Lopinavir and Ritonavir (Systemic)
VA CLASSIFICATION
Primary: AM830
Commonly used brand name(s): Kaletra.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Antiviral (systemic) —
Indications
Accepted
Human immunodeficiency virus (HIV) infection (treatment) —The combination of lopinavir and ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-infection{01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
Lopinavir: 628.8{01}
Ritonavir: 720.95{01}
Solubility
Lopinavir: Freely soluble in methanol and ethanol, soluble in isopropanol, and practically insoluble in water.{01}
Mechanism of action/Effect:
Lopinavir: Lopinavir inhibits the human immunodeficiency virus (HIV) protease and prevents cleavage of the Gag-Pol polyprotein, thus reducing the probability of viral particles reaching a mature, infectious state.{01}The antiviral activity of the combination product is due to the lopinavir component.{01}
Ritonavir: Ritonavir acts to increase plasma levels of lopinavir by inhibiting the CYP3A-mediated metabolism of lopinavir.{01}
Absorption:
The absorption of the combination of lopinavir and ritonavir is favorably affected by the presence of food. Administration with a high fat meal increases the area under the curve (AUC) of lopinavir by 97% and the maximum concentration (Cmax) by 43% for the capsules and by 130% and 56%, respectively, for the oral solution relative to administration during a fasting state.{01}
Protein binding:
Lopinavir: Very high (98–99%); predominantly to alpha-1-acid glycoprotein and albumin.{01}
Biotransformation:
The combination of lopinavir and ritonavir has been shown to inhibit CYP2D6 in vitro, but to a lesser extent than CYP3A. It does not inhibit CYP2C9, CYP2C19, CYP2E1, CYP2B6, or CYP1A2 at clinically relevant concentrations.{01}
Lopinavir: Extensively metabolized by CYP3A to at least 13 oxidative metabolites.{01}
Ritonavir: Has been shown to induce its own metabolism; furthermore, it is a potent CYP3A inhibitor, resulting in increased plasma levels of lopinavir.{01}
Half-life:
Lopinavir: 5–6 hours.{01}
Time to peak concentration:
Lopinavir: 4 hours following multiple doses of 400 mg of lopinavir and 100 mg of ritonavir for 3 to 4 weeks in HIV-positive patients.{01}
Peak plasma concentration:
Lopinavir: 9.6± 4.4 micrograms per mL following multiple doses of 400 mg of lopinavir and 100 mg of ritonavir for 3 to 4 weeks in HIV-positive patients.{01}
Elimination:
Following a single dose of 400 mg of lopinavir and 100 mg of ritonavir —
Fecal: 82.6 ± 2.5 % accounted for after 8 days.{01}
Renal: 10.4 ± 2.3% accounted for after 8 days.{01}
Precautions to Consider
Carcinogenicity
Lopinavir and Ritonavir: Long-term studies in animals have not been completed.{01}
Ritonavir: Incidences of both adenomas and combined adenomas and carcinomas in the liver increased with increasing doses (50, 100, or 200 mg per kg of body weight [mg/kg] per day) of ritonavir in male mice. The highest dose was approximately 4 times greater than the maximum recommended human dose. No carcinogenic effects were seen in female mice given doses as high as 9 times the recommended human dose or in rats given 7, 15, or 30 mg/kg per day.{01}
Mutagenicity
Neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in the Ames bacterial reverse mutation assay using S. typhimuriumand E. coli, the mouse lymphoma assay, and the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.{01}
Pregnancy/Reproduction
Fertility—
Neither male nor female rats experienced any effects on fertility following lopinavir/ritonavir doses of 10/5, 30/15, or 100/50 mg/kg per day (the exposures at high doses were approximately 0.7–fold for lopinavir and 1.8–fold for ritonavir of the exposures in humans at the recommended therapeutic dose).{01}
Pregnancy—
Studies in humans have not been done.{01}
Early reabsorption, decreased fetal viability, decreased fetal body weight, and increased incidence of skeletal variations and skeletal ossification delays were seen in rats given a maternally toxic dosage of 100/50 mg/kg per day of lopinavir and ritonavir (the exposures in rats were approximately 0.7–fold for lopinavir and 1.8–fold for ritonavir of the exposures in humans at the recommended therapeutic dose).{01} Developmental toxicity manifested as a decrease in survival of rat pups between birth and postnatal day 21 was seen in rats at doses of 40/20 mg/kg per day.{01} In contrast, no embryonic or fetal developmental toxicities were seen in rabbits given maternally toxic doses of 80/40 mg/kg per day (approximately 0.6 and 1 time the recommended human dose of lopinavir and ritonavir, respectively).{01}
FDA Pregnancy Category C{01}
Breast-feeding
