Lopinavir + ritonavir

Oral
HIV-1 infection
Adult: Available preparations: Lopinavir 100 mg and ritonavir 25 mg tab Lopinavir 200 mg and ritonavir 50 mg tab Lopinavir 80 mg and ritonavir 20 mg per mL oral solution In combination with other antiretroviral agents (without efavirenz, nevirapine, or nelfinavir): 400 mg/100 mg bid. Alternatively, 800 mg/200 mg may be given once daily (limited to patients having <3 mutations to protease inhibitor; not recommended in patients receiving carbamazepine, phenobarbital, or phenytoin). In combination with other antiretroviral agents, with efavirenz, nevirapine or nelfinavir): As tab: 500 mg/125 mg bid. As oral solution: 520 mg/130 mg (6.5 mL) bid; once-daily dosing is not recommended.
Child: W/ other antiretrovirals: As soln: W/o efavirenz, nevirapine, or nelfinavir: 2 wk to 6 mth 16 mg/4 mg/kg (0.2 mL/kg) or 300 mg/75 mg/m² bid. >6 mth to 18 yr 7-<15 kg: 12 mg/3 mg/kg or 230 mg/57.5 mg/m² bid; 15-40 kg: 10 mg/5 mg/kg or 230 mg/57.5 mg/m² bid. W/ efavirenz, nevirapine, or nelfinavir: 300 mg/75 mg/m² bid (Max: 533 mg/133 mg or 6.5 mL bid). As 100/25 mg tab: ≥2 yr W/o efavirenz, nevirapine, or nelfinavir: 15-25 kg or BSA ≥0.5-<0.9 m²: 200 mg/50 mg bid; >25-35 kg or BSA ≥0.9-<1.4 m²: 300 mg/75 mg bid; >35-40 mg or BSA ≥1.4 m²: 400 mg/100 mg bid. As 100 mg/25 mg or 200/50 mg tab: W/ efavirenz, nevirapine, or nelfinavir): BSA ≥0.5-<0.8 m²: 200 mg/50 mg bid; ≥0.8-<1.2 m²: 300 mg/75 mg bid; ≥1.2-<1.4 m²: 400 mg/100 mg bid; ≥1.4 m²: 500 mg/125 mg bid.
Hepatic impairment: Severe: Contraindicated.

Cap & oral soln: Should be taken with food.
Tab: May be taken with or without food. Swallow whole, do not chew/crush/break.

Hypersensitivity. Congenital long QT syndrome. Severe hepatic impairment. Lactation. Concomitant use with drugs which are highly dependent on CYP3A for clearance and for which increased plasma concentrations are associated with serious or life-threatening reactions (e.g. alfuzosin, ergot alkaloids), or with potent inducers of CYP3A4 where significantly reduced lopinavir concentration may be associated with potential loss of virologic response. (e.g. rifampicin, St John's wort).

Patient with diabetes, haemophilia A or B, current or history of pancreatitis, underlying structural heart disease, ischaemic heart disease, cardiomyopathies, hepatitis B, C or cirrhosis. Mild to moderate hepatic impairment. Children. Pregnancy (once-daily dosing not recommended; avoid use of oral solution). Monitoring Parameters Monitor LFT, electrolytes, viral load, CD4 count, and glucose levels. Obtain triglyceride and cholesterol level prior to initiation, then periodically thereafter.

