KEMERUVIR

Tenofovir disoproxil fumarate (a prodrug of tenofovir), marketed by Gilead Sciences under the trade name Viread, belongs to a class of antiretroviral drugs known as nucleotide analogue reverse transcriptase inhibitors (nRTIs).

This drug is prescribed in combination with other drugs for the management of HIV infection as well as for Hepatitis B therapy.

Tenofovir disoproxil was initially approved in 2001 Label.

Tenofovir disoproxil is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in patients ≥2 years old and weighing ≥10 kg.

It is also indicated for the treatment of chronic hepatitis B in patients ≥2 years old and weighing ≥10 kg.

Tenofovir disoproxil is also an ingredient in several combination products, all of which are indicated either alone or in combination with other antiretrovirals for the treatment of HIV-1 infection. 12, 13, 14, 15, 16, 17, 18 In addition, tenofovir disoproxil is available in combination with emtricitabine (under the brand name Truvada) for use as pre-exposure prophylaxis (PrEP) in at-risk adults and adolescents weighing ≥ 35 kg to reduce the risk of sexually-acquired HIV-1 infection.

This drug prevents viral

DNA chain elongation through inhibition of enzymes necessary for host cell infection viral replication in HIV-1 and Hepatitis B infections 9, 10.

In vitro effects

The antiviral activity of tenofovir against in laboratory and clinical isolates of HIV-1 was studied in lymphoblastoid cell lines, primary monocyte/macrophage cells, in addition to peripheral blood lymphocytes.

EC50 (50% effective concentration) values of tenofovir against HIV-1 virus ranged between 0.04 μM to 8.5 μM.

Tenofovir demonstrated antiviral activities in cell cultures against HIV-1 Label.

After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir 24.

Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-∞ of about 40% as well as an increase in Cmax of about 14%.

On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions.

The presence of ingested food slows 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 after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled Label.

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 Label.

After oral administration of tenofovir disoproxil, tenofovir is distributed to the majority tissues with the highest concentrations measured in the kidney, liver and the intestinal contents (based on data from preclinical studies) 24.

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil.

Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog.

Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell Label.

Two phosphorylation steps are required to convert tenofovir disoproxil to the active drug form 11.

The cytochrome

P450 enzyme system is not involved with the metabolism of tenofovir disoproxil or tenofovir Label.

Hover over products below to view reaction partners Tenofovir disoproxil Tenofovir Monophosphate Tenofovir Diphosphate.

Intravenous administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing.

Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion Label.

There may be competition for elimination with other compounds that are also eliminated by the kidneys.

When a single oral dose is given, the terminal elimination half-life is approximately 17 hours Label.

The clearance of tenofovir is highly dependent on renal function and may vary greatly.

Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min) 24.

On average, renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate.

This shows that active tubular secretion is an essential part of the elimination of tenofovir 24.

FDA label provides specific guidelines for dosing according to renal function.

It is important to consult product labeling before administering tenofovir to individuals with renal dysfunction, as the clearance of this drug may vary greatly among these patients Label.

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A note on breastfeeding The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1.

Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil Label.

Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection.

At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans.

In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose Label.

Pregnancy This drug is considered a pregnancy Category B drug.

Reproduction studies have been performed in rats and rabbits at doses up to and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required.

To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed.

Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil Label.

Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test).

In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.

There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation.

There was, however, changes in the estrous cycle in female rats Label.

• Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults and pediatric patients 12 years of age and older (35 kg or more): 300 mg once daily taken orally without regard to food.

• Recommended dose for the treatment of HIV-1 in pediatric patients (2 to less than 12 years of age): o Tablets: For pediatric patients weighing greater than or equal to 17 kg who can swallow an intact tablet, one tenofovir disoproxil fumarate tablet (300 mg based on body weight) once daily taken orally without regard to food.

• Dose recommended in renal impairment in adults: o Creatinine clearance to 49 mL/min: 300 mg every 48 hours. o Creatinine clearance to 29 mL/min: 300 mg every to 96 hours. o Hemodialysis: 300 mg every 7 days or after approximately 12 hours of dialysis. 2.1 Recommended Dose in Adults and Pediatric Patients 12 Years of Age and Older (35 kg or more) For the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg tenofovir disoproxil fumarate tablet once daily taken orally, without regard to food.