It is not known whether lopinavir and ritonavir is distributed in human milk. However, lopinavir has been shown to be distributed in rat milk.{01} Because of both the potential for HIV transmission and the potential for serious adverse effects in nursing infants, mothers should be instructed not to breast-feed if they are taking the combination of lopinavir and ritonavir.{01}
The Centers for Disease Control and Prevention recommend that HIV-infected mothers refrain from breast-feeding their infants to avoid risking postnatal transmission of HIV.{01}
Pediatrics
No information is available on the relationship of age to the effects of lopinavir and ritonavir in pediatric patients up to 6 months of age. Safety and efficacy have not been established.{01}
Appropriate studies performed to date have not demonstrated pediatrics-specific problems that would limit the usefulness of lopinavir and ritonavir in children 6 months to 12 years of age.{01}
Geriatrics
No information is available on the relationship of age to the effects of lopinavir and ritonavir in geriatric patients{01}.
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Abacavir or
Zidovudine (lopinavir and ritonavir may induce glucuronidation, thus reducing the plasma concentration of abacavir or zidovudine; clinical significance is unknown{01})
» Amiodarone or
» Bepridil or
» Lidocaine (systemic) or
» Quinidine (concentrations of antiarrhythmics may be increased, caution is warranted; therapeutic monitoring of antiarrhythmic concentration may be necessary{01})
Amprenavir or
Indinavir or
Saquinavir ( concomitant use may result in decreased peak plasma concentrations of amprenavir and indinavir and increased trough concentrations of amprenavir, indinavir, and saquinavir;{01} however, the clinical significance of these changes is not known{01})
» Astemizole or
» Cisapride or
» Flecainide or
» Pimozide or
» Propafenone or
» Terfenadine ( may cause serious and/or life threatening cardiac arrhythmias; concomitant use is contraindicated{01})
Atovaquone (atovaquone concentration may be decreased; increase in atovaquone dose may be required; clinical significance is unknown{01})
» Atorvastatin or
» Cerivastatin or
» Lovastatin or
» Simvastatin (concentration of lipid lowering agents is increased; dose of atorvastatin or cerivastatin should be lowered to the lowest possible level when used in combination with lopinavir and ritonavir; consider using pravastatin or fluvastatin{01})
(concomitant use of lovastatin or simvastatin with lopinavir and ritonavir may result in serious reactions such as myopathy, including rhabdomyolysis; concomitant use is not recommended{01})
» Carbamazepine or
» Dexamethasone or
» Phenobarbital or
» Phenytoin (concentration of lopinavir may be decreased with concurrent use, resulting in decreased effectiveness of lopinavir; caution is warranted{01})
» Clarithromycin (concentration of clarithromycin may be increased with concomitant administration; for patients with renal impairment, the dosage should be adjusted as follows: for creatinine clearance (CLCR) 30 to 60 mL/min, clarithromycin dose should be reduced by 50%; for CL CR<30 mL/min, the dose of clarithromycin should be reduced by 75%; no dosage adjustment is required in patients with normal renal function{01})
» Cyclosporine or
» Sirolimus or
» Tacrolimus ( concentrations of the immunosuppressants cyclosporine, sirolimus, and tacrolimus may be increased if administered concomitantly with lopinavir and ritonavir; therapeutic monitoring of immunosuppressant levels is recommended{01})
Delavirdine (lopinavir concentrations may be increased; appropriate doses of lopinavir and ritonavir when used concomitantly with delavirdine have not been established{01})
Didanosine (didanosine administration requires an empty stomach; administer didanosine one hour before or two hours after the combination of lopinavir and ritonavir{01})
» Dihydroergotamine or
» Ergonovine or
» Ergotamine or
» Methylergonovine (potential for serious and life-threatening acute ergot toxicity, characterized by peripheral vasospasm and ischemia of the extremities or other tissues, exists; concomitant use is contraindicated{01})
Disulfiram or
Metronidazole (lopinavir and ritonavir oral solution contains alcohol, which can produce a disulfiram-like reaction when administered concurrently with disulfiram or metronidazole{01})
» Efavirenz or
» Nevirapine (lopinavir concentration may be decreased due to induction of CYP3A by efavirenz and nevirapine; increased dosage of lopinavir and ritonavir may be required{01})
» Ethinyl estradiol (ethinyl estradiol concentrations may be decreased; alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives are administered with lopinavir and ritonavir{01})
» Felodipine or
» Nicardipine
» Nifedipine or (dihydropyridine calcium channel blocker concentrations may be increased; caution is warranted; clinical monitoring of patients is recommended{01})
