Approval of Complera: emtricitabine/rilpivirine/tenofovir DF fixed dose combination

On August 10, 2011, FDA approved CompleraTM, a fixed dose combination (FDC) drug product containing emtricitabine/rilpivirine/tenofovir DF (FTC/RPV/TDF) for the treatment of HIV. The recommended dose of CompleraTM 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 (EdurantTM) and pharmacokinetic studies that showed that the FDC was bioequivalent to the individual drugs.

The Phase 3 trials (TMC278-C209: ECHO and TMC278-C215: THRIVE) are randomized, double blind, active controlled trials in treatment naïve HIV-1 infected subjects and provided 48 week safety and efficacy data based on comparison of rilpivirine to efavirenz in antiretroviral-naïve subjects with baseline HIV-1 RNA = 5000 copies/mL and no NNRTI resistance. Both trials were identical in design, with the exception of the background regimen (BR). In TMC278 C209, the BR was fixed to the nucleoside (tide) reverse transcriptase inhibitors (N(t)RTIs), tenofovir disoproxil fumarate plus emtricitabine. In TMC278 C215, the BR consisted of 2 investigator-selected N(t)RTIs: tenofovir disoproxil fumarate plus emtricitabine or zidovudine plus lamivudine or abacavir plus lamivudine. In both trials, randomization was stratified by screening viral load. In TMC278 C215, randomization was also stratified by N(t)RTI BR.

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.

The Week 48 efficacy outcomes for the subset of subjects from TMC278-C209 and TIMC278-C215 who received tenofovir DF and emtricitabine as background regimen are as follows:

Overall, the proportion of subjects with HIV RNA < 50 copies/mL was 83% for rilpivirine based regimen compared to 81% for efavirenz based regimen. The predicted difference (95% CI) of response rates was 1.8 (-2.8, 6.4). The overall virologic failure rate was 13% for the rilpivirine compared to 8% for the efavirenz and 5% of rilpivirine subjects discontinued due to virologic failure compared to 1% of efavirenz subjects. The proportion of patients who discontinued study due to an adverse event or death was 2% for rilpivirine and 7% for efavirenz.

Virologic response to rilpivirine appears to be influenced by baseline HIV-1 RNA. At Week 48, in subjects with baseline HIV RNA < 100,000 copies/mL the virologic failure rate was 5% for rilpivirine and 3% for efavirenz. The virologic failure rates for rilpivirine were 20% and 30% for baseline HIV RNA strata > 100,000 - < 500,000 copies/mL and > 500,000 copies/mL, respectively compared to 11% and 18% in the efavirenz group.

In the pooled analysis for subjects receiving rilpivirine in combination with emtricitabine/tenofovir DF in clinical trials C209 and C215, the emergence of resistance among subjects was greater in the rilpivirine arm compared to the efavirenz arm. In the combined studies, 44% (34/77) of the virologic failures in the rilpivirine arms had genotypic and phenotypic resistance to rilpivirine compared to 23% (10/43) of the virologic failures in the efavirenz arms who had genotypic and phenotypic resistance to efavirenz. Moreover, phenotypic and/or genotypic resistance to emtricitabine and tenofovir emerged in 51% (39/77) and 9% (7/77) of the virologic failures, respectively, in the rilpivirine arms compared to 12% (5/43) and 7% (3/43) in the efavirenz arms.

Emerging NNRTI substitutions in the rilpivirine virologic failures included V90I, K101E/P/T, E138K/G, V179I/L, Y181I/C, V189I, H221Y, F227C/L and M230L, which were associated with a rilpivirine phenotypic fold change range of 2.6 - 621. The E138K substitution emerged most frequently on rilpivirine treatment commonly in combination with the M184I substitution. The emtricitabine and lamivudine resistance-associated substitutions M184I or V emerged more frequently in rilpivirine virologic failures compared to efavirenz virologic failures.

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 CompleraTM, 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. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV 1 and have discontinued emtricitabine or tenofovir DF, two of the components of CompleraTM. In some patients infected with HBV and treated with emtricitabine, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. 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 emtricitabine/rilpivirine/tenofovir DF FDC. If appropriate, initiation of hepatitis B therapy may be warranted.

