Dosing and uses of Kaletra (lopinavir/ritonavir)
Adult dosage forms and strengths
lopinavir/ritonavir
tablet
- 100mg/25mg
- 200mg/50mg
oral solution
- (400mg/100mg)/5mL
HIV-1 Infection
400 mg/100 mg PO q12hr, Or
800 mg/200 mg PO qDay in patients with <3 lopinavir resistance-associated substitutions
Once-daily dosing is only recommended for protease inhibitor-naïve patients and not for pregnant women or coadministration with efavirenz, nevirapine, fosamprenavir, nelfinavir, carbamazepine, phenytoin, or phenobarbitaL
Coadministration with efavirenz, nevirapine, fosamprenavir, or nelfinavir
- Protease inhibitor naive or experienced
- 500 mg/125 mg PO q12hr (ie, 2 x 200 mg/50 mg + 100 mg/25 mg), OR
- Oral solution or capsules: 533 mg/133 mg PO q12hr (ie, ~6.5 mL q12hr)
Pediatric dosage forms and strengths
lopinavir/ritonavir
tablet
- 100mg/25mg
- 200mg/50mg
oral solution
- (400mg/100mg)/5mL
HIV-1 Infection
Do not use once-daily dosing in children or adolescents (administer q12hr)
<2 weeks: Safety and efficacy not established (see cautions)
2 weeks-6 months
- PO solution: 300 mg/75 mg (LPV/r) per m² or 16 mg/4 mg LPV/r per kg PO q12hr
- Do not administer with efavirenz, nevirapine, fosamprenavir, or nelfinavir in infants aged <6 months
- Use of 300 mg/75 mg (LPV/r) per m² in infants aged <6 months associated with lower LPV trough levels than those found in adults; evaluate LPV dosing and adjusted for growth at frequent intervals
Oral solution: 6 months-18 years (not receiving concomitant efavirenz, nevirapine, fosamprenavir, or nelfinavir)
- 230 mg/57.5 mg/m² per dose PO q12hr, not to exceed 400 mg/dose of lipinavir, OR weight-based dosing listed below
- 7 to <15 kg: 12 mg/kg/dose PO q12hr based on lopinavir component
- 15-40 kg: 10 mg/kg/dose PO q12hr based on lopinavir componen; not to exceed 400 mg/100 mg PO q12hr
- >40 kg: As adults; 400 mg/100 mg PO q12hr
Oral tablets: 6 months-18 years (not receiving concomitant efavirenz, nevirapine, fosamprenavir, or nelfinavir)
- 15-20 kg or 0.6 to <0.8 m²: 200 mg/50 mg (2 tab) PO q12hr
- >20-30 kg or 0.8 to <1.2 m²: 300 mg/75 mg (3 tab) PO q12hr
- >30-45 kg or 1.2 to <1.7 m²: 400 mg/100 mg PO q12hr
- >45 kg or >1.7 m²: 400-600 mg/100-150 mg PO q12hr (use higher dose for treatment-experienced patients)
6 months-18 years (coadministered with efavirenz, nevirapine, fosamprenavir, or nelfinavir)
- 300 mg/75 mg (LPV/r)/m²/dose PO bid, not to exceed 400 mg/dose of lopinavir
- FDA-approved dose: 500 mg/125 mg LPV/r PO bid, administer as combination of 2 tab of 200/50 mg LPV/r and 1 tab of 100 mg/25 mg LPV/r
- Most NIH Panel members recommend 600 mg/150 mg LPV/r PO bid
Kaletra (lopinavir/ritonavir) adverse (side) effects
>10%
Diarrhea (7-9%)
Hyperlipidemia (3-39%)
Nausea (5-16%)
Rash (12%)
Abdominal pain (1-11%)
Nausea (5-16%)
ALT increased (1-11%)
1-10% (selected)
Headache (2-6%)
Elevated LFTs (2-10%)
Weakness (< 9%)
Hyperuricemia (< 5%)
Flatulence (1-4%)
Neutropenia (1-5%)
<1%
Stevens Johnson Syndrome
Erythema multiforme
Toxic epidermal necrolysis
Warnings
Contraindications
Hypersensitivity to ritonavir, lopinavir
Concomitant CYP3A4 inducers and/or major substrates
Drugs that are contraindicated with lopinavir/ritonavir include alpha1-adrenoreptor agonists (eg, alfuzosin), antiarrhythmics (amiodarone, bepridil, flecainide, propafenone, quinidine), rifampin, voriconazole, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, lovastatin, simvastatin, lurasidone, pimozide, sildenafil (when used for PAH), midazolam, and triazolam
Cautions
Pancreatitis reported; fatalities have occurred; suspend therapy as clinically appropriate
