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Generic Name
Ritonavir
Brand Names
Kaletra, Lopinavir, Norvir, Paxlovid
FDA approval date: June 18, 2010
Classification: Protease Inhibitor
Form: Tablet, Kit, Powder, Solution
What is Kaletra (Ritonavir)?
KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 14 days and older. Limitations of Use: Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA [see Microbiology ( 1.
Approved To Treat
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Brand Information
Kaletra (Lopinavir and Ritonavir)
1INDICATIONS AND USAGE
KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 14 days and older.
Limitations of Use:
- Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA
2DOSAGE FORMS AND STRENGTHS
- Tablets:
- Oral Solution:
3CONTRAINDICATIONS
- KALETRA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.
- KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions
- KALETRA is contraindicated with drugs that are potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance
4ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
- QT Interval Prolongation, PR Interval Prolongation
- Drug Interactions
- Pancreatitis
- Hepatotoxicity
4.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions in Adults
The safety of KALETRA has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine.
In clinical studies the incidence of diarrhea in patients treated with either KALETRA capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily. Any grade of diarrhea was reported by at least half of patients taking once daily Kaletra capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily Kaletra and 1.8-3.7% of those taking twice daily Kaletra reported ongoing diarrhea.
Commonly reported adverse reactions to KALETRA included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later. The following have been identified as adverse reactions of moderate or severe intensity (Table 8):
Table 8. Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving KALETRA in Combined Phase II/IV Studies (N=2,612)
Laboratory Abnormalities in Adults
The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 9 (treatment-naïve patients) and Table 10 (treatment-experienced patients).
Table 9. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients
Table 10. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients
Adverse Reactions in Pediatric Patients
KALETRA oral solution dosed up to 300/75 mg/m
Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric patients treated with combination therapy for up to 48 weeks in Study 940. A total of 8 patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the 8 subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in 2 or more subjects (N = 3).
KALETRA oral solution dosed at 300/75 mg/m
KALETRA oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m
Laboratory Abnormalities in Pediatric Patients
The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 11.
Table 11. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients in Study 940
4.2Postmarketing Experience
The following adverse reactions have been reported during postmarketing use of KALETRA. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to KALETRA exposure.
Body as a Whole
Redistribution/accumulation of body fat has been reported [see Warnings and Precautions (5.10)].
Redistribution/accumulation of body fat has been reported [see Warnings and Precautions (5.10)].
Cardiovascular
Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes [see Warnings and Precautions (5.5, 5.6)].
Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes [see Warnings and Precautions (5.5, 5.6)].
Renal and Urinary Disorders
Nephrolithiasis
Nephrolithiasis
Skin and Appendages
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.
5OVERDOSAGE
Overdoses with KALETRA oral solution have been reported. One of these reports described fatal cardiogenic shock in a 2.1 kg infant who received a single dose of 6.5 mL of KALETRA oral solution (520 mg lopinavir, approximately 10-fold above the recommended lopinavir dose) nine days prior. The following events have been reported in association with unintended overdoses in preterm neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure
KALETRA oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Ingestion of the product over the recommended dose by an infant or a young child could result in significant toxicity and could potentially be lethal.
Human experience of acute overdosage with KALETRA is limited. Treatment of overdose with KALETRA should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with KALETRA. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since lopinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both ethanol and propylene glycol in the case of overdose with KALETRA oral solution.
6DESCRIPTION
KALETRA is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV-1 protease. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.
