FDA Label for Emtriva

Warnings: Lactic Acidosis/Severe Hepatomegaly With Steatosis And Post Treatment Exacerbation Of Hepatitis B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs alone or in combination with other antiretrovirals [See Warnings and Precautions (5.1)].

EMTRIVA is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of EMTRIVA have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued EMTRIVA. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue EMTRIVA. If appropriate, initiation of anti-hepatitis B therapy may be warranted [See Warnings and Precautions (5.2)].

1 Indications And Usage

EMTRIVA^® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.

Additional important information regarding the use of EMTRIVA for the treatment of HIV-1 Infection:

• EMTRIVA should not be coadministered with ATRIPLA^®, TRUVADA^®, or lamivudine-containing products [See Warnings and Precautions (5.3)].
• In treatment-experienced patients, the use of EMTRIVA should be guided by laboratory testing and treatment history [See Clinical Pharmacology (12.4)].

2.1 Recommended Dose

EMTRIVA may be taken without regard to food.

2.2 Adult Patients (18 Years Of Age And Older)

• EMTRIVA capsules: one 200 mg capsule administered once daily orally.
• EMTRIVA oral solution: 240 mg (24 mL) administered once daily orally.

2.3 Pediatric Patients (0–3 Months Of Age)

• EMTRIVA oral solution: 3 mg/kg administered once daily orally.

2.4 Pediatric Patients (3 Months Through 17 Years)

• EMTRIVA oral solution: 6 mg/kg up to a maximum of 240 mg (24 mL) administered once daily orally.
• EMTRIVA capsules: for children weighing more than 33 kg who can swallow an intact capsule, one 200 mg capsule administered once daily orally.

2.5 Dose Adjustment In Adult Patients With Renal Impairment

Significantly increased drug exposures were seen when EMTRIVA was administered to patients with renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval or dose of EMTRIVA should be adjusted in patients with baseline creatinine clearance <50 mL/min using the following guidelines (see Table 1). The safety and effectiveness of these dose adjustment guidelines have not been clinically evaluated. Therefore, clinical response to treatment and renal function should be closely monitored in these patients.

Although there are insufficient data to recommend a specific dose adjustment of EMTRIVA in pediatric patients with renal impairment, a reduction in the dose and/or an increase in the dosing interval similar to adjustments for adults should be considered.

3 Dosage Forms And Strengths

EMTRIVA is available as capsules and oral solution.

EMTRIVA capsules, containing 200 mg of emtricitabine, are size 1 hard gelatin capsules with a blue cap and white body, printed with "200 mg" in black on the cap and "GILEAD" and the corporate logo in black on the body.

EMTRIVA oral solution is a clear, orange to dark orange liquid containing 10 mg of emtricitabine per mL.

4 Contraindications

EMTRIVA is contraindicated in patients with previously demonstrated hypersensitivity to any of the components of the products.

5.1 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. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver diseases; 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).

5.2 Patients Coinfected With Hiv-1 And Hbv

It is recommended that all patients with HIV-1 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 coinfected with HBV and HIV-1. 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 are coinfected with HIV-1 and HBV and discontinue EMTRIVA. If appropriate, initiation of anti-Hepatitis B therapy may be warranted.

5.3 Coadministration With Related Products

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 (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine).

5.4 New Onset Or Worsening Renal Impairment

Emtricitabine is principally eliminated by the kidney. Reduction of the dosage of EMTRIVA is recommended for patients with impaired renal function [See Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

5.5 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 currently unknown. A causal relationship has not been established.

5.6 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.

6 Adverse Reactions

The following adverse reactions are discussed in other sections of the labeling:

• Lactic acidosis/severe hepatomegaly with steatosis [See Boxed Warning, Warnings and Precautions (5.1)].
• Severe acute exacerbations of Hepatitis B [See Boxed Warning, Warnings and Precautions (5.2)].
• Immune reconstitution syndrome [See Warnings and Precautions (5.6)]

7 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 Drug interactions studies are described elsewhere in the labeling [See Clinical Pharmacology (12.3)]

8.3 Nursing Mothers

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1. It is not known whether emtricitabine is excreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving EMTRIVA.

8.4 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) subjects [See Clinical Studies(14.3)].

The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-positive mothers [See Clinical Studies (14.3)]. All neonates were HIV-1 negative at the end of the study; the efficacy of emtricitabine in preventing or treating HIV-1 could not be determined.

8.5 Geriatric Use

Clinical studies of EMTRIVA did not include 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.

