Emtricitabine and Tenofovir Disoproxil Fumarate (Page 9 of 11)

14.3 Clinical Trial Results for HIV-1 PrEP: iPrEx

The iPrEx trial was a randomized, double-blind, placebo-controlled multinational study evaluating emtricitabine and tenofovir disoproxil fumarate in 2,499 HIV-seronegative men or transgender women who have sex with men and with evidence of high-risk behavior for HIV-1 infection. Evidence of high-risk behavior included any one of the following reported to have occurred up to six months prior to study screening: no condom use during anal intercourse with an HIV-1 positive partner or a partner of unknown HIV status; anal intercourse with more than 3 sex partners; exchange of money, gifts, shelter, or drugs for anal sex; sex with male partner and diagnosis of sexually transmitted infection; no consistent use of condoms with sex partner known to be HIV-1 positive.

All subjects received monthly HIV-1 testing, risk-reduction counseling, condoms, and management of sexually transmitted infections. Of the 2,499 enrolled subjects, 1,251 received emtricitabine and tenofovir disoproxil fumarate and 1,248 received placebo. The mean age of subjects was 27 years; 5% were Asian, 9% Black, 18% White, and 72% Hispanic/Latino.

Subjects were followed for 4,237 person-years. The primary outcome measure was the incidence of documented HIV seroconversion. At the end of treatment, emergent HIV-1 seroconversion was observed in 131 subjects, of which 48 occurred in the emtricitabine and tenofovir disoproxil fumarate group and 83 occurred in the placebo group, indicating a 42% (95% CI: 18 to 60%) reduction in risk. Risk reduction was found to be higher (53%; 95% CI: 34 to 72%) among subjects who reported previous unprotected anal intercourse (URAI) at screening (732 and 753 subjects reported URAI within the last 12 weeks at screening in the emtricitabine and tenofovir disoproxil fumarate and placebo groups, respectively). In a post-hoc case control study of plasma and intracellular drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable intracellular tenofovir diphosphate concentrations. Efficacy was therefore strongly correlated with adherence.

14.4 Clinical Trial Results for HIV-1 PrEP: Partners PrEP

The Partners PrEP trial was a randomized, double-blind, placebo-controlled 3-arm trial conducted in 4,758 HIV-1 serodiscordant heterosexual couples in Kenya and Uganda to evaluate the efficacy and safety of TDF (N=1,589) and FTC/TDF (N=1,583) versus (parallel comparison) placebo (N=1,586) in preventing HIV-1 acquisition by the uninfected partner.

All uninfected partner subjects received monthly HIV-1 testing, evaluation of adherence, assessment of sexual behavior, and safety evaluations. Women were also tested monthly for pregnancy. Women who became pregnant during the trial had study drug interrupted for the duration of the pregnancy and while breastfeeding. The uninfected partner subjects were predominantly male (61 to 64% across study drug groups) and had a mean age of 33 to 34 years.

Following 7,827 person-years of follow-up, 82 emergent HIV-1 seroconversions were reported, with an overall observed seroincidence rate of 1.05 per 100 person-years. Of the 82 seroconversions, 13 and 52 occurred in partner subjects randomized to emtricitabine and tenofovir disoproxil fumarate and placebo, respectively. Two of the 13 seroconversions in the emtricitabine and tenofovir disoproxil fumarate arm and 3 of the 52 seroconversions in the placebo arm occurred in women during treatment interruptions for pregnancy. The risk reduction for emtricitabine and tenofovir disoproxil fumarate relative to placebo was 75% (95% CI: 55 to 87%). In a post-hoc case control study of plasma drug levels in about 10% of study subjects, risk reduction appeared to be greatest in subjects with detectable plasma tenofovir concentrations. Efficacy was therefore strongly correlated with adherence.

16 HOW SUPPLIED/STORAGE AND HANDLING

Emtricitabine and tenofovir disoproxil fumarate tablets are available in bottles containing 30 tablets with child-resistant closure as follows:

• Emtricitabine and Tenofovir Disoproxil Fumarate Tablets, 200 mg/300 mg are supplied as white to off-white, capsule shaped, film-coated tablets, debossed on one side with “AC24” and plain on other side. Each tablet contains 200 mg of emtricitabine (FTC) and 300 mg of tenofovir disoproxil fumarate (TDF) (which is equivalent to 245 mg of tenofovir disoproxil).

They are available as follows:

Bottles of 30: NDC 60219-2095-3

Store at 20° to 25ºC (68° to 77ºF); excursions permitted between 15º to 30ºC (59° to 86ºF) [see USP Controlled Room Temperature].