Lopinavir is chemically designated as [1
![The following structural formula for Lopinavir is chemically designated as [1S-[1R*,(R*), 3R*, 4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide. Its molecular formula is C37H48N4O5, and its molecular weight is 628.80. Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.](https://dailymed.nlm.nih.gov/dailymed/image.cfm?name=kaletra-tablets-and-oral-solution-spl-02.jpg&setid=8290add3-4449-4e58-6c97-8fe1eec972e3)
Ritonavir is chemically designated as 10-hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5
![The following structural formula for Ritonavir is chemically designated as 10-hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water.](https://dailymed.nlm.nih.gov/dailymed/image.cfm?name=kaletra-tablets-and-oral-solution-spl-03.jpg&setid=8290add3-4449-4e58-6c97-8fe1eec972e3)
KALETRA tablets are available for oral administration in two strengths:
- Yellow or red tablets containing 200 mg of lopinavir and 50 mg of ritonavir
- Pale yellow or pink tablets containing 100 mg of lopinavir and 25 mg of ritonavir.
The yellow, 200 mg lopinavir and 50 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and yellow ferric oxide E172.
The red, 200 mg lopinavir and 50 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and red ferric oxide E172.
The pale yellow, 100 mg lopinavir and 25 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow ferric oxide E172.
The pink, 100 mg lopinavir and 25 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and red ferric oxide E172.
KALETRA oral solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per milliliter with the following inactive ingredients: acesulfame potassium, artificial cotton candy flavor, citric acid, ethanol, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural & artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water.
KALETRA oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol.
7HOW SUPPLIED/STORAGE AND HANDLING
KALETRA
Recommended Storage:
8PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Medication Guide)
- Advise patients to pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of KALETRA.
- Advise patients and caregivers that the oral solution should be administered using the calibrated dosing cup (supplied) or oral dosing syringe.
- Advise caregivers to inform their healthcare provider if the child’s weight changes in order to make sure that the child’s KALETRA dose is adjusted as needed.
- Inform patients and caregivers that KALETRA tablets may be taken with or without food but KALETRA oral solution should be taken with food to enhance absorption.
- Advise patients to remain under the care of a healthcare provider while using KALETRA and to take KALETRA in combination with other antiretroviral drugs as prescribed.
- Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider. If a dose of KALETRA is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
- Inform patients that it is important to take KALETRA on a regular dosing schedule as directed and to avoid missing doses as that can result in development of resistance.
- Inform patients that there may be a greater chance of developing diarrhea with the once daily regimen as compared with the twice daily regimen.
- Inform patients that Kaletra is not a cure for HIV-1 infection and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.
Drug Interactions
Inform patients that KALETRA may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products such as St. John’s Wort
Pancreatitis
Advise patients that pancreatitis has been observed in patients receiving KALETRA and to alert their healthcare provider if they experience symptoms such as nausea, vomiting or abdominal pain
Skin Rash
Inform patients that skin rash ranging in severity from mild to toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema multiforme, urticaria, and angioedema have been reported in patients receiving KALETRA or its components lopinavir and/or ritonavir. Advise patients to contact their healthcare provider if they develop a rash while taking KALETRA
Hepatotoxicity
Pre-existing liver disease including Hepatitis B or C can worsen with use of KALETRA. This can be seen as worsening of transaminase elevations or hepatic decompensation. Advise patients that their liver function tests will need to be monitored closely especially during the first several months of KALETRA treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin
QT and PR Interval Prolongation
Advise patients that KALETRA may produce changes in the electrocardiogram (e.g., PR and/or QT prolongation) and to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness
Diabetes Mellitus/Hyperglycemia
Advise patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during KALETRA use. Advise patients to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on KALETRA as they may require a change in their diabetes treatment or new treatment
Immune Reconstitution Syndrome
Advise patients that immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including KALETRA
Lipid Disorders
Advise patients that treatment with KALETRA therapy can result in substantial increases in the concentration of total cholesterol and triglycerides
Fat Redistribution
Advise patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time
Patients with Hemophilia
Advise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as KALETRA
Pregnancy Exposure Registry
Inform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to KALETRA
Lactation
Instruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk
Manufactured by AbbVie Inc., North Chicago, IL 60064 USA
KALETRA is a trademark of AbbVie Inc.
The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products.
© 2023 AbbVie Inc. All rights reserved.
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