Prescription Drug Information: Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate

EFAVIRENZ, LAMIVUDINE AND TENOFOVIR DISOPROXIL FUMARATE — efavirenz, lamivudine and tenofovir disoproxil fumarate tablet, film coated
Laurus Labs Limited

WARNING: POST TREATMENT ACUTE EXACERBATIONS OF HEPATITIS B

Severe acute exacerbations of hepatitis B have been reported in patients who are co-infected with hepatitis B virus (HBV) and human immunodeficiency virus (HIV-1) and have discontinued lamivudine or tenofovir disoproxil fumarate, two components of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. Monitor hepatic function closely in these patients and, if appropriate, initiate anti-hepatitis B treatment [see Warnings and Precautions (5.1)].

1 INDICATIONS AND USAGE

Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients weighing at least 35 kg.

2 DOSAGE AND ADMINISTRATION

2.1 Testing Prior to Initiation and During Treatment with Efavirenz, Lamivudine and Tenofovir Disoproxil Fumarate Tablets

Prior to initiation of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

It is recommended that serum creatinine, serum phosphorus, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating efavirenz, lamivudine and tenofovir disoproxil fumarate tablets and during therapy in all patients as clinically appropriate [see Warnings and Precautions (5.4)].

Monitor hepatic function prior to and during treatment with efavirenz, lamivudine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.9)].

2.2 Recommended Dosage for Adult and Pediatric Patients Weighing at Least 35 kg

Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a three-drug fixed-dose combination product containing 400 mg of efavirenz (EFV), 300 mg of lamivudine (3TC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets in HIV-1-infected adults and pediatric patients weighing at least 35 kg is one tablet taken orally once daily. Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets should be taken on an empty stomach, preferably at bedtime. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)].

2.3 Not Recommended in Renal Impairment

Because efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are a fixed-dose combination tablet and cannot be dose adjusted, they are not recommended for patients with impaired renal function (creatinine clearance less than 50 mL/min) or patients with end-stage renal disease (ESRD) requiring hemodialysis [see Use in Specific Populations (8.6)].

2.4 Not Recommended in Moderate to Severe Hepatic Impairment

Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are not recommended in patients with moderate or severe hepatic impairment (Child-Pugh B or C) [see Warnings and Precautions (5.9) and Use in Specific Populations (8.7)].

3 DOSAGE FORMS AND STRENGTHS

Tablets: 400 mg of efavirenz, 300 mg of lamivudine, and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

The 400 mg/300 mg/300 mg tablets are white to off-white, film-coated, oval, biconvex tablets debossed with “L40” on one side and plain on other side.

4 CONTRAINDICATIONS

Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets are contraindicated:

5 WARNINGS AND PRECAUTIONS

5.1 Severe Acute Exacerbation of Hepatitis B in Patients Coinfected with HIV-1 and HBV

Posttreatment Exacerbations of Hepatitis: All patients with HIV-1 should be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy therapy [see Dosage and Administration (2.1)]. Discontinuation of anti-HBV therapy, including 3TC and TDF, may be associated with severe acute exacerbations of hepatitis B. Patients infected with HBV who discontinue efavirenz, lamivudine and tenofovir disoproxil fumarate should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.
Important Differences Among Lamivudine-Containing Products: Efavirenz, lamivudine and tenofovir disoproxil fumarate tablets contain a higher dose of the same active ingredient, 3TC, than EPIVIR-HBV® tablets. EPIVIR-HBV was developed for patients with chronic hepatitis B. The formulation and dosage of 3TC in EPIVIR- HBV are not appropriate for patients co-infected with HIV-1 and HBV. Safety and efficacy of 3TC have not been established for treatment of chronic hepatitis B in patients co-infected with HIV-1 and HBV.
If treatment with EPIVIR-HBV, TDF, or a tenofovir alafenamide (TAF)-containing product is prescribed for chronic hepatitis B for a patient with unrecognized or untreated HIV-1 infection, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy HIV-1 treatment.

5.2 Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs and other antiretrovirals. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Treatment should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations.

5.3 Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions

The concomitant use of efavirenz, lamivudine and tenofovir disoproxil fumarate and other drugs may result in known or potentially significant drug interactions, some of which may lead to [see Contraindications (4) and Drug Interactions (7.5)]:
•Loss of therapeutic effect of efavirenz, lamivudine and tenofovir disoproxil fumarate and possible development of resistance.
•Possible clinically significant adverse reactions from greater exposures of concomitant drugs.
See Table 5 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with efavirenz, lamivudine and tenofovir disoproxil fumarate; review concomitant medications during therapy with efavirenz, lamivudine and tenofovir disoproxil fumarate; and monitor for the adverse reactions associated with the concomitant drugs.

5.4 New Onset or Worsening Renal Impairment

TDF, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of TDF [see Adverse Reactions (6.2)].

Prior to initiation and during use of efavirenz, lamivudine and tenofovir disoproxil fumarate, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients.

