JULUCA 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-1 infection
• Antiretroviral therapy in treatment-naive patients
• Combination therapy with other antiretroviral agents

Dosage

Children: For paediatric patients aged 12 years and older, rilpivirine is recommended in combination with other antiretroviral medications. Specific dosing should be referred to in the BNF for Children.

Adults: The recommended initial dose is 900 mg administered as an intramuscular injection at month 2, following a lead-in period. Maintenance doses are 600 mg every month from month 3 onwards. For oral administration, the usual initial dose is 25 mg once daily.

Mechanism of action

Rilpivirine binds non-competitively to the reverse transcriptase enzyme of HIV-1. This binding inhibits the RNA and DNA-dependent DNA polymerase activities, effectively blocking HIV-1 replication. Its structural flexibility allows it to adapt to changes in the non-nucleoside RT binding pocket, making it less susceptible to resistance mutations compared to other NNRTIs.

Pharmacodynamics

As an NNRTI, rilpivirine inhibits the replication of HIV-1. It has a long duration of action, which permits once-daily oral dosing or monthly intramuscular injections. Patients are advised about potential side effects, including hypersensitivity reactions, hepatotoxicity, and mood disorders, alongside the possibility of body fat redistribution.

Pharmacokinetics

Rilpivirine exhibits variable absorption and a half-life that supports once-daily dosing. It is metabolized primarily by the liver, with a significant interaction profile that necessitates monitoring of liver function, especially during the initial treatment phase. Renal and hepatic impairment may affect drug clearance, requiring caution in these populations.

Contra-indications

• Severe hepatic impairment
• Severe renal impairment

Adverse effects

• Rash
• Depression
• Dizziness
• Drowsiness
• Gastrointestinal discomfort
• Headache
• Nausea
• Sleep disorders
• Vomiting
• Anxiety
• Asthenia
• Diarrhoea
• Fever
• Malaise
• Myalgia
• Weight increase
• General malaise
• Hypersensitivity reactions

Interactions

• Mitotane (unknown effect on rilpivirine exposure)
• Dabrafenib (unknown effect on rilpivirine exposure)

Precautions

• Monitor liver function closely during the first 18 weeks of treatment
• Monitor for skin reactions during the first 18 weeks
• Caution in patients with hepatic disease or co-infection with hepatitis B or C
• Patients should be informed about the risk of hypersensitivity reactions

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is unknown whether rilpivirine is excreted in human milk; caution should be exercised when administering to breastfeeding women.

Storage

Store in a cool, dry place, away from light. Do not freeze.

Formulations

• Rilpivirine hydrochloride 25 mg tablet (Edurant)
• Rilpivirine intramuscular injection (long-acting formulation)

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

Rilpivirine is a non-competitive NNRTI that binds to reverse transcriptase. Its binding results in the blockage of RNA and DNA- dependent DNA polymerase activities, like HIV-1 replication. It does not present activity against human DNA polymerases α, β and γ. Rilpivirine's flexible structure around the aromatic rings allows the adaptation to changes in the non-nucleoside RT binding pocket, reducing the likelihood of viral mutations conferring resistance. Rilpivirine, a diarylpyrimidine nonnucleoside reverse transcriptase inhibitor (NNRTI), inhibits replication of human immunodeficiency virus type 1 (HIV-1) by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase. Diarylpyrimidine NNRTIs (e.g., rilpivirine, etravirine) are capable of adapting to mutations in HIV-1 reverse transcriptase because of structural flexibility that allows for binding to the allosteric NNRTI binding pocket in a variety of conformations. Unlike other currently available NNRTIs, rilpivirine contains a cyanovinyl group that contributes to potency and maintains the drug's binding ability, despite the emergence of some resistance mutations.

Pharmacodynamics

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor that inhibits the replication of HIV-1. It has a long duration of action as the oral tablet is given daily and the intramuscular suspension is given monthly. Patients should be counselled regarding the risk of hypersensitivity reactions, hepatotoxicity, depressive disorders, and the redistribution or accumulation of body fat.