LAMIVIR-S-40 COMBINATION PRODUCT TABLET

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 infection in combination with other antiretroviral drugs when first-line nucleoside reverse transcriptase inhibitors cannot be used due to resistance or contraindications

Dosage

Children: For children, the dosing varies by weight: 1 mg

Adults: Refer to the BNF for appropriate adult dosing guidelines based on individual patient circumstances and renal function.

Mechanism of action

Stavudine inhibits the activity of HIV-1 reverse transcriptase (RT) by competing with the natural substrate deoxythymidine triphosphate (dTTP) and by being incorporated into viral DNA. It is phosphorylated to its active form, stavudine triphosphate, which competes with dTTP for incorporation into the viral DNA chain. The absence of a 3'-hydroxy group in stavudine triphosphate results in premature termination of DNA chain elongation, thus inhibiting viral replication.

Pharmacodynamics

As a nucleoside reverse transcriptase inhibitor (NRTI), stavudine exhibits antiviral activity against HIV-1 by phosphorylating to active metabolites that compete for incorporation into viral DNA. This action inhibits the reverse transcriptase enzyme competitively and acts as a chain terminator, preventing further viral DNA synthesis due to the lack of a 3'-OH group essential for DNA chain elongation.

Pharmacokinetics

Stavudine is absorbed orally and is converted to its active triphosphate form through a series of phosphorylation steps mediated by cellular kinases. The drug has a half-life that supports twice-daily dosing. It is primarily eliminated via renal pathways, and dose adjustments may be required in patients with renal impairment. Monitoring of renal function and plasma lipids is advised during treatment.

Contra-indications

• Hypersensitivity to stavudine or any of its components
• Severe hepatic impairment
• History of pancreatitis
• History of peripheral neuropathy

Adverse effects

• Very common: Depression, drowsiness
• Common: Abdominal distension, flatulence, sleep disorders
• Uncommon: Proximal renal tubulopathy, anxiety, arthralgia, emotional lability, hepatitis, nephritis, nephrogenic diabetes insipidus, renal impairment, gynaecomastia
• Rare: Acute tubular necrosis, angioedema, diabetes mellitus, hyperglycaemia
• Very rare: Neutropenia, muscle weakness

Interactions

• Increased risk of peripheral neuropathy when used with didanosine
• Caution with other antiretroviral medications

Precautions

• Use with caution in patients with a history of lactic acidosis, hepatomegaly, chronic hepatitis B infection, and other risk factors for liver disease
• Monitoring of renal function and serum phosphate is recommended before treatment and periodically thereafter
• Discontinue treatment if symptoms of hyperlactataemia, lactic acidosis, progressive hepatomegaly or rapid deterioration of liver function occur

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk.

Breast-feeding

Stavudine is excreted in breast milk; caution is advised.

Storage

Store at room temperature, away from moisture and heat.

Formulations

• Zerit 20 mg capsules
• Zerit 30 mg capsules
• Zerit 40 mg capsules

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.

Mechanism of action

Stavudine inhibits the activity of HIV-1 reverse transcriptase (RT) both by competing with the natural substrate dGTP and by its incorporation into viral DNA. Enzymatic conversion of stavudine to d4T-triphosphate appears to be complex, involving several steps and enzymes. Stavudine is first converted to dideoxydidehydrothymidine-5'-monophosphate (d4T-monophosphate) by thymidine kinase. Subsequently, d4T-monophosphate is converted to dideoxydidehydrothymidine-5'-diphosphate (d4T-diphosphate), and then to d4T-triphosphate, presumably by the same cellular kinases involved in the metabolism of zidovudine. ... d4T-Triphosphate is a structural analog of thymidine triphosphate, the natural substrate for viral RNA-directed DNA polymerase. ... d4T-triphosphate appears to compete with thymidine triphosphate for viral RNA-directed DNA polymerase and incorporation into viral DNA. Following incorporation of d4T-triphosphate into the viral DNA chain instead of thymidine triphosphate, synthesis is terminated prematurely because the absence of the 3'-hydroxy group on the drug prevents further 5' to 3' phosphodiester linkages. Stavudine is phosphorylated by cellular kinases to the active metabolite stavudine triphosphate. Stavudine triphosphate inhibits the activity of HIV reverse transcriptase both by competing with the natural substrate deoxythymidine triphosphate (Ki =0.0083 to 0.032 uM), and by its incorporation into viral DNA causing a termination of DNA chain elongation because stavudine lacks the essential 3'-OH group. Stavudine triphosphate inhibits cellular DNA polymerase beta and gamma, and markedly reduces the synthesis of mitochondrial DNA. d4T-Triphosphate can bind to and inhibit some mammalian cellular DNA polymerases, particularly beta- and gamma-polymerases, in vitro, and markedly reduce the synthesis of mitochondrial DNA. ...gamma-polymerase, an enzyme involved in mitochondrial DNA synthesis, is the polymerase most susceptible to inhibition. However, d4T-triphosphate and other dideoxynucleoside triphosphates appear to have much greater affinity for viral RNA-directed DNA polymerase than for mammalian DNA polymerases. ... Inhibition of beta- and gamma-polymerases by these drugs may account, to some extent, for the toxic effects associated with stavudine and other nucleosides in humans.

Pharmacodynamics

Stavudine is a nucleoside reverse transcriptase inhibitor (NRTI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). Stavudine is phosphorylated to active metabolites that compete for incorporation into viral DNA. They inhibit the HIV reverse transcriptase enzyme competitively and act as a chain terminator of DNA synthesis. The lack of a 3'-OH group in the incorporated nucleoside analogue prevents the formation of the 5' to 3' phosphodiester linkage essential for DNA chain elongation, and therefore, the viral DNA growth is terminated.