Emtricitabine and Tenofovir Disoproxil Fumarate: Package Insert and Label Information (Page 4 of 7)

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 30–49 mL/min. Emtricitabine and Tenofovir disoproxil fumarate tablet is 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 is 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 4-Amino-5-fluoro-1-[(2R,5S)-2-(hydroxy methyl)- 1,3-oxathiolan-5- yl]-2(1H)-pyrimidinone. 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 C 8 H 10 FN 3 O 3 S and a molecular weight of 247.24. It has the following structural formula:

Structure

FTC is a white to almost white crystalline powder and freely soluble in methonal and water, practically insoluble in dichloromethane. 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 C 19 H 30 N 5 O 10 P · C 4 H 4 O 4 and a molecular weight of 635.52. It has the following structural formula:

Structure
(click image for full-size original)

Tenofovir disoproxil fumarate is a white to off-white powder and Soluble in methanol, slightly soluble in water. The partition coefficient (log p) for tenofovir disoproxil is 1.25 and the pKa is 3.75.

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.

The tablets also include the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch (gluten free). The tablets are coated with Opadry white Y-1-7000, which contains hypromellose 2910 (5cP), polyethylene glycol 400 (macrogol) & titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Emtricitabine and Tenofovir disoproxil fumarate tablet is a fixed-dose combination of antiviral drugs FTC and TDF [see Microbiology (12.4)].

12.3 Pharmacokinetics

Emtricitabine and Tenofovir disoproxil fumarate tablets: One Emtricitabine and Tenofovir disoproxil fumarate tablets tablet was comparable to one FTC capsule (200 mg) plus one TDF tablet (300 mg) following single-dose administration to fasting healthy subjects (N=39).

Emtricitabine: The pharmacokinetic properties of FTC are summarized in Table 8. Following oral administration of FTC, FTC is rapidly absorbed with peak plasma concentrations occurring at 1–2 hours postdose. Less than 4% of FTC binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.02–200 μg/mL. Following administration of radiolabelled FTC, approximately 86% is recovered in the urine and 13% is recovered as metabolites. The metabolites of FTC include 3′-sulfoxide diastereomers and their glucuronic acid conjugate. Emtricitabine is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of FTC, the plasma FTC half-life is approximately 10 hours.

Tenofovir Disoproxil Fumarate: The pharmacokinetic properties of TDF are summarized in Table 8. Following oral administration of TDF, maximum tenofovir serum concentrations are achieved in 1.0 ± 0.4 hour. Less than 0.7% of tenofovir binds to human plasma proteins in vitro, and the binding is independent of concentration over the range of 0.01–25 µg/mL. Approximately 70–80% of the intravenous dose of tenofovir is recovered as unchanged drug in the urine. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. Following a single oral dose of TDF, the terminal elimination half-life of tenofovir is approximately 17 hours.

Table 8 Single Dose Pharmacokinetic Parameters for FTC and Tenofovir in Adults a
FTC Tenofovir
Fasted Oral Bioavailability b (%) 92 (83.1–106.4) 25 (NC–45.0)
Plasma Terminal Elimination Half- Life b (hr) 10 (7.4–18.0) 17 (12.0–25.7)
Cmax c (μg/mL) 1.8±0.72 d 0.30±0.09
AUC c (μg · hr/mL) 10.0±3.12 d 2.29±0.69
CL/F c (mL/min) 302±94 1043±115
CLrenal c (mL/min) l 213±89 243±33
a. NC=Not calculated b. Median (range) c. Mean (± SD) d. Data presented as steady state values

Effects of Food on Oral Absorption

Emtricitabine and Tenofovir disoproxil fumarate tablets may be administered with or without food. Administration of Emtricitabine and Tenofovir disoproxil fumarate tablets following a high fat meal (784 kcal; 49 grams of fat) or a light meal (373 kcal; 8 grams of fat) delayed the time of tenofovir Cmax by approximately 0.75 hour. The mean increases in tenofovir AUC and Cmax were approximately 35% and 15%, respectively, when administered with a high fat or light meal, compared to administration in the fasted state. In previous safety and efficacy trials, TDF (tenofovir) was taken under fed conditions. FTC systemic exposures (AUC and Cmax) were unaffected when Emtricitabine and Tenofovir disoproxil fumarate tablet was administered with either a high fat or a light meal.

