Kaletra
(lopinavir and ritonavir) Tablet, Film Coated for Oral use
Kaletra
(lopinavir and ritonavir) Solution for Oral use
KALETRA (lopinavir/ritonavir) 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 [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. Lopinavir has the following structural formula:
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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. Ritonavir has the following structural formula:
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KALETRA film-coated tablets are available for oral administration in two strengths:
The yellow, 200 mg lopinavir/50 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide E172, and polysorbate 80.
The pale yellow, 100 mg lopinavir/25 mg ritonavir, tablets contain the following inactive ingredients: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The following are the ingredients in the film coating: polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol 3350, and yellow 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, alcohol, artificial cotton candy flavor, citric acid, 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 42.4% alcohol (v/v).
Last updated on RxList: 4/24/2009
KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
The following points should be considered when initiating therapy with KALETRA:
KALETRA tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed.
KALETRA oral solution must be taken with food.
When initiating treatment with KALETRA in therapy-naïve patients, it should be noted the incidence of diarrhea was greater with KALETRA capsules once-daily compared to KALETRA capsules twice-daily in Study 418 (57% vs. 35% - reactions of all grades; 16% vs. 5% - reactions of at least moderate severity) [See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION].
Once-daily administration of KALETRA is not recommended in therapy-experienced patients.
[See CLINICAL PHARMACOLOGY and DRUG INTERACTIONS]
KALETRA tablets and oral solution should not be administered as a once-daily regimen in combination with efavirenz, nevirapine, (fos)amprenavir or nelfinavir.
KALETRA tablets and oral solution should not be administered once-daily in pediatric patients < 18 years of age.
Healthcare professionals should pay special attention to accurate calculation of the dose of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors, overdose, [see OVERDOSAGE] and underdose.
Prescribers should calculate the appropriate dose of KALETRA for each individual child based on body weight (kg) or body surface area (BSA) and should not exceed the recommended adult dose.
Body surface area (BSA) can be calculated as follows:
*BSA (m²)= √Ht(Cm) x Wt (kg)/3600
The KALETRA dose can be calculated based on weight or BSA:
Patient Weight (kg) × Prescribed lopinavir dose (mg/kg) = Administered lopinavir dose (mg)
Patient BSA (m²) × Prescribed lopinavir dose (mg/m²) = Administered lopinavir dose (mg)
If KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows:
Volume of KALETRA solution (mL) = Administered lopinavir dose (mg) ÷80 (mg/mL)
The dose of the oral solution should be administered using a calibrated dosing syringe.
Before prescribing KALETRA 100/25 mg tablets, children should be assessed for the ability to swallow intact tablets. If a child is unable to reliably swallow a KALETRA tablet, the KALETRA oral solution formulation should be prescribed.
In pediatric patients 14 days to 6 months of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution is 16/4 mg/kg or 300/75 mg/m² twice daily. Prescribers should calculate the appropriate dose based on body weight or body surface area.
Because no data exists for dosage when administered with efavirenz, nevirapine, (fos)amprenavir, or nelfinavir, it is recommended that KALETRA not be administered in combination with these drugs in patients < 6 months of age.
In children 6 months to 18 years of age, the recommended dosage of lopinavir/ritonavir using KALETRA oral solution without concomitant efavirenz, nevirapine, (fos)amprenavir, or nelfinavir is 230/57.5 mg/m² given twice daily, not to exceed the recommended adult dose. If weight-based dosing is preferred, the recommended dosage of lopinavir/ritonavir for patients < 15 kg is 12/3 mg/kg given twice daily and the dosage for patients ≥ 15 kg to 40 kg is 10/2.5 mg/kg given twice daily.
Table 1 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets.
Table 1. Pediatric Dosing Recommendations for Patients 6
Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets Without Concomitant
Efavirenz, Nevirapine, (Fos)amprenavir, or Nelfinavir
| Body Weight (kg) | Body Surface Area (m²)* | Recommended number of 100/25 mg Tablets Twice-Daily |
| 15 to 25 | ≥ 0.6 to < 0.9 | 2 |
| > 25 to 35 | ≥ 0.9 to < 1.4 | 3 |
| > 35 | ≥ 1.4 | 4 (or two 200/50 mg tablets) |
| * KALETRA oral solution is available for children with a BSA less than 0.6 m² or those who are unable to reliably swallow a tablet. | ||
A dose increase of KALETRA to 300/75 mg/m² is needed when co-administered with efavirenz, nevirapine, (fos)amprenavir, or nelfinavir in children (both treatment-naïve and treatmentexperienced) 6 months to 18 years of age, not to exceed the recommended adult dose. If weightbased dosing is preferred, the recommended dosage for patients < 15 kg is 13/3.25 mg/kg given twice daily and the dosage for patients > 15 kg to 45 kg is 11/2.75 mg/kg given twice daily.
Table 2 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, (fos)amprenavir, or nelfinavir.
Table 2. Pediatric Dosing Recommendations for Patients 6
Months to 18 Years of Age Based on Body Weight or Body Surface Area for KALETRA Tablets With
Concomitant Efavirenz†, Nevirapine, (Fos)amprenavir† or Nelfinavir†
| Body Weight (kg) |
Body Surface Area (m²)* |
Recommended number of 100/25 mg Tablets Twice-Daily |
| 15 to 20 | ≥ 0.6 to < 0.8 | 2 |
| > 20 to 30 | ≥ 0.8 to < 1.2 | 3 |
| > 30 to 45 | ≥ 1.2 to < 1.7 | 4 (or two 200/50 mg tablets) |
| > 45 | ≥ 1.7 | 4 or 6 (or two or three 200/50 mg tablets) See DOSAGE AND ADMINISTRATION, Adult Patients |
| * KALETRA oral solution is available for children with a BSA less than 0.6 m² or those who are unable to reliably swallow a tablet. † Please refer to the individual product labels for appropriate dosing in children. |
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Yellow, film-coated, ovaloid tablets debossed with the corporate Abbott “A” logo and the Abbo-Code KA providing 200 mg lopinavir/50 mg ritonavir.
