ENVUTEG TABLETS (Each film coated tablet contains Dolutegravir Sodium 50mg/ Lamivudine 300mg/ Tenovofir Alafenamide Fumarate 25mg

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 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
• HIV pre-exposure prophylaxis (PrEP)

Dosage

Children: Refer to the BNF for Children for appropriate dosing recommendations in pediatric populations.

Adults: Refer to the BNF for specific dosing guidelines based on individual patient factors and the presence of comorbidities.

Mechanism of action

Alafenamide is converted to its active form, tenofovir diphosphate, which inhibits the HIV reverse transcriptase enzyme. This inhibition interferes with viral RNA replication, preventing the virus from multiplying and reducing the viral load in the body. Additionally, tenofovir diphosphate is incorporated into viral DNA, leading to termination of the DNA chain and further impeding viral replication.

Pharmacodynamics

The pharmacodynamic profile of alafenamide is consistent with that of tenofovir, showing potent activity against HIV-1. Its mechanism involves the competitive inhibition of reverse transcriptase and incorporation into viral DNA, which results in reduced viral replication. Resistance can develop through mutations in the reverse transcriptase enzyme; however, alafenamide maintains activity against certain resistant strains.

Pharmacokinetics

Alafenamide has a high oral bioavailability, with peak plasma concentrations occurring within 0.5 to 1 hour after administration. It is rapidly converted to tenofovir after absorption. The drug has a tissue distribution that favors lymphoid tissues, where HIV is often harbored. Alafenamide is predominantly eliminated via renal pathways; however, its active metabolite, tenofovir, has a longer half-life, allowing for once-daily dosing regimens. The pharmacokinetics can be affected by renal function and other medications that impact renal clearance.

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Rash
• Elevated liver enzymes
• Renal impairment

Interactions

• CYP3A4 inducers may decrease alafenamide levels
• CYP3A4 inhibitors may increase alafenamide levels
• Other medications that affect renal function may interact

Precautions

• Monitor renal function before and during treatment
• Assess for signs of liver toxicity
• Use caution in patients with a history of liver disease

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Data on human pregnancy are limited.

Breast-feeding

It is not known whether alafenamide is excreted in human milk. Caution is advised when administered to breastfeeding women.

Storage

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

Formulations

• Oral tablet

Indications

• HIV-1 infection
• Chronic hepatitis B virus infection
• Pre-exposure prophylaxis (PrEP) for HIV prevention

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines based on the child's age and condition.

Adults: Refer to the BNF for specific dosing guidelines based on the condition being treated.

Mechanism of action

Tenofovir acts by inhibiting the reverse transcriptase enzyme, which is essential for the replication of HIV and hepatitis B virus. It competes with natural deoxyribonucleoside triphosphates for incorporation into the viral DNA, leading to chain termination and preventing further synthesis of viral genomes. This action effectively reduces viral load and helps restore immune function in HIV-infected individuals.

Pharmacodynamics

Tenofovir exhibits a dose-dependent antiviral effect and is effective against both HIV-1 and HIV-2, as well as hepatitis B virus. The drug has a high barrier to resistance, meaning that the likelihood of the virus developing resistance to tenofovir during treatment is relatively low. The pharmacodynamic profile is characterized by prolonged intracellular half-life, allowing for once-daily dosing in most cases.

Pharmacokinetics

After oral administration, tenofovir disoproxil fumarate is rapidly absorbed and converted to its active form. Peak plasma concentrations occur within 1 to 2 hours. Tenofovir is primarily eliminated through renal excretion, with a half-life of approximately 17 hours. The drug has minimal protein binding, and its pharmacokinetics can be affected by renal function, necessitating dosage adjustments in patients with impaired renal clearance.

Contra-indications

• Hypersensitivity to tenofovir or any component of the formulation
• Severe renal impairment (eGFR <30 mL/min)

Adverse effects

• Nausea
• Diarrhea
• Headache
• Fatigue
• Renal impairment
• Lactic acidosis
• Bone mineral density loss

Interactions

• Didanosine
• Adefovir
• Other nephrotoxic agents
• Antiretrovirals that require dose adjustments based on renal function

Precautions

• Monitor renal function regularly
• Use caution in patients with pre-existing renal disease or risk factors for renal impairment
• Evaluate for signs and symptoms of lactic acidosis
• Consider bone health monitoring in long-term use

Pregnancy

Tenofovir is classified as Category B. Limited data suggest it may be used during pregnancy, but benefits must be weighed against potential risks.

Breast-feeding

Tenofovir is excreted in breast milk. Caution is advised, but it may be used if the benefits outweigh the risks.

Storage

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

Formulations

• Tenofovir disoproxil fumarate tablet
• Tenofovir alafenamide tablet

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.

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.