8.6 Patients With Impaired Renal Function

It is recommended that the dose or dosing interval for EMTRIVA be modified in patients with creatinine clearance <50 mL/min or in patients who require dialysis [See Dosage and Administration (2.5)].

10 Overdosage

There is no known antidote for EMTRIVA. Limited clinical experience is available at doses higher than the therapeutic dose of EMTRIVA. In one clinical pharmacology study single doses of emtricitabine 1200 mg were administered to 11 patients. No severe adverse reactions were reported.

The effects of higher doses are not known. If overdose occurs the patient should be monitored for signs of toxicity, and standard supportive treatment applied as necessary.

Hemodialysis treatment removes approximately 30% of the emtricitabine dose over a 3-hour dialysis period starting within 1.5 hours of emtricitabine dosing (blood flow rate of 400 mL/min and a dialysate flow rate of 600 mL/min). It is not known whether emtricitabine can be removed by peritoneal dialysis.

11 Description

EMTRIVA is the brand name of emtricitabine, a synthetic nucleoside analog with activity against human immunodeficiency virus type 1 (HIV-1) reverse transcriptase.

The chemical name of emtricitabine is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine. Emtricitabine is the (-) enantiomer of a thio analog of cytidine, which differs from other cytidine analogs in that it has a fluorine in the 5-position.

It has a molecular formula of C₈H₁₀FN₃O₃S and a molecular weight of 247.24. It has the following structural formula:

Chemical Structure - emtriva 01

Emtricitabine is a white to off-white powder with a solubility of approximately 112 mg/mL in water at 25 °C. The log P for emtricitabine is -0.43 and the pKa is 2.65.

EMTRIVA is available as capsules or as an oral solution.

EMTRIVA capsules are for oral administration. Each capsule contains 200 mg of emtricitabine and the inactive ingredients, crospovidone, magnesium stearate, microcrystalline cellulose, and povidone.

EMTRIVA oral solution is for oral administration. One milliliter (1 mL) of EMTRIVA oral solution contains 10 mg of emtricitabine in an aqueous solution with the following inactive ingredients: cotton candy flavor, FD&C yellow No. 6, edetate disodium, methylparaben, and propylparaben (added as preservatives), sodium phosphate (monobasic), propylene glycol, water, and xylitol (added as a sweetener). Sodium hydroxide and hydrochloric acid may be used to adjust pH.

12.1 Mechanism Of Action

Emtricitabine is an antiviral drug. [See Clinical Pharmacology (12.4)]

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

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).

Emtricitabine was not genotoxic in the reverse mutation bacterial test (Ames test), mouse lymphoma or mouse micronucleus assays.

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.

14.3 Pediatric Patients

In three open-label, non-randomized clinical studies, 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 between 3 months and 21 years of age. 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-1 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-1 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 reaction profile observed during these clinical trials was similar to that of adult patients, with the exception of the occurrence of anemia and higher frequency of hyperpigmentation in children [See Adverse Reactions (6)].

The pharmacokinetics of emtricitabine were studied in 20 neonates born to HIV-1-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 once daily × 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 (12.3)]. 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-1 could not be determined.

17 Patient Counseling Information

See FDA-approved patient labeling (17.2)

17.1 Information For Patients

Patients should be advised that:

• EMTRIVA is not a cure for HIV-1 infection and patients may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Patients should remain under the care of a physician when using EMTRIVA.
• The use of EMTRIVA has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination.
• The long term effects of EMTRIVA are unknown.
• EMTRIVA capsules and oral solution are for oral ingestion only.
• It is important to take EMTRIVA with combination therapy on a regular dosing schedule to avoid missing doses.
• Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with EMTRIVA should be suspended in any patient who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity (including nausea, vomiting, unusual or unexpected stomach discomfort, and weakness) [See Warnings and Precautions (5.1)].
• Patients with HIV-1 should be tested for Hepatitis B virus (HBV) before initiating antiretroviral therapy.
• Severe acute exacerbations of Hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued EMTRIVA.
• EMTRIVA should not be coadministered with other drugs containing lamivudine, including Combivir (lamivudine/zidovudine), Epivir or Epivir-HBV (lamivudine), Epzicom (abacavir sulfate/lamivudine), or Trizivir (abacavir sulfate/lamivudine/zidovudine) [See Warnings and Precautions (5.3)].
• Dose or dosing interval of EMTRIVA may need adjustment in patients with renal impairment [See Dosage and Administration (2.5)].