The following adverse reactions have been identified during post-approval use for each of the individual components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets (EFV, 3TC, and TDF). Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. These reactions have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to EFV, 3TC, and TDF.
Body as a Whole: allergic reactions, asthenia, redistribution/accumulation of body fat [see Warnings and Precautions (5.15)].
Central and Peripheral Nervous System: abnormal coordination, ataxia, encephalopathy, cerebellar coordination and balance disturbances, convulsions, hypoesthesia, paresthesia, neuropathy, tremor, vertigo.
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.
Skin and Appendages: erythema multiforme, photoallergic dermatitis, Stevens-Johnson syndrome.
Special Senses: abnormal vision, tinnitus.
Body as a Whole: redistribution/accumulation of body fat [see Warnings and Precautions (5.15)].
Endocrine and Metabolic: hyperglycemia.
Hemic and Lymphatic: anemia (including pure red cell aplasia and severe anemias progressing on therapy).
Hypersensitivity: anaphylaxis, urticaria.
Musculoskeletal: muscle weakness, CPK elevation, rhabdomyolysis.
Skin: Alopecia, pruritus.
Tenofovir Disoproxil Fumarate
Immune System Disorders: allergic reaction, including angioedema.
Metabolism and Nutrition Disorders: lactic acidosis, hypokalemia, hypophosphatemia.
Respiratory, Thoracic, and Mediastinal Disorders: dyspnea.
Gastrointestinal Disorders: pancreatitis, increased amylase, abdominal pain.
Renal and Urinary Disorders: renal insufficiency, acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria [see Warnings and Precautions (5.4)].
Hepatobiliary Disorders: hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT).
Skin and Subcutaneous Tissue Disorders: rash.
Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy.
General Disorders and Administration Site Conditions: asthenia.
The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.
Efavirenz, lamivudine and tenofovir disoproxil fumarate is a complete regimen for the treatment of HIV-1 infection; therefore, it should not be administered with other antiretroviral medications for treatment of HIV-1 infection.
There is limited information available on the potential for a pharmacodynamic interaction between EFV and drugs that prolong the QTc interval. QTc prolongation has been observed with the use of EFV [see Clinical Pharmacology (12.2)]. Consider alternatives to EFV when coadministered with a drug with a known risk of Torsade de Pointes.
Tenofovir is primarily eliminated by the kidneys [see Clinical Pharmacology (12.3)]. Coadministration of EFV/3TC/TDF with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drugs. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs [see Warnings and Precautions (5.4)]. Drugs that decrease renal function may increase concentrations of tenofovir.
EFV does not bind to cannabinoid receptors. False-positive urine cannabinoid test results have been reported with some screening assays in uninfected and HIV-infected subjects receiving EFV. Confirmation of positive screening tests for cannabinoids by a more specific method is recommended.
EFV 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 EFV.
Drugs that induce CYP3A activity (e.g., phenobarbital, rifampin, rifabutin) would be expected to increase the clearance of EFV resulting in lowered plasma concentrations.
No drug interaction studies have been conducted using efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. However, drug interaction studies have been conducted with the individual components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets (EFV, 3TC, and TDF) [see Clinical Pharmacology (12.3)].
Drug interactions with EFV are summarized in Table 5 [for pharmacokinetics data see Clinical Pharmacology (12.3, Tables 8 and 9) ]. This table includes potentially significant interactions, but is not all inclusive.