Pale yellow, film-coated, ovaloid tablets debossed with the corporate Abbott “A” logo and the Abbo-Code KC providing 100 mg lopinavir/25 mg ritonavir.
Light yellow to orange colored liquid containing 400 mg lopinavir/100 mg ritonavir per 5 mL (80 mg lopinavir/20 mg ritonavir per mL).
KALETRA® (lopinavir/ritonavir) Film-Coated tablets and Oral Solution are available in the following strengths and package sizes:
Yellow film-coated ovaloid tablets debossed with the corporate Abbott “A” logo and the Abbo-Code KA:
Bottles of 120 tablets ….…………… (NDC 0074-6799-22)
Recommended Storage
Store KALETRA film-coated tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59° to 86°F)[see USP controlled room temperature]. Dispense in original container or USP equivalent tight container (250 mL or less). For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container (250 mL or less) for longer than 2 weeks is not recommended.
Pale yellow film-coated ovaloid tablets debossed with the corporate Abbott “A” logo and the Abbo- Code KC:
Bottles of 60 tablets ….…………… (NDC 0074-0522-60)
Recommended Storage
Store KALETRA film-coated tablets at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59° to 86°F)[see USP controlled room temperature]. Dispense in original container or USP equivalent tight container (100 mL or less). For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container (100 mL or less) for longer than 2 weeks is not recommended.
KALETRA (lopinavir/ritonavir) oral solution is a light yellow to orange colored liquid supplied in ambercolored multiple-dose bottles containing 400 mg lopinavir/100 mg ritonavir per 5 mL (80 mg lopinavir/20 mg ritonavir per mL) packaged with a marked dosing cup in the following size:
160 mL bottle……………………………….(NDC 0074-3956-46)
Recommended Storage
Store KALETRA oral solution at 2°-8°C (36°-46°F) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated KALETRA oral solution remains stable until the expiration date printed on the label. If stored at room temperature up to 25°C (77°F), oral solution should be used within 2 months.
KALETRA Tablets, 200 mg lopinavir/50 mg ritonavir Manufactured
by Abbott Pharmaceuticals PR Ltd., Barceloneta, PR 00617. For Abbott Laboratories,
North Chicago, IL 60064, U.S.A.
KALETRA Tablets, 100 mg lopinavir/25 mg ritonavir and KALETRA Oral Solution:
Abbott Laboratories, North Chicago, IL 60064, U.S.A. Rev. 04\2009
Last updated on RxList: 4/24/2009
The following adverse reactions are discussed in greater detail in other sections of the labeling.
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 practice.
The safety profile of KALETRA in adults is primarily based on 891 HIV-1 infected patients in clinical trials.
The most common adverse reaction was diarrhea, which was generally of mild to moderate severity. The incidence of diarrhea was greater for KALETRA capsules once-daily compared to KALETRA capsules twice-daily in Study 418 [See Table 4]. Rates of discontinuation of randomized therapy due to adverse reactions were 3.4% in KALETRA-treated and 3.7% in nelfinavir-treated patients in Study 863.
Treatment-emergent clinical adverse reactions of moderate or severe intensity in ≥ 2% of patients treated with combination therapy for up to 48 weeks (Study 863 and 418) and for up to 360 weeks (Study 720) are presented in Table 4 (treatment-naïve patients) and Table 5 (protease inhibitor experienced patients).
Table 4. Percentage of Adult Patients with Selected
Treatment-Emergent1 Adverse Reactions of Moderate or Severe Intensity Reported in ≥ 2% of Adult
Antiretroviral-Naïve Patients
| Study 863 (48 Weeks) |
Study 418 (48 Weeks) |
Study 720 (360 Weeks) |
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| KALETRA 400/100mg BID + d4T +3TC (N = 326) |
Nelfinavir 750mg TID + d4T +3TC (N = 327) |
KALETRA 800/200mg QD + TDF +FTC (N = 115) |
KALETRA 400/100mg BID + TDF +FTC (N = 75) |
KALETRA BID2 + d4T + 3TC (N = 100) |
|
| Body as a Whole | |||||
| Abdominal Pain | 4% | 3% | 3% | 3% | 11% |
| Asthenia | 4% | 3% | 0% | 0% | 9% |
| Headache | 2% | 2% | 3% | 3% | 6% |
| Cardiovascular System | |||||
| Vein distended | 0% | 0% | 0% | 0% | 3% |
| Digestive System | |||||
| Diarrhea | 16% | 17% | 16% | 5% | 28% |
| Nausea | 7% | 5% | 9% | 8% | 16% |
| Vomiting | 2% | 2% | 3% | 4% | 6% |
| Dyspepsia | 2% | < 1% | 0% | 1% | 6% |
| Flatulence | 2% | 1% | 2% | 1% | 4% |
| Anorexia | 1% | < 1% | < 1% | 1% | 2% |
| Metabolic and Nutritional | |||||
| Weight loss | 1% | < 1% | 0% | 0% | 2% |
| Musculoskeletal | |||||
| Myalgia | 1% | 1% | 0% | 0% | 2% |
| Nervous System | |||||
| Insomnia | 2% | 1% | 0% | 0% | 3% |
| Paresthesia | 1% | 1% | 0% | 0% | 2% |
| Depression | 1% | 2% | 1% | 0% | 0% |
| Libido decreased | < 1% | < 1% | 0% | 1% | 2% |
| Respiratory | |||||
| Bronchitis | 0% | 0% | 0% | 0% | 2% |
| Skin and Appendages | |||||