Specific Populations

Race

Emtricitabine: No pharmacokinetic differences due to race have been identified following the administration of FTC.

Tenofovir Disoproxil Fumarate: There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations following the administration of TDF.

Gender

Emtricitabine and Tenofovir Disoproxil Fumarate: FTC and tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients

Treatment of HIV-1 Infection: The pharmacokinetic data for tenofovir and FTC following administration of Emtricitabine and Tenofovir disoproxil fumarate tablets in pediatric subjects weighing 17 kg and above are not available. The dosage recommendations of Emtricitabine and Tenofovir disoproxil fumarate tablets in this population are based on the dosage recommendations of FTC and TDF in this population. Refer to the EMTRIVA and VIREAD prescribing information for pharmacokinetic information on the individual products in pediatric patients.

HIV-1 PrEP: The pharmacokinetic data for tenofovir and FTC following administration of Emtricitabine and Tenofovir disoproxil fumarate tablets in HIV-1 uninfected adolescents weighing 35 kg and above are not available. The dosage recommendations of Emtricitabine and Tenofovir disoproxil fumarate tablets for HIV-1 PrEP in this population are based on safety and adherence data from the ATN113 trial [see Use in Specific Populations (8.4)] and known pharmacokinetic information in HIV-infected adolescents taking TDF and FTC for treatment.

Geriatric Patients

Pharmacokinetics of FTC and tenofovir have not been fully evaluated in the elderly (65 years of age and older).

Patients with Renal Impairment

The pharmacokinetics of FTC and tenofovir are altered in subjects with renal impairment [see Warnings and Precautions (5.3)]. In adult subjects with creatinine clearance below 50 mL/min, Cmax and AUC 0–∞ of FTC and tenofovir were increased. No data are available to make dosage recommendations in pediatric patients with renal impairment.

Patients with Hepatic Impairment

The pharmacokinetics of tenofovir following a 300 mg dose of TDF have been studied in non-HIV infected subjects with moderate to severe hepatic impairment. There were no substantial alterations in tenofovir pharmacokinetics in subjects with hepatic impairment compared with unimpaired subjects. The pharmacokinetics of Emtricitabine and Tenofovir disoproxil fumarate tablets or FTC have not been studied in subjects with hepatic impairment; however, FTC is not significantly metabolized by liver enzymes, so the impact of liver impairment should be limited.

Assessment of Drug Interactions

The steady state pharmacokinetics of FTC and tenofovir were unaffected when FTC and TDF were administered together versus each agent dosed alone.

In vitro studies and clinical pharmacokinetic drug-drug interaction trials have shown that the potential for CYP mediated interactions involving FTC and tenofovir with other medicinal products is low.

TDF is a substrate of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) transporters. When TDF is coadministered with an inhibitor of these transporters, an increase in absorption may be observed.

No clinically significant drug interactions have been observed between FTC and famciclovir, indinavir, stavudine, TDF, and zidovudine (Tables 9 and 10). Similarly, no clinically significant drug interactions have been observed between TDF and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir in trials conducted in healthy volunteers (Tables 11 and 12).

