Viread^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gilead Sciences International, Ltd. (United Kingdom)

Manufactured By

Takeda GmbH (Germany)

Or

Gilead Sciences Ireland, UC (Ireland)

Or

Patheon Inc. (Canada)

ATC Code

J05AF07 (Tenofovir disoproxil)

Active Substance

Tenofovir (Rec.INN registered by WHO)

Dosage Form

Viread®

Film-coated tablets, 300 mg: 30 pcs.

Dosage Form, Packaging, and Composition

30 pcs. – high-density polyethylene bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Antiviral drug active against HIV

Pharmacotherapeutic Group

Antiviral agent

Pharmacological Action

Tenofovir disoproxil fumarate is converted in vivo to tenofovir, an analogue of nucleoside monophosphate (nucleotide) adenosine monophosphate.

Tenofovir is subsequently converted to the active metabolite, tenofovir diphosphate.

Tenofovir is a nucleotide reverse transcriptase inhibitor with specific activity against human immunodeficiency virus (HIV-1 and HIV-2) and hepatitis B virus.

Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and hepatitis B virus polymerase by a competitive mechanism, resulting in termination of DNA chain synthesis.

Tenofovir diphosphate is a weak inhibitor of mammalian DNA polymerases.

In in vitro tests, tenofovir at concentrations up to 300 µmol/L did not affect mitochondrial DNA synthesis and lactate formation.

Antiviral activity

Antiviral activity against HIV

The antiviral activity of tenofovir against laboratory and donor strains of HIV-1 was evaluated in lymphoblastoid cell lines, primary monocytes/macrophages, and peripheral blood lymphocytes.

The effective concentration of tenofovir ranged from 0.04 to 8.5 µmol.

In cell culture, tenofovir demonstrated antiviral activity against HIV-1 subtypes A, B, C, D, E, F, G, O (effective concentration ranged from 0.5 to 2.2 µmol), as well as inhibitory activity against some HIV-2 strains (effective concentration ranged from 1.6 µmol to 5.5 µmol).

When tenofovir was used in vitro, a synergy of antiviral activity of the drugs was noted.

In studies of the drug’s combination with HIV protease inhibitors and with nucleoside and non-nucleoside analogues of HIV-1 reverse transcriptase inhibitors, additive or synergistic effects were observed.

Antiviral activity against hepatitis B virus

The antiviral activity of tenofovir against hepatitis B virus was evaluated in the HepG2 2.2.15 cell line.

The effective concentration of tenofovir ranged from 0.14 to 1.5 µmol with an effective cytotoxic concentration of >100 µmol.

In cell culture studies of the antiviral activity of combinations of tenofovir with nucleoside reverse transcriptase inhibitors active against hepatitis B virus (emtricitabine, entecavir, lamivudine, and telbivudine), no antagonism of drug activities was found.

Resistance

Resistance in HIV-1

HIV-1 strains with reduced susceptibility to tenofovir and the K65R mutation in reverse transcriptase have been obtained in vitro and in some patients.

The use of tenofovir disoproxil fumarate should be avoided in patients with K65R mutant strains who have previously received antiretroviral therapy.

Resistance in hepatitis B

No hepatitis B virus mutations associated with resistance to tenofovir have been identified.

Pharmacokinetics

Absorption

After oral administration in HIV-infected patients, tenofovir disoproxil fumarate is rapidly absorbed and converted to tenofovir.

The C_max of tenofovir in blood serum was observed one hour after administration on an empty stomach and 2 hours after administration with food.

The bioavailability of tenofovir from tenofovir disoproxil fumarate after oral administration on an empty stomach was approximately 25%.

As a result of taking tenofovir disoproxil fumarate with food, oral bioavailability increased, with the AUC and average C_max of tenofovir increasing by approximately 40% and 14%, respectively.

After the first dose of tenofovir disoproxil fumarate with food, the C_max in blood serum ranges from 213 to 375 mg/ml.

Distribution

The V_d at steady state after intravenous administration of tenofovir was estimated to be approximately 800 ml/kg.

At tenofovir concentrations from 0.01 to 25 µg/ml, the binding of tenofovir to plasma and serum proteins in vitro was less than 0.7% and 7.2%, respectively.

Metabolism

In vitro studies have established that neither tenofovir disoproxil fumarate nor tenofovir are substrates of cytochrome P450 isoenzymes.

Moreover, at concentrations significantly (approximately 300 times) exceeding the drug concentrations observed in vivo, tenofovir in vitro did not inhibit metabolism mediated by the major human cytochrome P450 isoenzymes (CYP3A4, CYP2D6, CYP2C9, CYP2E1, or CYP1A1/2).