| Rash | 1% | 2% | 1% | 0% | 5% |
| Urogenital | |||||
| Hypogonadism male | 0% | 0% | 0% | 0% | 2% |
| Amenorrhea | 0% | 0% | 4.5% | 0% | 0% |
| 1 Includes adverse reactions of possible or probable relationship to study drug. 2 Includes adverse reaction data from dose group I (200/100 mg BID [N = 16] and 400/100 mg BID [N = 16]) and dose group II (400/100 mg BID [N = 35] and 400/200 mg BID [N = 33]). Within dosing groups, moderate to severe nausea of probable/possible relationship to KALETRA occurred at a higher rate in the 400/200 mg dose arm compared to the 400/100 mg dose arm in group II. Definitions: d4T = Stavudine; 3TC = Lamivudine; TDF = Tenofovir Disoproxil Fumarate; FTC = Emtricitabine |
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Table 5. Percentage of Adult Patients with Selected
Treatment-Emergent1 Adverse Reactions of
Moderate or Severe Intensity Reported in ≥ 2% of Adult
Protease Inhibitor-Experienced Patients
| Study 888 (48 Weeks) | Study 9572 and Study
7653 (84-144 Weeks) KALETRA BID + NNRTI + NRTIs (N = 127) |
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| KALETRA 400/100 mg BID + NVP + NRTIs (N = 148) |
Investigator-selected protease inhibitor(s) + NVP + NRTIs (N = 140) |
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| Body as a Whole | |||
| Asthenia | 3% | 6% | 9% |
| Abdominal Pain | 2% | 2% | 4% |
| Fever | 2% | 1% | 2% |
| Headache | 2% | 3% | 2% |
| Chills | 2% | 0% | 0% |
| Cardiovascularb> | |||
| Hypertension | 0% | 0% | 2% |
| Digestive System | |||
| Diarrhea | 7% | 9% | 23% |
| Nausea | 7% | 16% | 5% |
| Vomiting | 4% | 12% | 2% |
| Dyspepsia | 1% | 1% | 2% |
| Flatulence | 1% | 2% | 2% |
| Dysphagia | 2% | 1% | 0% |
| Anorexia | 1% | 3% | 0% |
| Metabolic and Nutritional | |||
| Weight loss | 0% | 1% | 3% |
| Musculoskeletal | |||
| Myalgia | 1% | 1% | 2% |
| Nervous System | |||
| Depression | 1% | 2% | 2% |
| Paresthesia | 1% | 0% | 2% |
| Insomnia | 0% | 2% | 2% |
| Skin and Appendages | |||
| Rash | 2% | 1% | 2% |
| 1 Includes adverse reactions of possible or probable relationship to study drug. 2 Includes adverse reaction data from patients receiving 400/100 mg BID (n = 29) or 533/133 mg BID (n = 28) for 84 weeks. Patients received KALETRA in combination with NRTIs and efavirenz. 3 Includes adverse reaction data from patients receiving 400/100 mg BID (n = 36) or 400/200 mg BID (n = 34) for 144 weeks. Patients received KALETRA in combination with NRTIs and nevirapine. Definitions: NVP = Nevirapine; NRTI = Nucleoside Reverse Transcriptase Inhibitors; NNRTI = Non-nucleoside Reverse Transcriptase Inhibitors |
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Treatment-emergent adverse reactions occurring in less than 2% of adult patients receiving KALETRA in the clinical trials supporting approval and of at least moderate intensity are listed below by body system.
Allergic reaction, back pain, chest pain, chest pain substernal, cyst, drug interaction, drug level increased, face edema, flu syndrome, hypertrophy, infection bacterial, malaise, neoplasm, and viral infection.
Atrial fibrillation, cerebral infarct, deep thrombophlebitis, deep vein thrombosis, migraine, myocardial infarct, palpitation, postural hypotension, thrombophlebitis, varicose vein, and vasculitis.
Cholangitis, cholecystitis, constipation, dry mouth, enteritis, enterocolitis, eructation, esophagitis, fecal incontinence, gastritis, gastroenteritis, hemorrhagic colitis, hepatitis, hepatomegaly, increased appetite, jaundice, liver fatty deposit, liver tenderness, mouth ulceration, pancreatitis, periodontitis, sialadenitis, stomatitis, and ulcerative stomatitis.
Cushing's syndrome, diabetes mellitus, and hypothyroidism.
Anemia, leukopenia, and lymphadenopathy.
Avitaminosis, dehydration, edema, glucose tolerance decreased, lactic acidosis, obesity, peripheral edema, and weight gain.
Arthralgia, arthrosis, bone necrosis, joint disorder, and myasthenia.
Abnormal dreams, agitation, amnesia, anxiety, apathy, ataxia, confusion, convulsion, dizziness, dyskinesia, emotional lability, encephalopathy, extrapyramidal syndrome, facial paralysis, hypertonia, nervousness, neuropathy, peripheral neuritis, somnolence, thinking abnormal, tremor, and vertigo.
Asthma, cough increased, dyspnea, lung edema, pharyngitis, rhinitis, and sinusitis.
Acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, maculopapular rash, nail disorder, pruritis, seborrhea, skin benign neoplasm, skin discoloration, skin striae, skin ulcer, and sweating.
Abnormal vision, eye disorder, otitis media, taste loss, taste perversion, and tinnitus.
Abnormal ejaculation, breast enlargement, gynecomastia, impotence, kidney calculus, nephritis, and urine abnormality.
The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 6 (treatment-naïve patients) and Table 7 (treatment-experienced patients).