Table 9 Drug Interactions: Changes in Pharmacokinetic Parameters for FTC in the Presence of the Coadministered Drug a
Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of FTC Pharmacokinetic Parameters b (90% CI)
C max AUC C min
TDF 300 once daily × 7 days 200 once daily × 7 days 17 ↑ 20 (↑ 12 to ↑ 29)
Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27
Indinavir 800 × 1 200 × 1 12 NA
Famciclovir 500 × 1 200 × 1 12 NA
Stavudine 40 × 1 200 × 1 6 NA
a. All interaction trials conducted in healthy volunteers b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable
Table 10 Drug Interactions: Changes in Pharmacokinetic Parameters for Co administered Drug in the Presence of FTC a
Coadministered Drug Dose of Coadministered Drug (mg) FTC Dose (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters b (90% CI)
C max AUC C min
TDF 300 once daily × 7 days 200 once daily × 7 days 17
Zidovudine 300 twice daily × 7 days 200 once daily × 7 days 27 ↑ 17 (↑ 0 to ↑ 38) ↑ 13 (↑ 5 to ↑ 20)
Indinavir 800 × 1 200 × 1 12 NA
Famciclovir 500 × 1 200 × 1 12 NA
Stavudine 40 × 1 200 × 1 6 NA
a. All interaction trials conducted in healthy volunteers b. ↑ = Increase; ⇔ = No Effect; NA = Not Applicable
Table 11 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovir a in the Presence of the Coadministered Drug
Coadministered Drug Dos e of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parameters b (90% CI)
C max AUC C min
Atazanavir c 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30)
Atazanavir/ Ritonavir c 300/100 once daily 12 ↑ 34 (↑ 20 to ↑ 51) ↑ 37 (↑ 30 to ↑ 45) ↑ 29 (↑ 21 to ↑ 36)
Darunavir/ Ritonavir d 300/100 twice daily 12 ↑ 24 (↑ 8 to ↑ 42) ↑ 22 (↑ 10 to ↑ 35) ↑ 37 (↑ 19 to ↑ 57)
Indinavir 800 three times daily × 7 days 13 ↑ 14 (↓ 3 to ↑ 33)
Ledipasvir/ Sofosbuvir e,f 90/400 once daily × 10 days 24 ↑ 47 (↑ 37 to ↑58) ↑ 35 (↑ 29 to ↑42 ) ↑ 47 (↑ 38 to ↑ 57)
Ledipasvir/ Sofosbuvir e,g 23 ↑ 64 (↑ 54 to ↑ 74) ↑ 50 (↑ 42 to ↑ 59) ↑ 59 (↑ 49 to ↑ 70)
Ledipasvir/ Sofosbuvir h 90/400 once daily × 14 days 15 ↑ 79 (↑ 56 to ↑ 104) ↑ 98 (↑ 77 to ↑ 123) ↑ 163 (↑ 132 to ↑ 197)
Ledipasvir/ Sofosbuvir i 90/400 once daily × 10 days 14 ↑ 32 (↑ 25 to ↑ 39 ) ↑ 40 (↑ 31 to ↑ 50 ) ↑ 91 (↑ 74 to ↑ 110)
Ledipasvir/ Sofosbuvir j 90/400 once daily × 10 days 29 ↑ 61 (↑ 51 to ↑ 72) ↑ 65 (↑ 59 to ↑ 71) ↑ 115 (↑ 105 to ↑ 126)
Lopinavir/ Ritonavir 400/100 twice daily × 14 days 24 ↑ 32 (↑ 25 to ↑ 38) ↑ 51 (↑ 37 to ↑ 66)
Saquinavir/ Ritonavir 1000/100 twice daily × 14 days 35 ↑ 23 (↑ 16 to ↑ 30)
Sofosbuvir k 400 single dose 16 ↑ 25 (↑ 8 to ↑45)
Sofosbuvir/ Velpatasvir l 400/100 once daily 24 ↑ 44 (↑ 33 to ↑ 55) ↑ 40 (↑ 34 to ↑ 46) ↑ 84 (↑ 76 to ↑ 92)
Sofosbuvir/ Velpatasvir m 400/100 once daily 30 ↑ 46 (↑ 39 to ↑ 54) ↑ 40 (↑ 34 to ↑ 45) ↑ 70 (↑ 61 to ↑ 79)
Sofosbuvir/ Velpatasvir/Voxilaprevir n 400/100/100 + Voxilapreviro 100 once daily 29 ↑ 48 (↑ 36 to ↑ 61) ↑ 39 (↑ 32 to ↑ 46) ↑ 47 (↑ 38 to ↑ 56)
Tacrolimus 0.05 mg/kg twice daily × 7 days 21 ↑13 ( ↑1 to ↑27)
Tipranavir/ Ritonavir p 500/100 twice daily 22 23 ( 32 to 13) 2 ( 9 to ↑5) ↑ 7 ( 2 to ↑17)
750/200 twice daily (23 doses) 20 38 ( 46 to 29) ↑2 ( 6 to ↑10) ↑ 14 ( ↑1 to ↑ 27)
a Subjects received Tenofovir Disoproxil Fumarate 300 mg once daily. b Increase = ↑; Decrease = ↓; No Effect = ⇔ c Reyataz Prescribing Information. d Prezista Prescribing Information. e Data generated from simultaneous dosing with HARVONI (ledipasvir/sofosbuvir). Staggered administration (12 hours apart) provided similar results. f Comparison based on exposures when administered as atazanavir/ritonavir + FTC/TDF. g Comparison based on exposures when administered as darunavir/ritonavir + FTC/TDF. h Study conducted with ATRIPLA (efavirenz/FTC/TDF) coadministered with HARVONI. i Study conducted with COMPLERA (FTC/rilpivirine/TDF) coadministered with HARVONI. j Study conducted with Emtricitabine and Tenofovir disoproxil fumarate tablets (FTC/TDF) + dolutegravir coadministered with HARVONI. k Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir). l Study conducted with COMPLERA coadministered with EPCLUSA; coadministration with EPCLUSA also results in comparable increases in tenofovir exposures when TDF is administered as ATRIPLA, STRIBILD, Emtricitabine and Tenofovir disoproxil fumarate tablets + atazanavir/ritonavir, or Emtricitabine and Tenofovir disoproxil fumarate tablets + darunavir/ritonavir. m Administered as raltegravir + FTC/TDF. n Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF. o Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV- infected patients p Aptivus Prescribing Information.

