Full Prescribing Information

Prescribing Information   

COMPOSITION:
TAFECTA Tablet: Each film coated tablet contains 28 mg ofTenofovirAlafenamidefumarate INN equivalent to TenofovirAlafenamide 25 mg.

CLINICAL PHARMACOLOGY
Mechanism Of Action
Tenofoviralafenamide is a phosphonamidateprodrug of tenofovir (2’-deoxyadenosine monophosphate analog). Tenofoviralafenamide as a lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofoviralafenamide is then converted to Tenofovir through hydrolysis primarily by carboxylesterase 1 (CES1) in primary hepatocytes. Intracellular tenofovir is subsequently phosphorylated by cellular kinases to the pharmacologically active metabolite tenofovirdiphosphate. Tenofovirdiphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse transcriptase, which results in DNA chain-termination.
Tenofovirdiphosphate is a weak inhibitor of mammalian DNA polymerases that include mitochondrial DNA polymerase γ and there is no evidence of toxicity to mitochondria in cell culture.

Pharmacodynamics
Cardiac Electrophysiology
In a thorough QT/QTc study in 48 healthy subjects, tenofoviralafenamide at the recommended dose or at a dose 5 times the recommended dose did not affect the QT/QTc interval and did not prolong the PR interval.

Pharmacokinetics

Pharmacokinetic Properties of TAF

CES1 = carboxylesterase 1; PBMCs = peripheral blood mononuclear cells.

Specific Populations

Geriatric Patients, Race, and Gender

No clinically relevant differences in tenofoviralafenamide or tenofovir pharmacokinetics due to race or gender have been identified. Limited data in subjects aged 65 and over suggest a lack of clinically relevant differences in tenofoviralafenamide or tenofovirpharmacokinetics .

Patients with Renal Impairment

Relative to subjects with normal renal function (estimated creatinine clearance ≥90 mL/min), the tenofoviralafenamide and tenofovir systemic exposures in subjects with severe renal impairment were 1.9-fold and 5.7-fold higher, respectively. The pharmacokinetics of tenofoviralafenamidehave not been evaluated in patients with creatinine clearance less than 15 mL per minute.

Patients with Hepatic Impairment

Relative to subjects with normal hepatic function, tenofoviralafenamide and tenofovir systemic exposures were 7.5% and 11% lower in subjects with mild hepatic impairment, respectively.
HIV and/or Hepatitis C Virus Co infection.

The pharmacokinetics of tenofoviralafenamidehave not been fully evaluated in subjects coinfected with HIV and/or hepatitis C virus.

INDICATION

TAF is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor and is indicated for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease
DOSAGE AND ADMINISTRATION
#Testing Prior to Initiation of TAF
Prior to initiation of TAF, patients should be tested for HIV-1 infection. TAF alone should not be used in patients with HIV infection [see Warnings and Precautions.
It is recommended that serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating TAF and during therapy in all patients as clinically appropriate.

#Recommended Dosage in Adults
The recommended dosage of TAF is 25 mg (one tablet) taken orally once daily with food.
# Dosage in Patients with Renal Impairment
No dosage adjustment of TAF is required in patients with mild, moderate, or severe renal impairment. TAF is not recommended in patients with end stage renal disease (estimated creatinine clearance below 15 mL per minute.
# Dosage in Patients with Hepatic Impairment
No dosage adjustment of TAF is required in patients with mild hepatic impairment (Child-Pugh A). TAF is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

USE IN SPECIAL POPULATION
Pregnancy:
There are no human data on the use of TAF in pregnant women to inform a drug-associated risks of adverse fetal developmental outcome. In animal studies, no adverse developmental effects were observed when tenofoviralafenamide was administered during the period of organogenesis at exposure equal to or 51 times (rats and rabbits, respectively) the tenofoviralafenamide exposure at the recommended daily dose of TAF. No adverse effects were observed in the offspring when TDF (tenofovirdisoproxilfumarate) was administered through lactation at tenofovir exposures of approximately 12 times the exposure at the recommended daily dosage of TAF.
Lactation:
It is not known whether TAF and its metabolites are present in human breast milk, affect human milk production, or have effects on the breastfed infant. Tenofovir has been shown to be present in the milk of lactating rats and rhesus monkeys after administration of TDF [see Data]. It is not known if tenofoviralafenamide can be present in animal milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TAF and any potential adverse effects on the breastfed infant from TAF or from the underlying maternal condition.
Pediatric use:
Safety and effectiveness of TAF in pediatric patients less than 18 years of age have not been established.
Geriatric Use:
Clinical trials of TAF did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.
Renal Impairment:
No dosage adjustment of TAF is required in patients with mild, moderate, or severe renal impairment. TAF is not recommended in patients with end stage renal disease (estimated creatinine clearance below 15 mL per minute).
Hepatic Impairment:

No dosage adjustment of TAF is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of TAF in patients with decompensated cirrhosis (Child-Pugh B or C) have not been established; therefore TAF is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment.

CONTRAINDICATION:
None
PRECAUTION:
Lactic Acidosis/Severe Hepatomegaly with Steatosis:
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovirdisoproxilfumarate in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with TAF should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).

Severe Acute Exacerbation of Hepatitis B after Discontinuation of Treatment:
Discontinuation of anti-hepatitis B therapy, including TAF, may result in severe acute exacerbations of hepatitis B. Patients who discontinue TAF should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.

Risk of Development of HIV-1 Resistance in Patients Coinfected with HBV and HIV-1:
Due to the risk of development of HIV-1 resistance, TAF alone is not recommended for the treatment of HIV-1 infection. The safety and efficacy of TAF have not been established in patients coinfected with HBV and HIV-1. HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with TAF, and, if positive, an appropriate antiretroviral combination regimen that is recommended for patients coinfected with HIV-1 should be used.

New Onset or Worsening Renal Impairment:
Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovirprodrugs in both animal toxicology studies and human trials. In clinical trials of TAF, there have been no cases of Fanconi syndrome or Proximal Renal Tubulopathy (PRT).
Patients taking tenofovirprodrugs who have impaired renal function and those taking nephrotoxic agents, including non-steroidal anti-inflammatory drugs, are at increased risk of developing renal-related adverse reactions
It is recommended that serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating TAF and during therapy in all patients as clinically appropriate. Discontinue TAF in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.
ADVERSE REACTIONS
Most common adverse reactions (incidence greater than or equal to 5%, all grades) are headache, abdominal pain, fatigue, cough, nausea, and back pain.
DRUG INTERACTION:
Tenofoviralafenamide does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or UGT1A1. Tenofoviralafenamide is a weak inhibitor of CYP3A in vitro. Tenofoviralafenamide is a substrate of P-gp, BCRP, OATP1B1, and OATP1B3 and a weak inhibitor of both OCT1 and MATE1. Drugs that inhibit P-gp and/or BCRP may increase the absorption of tenofoviralafenamide, while drugs that induce P-gp activity may decrease the absorption of tenofoviralafenamide. Tenofoviralafenamide does not interact with renal transporters OAT1 or OAT3.
PHARMACEUTICAL INFORMATION:
Storage condition:
Store below 30 °C (86 °F). Keep container tightly closed. Dispense only in original container.
Prescription & Packing
TenofovirAlafenamide 25 mg: Each Commercial box contains 30 tablets in Alu-Alu blister pack.