Significant: Altered cardiac conduction, fat redistribution, increased cholesterol, elevated AST/ALT, haemophilia, hepatitis or exacerbation of existing hepatic dysfunction, hypertriglyceridaemia, immune reconstitution inflammatory syndrome, osteonecrosis. Blood and lymphatic system disorders: Anaemia, leucopenia, neutropenia, lymphadenopathy. Gastrointestinal disorders: Diarrhoea, nausea, vomiting, GERD, gastroenteritis, colitis, abdominal pain or distention, dyspepsia, haemorrhoids, flatulence. General disorders and administration site conditions: Fatigue, asthenia. Metabolism and nutrition disorders: Blood glucose disorder, decreased weight. Musculoskeletal and connective tissue disorders: Myalgia, musculoskeletal pain, (e.g. weakness, spasms). Nervous system disorders: Headache, neuropathy, dizziness. Psychiatric disorders: Anxiety, insomnia. Reproductive system and breast disorders: Decreased libido, erectile dysfunction, menstrual disorders. Respiratory, thoracic and mediastinal disorders: Respiratory tract infection. Skin and subcutaneous tissue disorders: Rash, dermatitis. Vascular disorders: Hypertension.
Potentially Fatal: Hypersensitivity (e.g. angioedema, bronchospasm, erythema multiforme; rarely, anaphylaxis, Stevens-Johnson syndrome). Hepatotoxicity, pancreatitis, QT interval prolongation, torsade de pointes. cardiogenic shock.

Co-administration with other drugs that are primarily metabolised by CYP3A (e.g. dihydropyridine Ca channel blockers, rosuvastatin, immunosuppressants) may result in increased plasma concentrations of the other drugs that could increase or prolong their therapeutic and adverse effects.
Potentially Fatal: Increases the plasma concentration of ranolazine, amiodarone, dronedarone, alfuzosin, colchicine (when used in patients with renal and/or hepatic impairment), astemizole, terfenadine, lurasidone, pimozide, quetiapine, ergot alkaloids, cisapride, lovastatin, simvastatin, sildenafil or tadalafil (when used for the treatment of pulmonary arterial hypertension), oral midazolam, triazolam, fusidic acid, elbasvir grazoprevir, resulting to serious or life-threatening events. Concomitant use with potent CYP3A inhibitors (e.g. rifampicin) may result in suboptimal antiretroviral concentrations leading to loss of virologic response and development of resistance.

Increased bioavailability with high fat meal (oral solution). Decreased plasma concentration and reduced clinical effects with St John's wort, avoid combination.

Lopinavir and ritonavir are both inhibitors of HIV protease. Viral resistance develops rapidly when HIV protease inhibitors are given alone and therefore they are used with other antiretrovirals. Lopinavir mainly provides the antiviral activity by preventing the cleavage of the Gag-Pol polyprotein precursors into individual functional proteins. This leads to the formation of immature, non-infectious viral particles. Ritonavir enhances lopinavir activity by inhibiting its CYP3A-mediated metabolism, thus increasing plasma levels of lopinavir. Ritonavir dosage in the fixed combination is only sufficient to inhibit CYP3A, hence lopinavir is the active ingredient for antiretroviral activity.
Absorption: Lopinavir: Rapidly absorbed from the gastrointestinal tract. Increased bioavailability with high fat meals (oral solution). Time to peak plasma concentration: 4 hours. Ritonavir: Increased absorption with food. Time to peak plasma concentration: Oral solution: 2 hours (fasted); 4 hours (nonfasted).
Distribution: Lopinavir: Plasma protein binding: 98-99%, binds to both α₁ glycoprotein and albumin. Ritonavir: High concentrations in serum and lymph nodes. Enters breast milk. Volume of distribution: 0.41 ± 0.25 L/kg. Plasma protein binding: 98-99%.
Metabolism: Lopinavir: Extensively metabolised in the liver mainly via oxidation by CYP3A4 enzyme to 13 metabolites. Ritonavir: Metabolised in the liver by CYP3A4 and CYP2D6 into 5 metabolites.
Excretion: Lopinavir: Mainly via faeces (83%, 20% as unchanged drug); urine (10%, <3% as unchanged drug). Elimination half-life: 5-6 hours. Ritonavir: Mainly via faeces (approx 86%, with approx 34% as unchanged drug); via urine (approx 11%, with approx 4% as unchanged drug). Elimination half-life: 3-5 hours.

Oral: Tab: Store between 20-25°C. Oral solution: Store between 2-8°C. Protect from excessive heat.

Antivirals

J05AE03 - ritonavir ; Belongs to the class of protease inhibitors. Used in the systemic treatment of viral infections.