Tenvir L

Uses

Lamivudine is used for the treatment of chronic hepatitis B associated with evidence of hepatitis B viral replication and active liver inflammation.

Tenofovir disoproxil is a nucleotide analog reverse transcriptase inhibitor used in the treatment of Hepatitis B infection and used in the management of HIV-1 infection.

Tenofovir is indicated in combination with other antiretroviral agents for the management of HIV-1 infection in adults and pediatric patients 2 years of age and older. It is also indicated for the treatment of chronic hepatitis B in adults and pediatric patients 12 years of age and older . This drug is also a component of multiple products used for the management of HIV-1 infection , .

Safety and effectiveness of tenofovir disoproxil in pediatric patients younger than 2 years of age has not been established to this date .

Tenvir L is also used to associated treatment for these conditions: Hepatitis B Chronic Infection, Human Immunodeficiency Virus (HIV) InfectionsHepatitis B Chronic Infection, Human Immunodeficiency Virus Type 1 (HIV-1) Infection

How Tenvir L works

Lamivudine is a synthetic nucleoside analogue and is phosphorylated intracellularly to its active 5'-triphosphate metabolite, lamivudine triphosphate (L-TP). This nucleoside analogue is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, resulting in DNA chain termination.

Tenofovir belongs to a class of antiretroviral drugs known as nucleotide analog reverse transcriptase inhibitors (NtRTIs), which block reverse transcriptase, an enzyme necessary for viral production in HIV-infected individuals. This enables the management of HIV viral load through decreased viral replication .

Tenofovir disoproxil fumarate is the fumarate salt of the prodrug tenofovir disoproxil. Tenofovir disoproxil is absorbed and converted to its active form, tenofovir, a nucleoside monophosphate (nucleotide) analog. Tenofovir is then converted to the active metabolite, tenofovir diphosphate, a chain terminator, by constitutively expressed enzymes in the cell. Tenofovir diphosphate inhibits HIV-1 reverse transcriptase and the Hepatitis B polymerase by direct binding competition with the natural deoxyribonucleotide substrate (deoxyadenosine 5’-triphosphate) and, after integration into DNA, causes viral DNA chain termination , .

A note on resistance

HIV-1 isolates with decreased susceptibility to tenofovir have been identified in cell culture studies. These viruses expressed a K65R substitution in reverse transcriptase and showed a 2– 4 fold decrease in susceptibility to treatment with tenofovir .

Dosage

Tenvir L dosage

The recommended oral dose of Lamivudine for the treatment of chronic hepatitis B in adults is 100 mg once daily.

Side Effects

Several serious adverse events reported with lamivudine (lactic acidosis and severe hepatomegaly with steatosis, post treatment exacerbations of hepatitis B, pancreatitis, and emergence of viral mutants associated with reduced drug susceptibility and diminished treatment response). Malaise, fatigue, fever, ENT infections, sore throat, nausea, vomiting, abdominal discomfort, pain, diarrhea, myalgia, arthralgia, headache, skin rashes may occur. Lactic acidosis and severe hepatomegaly with steatosis, have been reported.

Toxicity

The most common reported adverse reactions (incidence ≥15%) in adults were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.

A note on breastfeeding

The Centers for Disease Control and Prevention recommend that HIV-1-infected mothers not breast-feed their infants to prevent postnatal transmission of HIV-1. Mothers should be advised not to breast-feed if they are receiving tenofovir disoproxil .

Carcinogenesis

Long-term oral carcinogenicity studies of tenofovir disoproxil fumarate in mice and rats were performed at exposures up to approximately 16 times (mice) and 5 times (rats) those observed in humans at the therapeutic dose for HIV-1 infection. At the higher dose in female mice, liver adenomas were increased at exposures 16 times that in humans. In rats, the study was negative for carcinogenic findings at exposures up to 5 times that observed in humans at the therapeutic dose .

Pregnancy

This drug is considered a pregnancy Category B drug. Reproduction studies have been performed in rats and rabbits at doses up to 14 and 19 times the recommended human dose based on body surface area comparisons and revealed no evidence of impaired fertility or harm to the fetus due to tenofovir. There are, however, no adequate and well-controlled studies in pregnant women.

Because animal reproduction studies are not consistently reflective of human effects, tenofovir disoproxil should be used during pregnancy only if clearly required. To monitor fetal outcomes of pregnant women taking tenofovir disoproxil, an Antiretroviral Pregnancy Registry has been formed. Healthcare providers are encouraged and advised to register patients by calling the number listed on the FDA label for tenofovir disoproxil .

Mutagenesis

Tenofovir disoproxil fumarate was mutagenic in the in vitro mouse lymphoma assay and negative for mutagenesis in an in vitro bacterial mutagenicity test (Ames test). In an in vivo mouse micronucleus assay, tenofovir disoproxil fumarate was negative when administered to male mice.

Impairment of Fertility

There were no observed effects on fertility, mating performance or early embryonic development when tenofovir disoproxil fumarate was given to male rats at a dose comparable to 10 times the human dose based on body surface area comparisons for 28 days before mating and to female rats for 15 days before mating through day seven of gestation. There was, however, changes in the estrous cycle in female rats .