No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with Emtricitabine and Tenofovir disoproxil fumarate tablets: abacavir, didanosine (buffered tablets), FTC, entecavir, and lamivudine.

Table 12 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir
Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parameters a (90% CI)
C max AUC C min
Abacavir 300 once 8 ↑ 12 (↓ 1 to ↑ 26) NA
Atazanavir b 400 once daily × 14 days 34 ↓ 21 (↓ 27 to ↓ 14) ↓ 25 (↓ 30 to ↓ 19) ↓ 40 (↓ 48 to � 32)
Atazanavir d Atazanavir/Ritonavir 300/100 once daily × 42 days 10 ↓ 28 (↓ 50 to ↑ 5) ↓ 25 c (↓ 42 to ↓ 3) ↓ 23 c (↓ 46 to ↑ 10)
Darunavir d Darunavir/Ritonavir 300/100 once daily 12 ↑ 16 (↓ 6 to ↑ 42) ↑ 21 (↓ 5 to ↑ 54) ↑ 24 (↓ 10 to ↑ 69)
Didanosine e 250 once, simultaneously with TDF and a light meal 33 ↓ 20 g (↓ 32 to ↓ 7) ⇔Þ NA
Emtricitabine 200 once daily × 7 days 17 ↑ 20 (↑ 12 to ↑ 29)
Indinavir 800 three times daily × 7 days 12 ↓ 11 (↓ 30 to ↑ 12)
Entecavir 1 once daily × 10 days 28 ↑ 13 (↑ 11 to ↑ 15)
Lamivudine 150 twice daily × 7 days 15 ↓ 24 (↓ 34 to ↓ 12)
Lopinavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24
Ritonavir
Saquinavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22 (↑ 6 to ↑41) ↑ 29 h (↑ 12 to ↑ 48) ↑ 47 h (↑ 23 to ↑ 76)
Ritonavir ↑ 23 (↑ 3 to ↑ 46)
Tacrolimus 0.05 mg/kg twice daily × 7 days 21
Tipranavir i Tipranavir/Ritonavir 500/100 twice daily 22 ↓ 17 (↓ 26 to ↓ 6) ↓ 18 (↓ 25 to ↓ 9) ↓ 21 (↓ 30 to ↓ 10)
Tipranavir/Ritonavir 750/200 twice daily (23 doses) 20 ↓ 11 (↓ 16 to ↓ 4) ↓ 9 (↓ 15 to ↓ 3) ↓ 12 (↓ 22 to 0)
a. Increase = ↑; Decrease = ↓; No Effect = ⇔; NA = Not Applicable b. Reyataz Prescribing Information. c. In HIV- infected subjects, addition of TDF to atazanavir 300 mg plus ritonavir 100 mg resulted in AUC and Cmin values of atazanavir that were 2.3- and 4 — fold higher than the respective values observed for atazanavir 400 mg when given alone. d. Prezista Prescribing Information. e. Videx EC Prescribing Information. Subjects received didanosine enteric- coated capsules. When didanosine 250 mg enteric- coated capsules were administered with TDF, systemic exposures of didanosine were similar to those seen with the 400 mg enteric- coated capsules alone under fasted conditions. f. 373 kcal, 8.2 g fat g. Compared with didanosine (enteric- coated) 400 mg administered alone under fasting conditions. h. Increases in AUC and Cmin are not expected to be clinically relevant; hence, no dose adjustments are required when TDF and ritonavir- boosted saquinavir are coadministered. i. Aptivus Prescribing Information.

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