In the treatment of chronic hepatitis

B, the optimal duration of treatment is unknown.

Safety and efficacy in pediatric patients with chronic hepatitis B weighing less than 35 kg have not been established. 2.2 Recommended Dose in Pediatric Patients 2 Years to Less than 12 Years of Age HIV-1 Infection For the treatment of HIV-1 in pediatric patients 2 years of age and older, the recommended oral dose of tenofovir disoproxil fumarate tablet is 8 mg of tenofovir disoproxil fumarate (tenofovir DF) per kilogram of body weight (up to a maximum of 300 mg) once daily administered as tablets.

Tenofovir disoproxil fumarate is available as tablets in 300 mg strength for pediatric patients who weigh greater than or equal to 17 kg and who are able to reliably swallow intact tablets.

The dose is one tablet once daily taken orally, without regard to food.

Table 2 contain dosing recommendations for tenofovir disoproxil fumarate tablets based on body weight.

Weight should be monitored periodically and the tenofovir disoproxil fumarate tablets dose adjusted accordingly.

Table 2 Dosing Recommendations for Pediatric Patients 2 Years of Age and Older and Weighing At Least 17 kg Using Tenofovir Disoproxil Fumarate Tablets Body Weight Kilogram (kg) Tablets Once Daily to less than 22 150 mg to less than 28 200 mg to less than 35 250 mg 35 or greater 300 mg Chronic Hepatitis B Safety and efficacy of tenofovir disoproxil fumarate tablets in patients younger than 12 years of age have not been established. 2.3 Dose Adjustment for Renal Impairment in Adults Significantly increased drug exposures occurred when tenofovir disoproxil fumarate tablets were administered to subjects with moderate to severe renal impairment.

Therefore, the dosing interval of tenofovir disoproxil fumarate tablets 300 mg should be adjusted in patients with baseline creatinine clearance below 50 mL/min using the recommendations in Table 3.

These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis.

The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment; therefore, clinical response to treatment and renal function should be closely monitored in these patients.

No dose adjustment of tenofovir disoproxil fumarate tablets 300 mg is necessary for patients with mild renal impairment (creatinine clearance to 80 mL/min).

Routine monitoring of estimated creatinine clearance, serum phosphorus, urine glucose, and urine protein should be performed in patients with mild renal impairment.

Table 3 Dosage Adjustment for Patients with Altered Creatinine Clearance Cre atinine Clearan ce (mL/min) a Hemodial ysis Patients 50 or greater 30.

• 29 Recomm en ded 300 mg Dosing Inte r v al Every 24 hours Every 48 hours Every to 96 hours Every 7 days or after a tot al of approximate ly 12 hours of dialysis a.

Calculated using ideal (lean) body weight. b.

Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration.

Tenofovir disoproxil fumarate tablets should be administered following completion of dialysis.

The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance below 10 mL/min; therefore, no dosing recommendation is available for these patients.

No data are available to make dose recommendations in pediatric patients with renal impairment.

Tenofovir disoproxil fumarate tablets, 300 mg, are white colored, almond shaped, film coated tablets contain 300 mg of tenofovir DF, which is equivalent to 245 mg of tenofovir disoproxil, are debossed with.H. on one side and.123. on other side.

They are packaged as follows

Bottle of 7 tablets (NDC 72789-361-07) Store at 20° to 25°C (68° to 77°F) .

Keep the bottle tightly closed.

Do not use if seal over bottle opening is broken or missing.

There are no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not always predictive of human response, tenofovir disoproxil fumarate tablets should be used during pregnancy only if clearly needed.

To monitor fetal outcomes of pregnant women exposed to tenofovir disoproxil fumarate tablets, an Antiretroviral Pregnancy Registry has been established.

Healthcare providers are encouraged to register patients by calling 1-800-258-4263.

Reproduction studies have been performed in rats and rabbits at doses up to and 19 times the human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir.

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.

Samples of breast milk obtained from five HIV-1 infected mothers in the first post-partum week show that tenofovir is secreted in human milk.

The impact of this exposure in breastfed infants is unknown.

