Tenofovir Disoproxil Drug Information

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 Chronic Hepatitis B Safety and efficacy of tenofovir disoproxil fumarate tablets in patients younger than 12 years of age have not been established.

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 50 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 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.

Adverse Reactions from Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials in Adult Patients with HIV-1 Infection More than 12,000 subjects have been treated with tenofovir disoproxil fumarate tablets alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access programs. A total of 1,544 subjects have received tenofovir disoproxil fumarate tablets 300 mg once daily in clinical trials; over 11,000 subjects have received tenofovir disoproxil fumarate tablets in expanded access programs.

The most common adverse reactions (incidence greater than or equal to 10%, Grades 2 to 4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea. Treatment-Naïve Patients Study 903 - Treatment-Emergent Adverse-Reactions: The most common adverse reactions seen in a double-blind comparative controlled trial in which 600 treatment-naïve subjects received tenofovir disoproxil fumarate tablets (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness. Mild adverse reactions (Grade 1) were common with a similar incidence in both arms and included dizziness, diarrhea, and nausea.

Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 4. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationship to study drug. b. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome. c.

Peripheral neuropathy includes peripheral neuritis and neuropathy. d. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash. Laboratory Abnormalities: With the exception of fasting cholesterol and fasting triglyceride elevations that were more common in the stavudine group (40% and 9%) compared with tenofovir disoproxil fumarate tablets (19% and 1%), respectively, laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate tablets and stavudine treatment arms.

A summary of Grades 3 to 4 laboratory abnormalities is provided in Table 5. Adverse reactions observed in this trial were generally consistent with those seen in previous studies in treatment-experienced or treatment-naïve subjects (Table 6). Changes in Bone Mineral Density In HIV-1 infected adult subjects in Study 903, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving tenofovir disoproxil fumarate tablets + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1% ± 4.6) through 144 weeks.

In both groups, the majority of the reduction in BMD occurred in the first 24 to 48 weeks of the trial and this reduction was sustained through Week 144. Twenty-eight percent of tenofovir disoproxil fumarate tablets-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the tenofovir disoproxil fumarate tablets group and 6 subjects in the stavudine group.

In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C telopeptide, and urinary N telopeptide) and higher serum parathyroid hormone levels and 1,25 Vitamin D levels in the tenofovir disoproxil fumarate tablets group relative to the stavudine group; however, except for bone-specific alkaline phosphatase, these changes resulted in values that remained within the normal range. From Weeks 96 to 144 of the trial, subjects received TRUVADA with efavirenz in place of tenofovir disoproxil fumarate tablets + EMTRIVA with efavirenz. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and rash vesicular.

Laboratory Abnormalities: Laboratory abnormalities observed in this trial were generally consistent with those seen in previous trials (Table 7). Treatment-Experienced Patients Treatment-Emergent Adverse Reactions: The adverse reactions seen in treatment-experienced subjects were generally consistent with those seen in treatment-naïve subjects including mild to moderate gastrointestinal events, such as nausea, diarrhea, vomiting, and flatulence. Less than 1% of subjects discontinued participation in the clinical trials due to gastrointestinal adverse reactions (Study 907).

A summary of moderate to severe treatment-emergent adverse reactions that occurred during the first 48 weeks of Study 907 is provided in Table 8. Peripheral neuropathy includes peripheral neuritis and neuropathy. c. Laboratory Abnormalities: Laboratory abnormalities observed in this trial occurred with similar frequency in the tenofovir disoproxil fumarate tablets and placebo-treated groups.

The adverse reactions observed in subjects who received treatment with tenofovir disoproxil fumarate tablets were consistent with those observed in clinical trials in adults. Of these, 4 subjects discontinued from the trial due to adverse reactions consistent with proximal renal tubulopathy. Three of these 4 subjects presented with hypophosphatemia and also had decreases in total body or spine BMD Z score.

Changes in Bone Mineral Density: Clinical trials in HIV-1 infected children and adolescents evaluated BMD changes. Six tenofovir disoproxil fumarate tablets-treated subjects and one placebo-treated subject had significant (greater than 4%) lumbar spine BMD loss at Week 48. In Study 352 (2 to less than 12 years), the mean rate of BMD gain in lumbar spine at Week 48 was similar between the tenofovir disoproxil fumarate tablets and the d4T or AZT treatment groups.

Total body BMD gain was less in the tenofovir disoproxil fumarate tablets compared to the d4T or AZT treatment groups. One tenofovir disoproxil fumarate-treated subject and none of the d4T or AZT-treated subjects experienced significant (greater than 4%) lumbar spine BMD loss at Week 48. In both trials, skeletal growth (height) appeared to be unaffected.

Clinical Trials in Adult Subjects with Chronic Hepatitis B and Compensated Liver Disease Treatment-Emergent Adverse Reactions: In controlled clinical trials in 641 subjects with chronic hepatitis B (0102 and 0103), more subjects treated with tenofovir disoproxil fumarate tablets during the 48-week double-blind period experienced nausea: 9% with tenofovir disoproxil fumarate tablets versus 2% with HEPSERA. Other treatment-emergent adverse reactions reported in more than 5% of subjects treated with tenofovir disoproxil fumarate tablets included: abdominal pain, diarrhea, headache, dizziness, fatigue, nasopharyngitis, back pain, and skin rash. No significant change in the tolerability profile was observed with continued treatment for up to 384 weeks.

