Indications of Protovir 25 mg

Protovir 25 mg is a hepatitis B virus (HBV) nucleoside analog reverse tranase inhibitor and is indicated for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease.

Theropeutic Class

Hepatic viral infections (Hepatitis B)

Pharmacology

Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2'-deoxyadenosine monophosphate analog). Tenofovir alafenamide as a lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide 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 tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse tranase, which results in DNA chain-termination.Tenofovir diphosphate 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.

Dosage and Administration of Protovir 25 mg

Testing Prior To Initiation Of Protovir 25 mg: Prior to initiation of Protovir 25 mg, patients should be tested for HIV-1 infection. Protovir 25 mg alone should not be used in patients with HIV infectionIt is recommended that serum creatinine, serum phosphorous, estimated creatinine clearance, urine glucose, and urine protein be assessed before initiating Protovir 25 mg and during therapy in all patients as clinically appropriateRecommended Dosage In Adults: The recommended dosage of Protovir 25 mg is 25 mg (one tablet) taken orally once daily with food

Dosage of Protovir 25 mg

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.

Interaction of Protovir 25 mg

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 lead to changes in Protovir 25 mg absorption. Drugs that induce P-gp activity are expected to decrease the absorption of Protovir 25 mg resulting in decreased plasma concentrations of Protovir 25 mg which may lead to loss of therapeutic effect of Tenofovir alafenamide. Coadministration of Tenofovir alafenamide with other drugs that inhibit P-gp and BCRP may increase the absorption and plasma concentration of Protovir 25 mg.Drugs Affecting Renal Function: Tenofovir is primarily excreted by the kidneys by a combination of glomerular filtration and active tubular secretion, coadministration of Tenofovir alafenamide 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 of drugs that are eliminated by active tubular secretion include but are not limited to acyclovir, cidofovir, ganciclovir, valacyclovir, valganciclovir, aminoglycosides (e.g., gentamicin) and high-dose or multiple NSAIDs.

Contraindications

None

Side Effects of Protovir 25 mg

The following adverse reactions are discussed in other sections of the labeling: Lactic Acidosis/Severe Hepatomegaly with Steatosis Severe Acute Exacerbation of Hepatitis B New Onset or Worsening of Renal Impairment The most common side effects are headache, stomach pain, tiredness, cough, nausea, back pain

Pregnancy and Lactation

Before you take Protovir 25 mg, tell your healthcare provider about all of your medical conditions, including if you are pregnant or plan to become pregnant. It is not known if Protovir 25 mg will harm your unborn baby. Tell your healthcare provider if you become pregnant during treatment with Protovir 25 mg. Pregnancy Registry: There is a pregnancy registry for women who take antiviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk with your healthcare provider about how you can take part in this registry.

Precautions and Warnings

Severe Acute Exacerbation of Hepatitis B after Discontinuation of Treatment: Discontinuation of anti-hepatitis B therapy, including Tenofovir alafenamide may result in severe acute exacerbations of hepatitis B. Patients who discontinue Tenofovir alafenamide should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate resumption of antihepatitis 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 Tenofovir alafenamide alone is not recommended for the treatment of HIV-1 infection. The safety and efficacy of Tenofovir alafenamide 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 Tenofovir alafenamide 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: Postmarketing cases of renal impairment, including acute renal failure, proximal renal tubulopathy (PRT) and Fanconi syndrome have been reported with TAF-containing products; while most of these cases were characterized by potential confounders that may have contributed to the reported renal events, it is also possible these factors may have predisposed patients to tenofovir- related adverse events. Patients taking tenofovir prodrugs 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. Prior to or when initiating Tenofovir alafenamide and during treatment with Tenofovir alafenamide 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 Tenofovir alafenamide in patients who develop clinically significant decreases in renal function or evidence of Fanconi syndrome.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 tenofovir disoproxil fumarate (TDF) another prodrug of tenofovir alone or in combination with other antiretrovirals. Treatment with Tenofovir alafenamide 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).

Overdose Effects of Protovir 25 mg

If overdose occurs, monitor patient for evidence of toxicity. Treatment of overdosage with Tenofovir alafenamide consists of general supportive measures including monitoring of vital signs as well as observation of the clinical status of the patient. Tenofovir is efficiently removed by hemo- dialysis with an extraction coefficient of approximately 54percent.

Storage Conditions

Store below 30°C. Keep it in its original container. protect from light. Keep out of children’s reach.

Use In Special Populations

Pediatric Use: Safety and effectiveness of Protovir 25 mg in pediatric patients less than 18 years of age have not been established.Geriatric Use: Clinical trials of Protovir 25 mg 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 Protovir 25 mg is required in patients with mild, moderate, or severe renal impairment. Protovir 25 mg is not recommended in patients with end stage renal disease (estimated creatinine clearance below 15 mL per minute) Hepatic Impairment: No dosage adjustment of Protovir 25 mg is required in patients with mild hepatic impairment (Child-Pugh A). The safety and efficacy of Protovir 25 mg in patients with decompensated cirrhosis (Child-Pugh B or C) have not been established; therefore Protovir 25 mg is not recommended in patients with decompensated (Child-Pugh B or C) hepatic impairment

Drug Classes

Hepatic viral infections (Hepatitis B)

Mode Of Action

Tenofovir alafenamide is a phosphonamidate prodrug of tenofovir (2’-deoxyadenosine monophosphate analog). Tenofovir alafenamide as a lipophilic cell-permeant compound enters primary hepatocytes by passive diffusion and by the hepatic uptake transporters OATP1B1 and OATP1B3. Tenofovir alafenamide 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 tenofovir diphosphate. Tenofovir diphosphate inhibits HBV replication through incorporation into viral DNA by the HBV reverse tranase, which results in DNA chain termination. Tenofovir diphosphate 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.

Pregnancy

Pregnancy: Based on prospective reports to the APR of over 660 exposures to TAF-containing regimens during pregnancy resulting in live births (including over 520 exposed in the first trimester and over 130 exposed in the second/third trimester), the prevalence of birth defects in live births was 4.2percent (95percent CI: 2.6percent to 6.3percent) and 3.0percent (95percent CI: 0.8percent to 7.5percent) following first and second/third trimester exposure, respectively, to TAF-containing regimens. Methodologic limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at less than 20 weeks gestation.Lactation: It is not known whether Tenofovir alafenamide 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. It is not known if Protovir 25 mg can be present in animal milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tenofovir alafenamide and any potential adverse effects on the breastfed infant from Tenofovir alafenamide or from the underlying maternal condition.