Ritonavir + Lopinavir

Indications

Ritonavir + Lopinavir is used for: HIV infection

Adult Dose

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)

Child Dose

HIV-1 Infection Do not use once-daily dosing in children or adolescents (administer q12hr) <2 weeks: Safety and efficacy not established 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

Renal Dose

Administration

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

Contra Indications

Hypersensitivity. Avoid concomitant use with ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, pimozide, and sedatives (midazolam, triazolam).

Precautions

Pancreatitis, hepatic impairment, haemophilia. Pregnancy, lactation, elderly, child <6 mth. Lactation: unknown if distributed in breast milk; HIV+ women shouldn't breastfeed anyway

Pregnancy-Lactation

Pregnancy Available data from the Antiretroviral Pregnancy Registry show no difference in risk of overall major birth defects compared to background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP); no treatment-related malformations observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses 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 Contraception Therapy may reduce efficacy of combined hormonal contraceptives; advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception Lactation The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1; because of potential for HIV transmission (in HIV-negative infants), developing viral resistance (in HIV-positive infants), and adverse reactions in breastfed infant, instruct mothers not to breastfeed if they are receiving therapy

Interactions

Ritonvir ....Decreased plasma conc with phenobarbital, carbamazepine, dexamethasone, phenytoin, rifabutin and rifampicn. Increased plasma conc of certain drugs highly metabolized by CYP3A. May increase serum levels of sildenafil. Potentially Fatal: Avoid concurrent admin of oral solution (contains alcohol) with disulfiram or metronidazole. Increased risk of myopathy when used with simvastatin or lovastatin. Concurrent use with alfuzosin may lead to serious hypotension. Increased risk of cardiac arrhythmias when used with amiodarone, cisapride, propafenone, quinidine, flecainide and pimozide. Risk of acute ergot toxicity when used with ergot derivatives. Increased risk of serious adverse reactions when used with midazolam or triazolam. Lopinavir....Most interactions reported with lopinavir are due to its combination with the potent inhibitor of CYP3A4 ritonavir. Lopinavir levels may be decreased by CYP3A4 inducers such as efavirenz, nevirapine, amprenavir, nelfinavir, rifampicin, phenytoin. Lopinavir level are increased by CYP3A4 inhibitors such as valproate and rifabutin. Potentially Fatal: Severe myelosuppression reported with paclitaxel.

Adverse Effects

Side effects of Ritonavir + Lopinavir : >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

Mechanism of Action

Lopinavir inhibits HIV protease, causing the enzyme incapable of processing the polyprotein precursor. This leads to the production of non-infectious and immature HIV particles. Ritonavir, a selectively competitive reversible inhibitor of HIV protease, interferes with the formation of essential proteins and enzymes. After which, the formation of immature and non-infectious viruses follows. It also interferes with the production of infectious HIV and limits further infectious spread of the virus.