Viropil 50/300/300 Tablets

Indications

• HIV infection without resistance to other inhibitors of HIV integrase
• HIV infection in patients with resistance to other inhibitors of HIV integrase (specialist use only)

Dosage

Children: Refer to BNF for Children for appropriate dosing.

Adults: 50 mg once daily.

Mechanism of action

Dolutegravir inhibits the HIV integrase enzyme by binding to its active site, blocking the strand transfer step of retroviral DNA integration into the host cell genome. This step is essential for the replication of HIV, and by preventing this integration, dolutegravir effectively inhibits viral activity and replication.

Pharmacodynamics

Clinical trials have demonstrated that dolutegravir leads to a rapid and dose-dependent reduction of HIV-1 RNA in infected subjects. The antiviral response can be sustained for several days following the last dose, indicating its long half-life and strong binding affinity. This characteristic contributes to a high barrier to the development of resistance, making dolutegravir a potent option in combination therapy regimens.

Pharmacokinetics

Dolutegravir exhibits favorable pharmacokinetics, with a mean elimination half-life of approximately 14 hours. It is well absorbed following oral administration, with food enhancing its bioavailability. The drug is metabolized primarily by UGT1A1 and UGT1A9 enzymatic pathways, and it is excreted mainly via feces. Drug interactions may occur, particularly with medications that induce or inhibit UGT enzymes.

Contra-indications

• Hypersensitivity to dolutegravir or any of its excipients

Adverse effects

• Nausea
• Vomiting
• Drowsiness
• Increased weight
• Skin reactions
• Sleep disorders
• Hepatotoxicity
• Pancreatitis
• Osteonecrosis

Interactions

• Moderate increase in exposure with dopaminergic receptor agonists
• Moderate increase in exposure with pramipexole
• Moderate increase in exposure with metformin
• Moderate increase in exposure with atazanavir
• Unknown decrease in exposure with carbamazepine
• Unknown decrease in exposure with oxcarbazepine
• Unknown decrease in exposure with phenytoin
• Unknown decrease in exposure with primidone
• Unknown increase in exposure with encorafenib
• Unknown increase in concentration with fampridine

Precautions

• Use with caution in patients with HIV-1 subtype A6/A1, or BMI of 30 kg/m2 or more
• Caution in severe hepatic impairment
• Patients or carers should be advised on how to recognize signs of hypersensitivity

Pregnancy

Avoid unless potential benefit outweighs risk, no information available.

Breast-feeding

Avoid; may be present in milk for up to 12 months or longer after last prolonged-release injection.

Storage

Store in a cool, dry place, away from direct light.

Formulations

• Tablets: 50 mg and 30 mg
• Powder and solvent for solution for injection

Indications

• HIV infection
• Chronic hepatitis B virus infection

Dosage

Children: Refer to BNF for Children for appropriate dosing information based on age and weight.

Adults: Refer to specific guidelines and BNF resources for accurate dosing regimens tailored to individual patient needs.

Mechanism of action

Lamivudine is a cytosine analogue that inhibits reverse transcriptase, an essential enzyme for the replication of retroviruses such as HIV. By incorporating itself into the viral DNA chain during replication, lamivudine causes termination of the DNA chain, preventing further synthesis of viral genetic material, which ultimately leads to a decrease in viral load.

Pharmacodynamics

The pharmacodynamics of lamivudine involve its action as a competitive inhibitor of HIV-1 reverse transcriptase. Lamivudine exhibits synergistic effects when used in combination with other antiretroviral drugs, contributing to a more substantial reduction in HIV replication. The drug has a selective toxicity profile, showing minimal effects on host DNA polymerases, which aids in its safety and tolerability.

Pharmacokinetics

Lamivudine is well absorbed after oral administration, with a bioavailability of approximately 80-85%. It has a volume of distribution of about 1.3 L/kg and is primarily eliminated through renal excretion as unchanged drug. The half-life of lamivudine is approximately 5-7 hours in individuals with normal renal function. Dose adjustments are necessary for patients with renal impairment to avoid accumulation and toxicity.

Contra-indications

• Hypersensitivity to lamivudine or any component of the formulation
• Severe hepatic impairment

Adverse effects

• Headache
• Nausea
• Diarrhea
• Fatigue
• Lactic acidosis
• Hepatomegaly
• Pancreatitis
• Neuropsychiatric effects

Interactions

• Co-administration with other antiviral agents may lead to increased risk of toxicity or reduced efficacy
• Zidovudine may increase the risk of hematologic toxicity when used with lamivudine

Precautions

• Renal impairment may necessitate dosage adjustment
• Monitor for signs of lactic acidosis, especially in patients with risk factors
• Caution in patients with a history of pancreatitis

Pregnancy

Lamivudine is classified as pregnancy category B. Studies in pregnant women have not shown an increased risk of fetal harm, but caution is advised.

Breast-feeding

Lamivudine is excreted in breast milk. The decision to continue breastfeeding should consider the benefits of breastfeeding and the mother's need for lamivudine.

Storage

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

Formulations

• 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

Dolutegravir is an HIV-1 antiviral agent. It inhibits HIV integrase by binding to the active site and blocking the strand transfer step of retroviral DNA integration in the host cell. The strand transfer step is essential in the HIV replication cycle and results in the inhibition of viral activity. Dolutegravir has a mean EC50 value of 0.5 nM (0.21 ng/mL) to 2.1 nM (0.85 ng/mL) in peripheral blood mononuclear cells (PBMCs) and MT-4 cells. Dolutegravir inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral deoxyribonucleic acid (DNA) integration which is essential for the HIV replication cycle. Strand transfer biochemical assays using purified HIV-1 integrase and pre-processed substrate DNA resulted in IC50 values of 2.7 nM and 12.6 nM.

Pharmacodynamics

HIV-1 infected subjects on dolutegravir monotherapy demonstrated rapid and dose-dependent reduction of antiviral activity with declines of HIV-1 RNA copies per ml. The antiviral response was maintained for 3 to 4 days after the last dose. The sustained response obtained in clinical trials indicates that dolutegravir has a tight binding and longer dissociative half-life providing it a high barrier to resistance. The combination therapy (ripivirine and dolutegravir) presented the same viral suppression found in previous three-drug therapies without integrase strand transfer inhibitor mutations or rilpivirine resistance.