Tenofovir Disproxil Fumarate (Page 4 of 10)

8.2 Lactation

Risk Summary
Based on published data, tenofovir has been shown to be present in human breast milk (see Data). It is not known if tenofovir affects milk production or has 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 tenofovir disoproxil fumarate for the treatment of HIV-1.
Treatment of HBV infection:
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for tenofovir disoproxil fumarate and any potential adverse effects on the breastfed infant from tenofovir disoproxil fumarate or from the underlying maternal condition.
Data
In a study of 50 HIV-uninfected, breastfeeding women on a tenofovir-containing regimen initiated between 1 and 24 weeks postpartum (median 13 weeks), tenofovir was undetectable in the plasma of most infants after 7 days of treatment in mothers. There were no serious adverse events in mothers or infants.

8.4 Pediatric Use

Pediatric Patients 2 Years and Older with HIV-1 Infection
The safety and effectiveness of tenofovir disoproxil fumarate in pediatric patients 2 years to less than 18 years of age is supported by data from two randomized trials. Trial 352 was a randomized controlled trial in 92 HIV-1 treatment experienced subjects 2 years to less than 12 years of age who were virologically suppressed on a stavudine-or zidovudine-containing regimen and were randomized to either switch to a tenofovir disoproxil fumarate -containing regimen (N=44) or stay on their original regimen (N=48) for 48 weeks. At Week 48, 89% of subjects in the tenofovir disoproxil fumarate treatment group and 90% of subjects in the d4T or AZT treatment group had HIV-1 RNA concentrations <400 copies/mL. Trial 321 was a placebo-controlled trial in 87 HIV-1 treatment experienced subjects 12 years to less than 18 years of age who were treated with tenofovir disoproxil fumarate (N=45) or placebo (N=42) in combination with an optimized background regimen for 48 weeks. Overall, the trial failed to show a difference in virologic response between the tenofovir disoproxil fumarate and placebo groups. Subgroup analyses suggest the lack of difference in virologic response may be attributable to imbalances between treatment arms in baseline viral susceptibility to tenofovir disoproxil fumarate and OBR [see Adverse Reactions (6.1) and Clinical Studies (14.3)].
Although changes in HIV-1 RNA in these highly treatment-experienced subjects in Trial 321 were less than anticipated, the pharmacokinetic profile of tenofovir in patients 2 years to less than 18 years of age at the recommended doses was similar to that found to be safe and effective in adult clinical trials [see Clinical Pharmacology (12.3)].
The effects of tenofovir disoproxil fumarate -associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in HIV-1 pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

Safety and effectiveness of tenofovir disoproxil fumarate in pediatric patients younger than 2 years of age and weighing less than 10 kg with HIV-1 infection have not been established.
Pediatric Patients 2 Years of Age and Older with Chronic Hepatitis B
The safety and effectiveness of tenofovir disoproxil fumarate in pediatric patients 2 years to less than 18 years of age is supported by data from two randomized trials (Trial 115 and Trial 144) in which tenofovir disoproxil fumarate was administered to HBV-infected treatment-experienced subjects.
In Trial 115, 106 HBeAg negative (9%) and positive (91%) subjects 12 years to less than 18 years of age with chronic HBV infection were randomized to receive blinded treatment with tenofovir disoproxil fumarate or placebo for 72 weeks. At Week 72, 88% of subjects in the tenofovir disoproxil fumarate group and 0% of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL).In Trial 144, 89 HBeAg positive (96%) and negative (4%) subjects 2 years to less than 12 years of age were treated with tenofovir disoproxil fumarate 8 mg/kg up to maximum dose of 300 mg or placebo once daily for 48 weeks. At Week 48, 77% of subjects in the tenofovir disoproxil fumarate group and 7% of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL).
The effects of tenofovir disoproxil fumarate-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk in chronic HBV-infected pediatric patients 2 years and older are unknown. The long-term effect of lower spine and total body BMD on skeletal growth in pediatric patients 2 years and older, and in particular, the effects of long-duration exposure in younger children is unknown [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

Safety and effectiveness of tenofovir disoproxil fumarate in chronic HBV-infected pediatric patients younger than 2 years of age and weighing less than 10 kg have not been established.

8.5 Geriatric Use

Clinical trials of tenofovir disoproxil fumarate did not include sufficient numbers of subjects aged 65 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 Renal Impairment

The dosing interval for tenofovir disoproxil fumarate should be modified in adult patients with estimated creatinine clearance below 50 mL/min or in patients with end stage renal disease requiring dialysis [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

If overdose occurs, the patient must be monitored for evidence of toxicity, and standard supportive treatment applied as necessary.
Tenofovir is efficiently removed by hemodialysis with an extraction coefficient of approximately 54%. Following a single 300 mg dose of tenofovir disoproxil fumarate, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.