New Onset or Worsening Renal Impairment: Renal impairment, including cases of acute renal failure and Fanconi's syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir DF. It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with emtricitabine/rilpivirine/tenofovir DF FDC. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving adefovir dipivoxil.

Emtricitabine/rilpivirine/tenofovir DF FDC should be avoided with concurrent or recent use of a nephrotoxic agent.

Emtricitabine and tenofovir are principally eliminated by the kidney; however, rilpivirine is not. Since emtricitabine/rilpivirine/tenofovir DF is a combination product and the dose of the individual components cannot be altered, patients with creatinine clearance below 50 mL per minute should not receive emtricitabine/rilpivirine/tenofovir DF FDC.

Drug Interactions: Caution should be given to prescribing emtricitabine/rilpivirine/tenofovir DF FDC with drugs that may reduce the exposure of rilpivirine.

In healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Emtricitabine/rilpivirine/tenofovir DF FDC should be used with caution when co-administered with a drug with a known risk of Torsades de Pointes.

Depressive Disorder: The adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with emtricitabine/rilpivirine/tenofovir DF. During the Phase 3 trials (n = 1368), the incidence of depressive disorders (regardless of causality, severity or background regimen) reported among those randomized to rilpivirine (n = 686) or efavirenz (n = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality or background regimen) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to rilpivirine, and if so, to determine whether the risks of continued therapy outweigh the benefits.

Decreases in Bone Mineral Density: Bone mineral density (BMD) monitoring should be considered for HIV-1 infected patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.

Tenofovir Disoproxil Fumarate: In a 144 week study of HIV-1 infected treatment-naive adult subjects treated with tenofovir DF (Study 903), decreases in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir DF + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the tenofovir DF group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24-48 weeks of the study and this reduction was sustained through 144 weeks. Twenty-eight percent of tenofovir DF treated subjects vs. 21% of the comparator subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir DF group and 6 subjects in the comparator group. Tenofovir DF was associated with significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide), suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25-vitamin D levels were also higher in subjects receiving tenofovir DF.

The effects of tenofovir DF -associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown. For additional information, please consult the tenofovir DF prescribing information.

Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir DF.

Coadministration with Other Products: Emtricitabine/rilpivirine/tenofovir DF FDC should not be administered concurrently with other products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir DF (EMTRIVA®, EdurantTM, VIREAD®, TRUVADA®, ATRIPLA®), with medicinal products containing lamivudine (Epivir®, Epivir-HBV®, Epzicom®, Combivir®, Trizivir®), or with adefovir dipivoxil (HEPSERA®).

 The most common adverse drug reactions (ADR) to rilpivirine (incidence > 2%) of at least moderate to severe intensity (= Grade 2) were insomnia and headache. The most common ADRs to rilpivirine leading to discontinuation were psychiatric disorders: 1% in the rilpivirine arm and 2% in the efavirenz arm. Rash led to discontinuation in 1 (0.1%) subject in the rilpivirine arm and 11 (2%) subjects in the efavirenz arm.

The most common adverse drug reactions (in at least 10% of treatment-naïve subjects) observed in other Phase 3 clinical trials of emtricitabine or tenofovir DF in combination with other antiretroviral agents are diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

 Emtricitabine/rilpivirine/tenofovir DF FDC is Pregnancy Category B (animal reproduction studies have not shown a risk to the animal fetus but adequate and well-controlled trials in pregnant women have not been conducted). Emtricitabine/rilpivirine/tenofovir DF FDC should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Safety and effectiveness of emtricitabine/rilpivirine/tenofovir DF FDC have not been established in pediatric patients.

Emtricitabine/rilpivirine/tenofovir DF FDC is a product of Gilead Sciences Inc.
 Labeling for emtricitabine/rilpivirine/tenofovir DF FDC will be posted soon to the FDA web site at [email protected]

Richard Klein
 Office of Special Health Issues
 Food and Drug Administration

Yodit Belew, M.D.
 Division of Antiviral Drug Products
 Food and Drug Administration