» Itraconazole or
» Ketoconazole (azole antifungal concentrations may be increased; high doses (>200 mg/day) are not recommended when taken with lopinavir and ritonavir {01})
Methadone (methadone concentration may be decreased; dose of methadone may need to be increased when taken with lopinavir and ritonavir{01})
» Midazolam or
» Triazolam (prolonged or increased sedation or respiratory depression may occur; concomitant use is contraindicated{01})
» Rifabutin (increased concentrations of rifabutin and rifabutin metabolite may occur; rifabutin dosage reduction by at least 75% of the usual daily dose is recommended (i.e., 150 mg three times per week); increased monitoring for adverse effects is recommended; further rifabutin dosage reduction may be necessary{01})
» Rifampin (may lead to loss of virologic response and possible resistance to lopinavir and ritonavir or to the class of protease inhibitors or other co-administered antiretroviral agents{01})
Ritonavir (safety and efficacy of additional doses of ritonavir have not been established{01})
» Sildenafil (concomitant use is likely to produce a large increase in the plasma concentration of sildenafil, which may result in sildenafil-associated adverse effects such as hypotention, prolonged erection, syncope, and visual changes;{01} reduced doses of sildenafil of 25 mg every 48 hours are recommended; increased monitoring for adverse effects also is recommended{01})
» St. John's wort (hypericum perforatum) ( concomitant use is likely to produce decreased concentrations of lopinavir and ritonavir resulting in suboptimal lopinavir concentrations, loss of virologic response, and possible resistance to lopinavir and ritonavir; concomitant use is not recommended{01})
» Warfarin (warfarin concentrations may be affected; International Normalized Ratio (INR) monitoring is recommended{01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) and
Gamma glutamyl transferase (GGT) ( values may be increased{01})
» Amylase or
» Cholesterol, total or
» Triglycerides{01} (large increases have been reported{01})
Bilirubin (increased concentrations have been observed in pediatric patients{01})
Glucose (levels may be increased{01})
Neutrophils ( counts may be decreased)
{01}
Phosphorus, inorganic (concentrations may be decreased{01})
Platelets (decreased counts have been observed in pediatric patients{01})
Sodium (decreased concentrations have been observed in pediatric patients{01})
Uric acid (levels may be increased{01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Hypersensitivity to either lopinavir or ritonavir{01}
Risk-benefit should be considered when the following medical problems exist
» Diabetes mellitus (may exacerbate existing diabetes or increase blood sugar levels;{01} adjustments in the dosage of insulin or oral antidiabetic agent may be necessary{01})
Hemophilia A or
Hemophilia B ( although a causal relationship has not been established, increased bleeding, including spontaneous skin hematomas and hemarthrosis, has been reported in patients receiving protease inhibitors{01})
» Hepatic function impairment or
» Hepatitis B or
» Hepatitis C (lopinavir is principally metabolized in the liver; caution is warranted due to the potential for increased lopinavir concentrations; patients with current transaminase elevations may be at risk for further elevation{01})
» Pancreatitis, history of (risk of recurrence may be increased{01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
» Cholesterol, total and
» Triglycerides (testing is recommended prior to initiation of lopinavir and ritonavir and periodically during the course of therapy{01})
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent
Diabetes mellitus or hyperglycemia {01}(blurred vision; dry mouth; fatigue; flushed, dry skin; fruit-like breath odor; increased hunger; increased thirst; increased urination; loss of consciousness; nausea ; stomachache; sweating; troubled breathing; unexplained weight loss; vomiting)
pancreatitis {01}(bloating; chills; constipation ; darkened urine; fast heartbeat; fever; indigestion; loss of appetite ; pains in stomach, side, or abdomen, possibly radiating to the back; yellow eyes or skin)
Note: If pancreatitis should occur, therapy with lopinavir and ritonavir and other antiretroviral agents should be suspended.{01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Diarrhea{01}
nausea {01}
Incidence less frequent
Abdominal pain{01}
abnormal stools{01}
asthenia{01} ( lack or loss of strength)
headache{01}
insomnia{01} (trouble in sleeping )
pain{01}
rash {01}
vomiting {01}
Those not indicating need for medical attention
Incidence more frequent
Redistribution of body fat {01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).
