Lopinavir + Ritonavir

Approved Indications:

• HIV-1 Infection (in combination with other antiretroviral agents):
• Indicated for the treatment of HIV-1 infection in adults and pediatric patients aged 14 days and older.
• Suitable for both treatment-naïve and treatment-experienced patients.

Clinically Accepted Off-Label Uses:

• Post-Exposure Prophylaxis (PEP) for HIV:
• Used as part of a combination regimen following potential HIV exposure (e.g., occupational or sexual).
• COVID-19 (Investigational Use):
• Previously studied during the COVID-19 pandemic; however, current guidelines do not recommend its use due to lack of efficacy.

Adults (≥18 years):

• Standard Dose (Tablets):
• 400 mg Lopinavir + 100 mg Ritonavir (2 tablets) twice daily.
• Alternative Dose for Treatment-Naïve Patients:
• 800 mg/200 mg once daily.
• Oral Solution:
• 5 mL (400 mg/100 mg) twice daily with food.

Pediatric Patients (14 days to 18 years):

• Dosage based on body weight or body surface area (BSA).
• BSA-Based Dosing Example:
• 230 mg/m² of Lopinavir + 57.5 mg/m² of Ritonavir twice daily.
• Do not exceed adult maximum dose.

Elderly:

• No specific dose adjustment required; use with caution and monitor hepatic and renal function.

Renal Impairment:

• No dosage adjustment necessary, but clinical monitoring is advised.

Hepatic Impairment:

• Use with caution in mild to moderate impairment.
• Contraindicated in severe hepatic impairment.

Route of Administration: Oral.
Administration Instructions:

• Tablets should be swallowed whole (not crushed, broken, or chewed).
• Oral solution should be taken with food.

Lopinavir is an HIV-1 protease inhibitor that blocks the cleavage of the Gag-Pol polyprotein, preventing the formation of mature infectious viral particles. Ritonavir, also a protease inhibitor, is included at a low dose to inhibit cytochrome P450 3A4 (CYP3A4) enzymes, thereby boosting plasma concentrations of Lopinavir. This pharmacokinetic enhancement improves antiviral efficacy by increasing the half-life and systemic exposure of Lopinavir. The combination leads to sustained suppression of viral replication.

• Absorption: Oral bioavailability of Lopinavir is significantly increased by co-administration with Ritonavir and when taken with food.
• Time to Peak Concentration: Approximately 4 hours (tablet), 5 hours (solution).
• Protein Binding: Lopinavir ~98–99%; Ritonavir ~98–99%.
• Metabolism:
• Lopinavir: Extensively metabolized by CYP3A4.
• Ritonavir: Metabolized by CYP3A4 and CYP2D6.
• Half-Life:
• Lopinavir: 5 to 6 hours.
• Ritonavir: 3 to 5 hours.
• Excretion:
• Lopinavir: ~82% in feces, <2% in urine.
• Ritonavir: ~86% in feces, ~11% in urine.

Pregnancy:

• FDA Pregnancy Category C.
• Use during pregnancy only if the potential benefit justifies the potential risk.
• Often used as part of antiretroviral therapy in pregnant women under expert supervision.

Lactation:

• Lopinavir and Ritonavir are excreted in breast milk in small amounts.
• Breastfeeding is not recommended in HIV-infected mothers due to risk of postnatal HIV transmission.

Summary: Use in pregnancy and lactation only under clinical supervision. Avoid breastfeeding in HIV-positive mothers.

• Primary Class: Antiretroviral Agent
• Subclass: Protease Inhibitor (PI) Combination
• Pharmacokinetic Enhancer: Ritonavir boosts the plasma level of Lopinavir via CYP3A4 inhibition.

• Known hypersensitivity to Lopinavir, Ritonavir, or any excipients.
• Severe hepatic impairment.
• Co-administration with drugs highly dependent on CYP3A4 for clearance and associated with serious or life-threatening reactions, such as:
• Astemizole, terfenadine, cisapride, pimozide, ergot derivatives, lovastatin, simvastatin, triazolam, midazolam (oral).
• Concurrent use with St. John's Wort.

• Hepatotoxicity: Monitor liver enzymes regularly, especially in patients with hepatitis B/C or liver disease.
• Pancreatitis: Discontinue if clinical signs or elevated amylase/lipase levels occur.
• Cardiac Effects: May cause PR and QT prolongation. Caution in patients with conduction abnormalities.
• Metabolic Effects: Monitor lipids and glucose due to risk of hyperlipidemia and hyperglycemia.
• Immune Reconstitution Syndrome: May reveal latent opportunistic infections upon initiation.
• Hemophilia: Increased bleeding episodes reported.
• Oral Solution Warning: Contains ethanol and propylene glycol—use with caution in infants, pregnant women, and patients with hepatic dysfunction.

Common:

• Gastrointestinal: Diarrhea, nausea, vomiting, abdominal pain
• Metabolic: Hypertriglyceridemia, hypercholesterolemia
• General: Headache, fatigue

Less Common:

• Rash, taste disturbances, elevated liver enzymes

Serious/Rare:

• Pancreatitis
• Hepatotoxicity
• PR and QT interval prolongation (arrhythmia risk)
• Immune reconstitution inflammatory syndrome
• Anemia or neutropenia (especially in pediatric patients)

Severity & Onset:

• Most adverse effects are mild to moderate and occur within the first few weeks of treatment.

Major Drug-Drug Interactions:

• CYP3A4 Inhibitors/Inducers:
• May significantly increase or decrease Lopinavir/Ritonavir levels.
• Contraindicated Drugs:
• Simvastatin, lovastatin, rifampin, St. John’s Wort, ergot alkaloids, oral midazolam, triazolam.
• Hormonal Contraceptives:
• Reduced efficacy due to enzyme induction—alternative contraception recommended.
• Warfarin:
• May alter INR—monitor closely.

Food & Alcohol:

• Take with food to improve absorption.
• Avoid alcohol, particularly with the oral solution due to high ethanol content.

• COVID-19:
• As per WHO and NIH, Lopinavir/Ritonavir is no longer recommended for COVID-19 due to lack of clinical efficacy.
• HIV Treatment Guidelines (WHO, DHHS, EACS):
• Still used in certain second-line or pediatric regimens.
• Not first-line in most adult treatment-naïve patients due to pill burden and side effects.
• Packaging and Formulation:
• Oral solution reformulated for improved safety in pediatric use.

Tablets:

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep in original container.

Oral Solution:

• Store refrigerated at 2°C to 8°C (36°F to 46°F).
• If refrigeration is not possible, can be stored at room temperature (≤25°C) for up to 2 months.
• Shake well before use.
• Do not freeze.
• Keep away from direct sunlight.