TABLETS (Each tablet contains Darunavir/ Rotanavir 400mg/500mg)

Indications

• HIV infection in combination with other antiretroviral drugs in patients previously treated with antiretroviral therapy
• HIV infection in combination with other antiretroviral drugs in treatment-naive patients

Dosage

Children: For children weighing 14-20 kg: 0.5 tablet twice daily; for children weighing 30 kg and above: 1 tablet twice daily. Refer to BNF for Children for detailed dosing guidelines.

Adults: 800 mg once daily or 600 mg twice daily, depending on previous treatment history and viral load.

Mechanism of action

Darunavir functions by binding to the HIV-1 protease enzyme, which is critical for viral protein processing and maturation necessary for HIV replication. By inhibiting the protease, darunavir prevents the cleavage of Gag-Pol proteins in infected cells, thus halting the formation of mature and infectious virions. Its ability to interact with multiple sites on the protease enzyme contributes to its effectiveness, particularly against resistant strains of HIV.

Pharmacodynamics

As a protease inhibitor, darunavir effectively lowers HIV viral load and enhances CD4 cell counts when used in combination with ritonavir and other antiretroviral medications. This mechanism leads to a significant decrease in morbidity and mortality rates in patients with HIV infection, improving overall health outcomes.

Pharmacokinetics

Darunavir is well-absorbed following oral administration. It has a high protein binding rate, primarily to albumin and alpha-1 acid glycoprotein. The drug undergoes hepatic metabolism, primarily via the cytochrome P450 system, particularly CYP3A4, and has a half-life that allows for once or twice daily dosing. The pharmacokinetics may vary based on the presence of food and other medications.

Adverse effects

• rash
• nausea
• diarrhea
• headache
• fatigue
• hepatotoxicity
• gastrointestinal disorders
• depression
• memory loss
• gynaecomastia
• nephrolithiasis
• severe cutaneous adverse reactions (SCARs)

Interactions

• darunavir + cobicistat: increased risk of adverse reactions
• darunavir + ritonavir: synergistic effect on HIV suppression
• darunavir + raltegravir: unknown interaction, increased risk of rash

Precautions

• monitor liver function tests
• watch for signs of severe skin reactions
• caution in patients with a history of drug allergies
• monitor for signs of nephrolithiasis
• consider potential drug interactions with other antiretrovirals

Pregnancy

Darunavir is generally considered safe to use during pregnancy; however, it should be used under the guidance of a healthcare provider as part of a comprehensive antiretroviral therapy plan.

Breast-feeding

Darunavir is excreted in breast milk; the decision to breastfeed while on darunavir should involve a risk-benefit assessment with a healthcare provider.

Storage

Store at room temperature, protect from moisture and light. Keep out of reach of children.

Formulations

• Darunavir oral suspension 100 mg/ml
• Darunavir 400 mg tablets
• Darunavir 600 mg tablets
• Darunavir 800 mg tablets
• Darunavir 75 mg tablets
• Darunavir 150 mg tablets

Indications

• HIV infection
• HIV-1 associated conditions

Dosage

Children: Refer to the BNF for Children for specific dosing information for paediatric patients.

Adults: Refer to the BNF for specific dosing guidelines based on individual patient circumstances.

Mechanism of action

Ritonavir works by inhibiting the HIV-1 protease enzyme, which is essential for the viral replication process. By blocking this enzyme, ritonavir prevents the cleavage of viral polyproteins into functional proteins, leading to the production of immature, non-infectious viral particles.

Pharmacodynamics

Ritonavir exhibits dose-dependent antiviral activity against HIV. It significantly reduces viral load and increases CD4 cell counts in patients. The drug's ability to inhibit CYP3A4 also facilitates higher plasma levels of co-administered protease inhibitors, enhancing their therapeutic effects.

Pharmacokinetics

Ritonavir is well absorbed after oral administration and has a bioavailability of approximately 60-70%. It is extensively metabolized in the liver via the cytochrome P450 system, primarily by CYP3A4. The elimination half-life is about 3-5 hours, but this can be extended when used in low doses as a booster. Ritonavir is excreted mostly in the form of metabolites in feces, with a small percentage eliminated in urine.

Contra-indications

• Hypersensitivity to ritonavir or any component of the formulation
• Severe hepatic impairment
• Concomitant use with certain medications that are contraindicated due to significant drug interactions

Adverse effects

• Nausea
• Diarrhea
• Abdominal pain
• Fatigue
• Headache
• Increased liver enzymes
• Changes in body fat distribution
• Potential for drug-induced pancreatitis

Interactions

• Ritonavir is a strong inhibitor of CYP3A4, which may increase the plasma concentrations of drugs metabolized by this enzyme
• Concomitant use with other protease inhibitors may increase the risk of toxicity
• Interactions with anticoagulants, anticonvulsants, and other medications metabolized by CYP enzymes should be evaluated

Precautions

• Monitor liver function tests before and during treatment
• Use caution in patients with a history of liver disease
• Be aware of potential for drug interactions due to multiple metabolic pathways
• Monitor for signs of pancreatitis

Pregnancy

Ritonavir is classified as Category C. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Ritonavir is excreted in breast milk. Breastfeeding is not recommended in mothers receiving ritonavir due to potential adverse effects on the infant.

Storage

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

Formulations

• Capsules
• Solution for oral administration

Mechanism of action

The HIV-1 protease enzyme is necessary for viral precursor protein processing and viral maturation in preparation for infection, and is therefore a target for antiretroviral therapy for HIV. Protease inhibitors are used as a part of highly active antiretroviral therapy (HAART) in patients diagnosed with HIV infection. It has been shown to effectively suppress the virus, leading to significantly decreased morbidity and mortality rates. Darunavir, a HIV protease inhibitor, prevents HIV replication through binding to the enzyme, stopping the dimerization and the catalytic activity of HIV-1 protease. In particular, it inhibits the cleavage of HIV encoded Gag-Pol proteins in cells that have been infected with the virus, halting the formation of mature virus particles, which spread the infection. The close contact that darunavir makes with the primary chains of the active site amino acids (Asp-29 and Asp-30) on the protease likely contributes to its potency and efficacy against resistant variants of HIV-1. Darunavir is known to bind to different sites on the enzyme: the active site cavity and the surface of one of the flexible flaps in the protease dimer. Darunavir can adapt to changes in the shape of a protease enzyme due to its molecular flexibility. Darunavir as a protease inhibitor inhibits the cleavage of HIV encoded gag-pol polyproteins in virus infected cells, thereby preventing the formation of mature and infectious new virions. It was selected for its potency against wild type HIV-1 and HIV strains resistant to currently approved protease inhibitors. Darunavir is an inhibitor of the HIV-1 protease. It selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in infected cells, thereby preventing the formation of mature virus particles.

Pharmacodynamics

Darunavir is an inhibitor of the human immunodeficiency virus (HIV) protease, which prevents HIV viral replication. When administered with ritonavir in combination antiretroviral therapy, darunavir significantly decreases viral load and increases CD4 cell counts, decreasing the morbidity and mortality of HIV infection.