.
Musculoskeletal: arthralgia, myalgia, myopathy
Psychiatric: aggressive reactions, agitation, delusions, emotional lability, mania, neurosis, paranoia, psychosis, suicide, catatonia
Respiratory: dyspnea
Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndromeSpecial Senses: abnormal vision, tinnitus

7 DRUG INTERACTIONS

7.1 Potential for Efavirenz to Affect other Drugs

Efavirenz has been shown in vivo to induce CYP3A and CYP2B6. Other compounds that are substrates of CYP3A or CYP2B6 may have decreased plasma concentrations when coadministered with efavirenz tablets.

7.2 Potential for Other Drugs to Affect Efavirenz

Drugs that induce CYP3A activity (eg, phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of efavirenz resulting in lowered plasma concentrations [see Dosage and Administration (2.2)].

7.3 QT Prolonging Drugs

There is limited information available on the potential for a pharmacodynamic interaction between efavirenz and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of efavirenz [see Clinical Pharmacology ( 12.2)].Consider alternatives to efavirenz when coadministered with a drug with a known risk of Torsade de Pointes.

7.4 Established and Other Potentially Significant Drug Interactions

Drug interactions with efavirenz tablets are summarized in Tables 5. For pharmacokinetics data, [see Clinical Pharmacology (12.3)]Tables 7 and 8. This table includes potentially significant interactions, but is not all inclusive.Table 5: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction

