EMTRICITABINE AND TENOFOVIR DISOPROXIL FUMARATE (Page 5 of 10)

8.2 Lactation

Risk Summary

Based on published data, FTC and tenofovir have been shown to be present in human breast milk (see Data). It is not known if the components of emtricitabine and tenofovir disoproxil fumarate tablets affect milk production or have effects on the breastfed child.

Treatment of HIV-1 Infection:

The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1.

Because of the potential for: (1) HIV transmission (in HIV-negative infants); (2) developing viral resistance (in HIV-positive infants); and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are taking emtricitabine and tenofovir disoproxil fumarate tablets for the treatment of HIV-1.

HIV-1 PrEP:

In HIV-uninfected women, the developmental and health benefits of breastfeeding and the mother’s clinical need for emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP should be considered along with any potential adverse effects on the breastfed child from emtricitabine and tenofovir disoproxil fumarate tablets and the risk of HIV-1 acquisition due to nonadherence and subsequent mother to child transmission.

Women should not breastfeed if acute HIV-1 infection is suspected because of the risk of HIV-1 transmission to the infant.

Data

HIV-1 PrEP: In a study of 50 breastfeeding women who received emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP between 1 and 24 weeks postpartum (median 13 weeks), after 7 days of treatment, tenofovir was undetectable but FTC was detectable in the plasma of most infants. In these infants, the average FTC plasma concentration was less than 1% of the FTC C_max observed in HIV-infected infants (up to 3 months of age) receiving the therapeutic dose of FTC (3 mg/kg/day). There were no serious adverse events. Two infants (4%) had an adverse event of mild diarrhea which resolved.

8.4 Pediatric Use

Treatment of HIV-1 Infection

No pediatric clinical trial was conducted to evaluate the safety and efficacy of emtricitabine and tenofovir disoproxil fumarate tablets in patients with HIV-1 infection. Data from previously conducted trials with the individual drug products, FTC and TDF, were relied upon to support dosage recommendations for emtricitabine and tenofovir disoproxil fumarate tablets. For additional information, consult the prescribing information for EMTRIVA and VIREAD.

Emtricitabine and tenofovir disoproxil fumarate tablets should only be administered to HIV-1 infected pediatric patients with body weight greater than or equal to 17 kg and who are able to swallow a tablet. Because it is a fixed-dose combination tablet, emtricitabine and tenofovir disoproxil fumarate tablets cannot be adjusted for patients of lower weight [see Warnings and Precautions (5.5), Adverse Reactions (6.1) and Clinical Pharmacology (12.3)]. Emtricitabine and tenofovir disoproxil fumarate tablets are not approved for use in pediatric patients weighing less than 17 kg.

HIV-1 PrEP

The safety and effectiveness of emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP in at-risk adolescents weighing at least 35 kg is supported by data from adequate and well-controlled studies of emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP in adults with additional data from safety and pharmacokinetic studies in previously conducted trials with the individual drug products, FTC and TDF, in HIV-1 infected adults and pediatric subjects [see Dosage and Administration (2.5), Adverse Reactions (6.1), Clinical Pharmacology (12.3 and 12.4),and Clinical Studies (14.3 and 14.4)].

Safety, adherence, and resistance were evaluated in a single-arm, open-label clinical trial (ATN113) in which 67 HIV-1 uninfected at-risk adolescent men who have sex with men received emtricitabine and tenofovir disoproxil fumarate tablets once daily for HIV-1 PrEP. The mean age of subjects was 17 years (range 15 to 18 years); 46% were Hispanic, 52% Black, and 37% White. The safety profile of emtricitabine and tenofovir disoproxil fumarate tablets in ATN113 was similar to that observed in the adult HIV-1 PrEP trials [see Adverse Reactions (6.1)].

In the ATN113 trial, HIV-1 seroconversion occurred in 3 subjects. Tenofovir diphosphate levels in dried blood spot assays indicate that these subjects had poor adherence. No tenofovir- or FTC- associated HIV-1 resistance substitutions were detected in virus isolated from the 3 subjects who seroconverted [see Microbiology (12.4)].

Adherence to study drug, as demonstrated by tenofovir diphosphate levels in dried blood spot assays, declined markedly after Week 12 once subjects switched from monthly to quarterly visits, suggesting that adolescents may benefit from more frequent visits and counseling [see Warnings and Precautions (5.2)].

Safety and effectiveness of emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP in pediatric patients weighing less than 35 kg have not been established.

8.5 Geriatric Use

Clinical trials of FTC, TDF, or emtricitabine and tenofovir disoproxil fumarate tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

8.6 Renal Impairment

Treatment of HIV-1 Infection

The dosing interval for emtricitabine and tenofovir disoproxil fumarate tablets should be modified in HIV-infected adult individuals with estimated creatinine clearance of 30 to 49 mL/min. emtricitabine and tenofovir disoproxil fumarate tablets are not recommended in individuals with estimated creatinine clearance below 30 mL/min and in individuals with end-stage renal disease requiring dialysis [see Dosage and Administration (2.6)].

HIV-1 PrEP

Emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP are not recommended in HIV-1 uninfected individuals with estimated creatinine clearance below 60 mL/min. If a decrease in estimated creatinine clearance is observed in uninfected individuals while using emtricitabine and tenofovir disoproxil fumarate tablets for HIV-1 PrEP, evaluate potential causes and re-assess potential risks and benefits of continued use [see Dosage and Administration (2.6)].

10 OVERDOSAGE

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.

Emtricitabine

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

Tenofovir Disoproxil Fumarate

Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of TDF, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

Emtricitabine and tenofovir disoproxil fumarate tablets are fixed-dose combination tablets containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). FTC is a synthetic nucleoside analog of cytidine. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5′-monophosphate. Both FTC and tenofovir exhibit inhibitory activity against HIV-1 reverse transcriptase.

Emtricitabine

The chemical name of FTC is 5-fluoro-1-(2R,5S)-[2-(hydroxymethyl)-1,3-oxathiolan-5 yl]cytosine. FTC 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 C₈ H₁₀ FN₃ O₃ S and a molecular weight of 247.24. It has the following structural formula:

FTC is a white to off-white colored powder with a solubility of approximately 112 mg/mL in water at 25 C. The partition coefficient (log p) for emtricitabine is -0.43 and the pKa is 2.65.

Tenofovir Disoproxil Fumarate

TDF is a fumaric acid salt of the bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. The chemical name of tenofovir DF is 9-[(R)-2 [[bis[[(isopropoxycarbonyl)oxy]- methoxy]phosphinyl]methoxy]propyl]adenine fumarate (1:1). It has a molecular formula of C₁₉ H₃₀ N₅ O₁₀ P • C₄ H₄ O₄ and a molecular weight of 635.51. It has the following structural formula:

Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 9.78 mg/mL in water at 25 C. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75. All dosages are expressed in terms of TDF except where otherwise noted.

Emtricitabine and tenofovir disoproxil fumarate tablets are for oral administration, and are available in the following strengths:

• Film-coated tablet containing 200 mg of FTC and 300 mg of TDF (which is equivalent to 245 mg of tenofovir disoproxil) as active ingredients

Emtricitabine and tenofovir disoproxil fumarate tablets also include the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, magnesium stearate, mannitol and microcrystalline cellulose. The tablets are coated with Opadry II White 32K180001, which contains hypromellose 2910, lactose monohydrate, titanium dioxide and triacetin.