Tenofovir disoproxil fumarate did not affect any cytochrome P450 isoenzymes, except for CYP1A1/2 (a small (6%) but statistically significant decrease in the metabolism of the CYP1A1/2 cytochrome substrate was noted).

Elimination

Elimination of tenofovir occurs mainly through the kidneys via filtration and an active tubular transport system.

Linearity/non-linearity

The pharmacokinetics of tenofovir were independent of the dose of tenofovir disoproxil fumarate (at doses from 75 to 600 mg); multiple administration of the drug at any dose also did not affect the pharmacokinetics of tenofovir.

Pharmacokinetics in special populations

Limited pharmacokinetic data in women indicate no significant gender differences.

No pharmacokinetic studies have been conducted in children, adolescents under 18 years of age, or elderly people over 65 years of age.

No specific pharmacokinetic studies have been conducted in different ethnic groups.

Indications

• Treatment of HIV-1 infection in adults in combination with other antiretroviral drugs;
• Treatment of chronic viral hepatitis B in adults with compensated liver failure, signs of active virus replication, persistently elevated serum alanine aminotransferase (ALT) activity, and histological evidence of active inflammation and/or fibrosis.

ICD codes

Dosage Regimen

Adults 1 tablet/day, orally during meals or on an empty stomach.

For patients with mild renal impairment (creatinine clearance 50-80 ml/min), taking Viread^® once a day is safe and effective, so there is no need to adjust the dose; these patients require constant monitoring of creatinine clearance and serum phosphate levels.

In patients with creatinine clearance from 30 to 49 ml/min, the interval between doses of the drug should be adjusted according to the recommendations given in Table 1.

Table 1. Dose adjustment in patients with altered creatinine clearance

Patients with impaired liver function do not require dose adjustment of the drug. Antiretroviral therapy is usually indicated for life.

In the treatment of chronic hepatitis B

• In HBeAg-positive patients without liver cirrhosis, treatment should be continued for at least 6-12 months after confirmation of HBe seroconversion (disappearance of HBeAg or disappearance of hepatitis B virus DNA, with detection of anti-HBe), or until HBs seroconversion, and until loss of efficacy. To detect any delayed virological relapses after the end of treatment, it is necessary to regularly measure ALT and hepatitis B virus DNA levels in the blood serum.
• In HBeAg-negative patients without liver cirrhosis, treatment should be continued at least until HBs seroconversion or until loss of efficacy. With long-term treatment for more than 2 years, it is recommended to regularly examine the patient to confirm that the treatment chosen for the particular patient remains adequate.

The duration of therapy with Viread^® is determined individually by the attending physician.

Adverse Reactions

Gastrointestinal diarrhea, vomiting, nausea, flatulence, pancreatitis, increased amylase activity, abdominal pain, bloating.

Nervous system dizziness, headache, depression.

Immune system allergic reactions, including angioedema.

Metabolism hypophosphatemia, lactic acidosis, hypokalemia.

Respiratory system: dyspnea.

Liver and biliary tract hepatic steatosis, increased activity of liver enzymes (most often AST, ALT, GGT), hepatitis.

Skin and subcutaneous tissue rash.

Musculoskeletal system and connective tissue rhabdomyolysis, osteomalacia (more often manifested by bone pain, occasionally leading to fractures), muscle weakness, myopathy.

Kidney and urinary tract renal function disorders, including acute ones, renal failure, acute renal tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis (including cases of acute nephritis), increased creatinine concentration, proteinuria, polyuria, nephrogenic diabetes insipidus.

Other fatigue, asthenia.

Contraindications

• Children under 18 years of age;
• Patients with renal failure with creatinine clearance <30 ml/min, as well as patients requiring hemodialysis;
• Lactation period;
• Hypersensitivity to any component of the drug.

With caution : age over 65 years, renal failure with creatinine clearance greater than 30 ml/min and less than 50 ml/min, simultaneous use with didanosine.

Not recommended for patients with lactase deficiency, lactose intolerance, glucose-galactose malabsorption, as the drug contains lactose.

Use in Pregnancy and Lactation

Viread^® should be used during pregnancy only if the expected benefit of treatment for the mother outweighs the potential risk to the fetus.

Animal studies have shown that tenofovir is excreted in breast milk. It is not known whether tenofovir is excreted in human breast milk. Breastfeeding is not recommended for mothers infected with HIV or hepatitis B virus who have received therapy with Viread^® to prevent the risk of postnatal transmission of HIV or hepatitis B virus.

