tenofovir AF (Rx)

>10%

Headache (9-12%)

Bone mineral density decline (5-11%)

1-10%

Abdominal pain (7-9%)

ALT >5 x ULN (8%)

Cough (8%)

Fatigue (6%)

Nausea (6%)

LDL-cholesterol fasted >190 mg/dL (6%)

Back pain (6%)

Glycosuria ≥3+ (5%)

Nausea (5%)

Arthralgia (5%)

Diarrhea (5%)

Dyspepsia (5%)

AST >5 x ULN (3%)

Creatine kinase ≥10 x ULN (3%)

Serum amylase >2 x ULN (3%)

Frequency Not Defined

Severe acute exacerbation of hepatitis B in patients with HBV infection

Postmarketing Reports

Skin and subcutaneous tissue disorders: Angioedema, urticaria

Acute renal failure, acute tubular necrosis, proximal renal tubulopathy, and Fanconi syndrome

Contraindications

None

Cautions

Lactic acidosis and severe hepatomegaly with steatosis, including fatalities, reported with nucleoside analogs, including tenofovir disoproxil fumarate in combination with other antiretrovirals; most were reported in women; obesity and prolonged nucleoside exposure may be risks factors (see Black Box Warnings)

Discontinuation of antihepatitis B drugs may result in severe acute exacerbations of hepatitis B (see Black Box Warnings); all patients should be tested for presence of chronic hepatitis B virus (HBV) before or when initiating therapy

Resumption of anti-hepatitis B therapy may be warranted, in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure

Owing to the risk of development of HIV-1 resistance, tenofovir AF alone is not recommended for the treatment of HIV-1 infection; test for HIV-1 before initiating treatment

Persistent or worsening bone pain, pain in extremities, fractures and/or muscular pain or weakness may be manifestations of proximal renal tubulopathy and should prompt an evaluation of renal function in patients at risk of renal dysfunction

Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir prodrugs; this has not been observed with tenofovir AF in clinical trials; prior to or when initiating therapy, and during treatment on a clinically appropriate schedule, assess serum creatinine, estimated creatinine clearance, urine glucose, and urine protein in all patients; in patients with chronic kidney disease, also assess serum phosphorus; discontinue therapy in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome

Drug interaction overview

• P-gp and BCRP

  • P-gp and BCRP substrate; drugs that strongly affect these transporters may lead to changes in tenofovir AF absorption
  • Drugs that induce P-gp result in decreased tenofovir AF absorption and plasma concentrations, which may lead to loss of therapeutic effect (eg, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, St John’s wort)
  • Drugs that inhibit P-gp and BCRP may increase tenofovir AF absorption and plasma concentration

• Drugs affecting renal function

  • Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT), and Fanconi syndrome reported with tenofovir AF-containing products
  • Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion
  • Coadministration of tenofovir AF with drugs that reduce renal function or compete for active tubular secretion may increase concentrations of tenofovir and other renally eliminated drugs, and this may increase the risk of adverse reactions
  • Some examples include acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides, high-dose or long-term NSAD use

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to drug during pregnancy; healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258- 4263

Available data from the APR show no significant difference in overall risk of birth defects for tenofovir alafenamide (TAF) compared with background rate for major birth defects of 2.7% in U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP); the rate of miscarriage is not reported in the APR

In animal studies, no adverse developmental effects were observed when tenofovir alafenamide was administered during the period of organogenesis at exposure equal to or 51 times (rats and rabbits, respectively) the tenofovir alafenamide exposure at the recommended daily dose

Lactation

Unknown if distributed in human breast milk

Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Tenofovir alafenamide (AF) is a nucleotide reverse transcriptase inhibitor (NRTI) and a phosphonamidate prodrug of tenofovir

Compared with tenofovir disoproxil fumarate (tenofovir DF, Viread), tenofovir AF is a more targeted form of tenofovir that has demonstrated high antiviral efficacy at a dose that is 10 times lower than tenofovir DF, as well as an improved renal and bone safety profile

Tenofovir AF as a lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3 and is converted to tenofovir diphosphate

Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain-termination

Absorption

Peak plasma time: ~30 minutes

Distribution

Protein bound: 80%

Metabolism

Converted from tenofovir AF to tenofovir through hydrolysis primarily by carboxyesterase 1 (CES1) in primary hepatocytes

Intracellular tenofovir is subsequently phosphorylated by cellular kinases to the pharmacologically active metabolite tenofovir diphosphate

Also metabolized by Cathepsin A in peripheral blood mononuclear cells (PBMCs)

CYP3A: Minimal

Elimination

Half-life: 0.5 hr

Excretion: <1% urine; 31.7% feces

Oral Administration

Take with food

Inform patients to take on a regular dosing schedule and to avoid missing doses, as it can result in development of resistance

Storage

Store at controlled room temperature <30°C (86°F)

Keep container tightly closed

Dispense only in original container