Efavirenz, Emtricitabine and Tenofovir Disoproxil Fumarate

EFAVIRENZ, EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE — efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet, film coated
Macleods Pharmaceuticals Limited

1 INDICATIONS & USAGE

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is indicated as a complete regimen or in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients weighing at least 40 kg.

2 DOSAGE & ADMINISTRATION

2.1 Testing Prior to Initiation and During Treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets

Prior to or when initiating efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, test patients for hepatitis B virus infection [see Warnings and Precautions (5.1)].

Prior to initiation and during use of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets, on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose and urine protein in all patients. In patients with chronic kidney disease, also assess serum phosphorus [see Warnings and Precautions (5.7)].

Monitor hepatic function prior to and during treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets [see Warnings and Precautions (5.3)].
Perform pregnancy testing before initiation of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in adolescents and adults of childbearing potential [see Warnings and Precautions (5.8), Use in Specific Populations (8.1, 8.3)].

2.2 Recommended Dosage for Adults and Pediatric Patients Weighing at Least 40 kg

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is a three-drug fixed-dose combination product containing 600 mg of efavirenz (EFV), 200 mg of emtricitabine (FTC), and 300 mg of tenofovir disoproxil fumarate (TDF). The recommended dosage of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets in adults and pediatric patients weighing at least 40 kg is one tablet once daily taken orally on an empty stomach. Dosing at bedtime may improve the tolerability of nervous system symptoms [see Clinical Pharmacology (12.3)].

2.3 Not Recommended in Patients with Moderate or Severe Renal Impairment

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is not recommended in patients with moderate or severe renal impairment (estimated creatinine clearance below 50 mL/min) [see Warnings and Precautions (5.7), Use in Specific Populations (8.6)].

2.4 Not Recommended in Patients with Moderate to Severe Hepatic Impairment

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is not recommended in patients with moderate to severe hepatic impairment (Child Pugh B or C) [see Warnings and Precautions (5.3) and Use in Specific Populations (8.7)].

2.5 Dosage Adjustment with Rifampin

If efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets is co-administered with rifampin in patients weighing 50 kg or more, take one tablet of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets once daily followed by one additional 200 mg per day of efavirenz [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

3 DOSAGE FORMS & STRENGTHS

Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is pink, capsule shaped, biconvex, film coated, debossed with “CL81” on one side, and plain faced on the other side. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine, and 300 mg of tenofovir disoproxil fumarate (equivalent to 245 mg of tenofovir disoproxil).

4 CONTRAINDICATIONS

• Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to efavirenz, a component of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet. [see Warnings and Precautions (5.2)].
• Efavirenz, emtricitabine and tenofovir disoproxil fumarate tablet is contraindicated to be coadministered with voriconazole or elbasvir/grazoprevir [see Drug Interactions (7.3) and Clinical Pharmacology (12.3)].

5 WARNINGS AND PRECAUTIONS

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

All patients should be tested for the presence of chronic HBV before or when initiating antiretroviral therapy [see Dosage and Administration (2.1)]. Severe acute exacerbations of hepatitis B (e.g., liver decompensation and liver failure) have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued FTC or TDF, two of the components of efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. Patients who are coinfected with HIV-1 and HBV should be closely monitored, with both clinical and laboratory follow-up for at least several months after stopping treatment with efavirenz, emtricitabine and tenofovir disoproxil fumarate tablets. If appropriate, initiation of antihepatitis B therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

5.2 Rash

In controlled clinical trials, 26% (266/1,008) of adult subjects treated with 600 mg EFV experienced new-onset skin rash compared with 17% (111/635) of those treated in control groups. Rash associated with blistering, moist desquamation, or ulceration occurred in 0.9% (9/1,008) of subjects treated with EFV. The incidence of Grade 4 rash (e.g., erythema multiforme, Stevens-Johnson syndrome) in adult subjects treated with EFV in all trials and expanded access was 0.1%. Rashes are usually mild-to-moderate maculopapular skin eruptions that occur within the first 2 weeks of initiating therapy with EFV (median time to onset of rash in adults was 11 days) and, in most subjects continuing therapy with EFV, rash resolves within 1 month (median duration, 16 days). The discontinuation rate for rash in adult clinical trials was 1.7% (17/1,008). Efavirenz, emtricitabine and tenofovir disoproxil fumarate can be reinitiated in patients interrupting therapy because of rash. Efavirenz, emtricitabine and tenofovir disoproxil fumarate should be discontinued in patients developing severe rash associated with blistering, desquamation, mucosal involvement, or fever. Appropriate antihistamines and/or corticosteroids may improve the tolerability and hasten the resolution of rash. For patients who have had a life-threatening cutaneous reaction (e.g., Stevens-Johnson syndrome), alternative therapy should be considered [See Contraindications (4) ].
Experience with EFV in subjects who discontinued other antiretroviral agents of the NNRTI class is limited. Nineteen subjects who discontinued nevirapine because of rash have been treated with EFV . Nine of these subjects developed mild-to-moderate rash while receiving therapy with EFV , and two of these subjects discontinued because of rash.
Rash was reported in 59 of 182 pediatric subjects (32%) treated with EFV [See Adverse Reactions (6.1) ].

Two pediatric subjects experienced Grade 3 rash (confluent rash with fever, generalized rash), and four subjects had Grade 4 rash (erythema multiforme). The median time to onset of rash in pediatric subjects was 28 days (range 3−1,642 days). Prophylaxis with appropriate antihistamines before initiating therapy with efavirenz, emtricitabine and tenofovir disoproxil fumarate in pediatric patients should be considered.