Table 6. Grade 3-4 Laboratory Abnormalities Reported in ≥
2% of Adult Antiretroviral-naïve Patients
| Variable | Limit1 | Study 863 (48 Weeks) | Study 418 (48 Weeks) | Study 720 (360 Weeks) | ||
| KALETRA 400/100 mg BID +d4T +3TC (N = 326) |
Nelfinavir 750mg TID + d4T +3TC (N = 327) |
KALETRA 800/200 mg QD +TDF + FTC (N = 115) |
KALETRA 400/100 mg BID +TDF + FTC (N = 75) |
KALETRA BID2 + d4T + 3TC (N = 100) |
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| Chemistry | High | |||||
| Glucose | > 250 mg/dL | 2% | 2% | 3% | 1% | 4% |
| Uric Acid | > 12 mg/dL | 2% | 2% | 0% | 3% | 5% |
| SGOT/AST | > 180U/L | 2% | 4% | 5% | 3% | 10% |
| SGPT/ALT | > 215U/L | 4% | 4% | 4% | 3% | 11% |
| GGT | > 300U/L | N/A | N/A | N/A | N/A | 10% |
| Total Cholesterol | > 300mg/dL | 9% | 5% | 3% | 3% | 27% |
| Triglycerides | > 750 | 9% | 1% | 5% | 4% | 29% |
| Amylase | > 2 x ULN | 3% | 2% | 7% | 5% | 4% |
| Hematology | Low | |||||
| Neutrophils | < 0.75 x 109/L | 1% | 3% | 5% | 1% | 5% |
| 1 ULN = upper limit of the normal
range; N/A = Not Applicable. 2 Includes adverse event data from dose group I (200/100 mg BID [N = 16] and 400/100 mg BID [N = 16]) and dose group II (400/100 mg BID [N = 35] and 400/200 mg BID [N = 33]). Within dosing groups, moderate to severe nausea of probable/possible relationship to KALETRA occurred at a higher rate in the 400/200 mg dose arm compared to the 400/100 mg dose arm in group II. |
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Table 7. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitorexperienced Patients
| Variable | Limit1 | Study 888 (48 Weeks) | Study 9572 and Study 7653(84-144 Weeks) |
|
| KALETRA 400/100 mg BID + NVP + NRTIs (N = 148) |
Investigator-selected protease inhibitor(s) + NVP + NRTIs (N = 140) |
KALETRA BID + NNRTI + NRTIs (N = 127) |
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| Chemistry | High | |||
| Glucose | > 250mg/dL | 1% | 2% | 5% |
| Total Bilirubin | > 3.48mg/dL | 1% | 3% | 1% |
| SGOT/AST | > 180 U/L | 5% | 11% | 8% |
| SGPT/ALT | > 215 U/L | 6% | 13% | 10% |
| GGT | > 300 U/L | N/A | N/A | 29% |
| Total Cholesterol | > 300mg/dL | 20% | 21% | 39% |
| Triglycerides | > 750mg/dL | 25% | 21% | 36% |
| Amylase | > 2 x ULN | 4% | 8% | 8% |
| Chemistry | Low | |||
| Inorganic Phosphorus | < 1.5mg/dL | 1% | 0% | 2% |
| Hematology | Low | |||
| Neutrophils | < 0.75 x 109/L | 1% | 2% | 4% |
| 1 ULN = upper limit of the normal
range; N/A = Not Applicable. 2 Includes clinical laboratory data from patients receiving 400/100 mg BID (n = 29) or 533/133 mg BID (n = 28) for 84 weeks. Patients received KALETRA in combination with NRTIs and efavirenz. 3 Includes clinical laboratory data from patients receiving 400/100 mg BID (n = 36) or 400/200 mg BID (n = 34) for 144 weeks. Patients received KALETRA in combination with NRTIs and nevirapine. |
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KALETRA oral solution dosed up to 300/75 mg/m² has been studied in 100 pediatric patients 6 months to 12 years of age. The adverse reaction profile seen during Study 940 was similar to that for adult patients.
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/m² has been studied in 31 pediatric patients 14 days to 6 months of age. The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included decreased neutrophil count (N=3), anemia (N=2), high potassium (N=2), and low sodium (N=2).
KALETRA oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m² (without concomitant NNRTI) and 480/120 mg/m² (with concomitant NNRTI) have been studied in 26 pediatric patients 7 to 18 years of age in Study 1038. Patients also had saquinavir mesylate added to their regimen at Week 4. Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal (12%) were the only adverse reactions reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in 2 or more subjects included rash (N=3), blood triglycerides abnormal (N=3), and electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities.
The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 8.
Table 8. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients in Study 940
| Variable | Limit1 | KALETRA BID+ RTIs (N = 100) |
| Chemistry | High | |
| Sodium | > 149 mEq/L | 3% |
| Total Bilirubin | ≥ 3.0 x ULN | 3% |
| SGOT/AST | > 180 U/L | 8% |
| SGPT/ALT | > 215 U/L | 7% |
| Total Cholesterol | > 300 mg/dL | 3% |
| Amylase | > 2.5 x ULN | 7%2 |
| Chemistry | Low | |
| Sodium | < 130 mEq/L | 3% |
| Hematology | Low | |
| Platelet Count | < 50 x 109/L | 4% |
| Neutrophils | < 0.40 x 109/L | 2% |
| 1 ULN = upper limit of the normal range. 2 Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase. |
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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.
Redistribution/accumulation of body fat has been reported [See WARNINGS AND PRECAUTIONS].
Bradyarrhythmias. First–degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes [See WARNINGS AND PRECAUTIONS].
Stevens Johnson Syndrome and erythema multiforme.
See also CONTRAINDICATIONS , CLINICAL PHARMACOLOGY
Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC ( > 3-fold) when co-administered with KALETRA. Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require a dose adjustment or additional monitoring as shown in Table 9.
Additionally, KALETRA induces glucuronidation.
Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRA's therapeutic effect. Although not observed in the KALETRA/ketoconazole drug interaction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Table 9 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction. [See CLINICAL PHARMACOLOGY for magnitude of interaction]
Table 9. Established and Other Potentially Significant Drug
Interactions
| Concomitant Drug Class: Drug Name |
Effect on Concentration of Lopinavir or Concomitant Drug |
Clinical Comment |
| HIV-1 Antiviral Agents | ||
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* | ↓ lopinavir | KALETRA dose increase is recommended in all patients
[See DOSAGE AND ADMINISTRATION and
CLINICAL PHARMACOLOGY]. Increasing the dose of KALETRA tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice-daily coadministered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice-daily without efavirenz. KALETRA should not be administered once-daily in combination with efavirenz or nevirapine. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. |
| Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine | ↑ lopinavir | Appropriate doses of the combination with respect to safety and efficacy have not been established. |
| Nucleoside Reverse Transcriptase Inhibitor: didanosine | KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). | |
| Nucleoside Reverse Transcriptase Inhibitor: tenofovir | ↑ tenofovir | KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. |
| Nucleoside Reverse Transcriptase Inhibitor: abacavir zidovudine | ↓ abacavir
↓ zidovudine |
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown. |
| HIV-1 Protease Inhibitor: amprenavir* | ↑ amprenavir
↓ lopinavir |
KALETRA should not be administered once-daily in combination with amprenavir. [See DOSAGE AND ADMINISTRATION]. |
| HIV-1 Protease Inhibitor: fosamprenavir/ritonavir | ↓ amprenavir
↓ lopinavir |
An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: indinavir* | ↑ indinavir | Decrease indinavir dose to 600 mg BID, when coadministered with KALETRA 400/100 mg BID [See CLINICAL PHARMACOLOGY]. KALETRA oncedaily has not been studied in combination with indinavir. |
| HIV-1 Protease Inhibitor: nelfinavir* | ↑ nelfinavir
↑ M8 metabolite of nelfinavir ↓ lopinavir |
KALETRA should not be administered once-daily in combination with nelfinavir. [See DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. |
| HIV-1 Protease Inhibitor: ritonavir* | ↑ lopinavir | Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established. |
| HIV-1 Protease Inhibitor: saquinavir* | ↑ saquinavir | The saquinavir dose is 1000 mg BID, when co-administered with KALETRA 400/100 mg BID. KALETRA once-daily has not been studied in combination with saquinavir. |
| HIV-1 Protease Inhibitor: tipranavir | ↓ lopinavir AUC and Cmin | KALETRA should not be administered with tipranavir (500 mg twice-daily) co-administered with ritonavir (200 mg twice-daily). |
| HIV CCR5 – antagonist: maraviroc | ↑ maraviroc | Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When coadministered, patients should receive 150 mg BID of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc). |
| Other Agents | ||
| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine | ↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticancer Agents: vincristine vinblastine | ↑ anticancer agents | Concentrations of vincristine or vinblastine may be
increased when co-administered with lopinavir/ritonavir
(KALETRA) resulting in the potential for increased adverse
events usually associated with these anticancer agents. |
| Anticoagulant: warfarin | Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin | ↓ lopinavir
↓ phenytoin |
KALETRA may be less effective due to decreased lopinavir
plasma concentrations in patients taking these agents
concomitantly and should be used with caution.
KALETRA should not be administered once-daily in
combination with carbamazepine, phenobarbital, or
phenytoin. |
| Antidepressant: bupropion | ↓ bupropion
↓ active metabolite, hydroxybupropion |
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. |
| Antidepressant: trazodone | ↑ trazodone | Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Anti-infective: clarithromycin | ↑ clarithromycin | For patients with renal impairment, the following dosage adjustments should be considered:
No dose adjustment for patients with normal renal function is necessary. |
| Antifungals: ketoconazole*, itraconazole, voriconazole | ↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole ( > 200 mg/day) or itraconazole
( > 200 mg/day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied. However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients. |
| Antimycobacterial: rifabutin* | ↑ rifabutin and rifabutin metabolite | Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., a maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary. |
| Antimycobacterial: rifampin | ↓ lopinavir | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. A study evaluated combination of rifampin 600 mg QD, with KALETRA 800/200 mg BID or KALETRA 400/100 mg + ritonavir 300 mg BID. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone. [See CLINICAL PHARMACOLOGY for magnitude of interaction] . |
| Antiparasitic: atovaquone | ↓ atovaquone | Clinical significance is unknown; however, increase in atovaquone doses may be needed. |
| Benzodiazepines: parenterally administered midazolam | ↑ midazolam | Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see CONTRAINDICATIONS]. If KALETRA is coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine | ↑ dihydropyridine calcium channel blockers | Caution is warranted and clinical monitoring of patients is recommended. |
| Corticosteroid: dexamethasone | ↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil | ↑ sildenafil
↑ tadalafil ↑ vardenafil |
Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in an increase in associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses:
|
| HMG-CoA Reductase Inhibitors: atorvastatin rosuvastatin | ↑ atorvastatin
↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin | ↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone | ↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Narcotic Analgesic: methadone* | ↓ methadone | Dosage of methadone may need to be increased when coadministered with KALETRA. |
| Contraceptive: ethinyl estradiol* | ↓ ethinyl estradiol | Because contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended. |
| * See CLINICAL PHARMACOLOGY for Magnitude of Interaction. | ||
Drug interaction studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), pravastatin, stavudine, lamivudine, omeprazole or ranitidine.
Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.
Last updated on RxList: 4/27/2009
See Tables 3 and 9 for listing of drugs that are contraindicated for use with KALETRA due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. [see CONTRAINDICATIONS and DRUG INTERACTIONS].
Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis. Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during KALETRA therapy.
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA.
There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of KALETRA treatment. [See Use In Specific Populations]
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA should be used with caution in patients with underlying structural heart disease, preexisting conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities.
The impact on the PR interval of co-administration of KALETRA with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As a result, co-administration of KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended. [See CLINICAL PHARMACOLOGY].
Postmarketing cases of QT interval prolongation and torsade de pointes have been reported although causality of KALETRA could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval [See CLINICAL PHARMACOLOGY].
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment.
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides [See ADVERSE REACTIONS]. Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors. [See CONTRAINDICATIONS and DRUG INTERACTIONS]
Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in KALETRA-treated patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors. [See CLINICAL PHARMACOLOGY]
See Medication Guide
Patients or parents of patients should be informed that:
Lopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC0-24hr measurement) at the recommended dose of 400/100 mg KALETRA twice-daily. Administration of lopinavir/ritonavir did not cause a statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats.
Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, there was a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg KALETRA twice-daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 9-fold for the females that of the exposure in humans. There were no carcinogenic effects in rats. In this study, the exposure at the high dose was approximately 0.7-fold that of the exposure in humans with the 400/100 mg KALETRA twice-daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. However, neither lopinavir nor ritonavir was found to be mutagenic or clastogenic in a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.
Lopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the 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 (400/100 mg twice-daily).
No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and fetal developmental toxicities (early resorption, decreased fetal viability, decreased fetal body weight, increased incidence of skeletal variations and skeletal ossification delays) occurred in rats at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir for males and females that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice-daily). In a peri- and postnatal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred.
No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6-fold for lopinavir and 1.0-fold for ritonavir that of the exposures in humans at the recommended therapeutic dose (400/100 mg twice-daily). There are, however, no adequate and wellcontrolled studies in pregnant women. KALETRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
To monitor maternal-fetal outcomes of pregnant women exposed to KALETRA, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Studies in rats have demonstrated that lopinavir is secreted in milk. It is not known whether lopinavir is secreted in human milk. Because of both the potential for HIV-1 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving KALETRA.
The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA once-daily has not been evaluated in pediatric patients.
An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of with 300/75 mg/m² twice daily plus two NRTIs in HIV-infected infants ≥ 14 days and < 6 months of age. Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC12 than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIV-RNA < 400 copies/mL at Week 24 [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies] .
Safety and efficacy in pediatric patients > 6 months of age was demonstrated in a clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve and experienced pediatric patients ages 6 months to 12 years. Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m² oral solution twice-daily regimen without nevirapine and the 300/75 mg/m² oral solution twice-daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen (without nevirapine) [see ADVERSE REACTIONS, CLINICAL PHARMACOLOGY, Clinical Studies].
A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m² twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m² twice daily + ≥ 1 NRTI + 1 NNRTI) in children and adolescents ≥ 2 years to < 18 years of age who had failed prior therapy. Patients also had saquinavir mesylate added to their regimen. This strategy was intended to assess whether higher than approved doses of KALETRA could overcome protease inhibitor cross-resistance. High doses of KALETRA exhibited a safety profile similar to those observed in previous trials; changes in HIV-1 RNA were less than anticipated; three patients had HIV-1 RNA < 400 copies/mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks, [see ADVERSE REACTIONS , CLINICAL PHARMACOLOGY].
Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
KALETRA is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased [See WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].
Last updated on RxList: 4/27/2009
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 nine days prior. However, a causal relationship between the overdose and the outcome could not be established. Healthcare professionals should be aware that KALETRA oral solution is highly concentrated and therefore, should pay special attention to accurate calculation of the dose of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors and overdose. This is especially important for infants and young children.
KALETRA oral solution contains 42.4% alcohol (v/v). Accidental ingestion of the product by a young child could result in significant alcohol-related toxicity and could approach the potential lethal dose of alcohol.
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 emesis or gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since KALETRA is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug.
Table 3. Drugs That Are Contraindicated With KALETRA
| Drug Class | Drugs Within Class That Are Contraindicated With KALETRA | Clinical comments: |
| Antimycobacterial | Rifampin | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. [see DRUG INTERACTIONS] |
| Ergot Derivatives | Dihydroergotamine, ergonovine, ergotamine, methylergonovine | Potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. |
| GI motility agent | Cisapride | Potential for cardiac arrhythmias. |
| Herbal Products | St Johns wort (hypericum perforatum) | May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors. |
| HMG-CoA Reductase Inhibitors | Lovastatin, simvastatin | Potential for myopathy including rhabdomyolysis. |
| Neuroleptic | Pimozide | Potential for cardiac arrhythmias. |
| Sedative/Hypnotics | Triazolam; orally administered midazolama | Prolonged or increased sedation or respiratory depression. |
| aSee DRUG INTERACTIONS, Table 9 for parenterally administered midazolam | ||
Last updated on RxList: 4/27/2009
Lopinavir is an antiviral drug.
The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-1 infected patients; no substantial differences were observed between the two groups. Lopinavir is essentially completely metabolized by CYP3A. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. Across studies, administration of KALETRA 400/100 mg twice-daily yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of ritonavir in HIV-1 infected patients. The plasma levels of ritonavir are less than 7% of those obtained after the ritonavir dose of 600 mg twice-daily. The in vitro antiviral EC50 of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of KALETRA is due to lopinavir.
Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after KALETRA 400/100 mg twice-daily with food for 3 weeks from a pharmacokinetic study in HIV-1 infected adult subjects (n = 19).
Figure 1. Mean Steady-state Plasma Concentrations with 95%
Confidence Intervals (CI) for HIV-1 Infected Adult Subjects (N = 19)
 |
In a pharmacokinetic study in HIV-1 positive subjects (n = 19), multiple dosing with 400/100 mg KALETRA twice-daily with food for 3 weeks produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 9.8 ± 3.7 μg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 μg/mL and minimum concentration within a dosing interval was 5.5 ± 2.7 μg/mL. Lopinavir AUC over a 12 hour dosing interval averaged 92.6 ± 36.7 μg•h/mL. The absolute bioavailability of lopinavir co-formulated with ritonavir in humans has not been established. Under nonfasting conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA co-formulated capsules and oral solution. When administered under fasting conditions, both the mean AUC and Cmax of lopinavir were 22% lower for the KALETRA oral solution relative to the capsule formulation.
Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg KALETRA tablets are similar to three 133.3/33.3 mg KALETRA capsules under fed conditions with less pharmacokinetic variability.
KALETRA Tablets
No clinically significant changes in Cmax and AUC were observed following administration of KALETRA tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA tablets with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 26.9% and 17.6%, respectively. Relative to fasting, administration of KALETRA tablets with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC by 18.9% but not Cmax. Therefore, KALETRA tablets may be taken with or without food.
KALETRA Oral Solution
Relative to fasting, administration of KALETRA oral solution with a moderate fat meal (500 - 682 Kcal, 23 to 25% calories from fat) increased lopinavir AUC and Cmax by 80 and 54%, respectively. Relative to fasting, administration of KALETRA oral solution with a high fat meal (872 Kcal, 56% from fat) increased lopinavir AUC and Cmax by 130% and 56%, respectively. To enhance bioavailability and minimize pharmacokinetic variability KALETRA oral solution should be taken with food.
