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 (with other antiretrovirals).

Action

  • Inhibits HIV viral protease.
  • 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 cytochrome P450 3A (CYP450 3A); ritonavir is a potent inhibitor of this enzyme.  Ritonavir– highly metabolized by the liver (by CYP450 3A and CYP2D6 enzymes); one metabolite has antiretroviral activity; 3.5% excreted unchanged in urine.

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

TIME/ACTION PROFILE (blood levels)

ROUTEONSETPEAKDURATION
Lopinavir POrapid4 hr12 hr
Ritonavir POrapid4 hr*12 hr
*Non-fasting.

Contraindication/Precautions

Contraindicated in:

  • Hypersensitivity (including toxic epidermal necrolysis, Stevens-Johnson syndrome, or erythema multiforme);
  • Concurrent use of alfuzosin, colchicine, dihydroergotamine, dronedarone, elbasvir/grazoprevir, ergotamine, lomitapide, lovastatin, lurasidone, methylergonovine, midazolam (PO), pimozide, ranolazone, 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;
  • Lactation: Breast feeding not recommended in HIV-infected patients;
  • 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);
  • OB:  Once daily regimen should not be used in pregnancy;
  • Pedi:   Children ≤6 mo (↑ risk of toxicity from alcohol and propylene glycol in oral solution); should not be used once daily in children.

Adverse Reactions/Side Effects

CNS: headache, insomnia, weakness

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

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

Endo: hyperglycemia

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

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  Rifampin  ↓ levels and effectiveness; 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.
  •  Delavirdine  ↑ lopinavir levels.
  • 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.
  • ↑  indinavir  levels; indinavir dose should be ↓.
  • ↑  saquinavir  levels.
  •  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 tipranavir 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 q 48 hr, vardenafil to 2.5 mg q 72 hr, and tadalafil to 10 mg q 72 hr recommended; do not use with avanafil).
  • May ↑  tadalafil (Adcirca)  levels; initiate tadalafil (Adcirca) at 20 mg once daily; if patient already receiving tadalfil (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

Drug-Natural Products:

Concurrent use with  St. John's wort  may ↓ levels and beneficial effect of lopinavir/ritonavir (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 k g: 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)

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

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

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.

Potential Diagnoses

Implementation

  • Do not confuse Kaletra (lopinavir/ritonavir) with Keppra (levetiracetam).
    • Patients taking didanosine with  Kaletra  solution should take didanosine 1 hr before or 2 hr after taking lopinavir/ritonavir.
  • PO  Tablets may be administered with or without food. 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 (PVC)); 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 AIDS or prevent associated or opportunistic infections. Lopinavir/ritonavir does not 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 the AIDS virus 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:  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 breast feeding. Encourage pregnant women exposed to lopinavir/ritonavir to enroll 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.
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