Tenofovir Alafenamide is a nucleoside analog reverse transcriptase inhibitor for hepatitis B virus. It is indicated for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.

Tenofovir Alafenamide is a phosphonamidate prodrug of tenofovir, which is a 2’-deoxyadenosine monophosphate analog. As a lipophilic cell-permeant compound, it enters liver cells (hepatocytes) through passive diffusion and by liver transporters OATP1B1 and OATP1B3. Inside the liver cells, Tenofovir Alafenamide is converted to tenofovir mainly by the enzyme carboxylesterase 1 (CES1). Tenofovir is then phosphorylated by cellular kinases to form the pharmacologically active metabolite tenofovir diphosphate. Tenofovir diphosphate works by incorporating into the viral DNA through the hepatitis B virus (HBV) reverse transcriptase, which stops viral DNA chain growth and inhibits HBV replication. It is a weak inhibitor of mammalian DNA polymerases including mitochondrial DNA polymerase γ, and no mitochondrial toxicity has been observed in cell studies.

Testing Prior to Initiation of Tenofovir alafenamide: Prior to initiation of Tenofovir alafenamide, patients should be tested for HIV-1 infection. Tenofovir alafenamide alone should not be used in patients with HIV-1 infection.

Recommended Dosage in Adults: The recommended dosage of Tenofovir alafenamide is 25 mg (one tablet) taken orally once daily with food.

Dosage in Patients with Renal Impairment: No dosage adjustment of Tenofovir alafenamide is required in patients with estimated creatinine clearance greater than or equal to 15 ml per minute or in patients with end stage renal disease (ESRD; estimated creatinine clearance below 15 ml per minute) who are receiving chronic hemodialysis. On days of hemodialysis administer Tenofovir alafenamide after completion of hemodialysis treatment. Tenofovir alafenamide is not recommended in patients with ESRD who are not receiving chronic hemodialysis.

Dosage in Patients with Hepatic Impairment: No dosage adjustment of Tenofovir alafenamide is required in patients with mild hepatic impairment (Child-Pugh A). Tenofovir alafenamide is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

Pediatric Use: Safety and effectiveness of Tenofovir alafenamide in pediatric patients less than 18 years of age have not been established.

Geriatric Use: In clinical trials, Tenofovir alafenamide was administered to 89 subjects aged 65 and over. No clinically significant differences in safety or efficacy have been observed between elderly subjects and subjects between 18 and less than 65 years of age.

Potential for Other Drugs to Affect Tenofovir Alafenamide: Tenofovir Alafenamide is a substrate of P-glycoprotein (P-gp) and BCRP. Drugs that strongly affect P-gp and BCRP activity may change the absorption of Tenofovir Alafenamide. Drugs that increase P-gp activity may decrease absorption and plasma levels of Tenofovir Alafenamide, which could reduce its therapeutic effect. Coadministration with drugs that inhibit P-gp and BCRP may increase absorption and plasma concentration of Tenofovir Alafenamide.

Drugs Affecting Renal Function: Tenofovir is mainly excreted by the kidneys through a combination of glomerular filtration and active tubular secretion. Using Tenofovir Alafenamide with drugs that reduce kidney function or compete for active tubular secretion may increase Tenofovir levels and other renally excreted drugs, raising the risk of side effects. Examples of drugs eliminated by active tubular secretion include acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (such as gentamicin), and high-dose or multiple NSAIDs.

The following adverse reactions are described in other sections of the prescribing information:

• Lactic acidosis/severe hepatomegaly with steatosis
• Severe acute exacerbation of hepatitis B
• New onset or worsening renal impairment

Commonly reported side effects include headache, abdominal pain, fatigue, cough, nausea, and back pain.

Pregnancy: Based on reports of over 660 exposures to TAF-containing regimens during pregnancy, which resulted in live births (including over 520 exposures in the first trimester and over 130 in the second or third trimester), the prevalence of birth defects was 4.2% following first trimester exposure and 3.0% following second/third trimester exposure. These results come from the Antiretroviral Pregnancy Registry (APR). Limitations of the registry include use of an external comparator group, limited geographic evaluation, and no data for pregnancies under 20 weeks.

Lactation: It is not known whether Tenofovir Alafenamide or its metabolites pass into human breast milk, affect milk production, or have effects on a breastfed infant. Animal studies show that tenofovir is present in the milk of lactating rats and rhesus monkeys after TDF administration, but it is not known if Tenofovir Alafenamide can appear in milk. The benefits of breastfeeding should be weighed against the mother’s clinical need for Tenofovir Alafenamide and potential adverse effects on the infant.

Severe Acute Exacerbation of Hepatitis B after Stopping Treatment: Stopping anti-hepatitis B therapy, including Tenofovir Alafenamide, may cause severe acute worsening of hepatitis B. Patients who stop taking Tenofovir Alafenamide should be closely monitored with clinical check-ups and laboratory tests for several months after stopping. Restarting anti-hepatitis B therapy may be necessary if indicated.

Risk of HIV-1 Resistance in Patients Coinfected with HBV and HIV-1: Tenofovir Alafenamide alone is not recommended for HIV-1 treatment because of the risk of developing HIV-1 resistance. Its safety and effectiveness in patients coinfected with HBV and HIV-1 have not been established. All HBV-infected patients should be tested for HIV before starting therapy. If positive, an appropriate antiretroviral combination regimen should be used.

New Onset or Worsening Kidney Problems: Cases of kidney impairment, including acute kidney failure, proximal renal tubulopathy, and Fanconi syndrome, have been reported with TAF-containing products. Patients with pre-existing kidney problems or those taking nephrotoxic drugs, including NSAIDs, are at higher risk. Before starting and during treatment with Tenofovir Alafenamide, kidney function should be checked using serum creatinine, estimated creatinine clearance, urine glucose, and urine protein. Patients with chronic kidney disease should also have serum phosphorus monitored. Tenofovir Alafenamide should be stopped if significant kidney function decline or Fanconi syndrome develops.

Lactic Acidosis and Severe Liver Enlargement with Fatty Liver (Steatosis): Lactic acidosis and severe hepatomegaly with steatosis, sometimes fatal, have been reported with nucleoside analogs, including Tenofovir. Tenofovir Alafenamide should be stopped if a patient shows clinical or laboratory signs of lactic acidosis or significant liver toxicity, including hepatomegaly and steatosis even without large increases in liver enzymes.

If an overdose of Tenofovir Alafenamide occurs, the patient should be monitored for any signs of toxicity. Treatment of overdose includes general supportive care, such as monitoring vital signs and observing the patient’s overall clinical condition. Tenofovir can be partially removed by hemodialysis, with an extraction efficiency of about 54 percent.

Hepatic viral infections (Hepatitis B)

Store Tenofovir Alafenamide below 30 degrees Celsius. Keep it in its original container and protect it from light. Keep out of the reach of children.