11 DESCRIPTION

Tenofovir disoproxil fumarate (TDF) (a prodrug of tenofovir) which is a fumaric acid salt of bis-isopropoxycarbonyloxymethyl ester derivative of tenofovir. TDF is converted in vivo to tenofovir, an acyclic nucleoside phosphonate (nucleotide) analog of adenosine 5’-monophosphate. Tenofovir exhibits activity against HIV-1 reverse transcriptase.

The chemical name of TDF 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 635.52. It has the following structural formula:
tenofovir-disoproxil-fumarate-fig-1
Tenofovir disoproxil fumarate is a white to off-white crystalline powder with a solubility of 13.4 mg/mL in distilled water at 25 °C. It has an octanol/phosphate buffer (pH 6.5) partition coefficient (log p) of 1.25 at 25 °C.
Tenofovir disoproxil fumarate is available as tablets.
Tenofovir disoproxil fumarate tablets are for oral administration and are available in strength of 300 mg of TDF, which are equivalent to 245 mg of tenofovir disoproxil.
Each tablet of tenofovir disoproxil fumarate contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch. The tablets are coated with Opadry II Blue 30K505001, which contains FD&C blue #2 aluminum lake, hypromellose, lactose monohydrate, titanium dioxide and triacetin.
In this insert, all dosages are expressed in terms of TDF except where otherwise noted.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Tenofovir disoproxil fumarate is an antiviral drug [see Microbiology (12.4)].

12.3 Pharmacokinetics

The pharmacokinetics of TDF have been evaluated in healthy volunteers and HIV-1 infected individuals. Tenofovir pharmacokinetics are similar between these populations.

Absorption
Tenofovir disoproxil fumarate is a water soluble diester prodrug of the active ingredient tenofovir. The oral bioavailability of tenofovir from tenofovir disoproxil fumarate in fasted subjects is approximately 25%. Following oral administration of a single dose of tenofovir disoproxil fumarate 300 mg to HIV-1 infected subjects in the fasted state, maximum serum concentrations (Cmax ) are achieved in 1.0 ± 0.4 hrs. Cmax and AUC values are 0.30 ± 0.09 μg/mL and 2.29 ± 0.69 μg.hr/mL, respectively.

The pharmacokinetics of tenofovir are dose proportional over a tenofovir disoproxil fumarate dose range of 75 to 600 mg and are not affected by repeated dosing.

In a single-dose bioequivalence study conducted under non-fasted conditions (dose administered with 4 oz. applesauce) in healthy adult volunteers, the mean Cmax of tenofovir was 26% lower for the oral powder relative to the tablet formulation. Mean AUC of tenofovir was similar between the oral powder and tablet formulations.
Distribution
In vitro binding of tenofovir to human plasma or serum proteins is less than 0.7 and 7.2%, respectively, over the tenofovir concentration range 0.01 to 25 μg/mL. The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg.
Metabolism and Elimination
In vitro studies indicate that neither tenofovir disoproxil nor tenofovir are substrates of CYP enzymes.
Following IV administration of tenofovir, approximately 70-80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Following single dose, oral administration of tenofovir disoproxil fumarate, the terminal elimination half-life of tenofovir is approximately 17 hours. After multiple oral doses of tenofovir disoproxil fumarate 300 mg once daily (under fed conditions), 32 ± 10% of the administered dose is recovered in urine over 24 hours.
Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion. There may be competition for elimination with other compounds that are also renally eliminated.

Effects of Food on Oral Absorption
Administration of tenofovir disoproxil fumarate 300 mg tablets following a high-fat meal (~700 to 1,000 kcal containing 40 to 50% fat) increases the oral bioavailability, with an increase in tenofovir AUC0-∞ of approximately 40% and an increase in Cmax of approximately 14%. However, administration of tenofovir disoproxil fumarate with a light meal did not have a significant effect on the pharmacokinetics of tenofovir when compared to fasted administration of the drug. Food delays the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL following multiple doses of tenofovir disoproxil fumarate 300 mg once daily in the fed state, when meal content was not controlled.

Specific Populations
Race
There were insufficient numbers from racial and ethnic groups other than Caucasian to adequately determine potential pharmacokinetic differences among these populations.

Gender
Tenofovir pharmacokinetics are similar in male and female subjects.