Lopinavir and ritonavir oral solution contains 42.4% alcohol (v/v). Accidental ingestion by a child could result in significant alcohol–related toxicity and could approach the potential lethal dose of alcohol.{01}
Treatment of overdose
Treatment is essentially symptomatic and supportive{01}.
To decrease absorption:
Induction of emesis or use of gastric lavage to empty the stomach.{01} Activated charcoal also may be administered.{01}
To enhance elimination :
Dialysis is not likely to be effective because lopinavir is highly protein-bound.{01}
Monitoring:
Vital signs and clinical status of the patient.{01}
Supportive care:
Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Lopinavir and Ritonavir (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to either lopinavir or ritonavir
Breast-feeding—Not recommended because of the potential for postnatal transmission of HIV and for adverse effects
Other medications, especially amiodarone, atorvastatin, astemizole, bepridil, carbamazepine, cerivastatin, cisapride, clarithromycin, cyclosporine, dexamethasone, dihydroergotamine, efavirenz, ergonovine, ergotamine, ethinyl estradiol, felodipine, flecainide, itraconazole, ketoconazole, lidocaine, lovastatin, methylergonovine, midazolam, nevirapine, nicardipine, nifedipine, phenobarbital, phenytoin, pimozide, propafenone, quinidine, rifabutin, rifampin, sildenafil, simvastatin, sirolimus, St. John's wort, tacrolimus, terfenadine, triazolam, or warfarin.
Other medical problems, especially diabetes mellitus, hepatic function impairment, hepatitis B, hepatitis C, or history of pancreatitis
Proper use of this medication
Reading patient package insert carefully
» Importance of taking medication with food
» Importance of not taking more medication than prescribed; importance of not discontinuing lopinavir and ritonavir without checking with physician
» Proper dosing
Taking as soon as possible; not taking if almost time for next scheduled dose; not doubling doses
Proper storage
Precautions while using this medication
» Regular visits to physician
When taking oral solution, limiting alcohol intake because dosage form contains 42% alcohol
Side/adverse effects
Signs of potential side effects, especially diabetes mellitus, hyperglycemia, or pancreatitis
General Dosing Information
Diet/Nutrition
For optimal absorption, lopinavir and ritonavir should be taken with food.{01}
Oral Dosage Forms
LOPINAVIR AND RITONAVIR CAPSULES
Usual adult and adolescent dose
Antiviral
Oral, 400 mg of lopinavir and 100 mg of ritonavir (3 capsules) two times a day with food.{01} The dose may be increased to 533 mg of lopinavir and 133 mg of ritonavir (4 capsules) two times a day with food when used in combination with efavirenz or nevirapine in treatment-experienced patients in whom reduced susceptibility to lopinavir is suspected.{01}
Usual pediatric dose
This dosage form is usually not used in children. See Lopinavir and Ritonavir Oral Solution.
Usual geriatric dose
See Usual adult and adolescent dose .
Strength(s) usually available
U.S.—
133.3 mg of lopinavir and 33.3 mg of ritonavir per capsule (Rx) [Kaletra (FD&C Yellow No. 6) ( gelatin) (glycerin) ( oleic acid) (polyoxyl 35 castor oil) (propylene glycol) (sorbitol special ) (titanium dioxide) ( water){01}]
Canada—
Not commercially available.
Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Protect from excessive heat.{01}
Stability:
If stored at room temperature, capsules should be used within 2 months.{01}
If refrigerated, capsules will remain stable until the expiration date printed on the label.{01}
LOPINAVIR AND RITONAVIR ORAL SOLUTION
Usual adult and adolescent dose
Antiviral
Oral, 400 mg of lopinavir and 100 mg of ritonavir (5 mL) two times a day with food.{01} The dose may be increased to 533 mg of lopinavir and 133 mg of ritonavir (6.5 mL) two times a day with food when used in combination with efavirenz or nevirapine in treatment-experienced patients in whom reduced susceptibility to lopinavir is suspected.{01}
Usual pediatric dose
Note: Dosing is based on the lopinavir component of the lopinavir and ritonavir oral solution.{01}
The manufacturer recommends that the prescriber calculate the appropriate milligram dose for each individual child less than 12 years old and determine the corresponding volume of oral solution or number of capsules. However, the dosing below provides guidelines for oral solution based on body weight. When possible the dose should be administered using a calibrated dosing syringe.{03}
Antiviral
For children 6 months to 12 years of age::
Without efavirenz or nevirapine——
• Children weighing 7 to <15 kg: Oral, 12 mg/kg twice daily, with food{03} • 7 to 10 kg: 1.25 mL{03}
• >10 kg to <15 kg: 1.75 mL{03}
• Children weighing 15 to 40 kg: Oral, 10 mg/kg twice daily, with food{03} • 15 to 20 kg: 2.25 mL{03}
• >20 to 25 kg: 2.75 mL{03}
• >25 to 30 kg: 3.5 mL{03}
• >30 to 35 kg: 4.0 mL{03}
• >35 to 40 kg: 4.75 mL{03}
• Children weighing more than 40 kg: See Usual adult and adolescent dose.{03}
Concomitant therapy with efavirenz or nevirapine——
• Children weighing 7 to <15 kg: Oral, 13 mg/kg twice daily, with food{03} • 7 to 10 kg: 1.5 mL{03}
• >10 kg to <15 kg: 2.0 mL{03}
• Children weighing 15 to 45 kg: Oral, 11 mg/kg twice daily, with food{03} • 15 to 20 kg: 2.5 mL{03}
• >20 to 25 kg: 3.25 mL{03}
• >25 to 30 kg: 4.0 mL{03}
• >30 to 35 kg: 4.5 mL{03}
• >35 to 40 kg: 5.0 mL (or 3 capsules){03}
• >40 to 45 kg: 5.75 mL{03}
• Children weighing more than 45 kg: See Usual adult and adolescent dose.{03}
For children up to 6 months of age::
Safety and efficacy have not been established.{01}
Usual Geriatric Dose
See Usual adult and adolescent dose .
Strength(s) usually available
U.S.—
80 mg of lopinavir per mL and 20 mg of ritonavir per mL (Rx) [Kaletra (Acesulfame potassium) ( alcohol (42.4% v/v)) (artificial cotton candy flavor ) (citric acid) ( glycerin ) ( high fructose corn syrup) ( Magnasweet-110 flavor) (menthol) ( natural and artificial vanilla flavor) ( peppermint oil ) (polyoxyl 40 hydrogenated castor oil ) (povidone) (propylene glycol ) (saccharin sodium) ( sodium chloride) ( sodium citrate ) (water){01}]
Packaging and storage:
Store between 2 and 8 °C (36 and 46 °F). Avoid excessive heat{01}
Stability:
If stored at room temperature, solution should be used within 2 months.{01}
If refrigerated, solution will remain stable until the expiration date printed on the label.{01}
Developed: 01/18/2001
Revised: 07/26/2001
References
- Product Information: Kaletra™, lopinavir and ritonavir. Abbott Laboratories, North Chicago, Illinois, (PI revised 9/2000) reviewed 12/2000.
- Retrovir package insert (Glaxo Wellcome—US), Rev 5/98, Rec 10/98.
- Product Information: Kaletra™, lopinavir and ritonavir. Abbott Laboratories, North Chicago, Illinois, (PI revised 3/2001) reviewed 7/2001.
