TENOFOVIR DISOPROXIL FUMARATE/LAMIVUDINE TABLETS 300MG/300MG

Indications

• HIV infection in combination with other antiretroviral drugs
• Chronic hepatitis B infection with evidence of viral replication and active liver inflammation or fibrosis

Dosage

Children: For children aged 3 months to

Adults: For HIV infection, the adult dose is 150 mg every 12 hours or alternatively 300 mg once daily. For chronic hepatitis B, the recommended dose is 300 mg once daily.

Mechanism of action

Lamivudine is phosphorylated intracellularly to its active form, lamivudine triphosphate (L-TP). This active metabolite is incorporated into viral DNA by HIV reverse transcriptase and HBV polymerase, leading to DNA chain termination. Lamivudine competes with deoxycytidine triphosphate for binding to reverse transcriptase, and its incorporation into DNA results in the disruption of DNA synthesis due to the absence of a 3'-OH group necessary for chain elongation.

Pharmacodynamics

As a nucleoside reverse transcriptase inhibitor (NRTI), lamivudine disrupts the viral DNA synthesis pathway, particularly for HIV-1 and HBV. The active metabolite formed competes with natural nucleotides and incorporates into the growing viral DNA chain, ultimately leading to chain termination. This action inhibits the replication of the virus, thereby reducing viral load in infected individuals.

Pharmacokinetics

Lamivudine is absorbed via passive diffusion and is rapidly phosphorylated to its active triphosphate form within cells. Its bioavailability is approximately 80-85% when taken orally. The drug has a half-life of about 5-7 hours in plasma and is primarily eliminated via the kidneys through glomerular filtration and active tubular secretion. Renal impairment necessitates dose adjustments, particularly in patients with creatinine clearance below 50 mL/min.

Contra-indications

• Severe hypersensitivity to lamivudine or any of its excipients
• Patients with decompensated liver disease when used for chronic hepatitis B

Adverse effects

• Peripheral neuropathy
• Headache
• Nausea
• Diarrhea
• Fatigue
• Insomnia
• Malaise
• Cough
• Pharyngitis
• Respiratory tract infections
• Alopecia
• Arthralgia

Interactions

• Trimethoprim may increase exposure to lamivudine
• Concomitant use with other antiretroviral drugs should be evaluated for cross-resistance

Precautions

• Monitor liver function tests every 3 months in patients with chronic hepatitis B
• Recurrent hepatitis may occur upon discontinuation in chronic hepatitis B patients
• Use with caution in renal impairment; dose adjustments may be necessary if creatinine clearance is less than 50 mL/min

Pregnancy

Lamivudine is classified as category B, indicating that there are no known risks in humans, but caution should be exercised. It may be used during pregnancy if deemed necessary by the healthcare provider.

Breast-feeding

Lamivudine can be used with caution while breastfeeding, provided adequate measures are taken to prevent hepatitis B infection in infants.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Lamivudine 150 mg tablets
• Lamivudine 300 mg tablets
• Epivir oral solution

Indications

• HIV-1 infection
• Chronic hepatitis B virus (HBV) infection

Dosage

Children: Refer to the BNF for

Adults: Refer to the relevant clinical guidelines or BNF for the appropriate dosing recommendations.

Mechanism of action

Disoproxil is converted intracellularly to its active form, tenofovir diphosphate. This active metabolite competes with natural deoxyadenosine triphosphate (dATP) for incorporation into viral DNA by the viral reverse transcriptase enzyme. Once incorporated, it leads to chain termination, thereby inhibiting viral replication. Additionally, tenofovir diphosphate interferes with the activity of HIV reverse transcriptase and HBV polymerase, further contributing to its antiviral effects.

Pharmacodynamics

Disoproxil exhibits a dose-dependent decrease in HIV-1 viral load and improves CD4 cell counts in patients. Its antiviral activity is primarily against HIV-1 and HBV, with a mechanism that does not exhibit cross-resistance with other classes of antiretroviral drugs. The drug has a long half-life, allowing for once-daily dosing, which improves adherence in patients. It is effective in both naïve and treatment-experienced patients.