• Keep container tightly closed.
• Dispense only in original container.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Important Information for Uninfected Individuals Taking Emtricitabine and Tenofovir Disoproxil Fumarate for HIV-1 PrEP

Advise HIV-uninfected individuals about the following [see Warnings and Precautions (5.2)]:

• The need to confirm that they are HIV-negative before starting to take emtricitabine and tenofovir disoproxil fumarate to reduce the risk of acquiring HIV-1.
• That HIV-1 resistance substitutions may emerge in individuals with undetected HIV-1 infection who are taking emtricitabine and tenofovir disoproxil fumarate, because emtricitabine and tenofovir disoproxil fumarate alone does not constitute a complete regimen for HIV-1 treatment.
• The importance of taking emtricitabine and tenofovir disoproxil fumarate on a regular dosing schedule and strict adherence to the recommended dosing schedule to reduce the risk of acquiring HIV-1. Uninfected individuals who miss doses are at greater risk of acquiring HIV-1 than those who do not miss doses.
• That emtricitabine and tenofovir disoproxil fumarate does not prevent other sexually acquired infections and should only be used as part of a complete prevention strategy including other prevention measures.
• To use condoms consistently and correctly to lower the chances of sexual contact with any body fluids such as semen, vaginal secretions, or blood.
• The importance of knowing their HIV-1 status and the HIV-1 status of their partner(s).
• The importance of virologic suppression in their partner(s) with HIV-1.
• The need to get tested regularly for HIV-1 (at least every 3 months, or more frequently for some individuals such as adolescents) and to ask their partner(s) to get tested as well.
• To report any symptoms of acute HIV-1 infection (flu-like symptoms) to their healthcare provider immediately.
• That the signs and symptoms of acute infection include fever, headache, fatigue, arthralgia, vomiting, myalgia, diarrhea, pharyngitis, rash, night sweats, and adenopathy (cervical and inguinal).
• To get tested for other sexually transmitted infections, such as syphilis, chlamydia, and gonorrhea, that may facilitate HIV-1 transmission.
• To assess their sexual risk behavior and get support to help reduce sexual risk behavior.

Severe Acute Exacerbation of Hepatitis B in Patients Infected with HBV

Inform individuals that severe acute exacerbations of hepatitis B have been reported in patients who are infected with HBV and have discontinued emtricitabine and tenofovir disoproxil fumarate [see Warnings and Precautions (5.1)]. Advise HBV-infected individuals to not discontinue emtricitabine and tenofovir disoproxil fumarate without first informing their healthcare provider.

New Onset or Worsening Renal Impairment

Inform HIV-1 infected patients and uninfected individuals that renal impairment, including cases of acute renal failure and Fanconi syndrome, has been reported in association with the use of TDF, a component of emtricitabine and tenofovir disoproxil fumarate tablet. Advise patients to avoid emtricitabine and tenofovir disoproxil fumarate with concurrent or recent use of a nephrotoxic agent (e.g., high-dose or multiple NSAIDs) [see Warnings and Precautions (5.3)]. The dosing interval of emtricitabine and tenofovir disoproxil fumarate may need adjustment in HIV-1 infected patients with renal impairment. Emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP should not be used in HIV-1 uninfected individuals if estimated creatinine clearance is less than 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see Dosage and Administration (2.6)].

Immune Reconstitution Syndrome

Inform HIV-1 infected patients that in some patients with advanced HIV infection (AIDS), signs and symptoms of inflammation from previous infections may occur soon after anti-HIV treatment is started. It is believed that these symptoms are due to an improvement in the body’s immune response, enabling the body to fight infections that may have been present with no obvious symptoms. Advise patients to inform their healthcare provider immediately of any symptoms of infection [see Warnings and Precautions (5.4)].

Bone Loss and Mineralization Defects

Inform patients that decreases in bone mineral density have been observed with the use of TDF or emtricitabine and tenofovir disoproxil fumarate. Consider bone monitoring in patients and uninfected individuals who have a history of pathologic bone fracture or at risk for osteopenia [see Warnings and Precautions (5.5)].

Lactic Acidosis and Severe Hepatomegaly

Inform HIV-1 infected patients and uninfected individuals that lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Treatment with emtricitabine and tenofovir disoproxil fumarate should be suspended in any person who develops clinical symptoms suggestive of lactic acidosis or pronounced hepatotoxicity [see Warnings and Precautions (5.6)].

Drug Interactions

Advise individuals that emtricitabine and tenofovir disoproxil fumarate may interact with many drugs; therefore, advise individuals to report to their healthcare provider the use of any other medication, including other HIV drugs and drugs for treatment of hepatitis C virus [see Warnings and Precautions (5.7) and Drug Interactions (7)].

Dosage Recommendations for Treatment of HIV-1 Infection

Inform HIV-1 infected patients that it is important to take emtricitabine and tenofovir disoproxil fumarate with other antiretroviral drugs for the treatment of HIV-1 on a regular dosing schedule with or without food and to avoid missing doses as it can result in development of resistance.

Pregnancy Registry

Inform individuals using emtricitabine and tenofovir disoproxil fumarate for HIV-1 treatment or HIV-1 PrEP that there is an antiretroviral pregnancy registry to monitor fetal outcomes of pregnant women exposed to emtricitabine and tenofovir disoproxil fumarate [see Use in Specific Populations (8.1)].

Lactation

Instruct mothers not to breastfeed if they are taking emtricitabine and tenofovir disoproxil fumarate for the treatment of HIV-1 infection or if acute HIV-1 infection is suspected in a mother taking emtricitabine and tenofovir disoproxil fumarate for HIV-1 PrEP because of the risk of passing the HIV-1 virus to the baby. In HIV-uninfected women, the benefits and risks of emtricitabine and tenofovir disoproxil fumarate while breastfeeding should be evaluated, including the risk of HIV-1 acquisition due to medication nonadherence and subsequent mother to child transmission [see Use in Specific Populations (8.2)].

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Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 08-2021-01