lopinavir/ritonavir

General

lopinavir/ritonavir

Pronunciation:
loe-pin-a-veer/ri-toe-na-veer

Trade Name(s)

Kaletra

Ther. Class.

antiretrovirals

Pharm. Class.

protease inhibitors

metabolic inhibitors

Indications

HIV infection (in combination with other antiretrovirals).

Action

Lopinavir: Inhibits HIV viral protease.
Ritonavir: Although ritonavir has antiretroviral activity of its own (inhibits the action of HIV protease and prevents the cleavage of viral polyproteins), it is combined with lopinavir to inhibit the metabolism of lopinavir thus increasing its plasma levels.

Therapeutic Effect(s):

Increased CD4 cell counts and decreased viral load with subsequent slowed progression of HIV infection and its sequelae.

Pharmacokinetics

Absorption: Well absorbed following oral administration; food enhances absorption.

Distribution: Ritonavir: poor CNS penetration.

Protein Binding: Lopinavir: 98–99% bound to plasma proteins.

Metabolism and Excretion: Lopinavir: completely metabolized in the liver by the CYP3A isoenzyme. Ritonavir: highly metabolized by the liver by the CYP3A and CYP2D6 isoenzymes; one metabolite has antiretroviral activity; 3.5% excreted unchanged in urine.

Half-life: Lopinavir: 5–6 hr Ritonavir: 3–5 hr.

TIME/ACTION PROFILE (plasma concentrations)

ROUTE	ONSET	PEAK	DURATION
Lopinavir PO	rapid	4 hr	12 hr
Ritonavir PO	rapid	4 hr*	12 hr

*Nonfasting.

Contraindication/Precautions

Contraindicated in:

Hypersensitivity (including toxic epidermal necrolysis, Stevens-Johnson syndrome, or erythema multiforme);
Concurrent use of alfuzosin, apalutamide, colchicine, dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, lomitapide, lovastatin, lurasidone, methylergonovine, midazolam (PO), pimozide, ranolazine, sildenafil (Revatio), simvastatin, and triazolam (may result in serious and/or life-threatening events);
Concurrent use with St. John's wort or rifampin (may lead to ↓ virologic response and possible resistance);
Hypersensitivity or intolerance to alcohol or castor oil (present in liquid);
Congenital long QT syndrome, concurrent use of QT-interval prolonging drugs, or hypokalemia (↑ risk of QT interval prolongation);
OB: Not recommended in pregnancy if ≥1 lopinavir resistance-associated substitution present; once-daily regimen should not be used in pregnancy;
Lactation: Breastfeeding not recommended in women with HIV;
Pedi: Preterm infants (should be avoided until 14 days after their due date) or full-term infants <14 days old (↑ risk of toxicity from alcohol and propylene glycol in oral solution).

Use Cautiously in:

Known alcohol intolerance (oral solution contains alcohol);
Impaired hepatic function, history of hepatitis (for ritonavir content);
Pre-existing conduction system disease (marked first-degree AV block or second- or third-degree AV block), ischemic heart disease, or concurrent use of other drugs that increase the PR interval (especially those metabolized by CYP3A4, including verapamil or diltiazem);
Pedi: Children ≤6 mo (↑ risk of toxicity from alcohol and propylene glycol in oral solution); once-daily regimen should not be used in children.

Adverse Reactions/Side Effects

CV: heart block, PR interval prolongation, QT interval prolongation, TORSADES DE POINTES

Derm: ERYTHEMA MULTIFORME, rash, STEVENS JOHNSON SYNDROME, TOXIC EPIDERMAL NECROLYSIS

Endo: hyperglycemia

GI: diarrhea (↑ in children), taste aversion (in children), abdominal pain, HEPATOTOXICITY, nausea, PANCREATITIS, vomiting (↑ in children)