|* The interaction between EFV and the drug was evaluated in a clinical study. All other drug interactions shown are predicted.This table is not all-inclusive.|
|Concomitant Drug Class: Drug Name||Effect||Clinical Comment|
|Anticoagulant: Warfarin||↑ or ↓ warfarin||Monitor INR and adjust warfarin dosage if necessary.|
|Anticonvulsants: Carbamazepine||↓carbamazepine* ↓EFV*||There are insufficient data to make a dose recommendation for EFV. Alternative anticonvulsant treatment should be used.|
|Phenytoin Phenobarbital||↓ anticonvulsant↓ EFV||Monitor anticonvulsant plasma levels periodically because of potential for reduction in anticonvulsant and/or EFV plasma levels.|
|Antidepressants: BupropionSertraline||↓ 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: ItraconazoleKetoconazolePosaconazole||Consider alternative antifungal treatment because no dose recommendation for itraconazole or ketoconazole can be made.Avoid concomitant use unless the benefit outweighs the risks.|
|↓ itraconazole*↓ hydroxyitraconazole* ↓ ketoconazole↓ posaconazole*|
|Anti-infective: Clarithromycin||↓ clarithromycin* ↑14-OH metabolite*||Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.|
|Antimycobacterial: RifabutinRifampin||↓ rifabutin* ↓ EFV*||Increase daily dose of rifabutin by 50%. Consider doubling the rifabutin dose in regimens where rifabutin is given 2 or 3 times a week.Increase EFV total daily dose to 800 mg once daily when coadministered with rifampin to patients weighing 50 kg or more.|
|Antimalarials: Artemether/lumefantrineAtovaquone/proguanil||↓ artemether* ↓ dihydroartemisinin* ↓ lumefantrine*↓ atovaquone↓ proguanil||Consider alternatives to artemether/lumefantrine because of the risk of QT interval prolongation [see Warnings and Precautions (5.16)].Concomitant administration is notrecommended.|
|Calcium channel blockers: DiltiazemOthers (e.g., felodipine, nicardipine, nifedipine,verapamil)||↓diltiazem* ↓ desacetyl diltiazem* ↓ N-monodesmethyldiltiazem*↓ calcium channel blocker||Diltiazem dose adjustments should be guided by clinical response (refer to the full prescribing information for diltiazem).When coadministered with EFV, dosage adjustment of calcium channel blockermay be needed and should be guided byclinical response (refer to the fullprescribing information for the calciumchannel blocker).|
|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.|
|Hepatitis C antiviral agents: BoceprevirElbasvir/GrazoprevirPibrentasvir/GlecaprevirSimeprevirVelpatasvir/SofosbuvirVelpatasvir/Sofosbuvir/ VoxilaprevirLedipasvir/Sofosbuvir||↓ boceprevir*↓ elbasvir↓ grazoprevir↓ pibrentasvir↓ glecaprevir↓ simeprevir* ↔ EFV↓ velpatasvir↓ velpatasvir↓ voxilaprevir ↑TDF||Concomitant administration of bocepreviris not recommended.Coadministration of EFV withelbasvir/grazoprevir is contraindicated[see Contraindications (4)] because it maylead to loss of virologic response toelbasvir/grazoprevir.Coadministration of EFV is notrecommended because it may lead toreduced therapeutic effect ofpibrentasvir/glecaprevir.Concomitant administration of simeprevir is not recommended.Coadministration of EFV and sofosbuvir/velpatasvir is notrecommended because it may result in lossof therapeutic effect ofsofosbuvir/velpatasvir.Coadministration of EFV and sofosbuvir/velpatasvir/voxilaprevir is not recommended because it may result in lossof therapeutic effect ofsofosbuvir/velpatasvir/voxilaprevir.Monitor for adverse reactions associated with TDF.|
|Hepatitis B antiviral agents Adefovir dipivoxil||Concomitant administration of adefovir dipivoxil is not recommended.|
|Hormonal contraceptives: Oral Ethinyl estradiol/ NorgestimateImplant Etonogestrel||↓ active metabolites of norgestimate* ↓ 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 EFV-exposed patients.|
|Immunosuppressants: Cyclosporine, tacrolimus,sirolimus, and othersmetabolized by CYP3A||↓ immunosuppressant||Dose adjustments of theimmunosuppressant may be required.Close monitoring of immunosuppressantconcentrations for at least 2 weeks (untilstable concentrations are reached) is recommended when starting or stopping treatment with EFV.|
|Narcotic analgesic: Methadone||↓ methadone*||Monitor for signs of methadone withdrawal and increase methadone dose if required to alleviate withdrawal symptoms.|
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