KALETRA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for KALETRA (KALETRA).
Lopinavir is an HIV protease inhibitor that prevents cleavage of viral Gag-Pol polyproteins, resulting in immature, non-infectious viral particles. Ritonavir inhibits CYP3A-mediated metabolism of lopinavir, increasing lopinavir plasma concentrations.
| Metabolism | Lopinavir is extensively metabolized by hepatic CYP3A isoenzymes. Ritonavir is also metabolized by CYP3A and acts as a potent CYP3A inhibitor. |
| Excretion | Following oral administration, approximately 82.1% of the lopinavir dose and 85.9% of the ritonavir dose are recovered in feces, with 10.4% of lopinavir and 2.2% of ritonavir recovered in urine. Biliary excretion is a major route for lopinavir. |
| Half-life | The terminal elimination half-life of lopinavir is approximately 5-6 hours when co-administered with ritonavir. In HIV-infected patients, the effective half-life is extended due to ritonavir's CYP3A4 inhibition, allowing twice-daily dosing. |
| Protein binding | Lopinavir is approximately 98-99% bound to plasma proteins, primarily alpha-1-acid glycoprotein (AAG) and albumin. |
| Volume of Distribution | The apparent volume of distribution (Vd/F) for lopinavir is approximately 0.5 L/kg, indicating extensive tissue distribution. The high Vd suggests penetration into tissues including lymph nodes and the central nervous system. |
| Bioavailability | The absolute oral bioavailability of lopinavir when co-formulated with ritonavir has not been directly determined, but the combination significantly increases lopinavir exposure. Relative to the soft gelatin capsule formulation, the tablet formulation has a bioavailability of approximately 80%. |
| Onset of Action | Oral administration: Antiviral activity begins within 2-4 hours after a dose, with peak plasma concentrations achieved approximately 4 hours post-dose. |
| Duration of Action | Twice-daily dosing maintains effective plasma concentrations above the IC50 for wild-type HIV-1 throughout the dosing interval (12 hours). The clinical duration of action is 12 hours with twice-daily administration. |
400 mg lopinavir/100 mg ritonavir (4 tablets of 100/25 mg or 2 tablets of 200/50 mg) orally twice daily with food. Alternatively, 800 mg lopinavir/200 mg ritonavir (4 tablets of 200/50 mg) orally once daily in patients with less than 3 lopinavir resistance-associated substitutions.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for renal impairment; drug is not significantly renally eliminated. However, patients with severe renal impairment should be monitored for ritonavir-associated nephrotoxicity. |
| Liver impairment | Child-Pugh Class A: No adjustment; Class B: Use with caution; reduce dose to 300 mg lopinavir/75 mg ritonavir twice daily (not recommended for once-daily dosing). Class C: Contraindicated. |
| Pediatric use | Weight-based dosing: 14 days to <6 months: 16 mg/kg lopinavir/4 mg/kg ritonavir twice daily; 6 months to <12 years: 12 mg/kg lopinavir/3 mg/kg ritonavir twice daily (max 400 mg/100 mg per dose). For children ≥12 years and >40 kg: adult dosing. |
| Geriatric use | No specific dose adjustment recommended; use with caution due to age-related decreased hepatic function and increased risk of comorbidities (e.g., QT prolongation, pancreatitis). Monitor renal function and electrolytes. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for KALETRA (KALETRA).
| Breastfeeding | Lopinavir is excreted into human breast milk at low concentrations; the milk-to-plasma (M/P) ratio is approximately 0.2 to 0.3. Ritonavir is also excreted but at very low levels. Given that HIV can be transmitted via breast milk, breastfeeding is not recommended in HIV-infected mothers regardless of antiretroviral therapy. |
| Teratogenic Risk | Kaletra (lopinavir/ritonavir) is classified as FDA Pregnancy Category C. Human data are limited; retrospective studies have not shown a significant increase in major birth defects above baseline. However, there are case reports of preterm delivery and low birth weight. Animal studies did not demonstrate teratogenicity at clinically relevant doses. Use during pregnancy is generally considered acceptable when benefit outweighs risk, especially for HIV treatment. |
■ FDA Black Box Warning
No FDA boxed warnings.
| Serious Effects |
["Hypersensitivity to lopinavir, ritonavir, or any component","Coadministration with drugs highly dependent on CYP3A clearance and for which elevated plasma levels are associated with serious events (e.g., alfuzosin, ranolazine, dronedarone, colchicine in renal/hepatic impairment, lurasidone, pimozide, triazolam, midazolam oral, ergot derivatives, amiodarone, bepridil, flecainide, propafenone, quinidine, simvastatin, lovastatin, avanafil, sildenafil for pulmonary arterial hypertension, vardenafil, St. John's wort)"]
| Precautions | ["Hepatotoxicity including transaminase elevations and clinical hepatitis","Pancreatitis","PR interval prolongation and heart block","QTc interval prolongation","Elevated cholesterol and triglycerides","New-onset diabetes mellitus or hyperglycemia","Increased bleeding in hemophiliacs","Loss of virologic response and possible resistance in patients with prior protease inhibitor therapy"] |
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| Fetal Monitoring | Monitor maternal liver function, lipid profile (triglycerides, cholesterol), glucose (risk of hyperglycemia/diabetes), and complete blood count. Fetal monitoring includes ultrasound for growth and anatomy. In third trimester, increased fetal surveillance (e.g., nonstress test) may be considered due to risk of preterm delivery. |
| Fertility Effects | No significant adverse effects on fertility have been reported in humans. Animal studies showed no impairment of fertility at doses similar to human exposure. However, HIV disease itself may affect fertility, and ART therapy may improve fertility outcomes in HIV-positive individuals. |