Neuro: headache, insomnia, weakness

Misc: immune reconstitution syndrome

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

May ↑ levels and risk of toxicity of alfuzosin, dronedarone, ergot derivatives (dihydroergotamine, ergotamine, methylergonovine ), elbasvir/grazoprevir, lomitapide, lovastatin, lurasidone, midazolam (oral), pimozide, sildenafil (Revatio), simvastatin, and triazolam ; concurrent use contraindicated.
May ↑ colchicine levels; concurrent use in patients with renal or hepatic impairment contraindicated; ↓ dose of colchicine in patients without renal or hepatic impairment.
Concurrent use of apalutamide and rifampin may ↓ levels and promote resistance; concurrent use contraindicated.
↑ risk of myopathy with atorvastatin or rosuvastatin ; use lowest possible dose of statin; do not exceed rosuvastatin dose of 10 mg/day.
Concurrent use with efavirenz or nevirapine ↓ lopinavir/ritonavir levels and effectiveness; dose ↑ recommended; once daily lopinavir/ritonavir regimen not recommended when these drugs are used.
May ↑ tenofovir and rilpivirine levels.
May ↓ abacavir, etravirine, and zidovudine levels.
Concurrent use with fosamprenavir ↓ lopinavir and fosamprenavir levels.
Concurrent use with nelfinavir ↓ lopinavir levels and ↑ nelfinavir levels; ↑ dose of lopinavir/ritonavir; once daily lopinavir/ritonavir regimen not recommended when these drugs are used.
Tipranavir ↓ lopinavir levels.
↑ maraviroc levels; maraviroc dose should be ↓ to 150 mg twice daily.
↑ levels of amiodarone, lidocaine, and quinidine (blood level monitoring recommended, if possible).
Concurrent use of carbamazepine, phenobarbital, or phenytoin may ↓ effectiveness of lopinavir (blood level monitoring recommended; once daily lopinavir/ritonavir regimen not recommended when these drugs are used); lopinavir may also ↓ phenytoin levels.
May ↓ bupropion levels/effects.
↑ levels/effects of trazodone.
↑ levels of dihydropyridine calcium channel blockers including felodipine, nifedipine, amlodipine, and nicardipine.
May alter levels and effectiveness of warfarin.
↑ levels of clarithromycin (dose ↓ recommended for patients with CCr ≤60 mL/min.
↑ levels of itraconazole, ketoconazole, and isavuconazonium ; high doses of itraconazole or ketoconazole not recommended.
↓ levels of voriconazole ; concurrent use not recommended.
↑ levels of rifabutin (dose ↓ recommended).
↓ levels of atovaquone (may require dose ↑).
May ↑ levels of bedaquiline.
Dexamethasone may ↓ levels/effectiveness of lopinavir; consider use of alternative corticosteroid, such as beclomethasone or prednisolone.
Oral solution contains alcohol, may produce intolerance when administered with disulfiram or metronidazole.
May ↑ levels and risk of toxicity with immunosuppressants including cyclosporine, tacrolimus, or sirolimus (blood level monitoring recommended).
May ↓ levels and effects of methadone (dose of methadone may need to be ↑).
May ↑ levels and effects of fentanyl ; monitor for respiratory depression.
May ↓ levels and contraceptive efficacy of some estrogen-based hormonal contraceptives, including ethinyl estradiol (alternative or additional methods of contraception recommended).
May ↑ levels of systemic, inhaled, nasal, or ophthalmic corticosteroids (betamethasone, budesonide, ciclesonide, dexamethasone, fluticasone, methylprednisolone, mometasone, prednisone, or triamcinolone ; consider alternative corticosteroid such as beclomethasone or prednisolone.
May ↑ vincristine and vinblastine levels; consider holding or switching to another antiretroviral regimen that does not contain a CYP3A or P-glycoprotein inhibitor.
May ↑ dasatinib and nilotinib levels; may need to ↓ doses of dasatinib and nilotinib.
May ↑ venetoclax and ibrutinib levels and ↑ risk of tumor lysis syndrome; avoid concurrent use.
May ↑ abemaciclib and neratinib levels and risk of toxicity; avoid concurrent use.
Concurrent use of other drugs known to ↑ PR interval may ↑ risk of heart block.
Concurrent use of other drugs known to ↑ QT interval should be avoided.
May ↑ risk of adverse effects with salmeterol ; concurrent use not recommended.
May ↑ bosentan levels; initiate bosentan at 62.5 mg once daily or every other day; if patient already receiving bosentan, discontinue bosentan at least 36 hr before initiation of lopinavir/ritonavir and then restart bosentan at least 10 days later at 62.5 mg once daily or every other day.
May ↑ levels of sildenafil (Viagra), vardenafil, tadalafil (Cialis) or avanafil ; may result in hypotension, syncope, visual changes, and prolonged erection (↓ dose of sildenafil to 25 mg every 48 hr, vardenafil to 2.5 mg every 72 hr, and tadalafil to 10 mg every 72 hr recommended; do not use with avanafil).
May ↑ tadalafil (Adcirca) levels; initiate tadalafil (Adcirca) at 20 mg once daily; if patient already receiving tadalafil (Adcirca), discontinue tadalafil (Adcirca) at least 24 hr before initiation of tipranavir and then restart tadalafil (Adcirca) at least 7 days later at 20 mg once daily.
May ↑ levels of, glecaprevir/pibrentasvir, and sofosbuvir/velpatasvir/voxilaprevir, ombitasvir, and paritaprevir ; avoid concurrent use
May ↓ levels of valproate and lamotrigine ; may need to ↑ dose of valproate or lamotrigine
May ↑ levels of rivaroxaban ; avoid concurrent use
May ↑ quetiapine levels; ↓ quetiapine dose to ⅙ of current dose
Encorafenib and ivosidenib may ↑ risk of QT interval prolongation; avoid concurrent use, if possible. If concurrent use necessary, ↓ dose of encorafenib and ivosidenib.
Concurrent use with elagolix may ↑ elagolix levels and ↓ ritonavir levels; do use with elagolix 200 mg twice daily for longer than 1 mo; do not use with elagolix 150 mg once daily for longer than 6 mo.
May ↑ levels of active metabolite of fostamatinib, which can ↑ risk of hepatotoxicity and neutropenia; may need to ↓ dose of fostamatinib.