Use in Hepatic Impairment

Patients with impaired liver function do not require dose adjustment of the drug. Antiretroviral therapy is usually indicated for life.

In the treatment of chronic hepatitis B

• In HBeAg-positive patients without liver cirrhosis, treatment should be continued for at least 6-12 months after confirmation of HBe seroconversion (disappearance of HBeAg or disappearance of hepatitis B virus DNA, with detection of anti-HBe), or until HBs seroconversion, and until loss of efficacy. To detect any delayed virological relapses after the end of treatment, it is necessary to regularly measure ALT and hepatitis B virus DNA levels in the blood serum.
• In HBeAg-negative patients without liver cirrhosis, treatment should be continued at least until HBs seroconversion or until loss of efficacy. With long-term treatment for more than 2 years, it is recommended to regularly examine the patient to confirm that the treatment chosen for the particular patient remains adequate.

The duration of therapy with Viread^® is determined individually by the attending physician.

Use in Renal Impairment

For patients with mild renal impairment (creatinine clearance 50-80 ml/min), taking Viread^® once a day is safe and effective, so there is no need to adjust the dose; these patients require constant monitoring of creatinine clearance and serum phosphate levels.

In patients with creatinine clearance from 30 to 49 ml/min, the interval between doses of the drug should be adjusted according to the recommendations given in Table 1.

Table 1. Dose adjustment in patients with altered creatinine clearance

Pediatric Use

Contraindicated in children under 18 years of age.

Special Precautions

General

The drug should not be used simultaneously with Truvada (tenofovir/emtricitabine), Atripla (efavirenz/emtricitabine/tenofovir), or with the drug Hepsera (adefovir).

Patients should be informed that treatment with antiretroviral drugs does not prevent the risk of transmitting HIV and hepatitis B to others. Appropriate precautions should be taken during sexual contact.

Lactic acidosis, severe hepatomegaly with steatosis

When using nucleoside analogues, including tenofovir disoproxil fumarate, in HIV-infected individuals in combination with other antiretroviral drugs, cases of lactic acidosis and severe liver enlargement with steatosis, sometimes fatal, have been reported.

If a patient develops clinical (gastrointestinal – nausea, vomiting, abdominal pain; general malaise, loss of appetite, weight loss; respiratory distress; neurological symptoms – motor dysfunction, muscle weakness) or laboratory signs (serum lactic acid level above 5 mmol/L) indicating lactic acidosis or severe hepatotoxicity, therapy with Viread^® should be suspended.

Patients with impaired renal function

Elimination of tenofovir occurs mainly through the kidneys.

In clinical practice with tenofovir, cases of renal failure, increased creatinine concentration, hypophosphatemia, and Fanconi syndrome have been reported.

In all patients, before starting therapy and, if clinically indicated, during therapy with Viread^®, creatinine clearance should be calculated.

In patients at risk of developing renal impairment, including patients who previously had renal disorders during therapy with adefovir, regular monitoring of estimated creatinine clearance and serum phosphorus concentration should be performed.

The drug should not be used simultaneously with nephrotoxic drugs or in case of recent use of such drugs.

The safety and efficacy of the drug in patients with creatinine clearance from 30 to 49 ml/min have not been determined, and therefore the ratio of the potential benefit of therapy with the drug to the possible risk of toxic effects on the kidneys should be assessed.

If there is still a need to use the drug, then adjustment of the intervals between drug doses is required.

Such patients should be carefully monitored for renal function.

Adverse reactions listed in the Adverse Reactions section above may occur as a result of proximal renal tubulopathy: rhabdomyolysis, osteomalacia (manifested by bone pain, occasionally leading to fractures), hypokalemia, muscle weakness, myopathy, hypophosphatemia.

It is believed that the cause of these phenomena is not associated with tenofovir therapy in the absence of proximal renal tubulopathy.

Patients co-infected with HIV and hepatitis B virus

In patients co-infected with HIV and hepatitis B virus, severe exacerbations of hepatitis may occur after discontinuation of therapy with Viread^®.

Patients co-infected with HIV and hepatitis B virus should be closely monitored, both clinically and laboratory, for at least several months after discontinuation of therapy.

In some cases, it may be necessary to resume hepatitis B virus therapy.

In patients with severe liver disease (cirrhosis), discontinuation of treatment is not recommended, since the exacerbation of hepatitis that occurs after discontinuation of therapy can lead to decompensation of liver function.

Testing for HIV antibodies should be available for all patients infected with hepatitis B virus before starting therapy with Viread^®.