Concomitant Drug Class: Drug Name Effect Clinical Comment
HIV antiviral agents
Protease inhibitor: Fosamprenavir calcium ↓amprenavir Fosamprenavir (unboosted): Appropriate doses of the combinations with respect to safety and efficacy have not been established.Fosamprenavir/ritonavir: An additional 100 mg/day (300 mg total) of ritonavir is recommended when efavirenz tablets are administered with fosamprenavir/ritonavir once daily. No change in the ritonavir dose is required when efavirenz tablets are administered with fosamprenavir plus ritonavir twice daily.
Protease inhibitor: Atazanavir ↓atazanavir* Treatment-naive patients: When coadministered with efavirenz tablets, the recommended dose of atazanavir is 400 mg with ritonavir 100 mg (together once daily with food) and efavirenz tablets 600 mg (once daily on an empty stomach, preferably at bedtime).Treatment-experienced patients: Coadministration of efavirenz tablets and atazanavir is not recommended.
Protease inhibitor: Indinavir ↓indinavir* The optimal dose of indinavir, when given in combination with efavirenz tablets, is not known. Increasing the indinavir dose to 1,000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz tablets.
Protease inhibitor: Lopinavir/ritonavir ↓lopinavir* Lopinavir/ritonavir once daily dosing is not recommended when coadministered with efavirenz tablets. The dose of lopinavir/ritonavir must be increased when coadministered with efavirenz tablets. See the lopinavir/ritonavir prescribing information for dose adjustments of lopinavir/ritonavir when coadministered with efavirenz in adult and pediatric patients.
Protease inhibitor: Ritonavir ↑ritonavir* ­ ↑efavirenz* Monitor for elevation of liver enzymes and for adverse clinical experiences (e.g., dizziness, nausea, paresthesia) when efavirenz tablet is coadministered with ritonavir.
Protease inhibitor: Saquinavir ↓saquinavir* Appropriate doses of the combination of efavirenz tablets and saquinavir/ritonavir with respect to safety and efficacy have not been established.
NNRTI: Other NNRTIs ­ ↑ or ↓efavirenz and/or NNRTI Combining two NNRTIs has not been shown to be beneficial. ↑Efavirenz tablets should not be coadministered with other NNRTIs.
CCR5 co-receptor antagonist: Maraviroc ↓maraviroc* Refer to the full prescribing information for maraviroc for guidance on coadministration with efavirenz.
Hepatitis C antiviral agents
Boceprevir ↓ boceprevir* Concomitant administration of boceprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of boceprevir.
Elbasvir/Grazoprevir ↓ elbasvir ↓ grazoprevir Coadministration of clopidogrel with elbasvir/grazoprevir is contraindicated [see Contraindications (4) ] because it may lead to loss of virologic response to elbasvir/grazoprevir.
Pibrentasvir/Glecaprevir ↓ pibrentasvir↓ glecaprevir Coadministration of clopidogrel is not recommended because it may lead to reduced therapeutic effect of pibrentasvir/glecaprevir.
Simeprevir ↓ simeprevir* ↔efavirenz* Concomitant administration of simprevir with efavirenz tablet is not recommended because it may result in loss of therapeutic effect of simeprevir.
Velpatasvir/ Sofosbuvir ↓ velpatasvir Coadministration of efavirenz and sofosbuvir/velpatasvir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir.
Velpatasvir /Sofosbuvir/Voxilaprevir velpatasvir sofosbuvir Coadministration of efavirenz and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in loss of therapeutic effect of sofosbuvir/velpatasvir/voxilaprevir.
Other agents
Anticoagulant: Warfarin ­ ↑ or ↓warfarin Monitor INR and adjust warfarin dosage if necessary.
Anticonvulsants: Carbamazepine ↓carbamazepine* ↓efavirenz* There are insufficient data to make a dose recommendation for efavirenz. Alternative anticonvulsant treatment should be used.
Phenytoin Phenobarbital ↓anticonvulsant ↓efavirenz Potential for reduction in anticonvulsant and/or efavirenz plasma levels; periodic monitoring of anticonvulsant plasma levels should be conducted.
Antidepressants: Bupropion Sertraline ↓bupropion* ↓sertraline* Increases in bupropion dosage should be guided by clinical response. Bupropion dose should not exceed the maximum recommended dose.Increases in sertraline dosage should be guided by clinical response.
Antifungals: Voriconazole ↓voriconazole* ­ ↑efavirenz* Efavirenz tablets and voriconazole should not be coadministered at standard doses. When voriconazole is coadministered with efavirenz tablets, voriconazole maintenance dose should be increased to 400 mg every 12 hours and efavirenz tablets dose should be decreased to 300 mg once daily using the capsule formulation. Efavirenz tablets must not be broken. [See Dosage and Administration (2.2) and Clinical Pharmacology (12.3, Tables 7 and 8).]
Itraconazole ↓itraconazole* ↓hydroxyitraconazole* Consider alternative antifungal treatment because no dose recommendation for itraconazole can be made.
Ketoconazole ↓ketoconazole Consider alternative antifungal treatment because no dose recommendation for ketoconazole can be made.
Posaconazole ↓posaconazole* Avoid concomitant use unless the benefit outweighs the risks.
Anti-infective: Clarithromycin ↓ clarithromycin* ­ ↑14-OH metabolite* Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.
Antimycobacterials: Rifabutin ↓ rifabutin* Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.
Rifampin ↓efavirenz* Increase efavirenz tablets to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more.
Antimalarials: Artemether/ lumefantrine Atovaquone/ proguanil ↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine* ↓ atovaquone↓ proguanil Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation. Concomitant administration is not recommended.
Calcium channel blockers: Diltiazem ↓diltiazem* ↓desacetyl diltiazem* ↓N-monodesmethyldiltiazem* Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem). No dose adjustment of efavirenz is necessary when administered with diltiazem.
Others (eg, felodipine,nicardipine, nifedipine,verapamil) ↓ calcium channel blocker When coadministered with efavirenz tablets, dosage adjustment of calcium channels blocker may be needed and should be guided by clinical response (refer to the full prescribing information for the calcium channel blocker).
HMG-CoA reductase inhibitors: Atorvastatin Pravastatin Simvastatin ↓atorvastatin* ↓pravastatin* ↓simvastatin* Plasma concentrations of atorvastatin, pravastatin, and simvastatin decreased. Consult the full prescribing information for the HMG-CoA reductase inhibitor for guidance on individualizing the dose.
Hormonal contraceptives: Oral Ethinyl estradiol/ NorgestimateImplant Etonogestrel ↓ active metabolites ofnorgestimate* ↓ etonogestrel A reliable method of barrier contraception should be used in addition to hormonal contraceptives.A reliable method of barrier contraception should be used in addition to hormonal contraceptives. Decreased exposure of etonogestrel may be expected. There have been postmarketing reports of contraceptive failure with etonogestrel in efavirenz-exposed patients.
Immunosuppressants: Cyclosporine, tacrolimus, sirolimus, and others metabolized by CYP3A ↓ immunosuppressant Dose adjustments of the immunosuppressant may be required. Close monitoring of immunosuppressant concentrations for at least 2 weeks (until stable concentrations are reached) is recommended when starting or stopping treatment with efavirenz.
Narcotic analgesic: Methadone ↓methadone* Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms.

* The interaction between efavirenz tablets and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.This table is not all-inclusive.

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