Drug information of Lopinavir and Ritonavir

Lopinavir and Ritonavir


Antiretroviral

Mechanism of effect

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%)

Drug indications

HIV-1 Infection

Dosage

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

(PEDIATRIC)

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 lopinavir, 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 component; 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)

  • ≥15-25 kg or ≥0.6-<0.9 m²: 200 mg/50 mg (two 100/25 mg-tab) PO q12hr
  • >25-35 kg or ≥0.9-<1.4 m²: 300 mg/75 mg (three 100/25 mg-tab) PO q12hr
  • >35 kg or ≥1.4 m²: 400 mg/100 mg PO q12hr

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,

Drug contraindications

Hypersensitivity to this drug , Concurrent use of strong CYP3A inducers

-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, dronedarone), rifampin, lomitapide, voriconazole, ergot derivatives (dihydroergotamine, ergonovine, ergotamine, methylergonovine), cisapride, St. John’s wort, lovastatin, simvastatin, lurasidone, ranolazine, pimozide, sildenafil (when used for PAH), midazolam, and triazolam, apalutamide, colchicine, elbasvir/grazoprevir

Side effects

Diarrhea , Headache , nausea , abdominal pain , asthenia , Stevens-Johnson syndrome , Increased ALT , flatulence , toxic epidermal necrolysis , Rash

Diarrhea

Hyperlipidemia

Nausea

Rash

Abdominal pain

Nausea

ALT increased

Headache

Elevated LFTs

Weakness

Hyperuricemia

Flatulence

Neutropenia

Stevens Johnson Syndrome

Erythema multiforme

Toxic epidermal necrolysis

Interactions

Aripiprazole , Alprazolam , Amlodipine , Amiodarone , Aprepitant , Erlotinib , Brentuximab , Artesunate , Blonanserin , st. john's wort , Bictegravir , Elexacaftor, Tezacaftor, and Ivacaftor , Benperidol , Dronabinol , Brexpiprazole , conivaptan , bosutinib , bedaquiline , Dasatinib , Cannabidiol , Cariprazine , Cobimetinib , Ceritinib , Cannabis , Eliglustat , Elvitegravir , Alitretinoin , Darolutamide , Entrectinib , Doxercalciferol , Clorazepate , Cabozantinib , elagolix , tezacaftor/ivacaftor , Alpelisib , Crizotinib , Avanafil , Edoxaban , Alfuzosin , Erdafitinib , Betrixaban , Duvelisib , Apalutamide , encorafenib , Cabazitaxel , Darifenacin , cobicistat , Delavirdine , Abacavir , Atovaquone , Canagliflozin , Dutasteride , Efavirenz , Copanlisib , Dabrafenib , Acalabrutinib , Eluxadoline , Dofetilide , brigatinib , Budesonide , Alosetron , Celiprolol , Almotriptan , dronedarone , eletriptan , Apixaban , Acenocoumarol , Afatinib , astemizole , Didanosine , Buprenorphine , Quinidine , codeine , Axitinib , Disulfiram , Dapoxetine , Daclatasvir , eplerenone , Ranolazine , Darunavir , cladribine , Clarithromycin , Colchicine , Clopidogrel , Clozapine , Enzalutamide , Simvastatin , Cinacalcet , Cyclosporine , Cyclophosphamide , Midazolam , Carbamazepine , Doxorubicin , Dihydroergotamine , Digoxin , Rifampin , Cisapride , Cilostazol , Drospirenone , Deferasirox , Deflazacort , Dexamethasone , Docetaxel , Domperidone , Bortezomib , Buspirone , Bosentan , Propafenone , Pimozide , Trastuzumab , Estrogen , Betamethasone , Bromocriptine , Brinzolamide , Bupropion , Budesonide

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Alerts

-Pancreatitis reported; fatalities have occurred

-Risk of immune reconstitution syndrome if used with HAART

-Hepatotoxicity reported; fatalities have occurred

-QT and PR interval prolonation and torsades de pointes have been reported rarely

-Cases of second and third degree heart block reported

-Increased bleeding, including spontaneous skin hematomas and hemarthrosis reported in patients with hemophilia type A and B treated with protease inhibitors

-New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy;

-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 , lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates

Points of recommendation

-monitor liver function before and during therapy, especially in patients with underlying hepatic disease

-Total cholesterol and triglycerides elevations may occur; monitor prior to therapy and periodically thereafter

-Risks of fat redistribution, hemolytic anemia, hyperglycemia, hyperbilirubinemia if used in combination with other antiretroviral drugs

-In such cases, FDA strongly recommends monitoring for increases in serum osmolality, serum creatinine, and other signs of toxicity

Pregnancy level

Animal studies have failed to reveal evidence of treatment-related malformations.This drug should be used during pregnancy only if clearly needed and the benefit outweighs the risk to the fetus
-Once-daily dosing is not recommended during pregnancy.
-The oral solution should not be used during pregnancy; it contains alcohol and propylene glycol.
-No dose adjustment needed during postpartum period

Breast feeding warning

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

Drug forms

Kaletra

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