Risk of immune reconstitution syndrome if used with HAARt
Hepatotoxicity reported; fatalities have occurred; monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations
Total cholesterol and triglycerides elevations may occur; monitor prior to therapy and periodically thereafter
QT and PR interval prolonation and torsades de pointes have been reported rarely; do not use saquinavir/ritonavir with congenital or documented acquired QT prolongation (>450 msec), refractory hypokalemia or magnesemia, and in combination with drugs that prolong QT intervaL
Cases of second and third degree heart block reported; use with caution in patients with pre-existing conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR intervaL
Risks of fat redistribution, hemolytic anemia, hyperglycemia, hyperbilirubinemia if used in combination with other antiretroviral drugs
Increased bleeding, including spontaneous skin hematomas and hemarthrosis reported in patients with hemophilia type A and B treated with protease inhibitors; A causal relationship between protease inhibitor therapy and these events has not been established
Adverse effects reported but casual link unclear includes new-onset or worsening of DM and bleeding problems
Oral solution in newborns
- Contains alcohol 42.4% and propylene glycol
- Increased risk for toxicities (ie, serious heart, kidney, or breathing problems) in premature babies or newborns because of decreased ability to eliminate propylene glycol
- Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates
- Avoid oral solution in premature babies until PMA 42 weeks (ie, 14 days after their due date), or in full-term babies younger than 14 days of age unless a healthcare professional believes that the benefit of using Kaletra oral solution to treat HIV infection immediately after birth outweighs the potential risks
- In such cases, FDA strongly recommends monitoring for increases in serum osmolality, serum creatinine, and other signs of toxicity
Pregnancy and lactation
Pregnancy category: C
Newborn infants exposed in utero and then as neonates have an increased risk for congenital adrenal hyperplasia characterized by excessive production of 17-hydroxyproesterone (17OHP) and above-normal levels of DHEA-S; Simon A, et al. JAMA 2011;306(1):11
Lactation: unknown if distributed in breast milk; HIV+ women shouldn't breastfeed anyway
Pregnancy categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA: Information not available.
Pharmacology of Kaletra (lopinavir/ritonavir)
Mechanism of action
Protease Inhibitor; inhibits cleavage of Gag-Pol polyprotein precursors, which in turn causes the formation of immature, noninfectious viral particles.
Main antiretroviral effect due to lopinavir; ritonavir inhibits metabolism to prolong action/increase serum concentration
Pharmacokinetics
Lopinavir
- Peak Plasma Time: 4 hr
- Peak Plasma Concentration: (800 mg qDay x 4 wk): 11.8±3.7 mcg/mL
- Half-life: 5-6 hr
- Protein Bound: 98-99%
- Metabolism: CYP3A4 which is inhibited by ritonavir
- Excretion: Feces (83%); urine (10%)
Ritonavir
- Absorption: variable, with or without food
- Vd: 0.16-0.66 L/kg (high concentrations in serum & lymph nodes)
- Protein Bound: 98-99%
- Metabolism: Hepatic; five metabolites, low concentration of an active metabolite achieved in plasma (oxidative)
- Half-life: 3-5 hr
- Peak plasma time: 2 hr (oral solution)
- Excretion: Urine (11%); feces (86%)
Administration
Oral Administration
Do not administer qDay in pediatric patients <18 yr; administer q12hr
Tablets: Administer with or without food
Oral solution: Administer with food
