FDA Notifications

Complera approved

On Aug. 10, 2011, the Food and Drug Administration (FDA) approved Complera™, a fixed dose combination (FDC) drug product containing emtricitabine/rilpivirine/tenofovir DF (FTC/RPV/TDF) for the treatment of HIV. The recommended dose of Complera™ is one tablet, containing 200mg/25mg/300mg of FTC/RPV/TDF, once daily, taken orally with a meal.

Emtricitabine/rilpivirine/tenofovir DF FDC is indicated for the treatment of human immunodeficiency virus type 1 (HIV 1) infection in antiretroviral treatment naïve adult patients (patients who have never taken HIV therapies, and are starting HIV therapy for the first time).

Emtricitabine/rilpivirine/tenofovir DF FDC is a complete regimen for treatment of HIV infection in treatment naïve patients because it contains a Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) (rilpivirine) and 2 Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (emtricitabine and tenofovir DF).

The following points should be considered when initiating therapy with emtricitabine/rilpivirine/tenofovir DF FDC:

- More rilpivirine treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy.

- The observed virologic failure rate in rilpivirine treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz.

- More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz.

No new safety and efficacy studies were conducted using the FDC, emtricitabine/rilpivirine/tenofovir DF. The approval of emtricitabine/rilpivirine/tenofovir DF FDC is based on previously conducted Phase 3 clinical trials which supported the approval of rilpivirine (Edurant™) and pharmacokinetic studies that showed that the FDC was bioequivalent to the individual drugs.

The approval of emtricitabine/rilpivirine/tenofovir DF FDC is based on Week 48 safety and efficacy analyses of a subset of subjects who received tenofovir and emtricitabine as background regimen.

Cross-resistance to efavirenz, etravirine and/or nevirapine is likely after virologic failure and development of rilpivirine resistance. In the pooled analysis for subjects receiving rilpivirine in combination with emtricitabine/tenofovir DF in clinical trials C209 and C215, 34 virologic failure subjects had evidence of rilpivirine resistance. Of these subjects, 91% (n = 31) were resistant to etravirine and efavirenz, and 65% (n = 22) were resistant to nevirapine. In the efavirenz arm, none of the 10 efavirenz-resistant virologic failures were resistant to etravirine at failure. Subjects experiencing virologic failure on rilpivirine developed more NNRTI resistance-associated substitutions conferring more cross-resistance to the NNRTI class and had a higher likelihood of cross-resistance to all NNRTIs in the class than subjects who failed on efavirenz.

Emtricitabine/rilpivirine/tenofovir DF FDC is contraindicated with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs: the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin; the antimycobacterials rifabutin, rifampin, rifapentine; proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole; the glucocorticoid systemic dexamethasone (more than a single dose) ; St John's wort.

The Warnings and Precautions for emtricitabine/rilpivirine/tenofovir DF FDC include fat redistribution, immune reconstitution syndrome and the following:

- Lactic Acidosis/Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir DF, a component of Complera™, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with emtricitabine/rilpivirine/tenofovir DF FDC 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).

Patients Co-infected with HIV 1 and HBV: It is recommended that all patients with HIV 1 be tested for the presence of chronic hepatitis B virus before initiating antiretroviral therapy.

Emtricitabine/rilpivirine/tenofovir DF FDC is not approved for the treatment of chronic HBV infection and the safety and efficacy of emtricitabine/rilpivirine/tenofovir DF FDC have not been established in patients coinfected with HBV and HIV 1.

Labeling for emtricitabine/rilpivirine/tenofovir DF FDC will be posted soon to the FDA web site at Drugs@FDA.

Renal impairment addressed in labeling

The FDA approved changes to the product labeling for Pegasys™ and Copegus™. The following new recommendations for dosing of Pegasys and Copegus in patients with renal impairment have been added to product labeling based on a clinical study of 50 chronic hepatitis C subjects with moderate or severe renal impairment or end stage renal disease, and on pharmacokinetic modeling or simulation.

In the Copegus package insert: 2.4 Renal Impairment; The total daily dose of Copegus should be reduced for patients with creatinine clearance less than or equal to 50 mL/min,; and the weekly dose of Pegasys should be reduced for creatinine clearance less than 30 mL/min.

The FDA recommends clinicians check the pharmaceutical package inserts for further information.

The dose of Copegus should not be further modified in patients with renal impairment. If severe adverse reactions or laboratory abnormalities develop, the drug should be discontinued.