WARNINGS
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 alone or in combination, including emtricitabine and other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. However, cases have also been reported in patients with no known risk factors. Treatment with EMTRIVA 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 and Hepatitis B Virus
It is recommended that all patients with HIV be tested for the presence of chronic hepatitis B virus (HBV) before initiating antiretroviral therapy. EMTRIVA is not approved for the treatment of chronic HBV infection and the safety and efficacy of EMTRIVA have not been established in patients co-infected with HBV and HIV. Severe acute exacerbations of hepatitis B have been reported in patients after the discontinuation of EMTRIVA. In some patients infected with HBV and treated with EMTRIVA, the exacerbations of hepatitis B were associated with liver decompensation and liver failure. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who discontinue EMTRIVA and are co-infected with HIV and HBV. If appropriate, initiation of anti-hepatitis B therapy may be warranted.
Other
EMTRIVA is a component of TRUVADA (a fixed-dose combination of emtricitabine and tenofovir disoproxil fumarate) and ATRIPLA (a fixed-dose combination of efavirenz, emtricitabine, and tenofovir disoproxil fumarate). EMTRIVA should not be coadministered with TRUVADA or ATRIPLA. Due to similarities between emtricitabine and lamivudine, EMTRIVA should not be coadministered with other drugs containing lamivudine, including Combivir, Epivir, Epivir-HBV, Epzicom, or Trizivir.
PRECAUTIONS
Patients with Impaired Renal Function
Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of EMTRIVA is recommended for patients with impaired renal function (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Drug Interactions
The potential for drug interactions with EMTRIVA has been studied in combination with zidovudine, indinavir, stavudine, famciclovir, and tenofovir disoproxil fumarate. There were no clinically significant drug interactions for any of these drugs (see CLINICAL PHARMACOLOGY, Drug Interactions).
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy.
The mechanism and long-term consequences of these events are unknown. A causal relationship has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including EMTRIVA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis), which may necessitate further evaluation and treatment.
Information for Patients
EMTRIVA is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a physician when using EMTRIVA.
Patients should be advised that:
- the use of EMTRIVA has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
- the long term effects of EMTRIVA are unknown.
- EMTRIVA Capsules are for oral ingestion only.
- it is important to take EMTRIVA with combination therapy on a regular dosing schedule to avoid missing doses.
- redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
In long-term oral carcinogenicity studies of emtricitabine, no drug-related increases in tumor incidence were found in mice at doses up to 750 mg/kg/day (26 times the human systemic exposure at the therapeutic dose of 200 mg/day) or in rats at doses up to 600 mg/kg/day (31 times the human systemic exposure at the therapeutic dose).
Mutagenesis
Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.
Impairment of Fertility
Emtricitabine did not affect fertility in male rats at approximately 140-fold or in male and female mice at approximately 60-fold higher exposures (AUC) than in humans given the recommended 200 mg daily dose. Fertility was normal in the offspring of mice exposed daily from before birth (in utero) through sexual maturity at daily exposures (AUC) of approximately 60-fold higher than human exposures at the recommended 200 mg daily dose.
Pregnancy
Pregnancy Category B
The incidence of fetal variations and malformations was not increased in embryofetal toxicity studies performed with emtricitabine in mice at exposures (AUC) approximately 60-fold higher and in rabbits at approximately 120-fold higher than human exposures at the recommended daily dose. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, EMTRIVA should be used during pregnancy only if clearly needed.
Antiretroviral Pregnancy Registry
To monitor fetal outcomes of pregnant women exposed to emtricitabine, an antiretroviral Pregnancy Registry has been established. Healthcare providers are encouraged to register patients by calling 1–800–258–4263.
Nursing Mothers
The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV:
It is not known whether emtricitabine is secreted into human milk. Because of both the potential for HIV transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving EMTRIVA.
Pediatric Use
The safety and efficacy of emtricitabine in patients between 3 months and 21 years of age is supported by data from three open-label, non-randomized clinical studies in which emtricitabine was administered to 169 HIV-1 infected treatment-naive and experienced (defined as virologically suppressed on a lamivudine containing regimen for which emtricitabine was substituted for lamivudine). Patients received once-daily EMTRIVA Oral Solution (6 mg/kg to a maximum of 240 mg/day) or EMTRIVA Capsules (a single 200 mg capsule once daily) in combination with at least two other antiretroviral agents.
Patients had a mean age of 7.9 years (range 0.3–21), 49% were male, 15% Caucasian, 61% Black and 24% Hispanic. Patients had a median baseline HIV RNA of 4.6 log10 copies/mL (range 1.7–6.4) and a mean baseline CD4 cell count of 745 cells/mm3 (range 2–2650). Through 48 weeks of therapy, the overall proportion of patients who achieved and sustained an HIV RNA <400 copies/mL was 86%, and <50 copies/mL was 73%. The mean increase from baseline in CD4 cell count was 232 cells/mm3 (-945, +1512). The adverse event profile observed during these clinical trials was similar to that of adult patients, with the exception of a higher frequency of hyperpigmentation (see ADVERSE REACTIONS).
The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-positive mothers. Each mother received prenatal and intrapartum combination antiretroviral therapy. Neonates received up to 6 weeks of zidovudine prophylactically after birth. The neonates were administered two short courses of emtricitabine oral solution (each 3 mg/kg QD × 4 days) during the first 3 months of life. Emtricitabine exposures in neonates were similar to the exposures achieved in patients >3 months to 17 years (see CLINICAL PHARMACOLOGY: Pediatrics). During the two short dosing periods on emtricitabine there were no safety issues identified in the treated neonates. All neonates were HIV-1 negative at the end of the study; the efficacy of emtricitabine in preventing or treating HIV could not be determined.
Geriatric Use
Clinical studies of EMTRIVA did not contain sufficient numbers of subjects aged 65 years and over to determine whether they respond differently from younger subjects. In general, dose selection for the elderly patient should be cautious, keeping in mind the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy (see PRECAUTIONS, Patients with Impaired Renal Function and DOSAGE AND ADMINISTRATION).
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