Avoid efavirenz, lamivudine and tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple non-steroidal anti-inflammatory drugs [NSAIDs]) [see Drug Interactions (7.3)]. Cases of acute renal failure after initiation of high-dose or multiple NSAIDs have been reported in HIV-infected patients with risk factors for renal dysfunction who appeared stable on TDF. Some patients required hospitalization and renal replacement therapy. Alternatives to NSAIDs should be considered, if needed, in patients at risk for renal dysfunction.

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction.

5.5 Psychiatric Symptoms

Serious psychiatric adverse experiences have been reported in patients treated with EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets. In controlled trials of 1,008 patients treated with regimens containing EFV for a mean of 2.1 years and 635 patients treated with control regimens for a mean of 1.5 years, the frequency (regardless of causality) of specific serious psychiatric events among patients who received EFV or control regimens, respectively, were severe depression (2.4%, 0.9%), suicidal ideation (0.7%, 0.3%), nonfatal suicide attempts (0.5%, 0), aggressive behavior (0.4%, 0.5%), paranoid reactions (0.4%, 0.3%), and manic reactions (0.2%, 0.3%). When psychiatric symptoms similar to those noted above were combined and evaluated as a group in a multifactorial analysis of data from a study using EFV 600 mg, treatment with EFV was associated with an increase in the occurrence of these selected psychiatric symptoms. Other factors associated with an increase in the occurrence of these psychiatric symptoms were history of injection drug use, psychiatric history, and receipt of psychiatric medication at study entry; similar associations were observed in both the EFV and control treatment groups. In a study using EFV 600 mg, onset of new serious psychiatric symptoms occurred throughout the study for both EFV-treated and control-treated patients. One percent of EFV-treated patients discontinued or interrupted treatment because of one or more of these selected psychiatric symptoms.
In the ENCORE1 (Evaluation of Novel Concepts in Optimization of antiRetroviral Efficacy) study, at Week 48 the frequency (regardless of causality) of the most common (occurring in > 1% patients) psychiatric events among patients who received EFV 400 mg (N = 321) or EFV 600 mg (N = 309) regimens, respectively, were: abnormal dreams (8.7%, 11.3%), insomnia (6.2%, 6.5%), somnolence (3.1%, 3.9%), depression (3.1%, 1.6%), nightmare (1.9%, 2.6%), sleep disorder (2.2%, 1.3%), and anxiety (1.2%, 1.3%). There have also been occasional postmarketing reports of death by suicide, delusions, psychosis-like behavior, although a causal relationship to the use of EFV cannot be determined from these reports [see Adverse Reactions (6.2)]. Postmarketing cases of catatonia have also been reported and may be associated with increased efavirenz exposure. Patients with serious psychiatric adverse experiences should seek immediate medical evaluation to assess the possibility that the symptoms may be related to the use of EFV, and if so, to determine whether the risks of continued therapy outweigh the benefits.

5.6 Nervous System Symptoms

Fifty-three percent (531/1,008) of patients receiving EFV, a component of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets, in controlled trials reported central nervous system symptoms (any grade, regardless of causality) compared to 25% (156/635) of patients receiving control regimens. These symptoms included, but were not limited to, dizziness (28.1% of the 1,008 patients), insomnia (16.3%), impaired concentration (8.3%), somnolence (7.0%), abnormal dreams (6.2%), and hallucinations (1.2%). These symptoms were severe in 2.0% of patients and 2.1% of patients discontinued therapy as a result. These symptoms usually begin during the first or second day of therapy and generally resolve after the first 2 to 4 weeks of therapy. After 4 weeks of therapy, the prevalence of nervous system symptoms of at least moderate severity ranged from 5% to 9% in patients treated with regimens containing EFV and from 3% to 5% in patients treated with a control regimen. Inform patients that these common symptoms were likely to improve with continued therapy and were not predictive of subsequent onset of the less frequent psychiatric symptoms [see Warnings and Precautions (5.5)]. Dosing at bedtime may improve the tolerability of these nervous system symptoms [see Dosage and Administration (2.2)].

In the ENCORE1 study, at Week 48, 40% of EFV 400 mg recipients and 48% of EFV 600 mg recipients reported central nervous system disorders. The most common symptoms (> 10%) were dizziness (27% vs. 35%) and headache (11% vs. 11%).

Late-onset neurotoxicity, including ataxia and encephalopathy (impaired consciousness, confusion, psychomotor slowing, psychosis, delirium), may occur months to years after beginning efavirenz therapy. Some events of late-onset neurotoxicity have occurred in patients with CYP2B6 genetic polymorphisms which are associated with increased efavirenz levels despite daily dosages of 600 mg of efavirenz. Patients presenting with signs and symptoms of serious neurologic adverse experiences should be evaluated promptly to assess the possibility that these events may be related to efavirenz use, and whether discontinuation of efavirenz, lamivudine and tenofovir disoproxil fumarate tablets is warranted.

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