Due to the risk of developing resistance, Viread^® should be used as part of appropriate antiretroviral therapy in the treatment of patients co-infected with HIV and hepatitis B.

Lipodystrophy

Redistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy, including central obesity, increased deposition of fatty tissue on the back and neck (“buffalo hump”), reduction in peripheral fat volume and subcutaneous facial fat, breast hypertrophy, and so-called Cushingoid appearance.

The mechanisms and long-term consequences of these phenomena are currently unknown, and their causal relationship with the use of any specific drugs has not been established.

Effect on the Skeletal System

In animals, tenofovir administration demonstrated toxicity to bone tissue, including a reduction in bone mineral density. However, long-term clinical studies of the drug (over 3 years) did not reveal clinically significant pathological changes in bone tissue. Nevertheless, pathological changes in bone tissue (occasionally leading to fractures) may be observed in cases of proximal renal tubulopathy. If disorders of the skeletal system are suspected, consultation with an appropriate specialist should be sought.

Early Virologic Failure

Clinical studies in HIV-infected patients have shown that certain therapeutic regimens using only three nucleoside reverse transcriptase inhibitors are generally less effective than triple regimens using two nucleoside reverse transcriptase inhibitors in combination with either a non-nucleoside reverse transcriptase inhibitor or an HIV-1 protease inhibitor. In particular, early virologic failure and a high frequency of resistance-associated mutations (substitution type) have been reported. Therefore, regimens using three nucleoside inhibitors should be used with caution. Patients on a regimen consisting solely of three nucleoside inhibitors should be carefully monitored; in such cases, a change in the treatment regimen should also be considered.

Immune Reconstitution Syndrome

HIV-infected patients receiving combination antiretroviral therapy may develop immune reconstitution syndrome.

In patients with severe immunodeficiency at the initiation of antiretroviral therapy, an inflammatory reaction to asymptomatic or residual opportunistic infections may occur, which can lead to the development of serious clinical conditions or an exacerbation of symptoms. Such reactions are typically observed within the first few weeks or months of antiretroviral therapy. Examples include cytomegalovirus retinitis, generalized and/or focal mycobacterial infections, and Pneumocystis jirovecii pneumonia. Any inflammatory symptoms require appropriate evaluation and, if necessary, initiation of treatment. Patients should be under the careful clinical supervision of specialists experienced in treating HIV-related conditions.

Effect on the Ability to Drive and Operate Machinery

No studies have been conducted on the effect of tenofovir disoproxil fumarate on the ability to drive a car or operate machinery. However, patients should be informed that cases of dizziness have been observed during treatment with tenofovir disoproxil fumarate.

Patients taking Viread^® should take precautions or avoid driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions, taking into account the side effect profile.

Overdose

In case of overdose, the patient should be monitored for signs of toxicity; if necessary, standard supportive treatment should be administered. Tenofovir can be removed from the body by hemodialysis; the median clearance of tenofovir is 134 ml/min.

There is limited clinical experience with Viread^® at doses exceeding the therapeutic dose of 300 mg. In a study, 901 patients received 600 mg of tenofovir disoproxil fumarate for 28 days, with no severe adverse reactions observed. Symptoms of overdose at higher doses are unknown.

Drug Interactions

Concomitant administration of tenofovir and didanosine 400 mg/day (in enteric-coated tablets) resulted in increased systemic exposure to didanosine. Such patients should be closely monitored for didanosine-related adverse events, such as pancreatitis and lactic acidosis. Concomitant use of tenofovir and didanosine 400 mg/day is associated with a decrease in CD4+ lymphocyte count. In patients weighing more than 60 kg, the daily dose of didanosine should be reduced to 250 mg. There are insufficient data to provide dosing recommendations for patients weighing less than 60 kg.

Tenofovir alters the pharmacokinetics of atazanavir. Tenofovir should only be used concomitantly with atazanavir in combination with ritonavir (atazanavir 300 mg/ritonavir 100 mg).

Studies in healthy volunteers showed no clinically significant interaction when tenofovir was used concomitantly with abacavir, efavirenz, emtricitabine, lamivudine, indinavir, lopinavir/ritonavir, nelfinavir, oral contraceptives, ribavirin, saquinavir/ritonavir.

Tenofovir is primarily eliminated from the body by the kidneys. Concomitant use of tenofovir with drugs that affect renal function or reduce/cease active tubular secretion may increase the serum concentration of tenofovir and/or increase the concentration of co-administered drugs eliminated by the kidneys.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 30°C (86°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.