At steady state, lopinavir is approximately 98-99% bound to plasma proteins. Lopinavir binds to both alpha-1-acid glycoprotein (AAG) and albumin; however, it has a higher affinity for AAG. At steady state, lopinavir protein binding remains constant over the range of observed concentrations after 400/100 mg KALETRA twice-daily, and is similar between healthy volunteers and HIV-1 positive patients.
In vitro experiments with human hepatic microsomes indicate that lopinavir primarily undergoes oxidative metabolism. Lopinavir is extensively metabolized by the hepatic cytochrome P450 system, almost exclusively by the CYP3A isozyme. Ritonavir is a potent CYP3A inhibitor which inhibits the metabolism of lopinavir, and therefore increases plasma levels of lopinavir. A 14C-lopinavir study in humans showed that 89% of the plasma radioactivity after a single 400/100 mg KALETRA dose was due to parent drug. At least 13 lopinavir oxidative metabolites have been identified in man. Ritonavir has been shown to induce metabolic enzymes, resulting in the induction of its own metabolism. Predose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.
Following a 400/100 mg 14C-lopinavir/ritonavir dose, approximately 10.4 ± 2.3% and 82.6 ± 2.5% of an administered dose of 14C-lopinavir can be accounted for in urine and feces, respectively, after 8 days. Unchanged lopinavir accounted for approximately 2.2 and 19.8% of the administered dose in urine and feces, respectively. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The apparent oral clearance (CL/F) of lopinavir is 5.98 ± 5.75 L/hr (mean ± SD, n = 19).
The pharmacokinetics of once-daily KALETRA have been evaluated in HIV-1 infected subjects naïve to antiretroviral treatment. KALETRA 800/200 mg was administered in combination with emtricitabine 200 mg and tenofovir DF 300 mg as part of a once-daily regimen. Multiple dosing of 800/200 mg KALETRA once-daily for 4 weeks with food (n = 24) produced a mean ± SD lopinavir peak plasma concentration (Cmax) of 11.8 ± 3.7 μg/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 μg/mL and minimum concentration within a dosing interval was 1.7 ± 1.6 μg/mL. Lopinavir AUC over a 24 hour dosing interval averaged 154.1 ± 61.4 μgh/mL.
QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 39 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice-daily and supratherapeutic 800/200 mg twice-daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax observed with the approved once daily and twice daily KALETRA doses at steady state.
PR interval prolongation was also noted in subjects receiving KALETRA in the same study on Day 3. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice-daily and supratherapeutic 800/200 mg twice-daily KALETRA, respectively [See WARNINGS AND PRECAUTIONS] .
No gender related pharmacokinetic differences have been observed in adult patients. No clinically important pharmacokinetic differences due to race have been identified. Lopinavir pharmacokinetics have not been studied in elderly patients.
The pharmacokinetics of KALETRA oral solution 300/75 mg/m² twice-daily and 230/57.5 mg/m² twicedaily have been studied in a total of 53 pediatric patients in Study 940, ranging in age from 6 months to 12 years [see Clinical Studies]. The 230/57.5 mg/m² twice-daily regimen without nevirapine and the 300/75 mg/m² twice-daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice-daily regimen (without nevirapine).
The mean steady-state lopinavir AUC, Cmax, and Cmin were 72.6 ± 31.1 μg•h/mL, 8.2 ± 2.9 and 3.4 ± 2.1 μg/mL, respectively after KALETRA oral solution 230/57.5 mg/m² twice-daily without nevirapine (n = 12), and were 85.8 ± 36.9 μgh/mL, 10.0 ± 3.3 and 3.6 ± 3.5 μg/mL, respectively, after 300/75 mg/m² twice-daily with nevirapine (n = 12). The nevirapine regimen was 7 mg/kg twice-daily (6 months to 8 years) or 4 mg/kg twice-daily ( > 8 years).
The pharmacokinetics of KALETRA oral solution at approximately 300/75 mg/m² twice-daily have also been evaluated in infants at approximately 6 weeks of age (n = 9) and between 6 weeks and 6 months of age (n = 18) in Study 1030. The mean steady-state lopinavir AUC12, Cmax, and C12 were 43.4 ± 14.8 μgh/mL, 5.2 ± 1.8 μg/mL and 1.9 ± 1.1 μg/mL, respectively, in infants at approximately 6 weeks of age, and 74.5 ± 37.9 μgh/mL, 9.4 ± 4.9 and 3.1 ± 1.8 μg/mL, respectively, in infants between 6 weeks and 6 months of age after KALETRA oral solution was administered at approximately 300/75 mg/m² twice-daily without concomitant NNRTI therapy.
The pharmacokinetics of KALETRA soft gelatin capsule and oral solution (Group 1: 400/100 mg/m² twice daily + 2 NRTIs; Group 2: 480/120 mg/m² twice daily + ≥ 1 NRTI + 1 NNRTI) have been evaluated in children and adolescents age ≥ 2 years to < 18 years of age who had failed prior therapy (n=26) in Study 1038. KALETRA doses of 400/100 and 480/120 mg/m² resulted in high lopinavir exposure, as almost all subjects had lopinavir AUC12 above 100 μg•h/mL. Both groups of subjects also achieved relatively high average minimum lopinavir concentrations.
KALETRA once-daily has not been evaluated in pediatric patients.
Lopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, a decrease in total body clearance is not expected in patients with renal impairment.
Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of KALETRA 400/100 mg twice-daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n = 12) resulted in a 30% increase in lopinavir AUC and 20% increase in Cmax compared to HIV-1 infected subjects with normal hepatic function (n = 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). Caution should be exercised when administering KALETRA to subjects with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment [See WARNINGS AND PRECAUTIONS and Use In Specific Populations].
KALETRA is an inhibitor of the P450 isoform CYP3A in vitro. Co-administration of KALETRA and drugs primarily metabolized by CYP3A may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects [See CONTRAINDICATIONS and DRUG INTERACTIONS].