Grades 3 to 4 laboratory abnormalities were similar in subjects continuing tenofovir disoproxil fumarate tablets treatment for up to 384 weeks in these trials. ALT flares generally occurred within the first 4 to 8 weeks of treatment and were accompanied by decreases in HBV DNA levels. No subject had evidence of decompensation.

ALT flares typically resolved within 4 to 8 weeks without changes in study medication. Clinical Trials in Adult Subjects with Chronic Hepatitis B and Decompensated Liver Disease In a small randomized, double-blind, active-controlled trial, subjects with CHB and decompensated liver disease received treatment with tenofovir disoproxil fumarate tablets or other antiviral drugs for up to 48 weeks. Among the 45 subjects receiving tenofovir disoproxil fumarate tablets, the most frequently reported treatment-emergent adverse reactions of any severity were abdominal pain subjects died through Week 48 of the trial due to progression of liver disease.

Three of 45 (7%) subjects discontinued treatment due to an adverse event. Three of these subjects (each of whom had a Child-Pugh score greater than or equal to 10 and MELD score greater than or equal to 14 at entry) developed renal failure. Because both tenofovir disoproxil fumarate tablets and decompensated liver disease may have an impact on renal function, the contribution of tenofovir disoproxil fumarate tablets to renal impairment in this population is difficult to ascertain.

One of 45 subjects experienced an on-treatment hepatic flare during the 48-Week trial. Clinical Trials in Pediatric Subjects 12 Years of Age and Older with Chronic Hepatitis B Assessment of adverse reactions is based on one randomized study (Study GS-US-174-0115) in 106 pediatric subjects (12 to less than 18 years of age) infected with chronic hepatitis B receiving treatment with tenofovir disoproxil fumarate tablets (N=52) or placebo (N=54) for 72 weeks. In this study, both the tenofovir disoproxil fumarate tablets and placebo treatment arms experienced an overall increase in mean lumbar spine BMD over 72 weeks, as expected for an adolescent population.

Three subjects in the tenofovir disoproxil fumarate tablets group and two subjects in the placebo group had significant (greater than 4%) lumbar spine BMD loss at Week 72. At baseline, mean BMD Z-scores in subjects randomized to tenofovir disoproxil fumarate tablets were −0.43 for lumbar spine and −0.20 for total body, and mean BMD Z-scores in subjects randomized to placebo were −0.28 for lumbar spine and −0.26 for total body. As observed in pediatric studies of HIV-infected patients, skeletal growth (height) appeared to be unaffected.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of tenofovir disoproxil fumarate tablets. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders allergic reaction, including angioedema Metabolism and Nutrition Disorders lactic acidosis, hypokalemia, hypophosphatemia Respiratory, Thoracic, and Mediastinal Disorders dyspnea Gastrointestinal Disorders pancreatitis, increased amylase, abdominal pain Hepatobiliary Disorders hepatic steatosis, hepatitis, increased liver enzymes (most commonly AST, ALT gamma GT) Skin and Subcutaneous Tissue Disorders rash Musculoskeletal and Connective Tissue Disorders rhabdomyolysis, osteomalacia (manifested as bone pain and which may contribute to fractures), muscular weakness, myopathy Renal and Urinary Disorders acute renal failure, renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including acute cases), nephrogenic diabetes insipidus, renal insufficiency, increased creatinine, proteinuria, polyuria General Disorders and Administration Site Conditions asthenia The following adverse reactions, listed under the body system headings above, may occur as a consequence of proximal renal tubulopathy: rhabdomyolysis, osteomalacia, hypokalemia, muscular weakness, myopathy, hypophosphatemia.

Drugs Affecting Renal Function Tenofovir is primarily eliminated by the kidneys. Coadministration of tenofovir disoproxil fumarate tablets with drugs that are eliminated by active tubular secretion may increase concentrations of tenofovir and/or the coadministered drug. Some examples include, but are not limited to, acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin), and high-dose or multiple NSAIDs.

Drugs that decrease renal function may increase concentrations of tenofovir. In the treatment of chronic hepatitis B, tenofovir disoproxil fumarate tablets should not be administered in combination with HEPSERA (adefovir dipivoxil).

Established and Significant Interactions Table 11 provides a listing of established or clinically significant drug interactions. The drug interactions described are based on studies conducted with tenofovir DF. Table 11 Established and Significanta Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Trials a.

This table is not all inclusive. b. ↑=Increase, ↓=Decrease

Pregnancy Pregnancy Category B 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. Antiretroviral Pregnancy Registry: 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. Risk Summary Animal Data Reproduction studies have been performed in rats and rabbits at doses up to 14 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.

Pediatric Use Pediatric Patients 2 Years of Age and Older with HIV-1 infection The safety of tenofovir disoproxil fumarate tablets in pediatric patients aged 2 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 2 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 2 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 12 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. 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.

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. 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. 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.

Limited clinical experience at doses higher than the therapeutic dose of tenofovir disoproxil fumarate tablets 300 mg are available. No severe adverse reactions were reported. The effects of higher doses are not known.

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 tablets, a four-hour hemodialysis session removed approximately 10% of the administered tenofovir dose.