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 breastfeed if they are receiving tenofovir disoproxil fumarate tablets.

Patients 2 Years of Age and Older with HIV-1 infection The safety of tenofovir disoproxil fumarate tablets in pediatric patients aged to less than 18 years is supported by data from two randomized trials in which tenofovir disoproxil fumarate tablets were administered to HIV-1 infected treatment-experienced subjects.

In addition, the pharmacokinetic profile of tenofovir in patients 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.

In Study 352, 92 treatment-experienced subjects to less than 12 years of age with stable, virologic suppression on stavudine.

• or zidovudine-containing regimen were randomized to either replace stavudine or zidovudine with tenofovir disoproxil fumarate tablets (N=44) or continue their original regimen (N=48) for 48 weeks.

Five additional subjects over the age of were enrolled and randomized (tenofovir disoproxil fumarate tablets N=4, original regimen N=1) but are not included in the efficacy analysis.

After 48 weeks, all eligible subjects were allowed to continue in the study receiving open-label tenofovir disoproxil fumarate tablets.

At Week 48, 89% of subjects in the tenofovir disoproxil fumarate treatment group and 90% of subjects in the stavudine or zidovudine treatment group had HIV-1 RNA concentrations less than 400 copies/mL.

During the 48 week randomized phase of the study, 1 subject in the tenofovir disoproxil fumarate tablets group discontinued the study prematurely because of virologic failure/lack of efficacy and 3 subjects (2 subjects in the tenofovir disoproxil fumarate tablets group and 1 subject in the stavudine or zidovudine group) discontinued for other reasons.

In Study 321, 87 treatment-experienced subjects to less than 18 years of age were treated with tenofovir disoproxil fumarate tablets (N=45) or placebo (N=42) in combination with an optimized background regimen (OBR) for 48 weeks.

The mean baseline

CD4 cell count was 374 cells/mm and the mean baseline plasma HIV-1 RNA was 4.6 log 10 copies/mL.

At baseline, 90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates.

Overall, the trial failed to show a difference in virologic response between the tenofovir disoproxil fumarate tablets and placebo treatment 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 tablets and OBR.

Although changes in

HIV-1 RNA in these highly treatment-experienced subjects were less than anticipated, the comparability of the pharmacokinetic and safety data to that observed in adults supports the use of tenofovir disoproxil fumarate tablets in pediatric patients 12 years of age and older who weigh greater than or equal to 35 kg and whose HIV-1 isolate is expected to be sensitive to tenofovir disoproxil fumarate tablets. .

Safety and effectiveness of tenofovir disoproxil fumarate tablets in pediatric patients younger than 2 years of age with HIV-1 infection have not been established.

Patients 12 Years of Age and Older with Chronic Hepatitis B In Study 115, 106 HBeAg negative (9%) and positive (91%) subjects aged to less than 18 years with chronic HBV infection were randomized to receive blinded treatment with tenofovir disoproxil fumarate tablets 300 mg (N=52) or placebo (N=54) for 72 weeks.

At study entry, the mean HBV DNA was 8.1 log10 copies/mL and mean ALT was 101 U/L. Of 52 subjects treated with tenofovir disoproxil fumarate tablets, 20 subjects were nucleos(t)ide-naïve and 32 subjects were nucleos(t)ide-experienced.

Thirty-one of the 32 nucleos(t)ide-experienced subjects had prior lamivudine experience.

At Week 72, 88% (46/52) of subjects in the tenofovir disoproxil fumarate tablets group and 0% (0/54) of subjects in the placebo group had HBV DNA <400 copies/mL (69 IU/mL).

Among subjects with abnormal

ALT at baseline, 74% (26/35) of subjects receiving tenofovir disoproxil fumarate tablets had normalized ALT at Week 72 compared to 31% (13/42) in the placebo group.

One tenofovir disoproxil fumarate-treated subject experienced sustained HBsAg-loss and seroconversion to anti-HBs during the first 72 weeks of study participation.

Safety and effectiveness of tenofovir disoproxil fumarate tablets in pediatric patients younger than 12 years of age or less than 35 kg with chronic hepatitis B have not been established.

Clinical trials of tenofovir disoproxil fumarate tablets did not include sufficient numbers of subjects aged 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.