KOCITAF-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

Dosage

Children: Child 4 months–17 years (body-weight up to 33 kg): 6 mg/kg once daily. Child 4 months–17 years (body-weight 33 kg and above): 240 mg once daily.

Adults: 200 mg once daily by mouth using capsules or 240 mg once daily by mouth using oral solution.

Mechanism of action

Emtricitabine is a cytidine analog that, when phosphorylated to emtricitabine 5'-triphosphate, competes with deoxycytidine 5'-triphosphate for HIV-1 reverse transcriptase. It incorporates itself into the viral DNA during replication, leading to chain termination. This prevents the incorporation of additional nucleotides and inhibits the transcription of viral RNA into DNA, thereby preventing viral replication.

Pharmacodynamics

Emtricitabine acts by competing with natural substrates of HIV-1 reverse transcriptase, leading to the termination of viral DNA synthesis. It has a long duration of action, allowing for once-daily dosing. Clinicians should monitor for potential side effects, including lactic acidosis and hepatomegaly with steatosis, which can occur with nucleoside analogs.

Pharmacokinetics

Emtricitabine is absorbed well following oral administration, with peak plasma concentrations occurring approximately 1 to 2 hours post-dose. It has a long half-life, allowing for its once-daily administration. Emtricitabine is primarily excreted through the kidneys, and dosage adjustments may be necessary in patients with renal impairment. It is metabolized minimally by the liver.

Contra-indications

• Severe hepatic impairment
• Severe renal impairment (creatinine clearance <30 mL/min)

Adverse effects

• Decreased appetite
• Asthenia
• Constipation
• Diarrhoea
• Dizziness
• Electrolyte imbalance
• Flatulence
• Gastrointestinal discomfort
• Headache
• Abnormal dreams
• Dyspepsia
• Hyperbilirubinaemia
• Hyperglycaemia
• Hypersensitivity reactions
• Hypertriglyceridaemia
• Neutropenia
• Pain
• Rash
• Pustular skin reactions
• Sleep disorders
• Angioedema (uncommon)

Interactions

• Cobicistat and elvitegravir may impact emtricitabine efficacy
• Potential for increased risk of treatment failure in pregnancy when used with elvitegravir
• Monitor for changes in drug levels when co-administered with other antiretrovirals

Precautions

• Caution in patients with hepatic impairment due to increased risk of side effects
• Monitor renal function regularly, particularly in those with existing renal impairment
• Patients should be advised on the risks of lactic acidosis and hepatomegaly with steatosis

Pregnancy

Not recommended for initiation during pregnancy due to risk of treatment failure and maternal-to-child transmission of HIV-1. Women who become pregnant during therapy should be switched to an alternative regimen.

Breast-feeding

Emtricitabine is excreted in human breast milk, caution is advised when administering to breastfeeding mothers.

Storage

Store in the original container, protected from moisture, and keep out of reach of children.

Formulations

• 200 mg capsules
• 240 mg oral solution

Indications

• Chronic hepatitis B infection
• Chronic hepatitis C infection

Dosage

Children: For children aged 3 to 17 years with chronic hepatitis B, the recommended dose is 15 mg/kg daily for those weighing up to 47 kg, and 25 mg for those weighing 35 kg and above, divided into two doses. For those weighing 50 to 64 kg, a dose of

Adults: For chronic hepatitis B, the recommended adult dose is 25 mg once daily. For chronic hepatitis C, dosing may vary based on the specific treatment regimen; consultation with product literature is advised.

Mechanism of action

Tenofovir alafenamide acts by inhibiting the reverse transcriptase enzyme, which is crucial for the replication of hepatitis B and C viruses. Once inside the cells, it is converted to its active form, tenofovir diphosphate, which competes with the natural nucleotide substrates, leading to premature termination of viral DNA synthesis. This mechanism effectively reduces the viral load in infected patients.

Pharmacodynamics

The drug exhibits antiviral activity against hepatitis B virus (HBV) and hepatitis C virus (HCV) by blocking the reverse transcriptase enzyme. The reduction in viral replication is associated with a decrease in liver inflammation and fibrosis progression. Tenofovir alafenamide has a high barrier to resistance, making it a preferred choice in antiviral therapy.

Pharmacokinetics

Tenofovir alafenamide is rapidly absorbed after oral administration and undergoes metabolism to tenofovir. It has a bioavailability significantly higher than tenofovir disoproxil fumarate, allowing for lower dosing. The drug is primarily eliminated by the kidneys, and its half-life is approximately 12 to 18 hours. Drug interactions with potent CYP450 inducers, such as rifamycins and antiepileptics, may significantly reduce exposure and efficacy.

Adverse effects

• Lactic acidosis
• Renal impairment
• Nausea
• Diarrhea
• Fatigue
• Headache
• Abdominal pain

Interactions

• Antiepileptics (carbamazepine, fosphenytoin, oxcarbazepine, phenobarbital, phenytoin, primidone) - Severe (decreases exposure)
• Tipranavir - Severe (decreases exposure)
• Rifamycins - Severe (decreases exposure)
• St. John's Wort - Severe (decreases exposure)
• Fostemsavir - Moderate (increases exposure)
• Ciclosporin - Unknown (increases exposure)
• Eltrombopag - Unknown (increases exposure)
• Leflunomide - Unknown (increases exposure)
• Teriflunomide - Unknown (increases exposure)

Precautions

• Monitor renal function regularly
• Use with caution in patients with a history of renal disease
• Lactic acidosis risk in patients with liver disease

Pregnancy

Manufacturer advises use only if potential benefit outweighs risk due to toxicity in animal studies.

Breast-feeding

Manufacturer advises avoiding use as it is present in milk in animal studies.

Storage

Store in a cool, dry place, away from light and moisture.

Formulations

• Oral tablet: 25 mg
• Oral tablet: 10 mg

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

Emtricitabine is a cytidine analog which, when phosphorylated to emtricitabine 5'-triphosphate, competes with deoxycytidine 5'-triphosphate for HIV-1 reverse transcriptase. As HIV-1 reverse transcriptase incorporates emtricitabine into forming DNA strands, new nucleotides are unable to be incorporated, leading to viral DNA chain termination. Inhibition of reverse transcriptase prevents transcription of viral RNA into DNA, therefore the virus is unable to incorporate its DNA into host DNA and replicate using host cell machinery. This reduces viral load. Emtricitabine, a synthetic nucleoside analog of cytosine, is phosphorylated by cellular enzymes to form emtricitabine 5'-triphosphate. Emtricitabine 5'-triphosphate inhibits the activity of the HIV-1 reverse transcriptase by competing with the natural substrate deoxycytidine 5'-triphosphate and by being incorporated into nascent viral DNA which results in chain termination. Emtricitabine 5'-triphosphate is a weak inhibitor of mammalian DNA polymerase alpha, beta, epsilon and mitochondrial DNA polymerase gamma.

Pharmacodynamics

Emtricitabine is a cytidine analog that competes with the natural substrate of HIV-1 reverse transcriptase to be incorporated into newly formed DNA, terminating its transcription. It is administered once daily so it has a long duration of action. Patients should be counselled regarding the risk of lactic acidosis and hepatomegaly with steatosis.