Drug-Natural Products:

St. John's wort may ↓ levels and promote resistance; concurrent use contraindicated.

Route/Dosage

Without Concurrent Efavirenz, Nevirapine, or Nelfinavir

PO (Adults): Patients with <3 lopinavir resistance-associated substitutions: 400/100 mg (two 200/50-mg tablets or 5 mL oral solution) twice daily or 800/200 mg (four 200/50-mg tablets or 10 mL oral solution) once daily; Patients with ≥3 lopinavir resistance-associated substitutions: 400/100 mg (two 200/50-mg tablets or 5 mL oral solution) twice daily; Pregnant women with no lopinavir resistance-associated substitutions: 400/100 mg (two 200/50-mg tablets) twice daily; Pregnant women with ≥1 lopinavir resistance-associated substitution: Not recommended.

PO (Children 14 days–6 mo): Oral solution: 16/4 mg/kg lopinavir/ritonavir content twice daily.

PO (Children ≥6 mo and <15 kg): Oral solution: 12/3 mg/kg lopinavir/ritonavir twice daily.

PO (Children ≥6 mo and 15–40 kg): Oral solution: 10/2.5 mg/kg lopinavir/ritonavir twice daily.

PO (Children ≥6 mo): Tablets: 15–25 kg: 200/50 mg (two 100/25-mg tablets) twice daily; 26–35 kg: 300/75 mg (three 100/25-mg tablets) twice daily; >35 kg: 400/100 mg (four 100/25-mg tablets or two 200/50-mg tablets) twice daily.

With Concurrent Efavirenz, Nevirapine, or Nelfinavir

PO (Adults): Therapy-naive or therapy-experienced: 500/125 mg (two 200/50-mg tablets and one 100/25-mg tablet or 6.5 mL oral solution) twice daily.

PO (Children 14 days–6 mo): Not recommended for concomitant administration with these drugs.

PO (Children ≥6 mo and <15 kg): Oral solution: 13/3.25 mg/kg lopinavir/ritonavir twice daily.

PO (Children ≥6 mo and 15–45 kg): Oral solution: 11/2.75 mg/kg lopinavir/ritonavir twice daily.

PO (Children ≥6 mo): Tablets: 15–20 kg: 200/50 mg (two 100/25-mg tablets) twice daily; 21–30 kg: 300/75 mg (three 100/25-mg tablets) twice daily; 31–45 kg: 400/100 mg (four 100/25-mg tablets or two 200/50-mg tablets) twice daily.