Pediatric Patients
2 Years and Older: Steady-state pharmacokinetics of tenofovir were evaluated in 31 HIV-1 infected pediatric subjects 2 years to less than 18 years of age (Table 13). Tenofovir exposure achieved in these pediatric subjects receiving oral once daily doses of tenofovir disoproxil fumarate 300 mg (tablet) was similar to exposures achieved in adults receiving once-daily doses of tenofovir disoproxil fumarate 300 mg.Table 13 Mean (± SD) Tenofovir Pharmacokinetic Parameters by Age Groups for HIV-1-infected Pediatric Patients 2 years and older for the Tablet.

Dose and Formulation 300 mg Tablet
12 Years to <18 Years (N=8)
Cmax (μg/mL) 0.38 ± 0.13
AUCtau (μg hr/mL) 3.39 ± 1.22

Tenofovir exposures in HBV-infected pediatric subjects (12 years to less than 18 years of age) receiving oral once-daily doses of tenofovir disoproxil fumarate 300 mg tablet and pediatric subjects 2 years to less than 12 years of age receiving tenofovir disoproxil fumarate 8 mg/kg of body weight (tablet or powder) up to a maximum dose of 300 mg were comparable to exposures achieved in HIV-1 infected adult subjects receiving identical doses.
Geriatric Patients
Pharmacokinetic trials have not been performed in the elderly (65 years and older).
Patients with Renal Impairment
The pharmacokinetics of tenofovir are altered in subjects with renal impairment [see Warnings and Precautions (5.2)]. In subjects with creatinine clearance below 50 mL/min or with end-stage renal disease (ESRD) requiring dialysis, Cmax , and AUC0-∞ of tenofovir were increased (Table 14).

Table 14 Pharmacokinetic Parameters (Mean ± SD) of Tenofovira in Subjects with Varying Degrees of Renal Function

Baseline Creatinine Clearance (mL/min) >80 N=3 50-80 N=10 30-49 N=8 12-29 N=11
Cmax (μg/mL) 0.34 ± 0.03 0.33 ± 0.06 0.37 ± 0.16 0.60 ± 0.19
AUC0-∞ (μg hr/mL) 2.18 ± 0.26 3.06 ± 0.93 6.01 ± 2.50 15.98 ± 7.22
CL/F (mL/min) 1043.7 ± 115.4 807.7 ± 279.2 444.4 ± 209.8 177.0 ± 97.1
CLrenal (mL/min) 243.5 ± 33.3 168.6 ± 27.5 100.6 ± 27.5 43.0 ± 31.2

a. 300 mg, single dose of tenofovir disoproxil fumarate tablets
Patients with Hepatic Impairment
The pharmacokinetics of tenofovir following a 300 mg single dose of tenofovir disoproxil fumarate 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. No change in tenofovir disoproxil fumarate dosing is required in patients with hepatic impairment.
Assessment of Drug Interactions
At concentrations substantially higher (~300-fold) than those observed in vivo, tenofovir did not inhibit in vitro drug metabolism mediated by any of the following human CYP isoforms: CYP3A4, CYP2D6, CYP2C9, or CYP2E1. However, a small (6%) but statistically significant reduction in metabolism of CYP1A substrate was observed. Based on the results of in vitro experiments and the known elimination pathway of tenofovir, the potential for CYP-mediated interactions involving tenofovir with other medicinal products is low.
Tenofovir disoproxil fumarate has been evaluated in healthy volunteers in combination with other antiretroviral and potential concomitant drugs. Tables 15 and 16 summarize pharmacokinetic effects of coadministered drug on tenofovir pharmacokinetics and effects of tenofovir disoproxil fumarate on the pharmacokinetics of coadministered drug.
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 tenofovir disoproxil fumarate and efavirenz, methadone, nelfinavir, oral contraceptives, ribavirin, or sofosbuvir.Table 15 Drug Interactions: Changes in Pharmacokinetic Parameters for Tenofovira in the Presence of the Coadministered Drug

Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Tenofovir Pharmacokinetic Parametersb (90% CI)
Cmax AUC Cmin
Atazanavirc 400 once daily × 14 days 33 ↑ 14 (↑ 8 to ↑ 20) ↑ 24 (↑ 21 to ↑ 28) ↑ 22 (↑ 15 to ↑ 30)
Atazanavir/ Ritonavirc 300/100 once daily 12 ↑ 34 (↑ 20 to ↑ 51) ↑ 37 (↑ 30 to ↑ 45) ↑ 29 (↑ 21 to ↑ 36)
Darunavir/ Ritonavird 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/ Sofosbuvire,f 90/400 once daily × 10 days 24 ↑ 47 (↑ 37 to ↑ 58) ↑ 35 (↑ 29 to ↑ 42 ) ↑ 47 (↑ 38 to ↑ 57)
Ledipasvir/ Sofosbuvire,g 23 ↑ 64 (↑ 54 to ↑ 74) ↑ 50 (↑ 42 to ↑ 59) ↑ 59 (↑ 49 to ↑ 70)
Ledipasvir/ Sofosbuvirh 90/400 once daily × 14 days 15 ↑ 79 (↑ 56 to ↑ 104) ↑ 98 (↑ 77 to ↑ 123) ↑ 163 (↑ 132 to↑197)
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)
Sofosbuviri 400 single dose 16 ↑ 25 (↑ 8 to ↑ 45)
Sofosbuvir/ Velpatasvirj 400/100 once daily 24 ↑ 44 (↑ 33 to ↑ 55) ↑ 40 (↑ 34 to ↑ 46) ↑ 84 (↑ 76 to ↑ 92)
Sofosbuvir/ Velpatasvirk 400/100 once daily 30 ↑ 46 (↑ 39 to ↑ 54) ↑ 40 (↑ 34 to ↑ 45) ↑ 70 (↑ 61 to ↑ 79)
Sofosbuvir/ Velpatasvir/ Voxilaprevirl 400/100/100 + Voxilaprevirm 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/ Ritonavirn 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 (EFV/FTC/TDF) coadministered with HARVONI; coadministration with HARVONI also results in comparable increases in tenofovir exposure when TDF is administered as COMPLERA (FTC /rilpivirine/TDF.), or TRUVADA + dolutegravir.
i. Study conducted with ATRIPLA coadministered with SOVALDI® (sofosbuvir).
j. 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, (elvitegravir/cobicistat/FTC/TDF), TRUVADA + atazanavir/ritonavir, or TRUVADA + darunavir/ritonavir.
k. Administered as raltegravir + FTC/TDF.
l. Comparison based on exposures when administered as darunavir + ritonavir + FTC/TDF.
m. Study conducted with additional voxilaprevir 100 mg to achieve voxilaprevir exposures expected in HCV-infected patients.
n. Aptivus Prescribing Information.
No effect on the pharmacokinetic parameters of the following coadministered drugs was observed with tenofovir disoproxil fumarate: abacavir, didanosine (buffered tablets), emtricitabine, entecavir and lamivudine.Table 16 Drug Interactions: Changes in Pharmacokinetic Parameters for Coadministered Drug in the Presence of Tenofovir Disoproxil Fumarate

Coadministered Drug Dose of Coadministered Drug (mg) N % Change of Coadministered Drug Pharmacokinetic Parametersa (90% CI)
Cmax AUC Cmin
Abacavir 300 once 8 ↑ 12(↓ 1 to ↑ 26) ó NA
Atazanavirb 400 once daily × 14 days 34 ↓ 21(↓ 27 to ↓ 14) ↓ 25(↓ 30 to ↓ 19) ↓ 40(↓ 48 to ↓ 32)
Atazanavirb Atazanavir/ Ritonavir 300/100 once daily × 42 days 10 ↓ 28(↓ 50 to ↑ 5) ↓ 25c (↓ 42 to ↓ 3) ↓ 23c (↓ 46 to ↑ 10)
Darunavird Darunavir/Ritonavir 300/100 once daily 12 ↑ 16(↓ 6 to ↑ 42) ↑ 21↓ 5 to ↑ 54) ↑ 24(↓ 10 to ↑ 69)
Didanosinee 250 once, simultaneously with tenofovir disoproxil fumarate and a light mealf 33 ↓ 20g (↓ 32 to ↓ 7) óg NA
Emtricitabine 200 once daily × 7 days 17 ó ó ↑ 20(↑ 12 to ↑ 29)
Entecavir 1 mg once daily x 10 days 28 ó ↑ 13(↑ 11 to ↑ 15) ó
Indinavir 800 three times daily × 7 days 12 ↓ 11(↓ 30 to ↑ 12) ó ó
Lamivudine 150 twice daily × 7 days 15 ↓ 24(↓ 34 to ↓ 12) ó ó
Lopinavir Ritonavir Lopinavir/Ritonavir 400/100 twice daily × 14 days 24 ó ó ó
Saquinavir Ritonavir Saquinavir/Ritonavir 1000/100 twice daily × 14 days 32 ↑ 22(↑ 6 to ↑ 41)ó ↑ 29h(↑ 12 to ↑ 48)ó ↑ 47h(↑ 23 to ↑ 76)↑ 23(↑ 3 to ↑ 46)
Tacrolimus 0.05 mg/kg twice daily x 7 days 21 ó ó ó
Tipranaviri 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.
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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