Pharmacokinetics

Disoproxil is absorbed following oral administration; its bioavailability is approximately 25% when taken without food. The drug is extensively distributed in the body, with a volume of distribution of about 1.3 L/kg. It undergoes renal clearance, with about 70% of the drug eliminated unchanged in the urine. The elimination half-life of disoproxil is around 17 hours, allowing for once-daily dosing. It is not significantly metabolized by the liver, which reduces the risk of drug-drug interactions associated with hepatic metabolism.

Contra-indications

• Hypersensitivity to disoproxil or any component of the formulation
• Severe renal impairment

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal toxicity
• Liver function abnormalities
• Bone mineral density loss
• Lactic acidosis

Interactions

• Potential interactions with nephrotoxic drugs
• May interact with other antiviral agents
• Can affect the metabolism of drugs that are substrates of CYP450 enzymes

Precautions

• Monitor renal function regularly during therapy
• Assess bone mineral density before and during treatment
• Use with caution in patients with a history of pancreatitis
• Evaluate liver function before initiation and during treatment

Pregnancy

Disoproxil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Limited data on human use.

Breast-feeding

Disoproxil is excreted in breast milk. A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Storage

Store at room temperature, away from moisture and heat. Keep out of reach of children.

Formulations

• Oral tablets
• Oral solution

Indications

• HIV infection
• Chronic hepatitis B virus (HBV) infection

Dosage

Children: Refer to the BNF for Children for specific dosing recommendations in paediatric patients.

Adults: Refer to the current clinical guidelines or BNF for specific dosing recommendations in adults.

Mechanism of action

Tenofovir is converted intracellularly to its active form, tenofovir diphosphate. This active form competes with natural deoxyadenosine triphosphate for incorporation into viral DNA by reverse transcriptase, leading to chain termination and preventing further viral replication.

Pharmacodynamics

Tenofovir has a high barrier to resistance, and its efficacy is enhanced when used in combination with other antiretroviral drugs. It exhibits a dose-dependent antiviral effect against HIV and HBV, effectively reducing viral loads and improving immune function as indicated by CD4 cell counts.

Pharmacokinetics

Tenofovir is administered orally and has a bioavailability of approximately 25% when taken on an empty stomach. It is primarily excreted unchanged in the urine. The elimination half-life is about 17 hours, allowing for once-daily dosing in most cases. Food can increase the absorption of tenofovir, leading to higher plasma concentrations.

Contra-indications

• Hypersensitivity to tenofovir or any of its components
• Severe renal impairment (CrCl < 50 mL/min)

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal toxicity
• Bone mineral density loss
• Hepatotoxicity

Interactions

• Coadministration with nephrotoxic agents may increase risk of renal impairment
• Tenofovir may decrease the effectiveness of atazanavir and other protease inhibitors

Precautions

• Monitor renal function regularly
• Assess bone mineral density in patients at risk for osteoporosis
• Use with caution in patients with a history of liver disease

Pregnancy

Tenofovir is classified as FDA pregnancy category B. Animal studies have not shown teratogenic effects, but adequate and well-controlled studies in pregnant women are lacking.

Breast-feeding

Tenofovir is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store in a cool, dry place away from light. Keep out of reach of children.

Formulations

• Tenofovir disoproxil fumarate tablet
• Tenofovir alafenamide tablet
• Tenofovir disoproxil fumarate oral powder

Mechanism of action

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. Lamivudine enters cells by passive diffusion and is phosphorylated to its active metabolite, lamivudine triphosphate. Lamivudine triphosphate competes with deoxycytidine triphosphate for binding to reverse transcriptase, and incorporation into DNA results in chain termination. Lamivudine has very low affinity for human alpha and omega DNA polymerases, moderate affinity for beta DNA polymerase, and higher affinity for gamma DNA polymerase.

Pharmacodynamics

Lamivudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1) and hepatitis B (HBV) to disrupt viral DNA synthesis. When phosphorylated, lamivudine can form active metabolites that compete for incorporation into viral DNA. Via DNA incorporation, lamivudine metabolites competitively inhibit the activity of the HIV reverse transcriptase enzyme and act as a chain terminator of DNA synthesis. Due to the lack of a 3'-OH group, incorporated nucleoside analogues prevent the formation of a 5' to 3' phosphodiester linkage that is essential for DNA chain elongation.