Availability (generic available)

Tablets: lopinavir 100 mg/ritonavir 25 mg, lopinavir 200 mg/ritonavir 50 mg

Oral solution: lopinavir 80 mg/ritonavir 20 mg per mL (contains 42.4% alcohol)

Assessment

Assess for change in severity of HIV symptoms and for symptoms of opportunistic infections during therapy.
Assess patient for signs of pancreatitis (nausea, vomiting, abdominal pain, increased serum lipase or amylase) periodically during therapy. May require discontinuation of therapy.
Assess patient for rash (mild to moderate rash usually occurs in the 2nd wk of therapy and resolves within 1–2 wk of continued therapy). If rash is severe (extensive erythematous or maculopapular rash with moist desquamation or angioedema) or accompanied by systemic symptoms (serum sickness-like reaction, Stevens-Johnson syndrome, toxic epidermal necrolysis), therapy must be discontinued immediately.

Lab Test Considerations:

Monitor viral load and CD4 counts regularly during therapy.

Monitor triglyceride and cholesterol levels prior to initiating therapy and periodically during therapy.
May cause hyperglycemia.
Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis B and hepatitis C, or marked transaminase elevations. May cause ↑ serum AST, ALT, GGT, and total bilirubin concentrations.
Monitor serum lipase and amylase levels during therapy.
Monitor blood glucose during therapy. May cause hyperglycemia.

Implementation

Do not confuse Kaletra with Keppra.
PO Tablets may be administered with or without food. DNC: Swallow whole, do not break, crush, or chew.
- Oral solution must be taken with food. Oral solution is light yellow to orange. Solution is stable if refrigerated until expiration date on label or 2 mo at room temperature. Oral solution should be avoided in premature babies until 14 days after their due date, or in full-term babies younger than 14 days of age unless a health care professional believes that the benefit of using Kaletra oral solution to treat HIV infection immediately after birth outweighs the potential risks. If oral solution is used in babies younger than 14 days, monitor for increases in serum osmolality, serum creatinine, and other signs of toxicity.
- Feeding Tube: Oral solution contains ethanol and propylene glycol. Use only compatible feeding tubes (silicone and polyvinyl chloride); avoid use with polyurethane feeding tubes due to potential incompatibility. Follow instructions for use of the feeding tube to administer the medicine.

Patient/Family Teaching

Emphasize the importance of taking lopinavir/ritonavir as directed, at evenly spaced times throughout day. Do not take more than prescribed amount, and do not stop taking this or other antiretrovirals without consulting health care professional. Take missed doses as soon as remembered; do not double doses. Advise patient to read the Patient Information prior to taking this medication and with each Rx refill in case of changes.
Instruct parent/patient to measure oral solution carefully.
Instruct patient that lopinavir/ritonavir should not be shared with others.
Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's wort.
Inform patient that lopinavir/ritonavir does not cure HIV or prevent associated or opportunistic infections. Lopinavir/ritonavir may reduce the risk of transmission of HIV to others through sexual contact or blood contamination. Caution patient to use a condom during sexual contact and to avoid sharing needles or donating blood to prevent spreading HIV to others. Advise patient that the long-term effects of lopinavir/ritonavir are unknown at this time.
Instruct patient to notify health care professional immediately if rash, symptoms of lactic acidosis (tiredness or weakness, unusual muscle pain, trouble breathing, stomach pain with nausea and vomiting, cold especially in arms or legs, dizziness, fast or irregular heartbeat) or if signs of hepatotoxicity (yellow skin or whites of eyes, dark urine, light-colored stools, lack of appetite for several days or longer, nausea, abdominal pain) occur.
Inform patient that lopinavir/ritonavir may cause hyperglycemia. Advise patient to notify health care professional if increased thirst or hunger; unexplained weight loss; or increased urination occurs.
Caution patients taking sildenafil, vardenafil, or tadalafil of increased risk of associated side effects (hypotension, visual changes, sustained erection). Notify health care professional promptly if these occur.
Inform patient that redistribution and accumulation of body fat may occur, causing central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and cushingoid appearance. The cause and long-term effects are not known.
Rep: May cause fetal harm. Advise patients taking oral contraceptives to use a nonhormonal method of birth control during lopinavir/ritonavir therapy. Instruct patient to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding. Inform pregnant women exposed to lopinavir/ritonavir of pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Kaletra during pregnancy. Enroll patient in the Antiviral Pregnancy Registry by calling 1-800-258-4263 to monitor maternal/fetal outcomes.
Emphasize the importance of regular follow-up exams and blood counts to determine progress and monitor for side effects.

Evaluation/Desired Outcomes

Delayed progression of AIDS and decreased opportunistic infections in patients with HIV.
Decrease in viral load and improvement in CD4 cell counts.