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

  • 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 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

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 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)

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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