Precaution

Patients should be assessed before beginning treatment and during treatment with lamivudine by a physician experienced in the management of chronic hepatitis B.

Interaction

Trimethoprim 160 mg / Sulfamethoxazole 800 mg once daily has been shown to increase lamivudine exposure (AUC). The effect of higher doses of trimethoprim /sulfamethoxazole on lamivudine pharmacokinetics has not been investigated.

Volume of Distribution

Apparent volume of distribution, IV administration = 1.3 ± 0.4 L/kg. Volume of distribution was independent of dose and did not correlate with body weight.

The volume of distribution at steady-state is 1.3 ± 0.6 L/kg and 1.2 ± 0.4 L/kg, following intravenous administration of tenofovir 1.0 mg/kg and 3.0 mg/kg .

After oral administration of tenofovir disoproxil, tenofovir is distributed to the majority tissues with the highest concentrations measured in the kidney, liver and the intestinal contents (based on data from preclinical studies) .

Elimination Route

Lamivudine was rapidly absorbed after oral administration in HIV-infected patients. Absolute bioavailability in 12 adult patients was 86% ± 16% (mean ± SD) for the 150-mg tablet and 87% ± 13% for the oral solution. The peak serum lamivudine concentration (Cmax) was 1.5 ± 0.5 mcg/mL when an oral dose of 2 mg/kg twice a day was given to HIV-1 patients. When given with food, absorption is slower, compared to the fasted state.

After oral administration of tenofovir disoproxil to patients with HIV infection, tenofovir disoproxil is quickly absorbed and metabolized to tenofovir .

Administration of tenofovir disoproxil 300 mg tablets after a high-fat meal increases the oral bioavailability of this drug, as demonstrated by an increase in tenofovir AUC0-∞ of about 40% as well as an increase in Cmax of about 14%. On the contrary, the administration of tenofovir disoproxil with a light meal did not exert a relevant effect on the pharmacokinetics of tenofovir when compared to administration under fasting conditions. The presence of ingested food slows the time to tenofovir Cmax by approximately 1 hour. Cmax and AUC of tenofovir are 0.33 ± 0.12 μg/mL and 3.32 ± 1.37 μg•hr/mL after several doses of tenofovir disoproxil 300 mg once daily in the fed state when meal content is not controlled .

Half Life

5 to 7 hours (healthy or HBV-infected patients)

When a single oral dose is given, the terminal elimination half-life is approximately 17 hours .

Clearance

• Renal clearance = 199.7 ± 56.9 mL/min [300 mg oral dose, healthy subjects]
• Renal clearance = 280.4 ± 75.2 mL/min [single IV dose, HIV-1-infected patients]
• Total clearance = 398.5 ± 69.1 mL/min [HIV-1-infected patients]

The clearance of tenofovir is highly dependent on renal function and may vary greatly. Total clearance has been estimated to be approximately 230 ml/h/kg (approximately 300 ml/min) .

On average, renal clearance has been estimated to be approximately 160 ml/h/kg (approximately 210 ml/min), which is in excess of the glomerular filtration rate. This shows that active tubular secretion is an essential part of the elimination of tenofovir .

The FDA label provides specific guidelines for dosing according to renal function. It is important to consult product labeling before administering tenofovir to individuals with renal dysfunction, as the clearance of this drug may vary greatly among these patients .

Elimination Route

The majority of lamivudine is eliminated unchanged in urine by active organic cationic secretion. 5.2% ± 1.4% (mean ± SD) of the dose was excreted as the trans-sulfoxide metabolite in the urine. Lamivudine is excreted in human breast milk and into the milk of lactating rats.

Following IV administration of tenofovir, approximately 70–80% of the dose is recovered in the urine as unchanged tenofovir within 72 hours of dosing. Tenofovir is eliminated by a combination of glomerular filtration and active tubular secretion . There may be competition for elimination with other compounds that are also eliminated by the kidneys.

Pregnancy & Breastfeeding use

There is no adequate and well-controlled study in pregnant women. Lamivudine should be used during pregnancy only if the potential benefits outweigh the risks. Although it is not known if lamivudine is excreted in human milk, there is the potential for adverse effects from lamivudine in nursing infants. Mothers should be instructed not to breast feed if they are receiving lamivudine.

Contraindication

Lamivudine is contraindicated in patients hypersensitive to any of the components of the product.

Special Warning

It is recommended that doses of Lamivudine should be adjusted in accordance with renal function. Dosage adjustment of Lamivudine in accordance with creatinine clearance is as follows:

• CrCl 50 ml/min: 100 mg once daily
• CrCl 30-49 ml/min: 100 mg first dose, then 50 mg once daily
• CrCl 15-29 ml/min: 100 mg first dose, then 25 mg once daily
• CrCl 5-14 ml/min: 35 mg first dose, then 15 mg once daily
• CrCl <5 ml/min: 35 mg first dose, then 10 mg once daily

Use in children: Safety and efficacy of lamivudine for the treatment of chronic hepatitis B in children have not been established.

Storage Condition

Store below 30˚C. Protect from light. Keep out of the reach of children.

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