KALETRA does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.
KALETRA has been shown in vivo to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.
KALETRA is metabolized by CYP3A. Drugs that induce CYP3A activity would be expected to increase the clearance of lopinavir, resulting in lowered plasma concentrations of lopinavir. Although not noted with concurrent ketoconazole, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Drug interaction studies were performed with KALETRA and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of KALETRA on the AUC, Cmax and Cmin are summarized in Table 10 (effect of other drugs on lopinavir) and Table 11 (effect of KALETRA on other drugs). The effects of other drugs on ritonavir are not shown since they generally correlate with those observed with lopinavir (if lopinavir concentrations are decreased, ritonavir concentrations are decreased) unless otherwise indicated in the table footnotes. For information regarding clinical recommendations, see Table 9 in DRUG INTERACTIONS.
Table 10. Drug Interactions: Pharmacokinetic Parameters for
Lopinavir in the Presence of the Coadministered Drug for Recommended Alterations in Dose or Regimen
| Co-administered Drug | Dose of Coadministered Drug |
Dose of KALETRA (mg) |
n | Ratio (in combination with co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | ||
| Cmax | AUC | C min | ||||
| Amprenavir | 750 BID, 10 d | 400/100 capsule BID, 21 d | 12 | 0.72 | 0.62 | 0.43 |
| (0.65,0.79) | (0.56, 0.70) | (0.34, 0.56) | ||||
| Efavirenz1,10 | 600 QHS, 9 d | 400/100 capsule BID, 9 d | 11,7* | 0.97 | 0.81 | 0.61 |
| (0.78,1.22) | (0.64, 1.03) | (0.38, 0.97) | ||||
| 600 QHS, 9 d | 500/125 tablet BID,10 d | 19 | 1.12 | 1.06 | 0.90 | |
| (1.02,1.23) | (0.96, 1.17) | (0.78, 1.04) | ||||
| 600 QHS, 9 d | 600/150 tablet BID, 10 d | 23 | 1.36 | 1.36 | 1.32 | |
| (1.28,1.44) | (1.28, 1.44) | (1.21, 1.44) | ||||
| Fosamprenavir2 | 700 BID plus ritonavir 100 BID, 14 d | 400/100 capsule BID, 14 d | 18 | 1.30 | 1.37 | 1.52 |
| (0.85,1.47) | (0.80, 1.55) | (0.72, 1.82) | ||||
| Ketoconazole | 200 single dose | 400/100 capsule BID, 16 d | 12 | 0.89 | 0.87 | 0.75 |
| (0.80,0.99) | (0.75, 1.00) | (0.55, 1.00) | ||||
| Nelfinavir | 1000 BID, 10 d | 400/100 capsule BID, 21 d | 13 | 0.79 | 0.73 | 0.62 |
| (0.70,0.89) | (0.63, 0.85) | (0.49, 0.78) | ||||
| Nevirapine | 200 BID, steadystate ( > 1 yr)3 | 400/100 capsule BID, steady-state | 22,19* | 0.81 | 0.73 | 0.49 |
| (0.62,1.05) | 0.53, 0.98) | (0.28, 0.74) | ||||
| 7 mg/kg or 4 mg/kg QD, 2 wk; BID 1 wk4 | (> 1 yr)3 00/75 mg/m² oral solution BID, 3 wk | 12,15* | 0.86 | 0.78 | 0.45 | |
| (0.64,1.16) | 0.56, 1.09) | (0.25, 0.81) | ||||
| Omeprazole | 40 QD, 5 d | 400/100 tablet BID,10 d | 12 | 1.08 | 1.07 | 1.03 |
| (0.99,1.17) | 0.99, 1.15) | (0.90, 1.18) | ||||
| 40 QD, 5 d | 800/200 tablet QD,10 d | 12 | 0.94 | 0.92 | 0.71 | |
| (0.88,1.00) | 0.86, 0.99) | (0.57, 0.89) | ||||
| Pravastatin | 20 QD, 4 d | 400/100 capsule BID, 14 d | 12 | 0.98 | 0.95 | 0.88 |
| (0.89,1.08) | 0.85, 1.05) | (0.77, 1.02) | ||||
| Rifabutin | 150 QD, 10 d | 400/100 capsule BID, 20 d | 14 | 1.08 | 1.17 | 1.20 |
| (0.97,1.19) | 1.04, 1.31) | (0.96, 1.65) | ||||
| Ranitidine | 150 single dose | 400/100 tablet BID,10 d | 12 | 0.99 | 0.97 | 0.90 |
| (0.95,1.03) | 0.93, 1.01) | (0.85, 0.95) | ||||
| 150 single dose | 800/200 tablet QD,10 d | 10 | 0.97 | 0.95 | 0.82 | |
| (0.95,1.00) | 0.91, 0.99) | (0.74, 0.91) | ||||
| Rifampin | 600 QD,10 d | 400/100 capsule BID, 20 d | 22 | 0.45 | 0.25 | 0.01 |
| (0.40,0.51) | 0.21, 0.29) | (0.01, 0.02) | ||||
| 600 QD,14 d | 800/200 capsule BID, 9 d5 | 10 | 1.02 | 0.84 | 0.43 | |
| (0.85,1.23) | 0.64, 1.10) | (0.19, 0.96) | ||||
| 600 QD,14 d | 400/400 capsule BID, 9 d6 | 9 | 0.93 | 0.98 | 1.03 | |
| (0.81,1.07) | 0.81, 1.17) | (0.68, 1.56) | ||||
| Co-administration of KALETRA and rifampin is contraindicated.[See CONTRAINDICATIONS] | ||||||
| Ritonavir3 | 100 BID, 3-4 wk | 400/100 capsule BID,3-4 wk | 8,21* | 1.28 | 1.46 | 2.16 |
| (0.94,1.76) | 1.04, 2.06) | (1.29, 3.62) | ||||
| Tenofovir7 | 300 mg QD, 14 d | 400/100 capsule BID, 14 d | 24 | NC† | NC† | NC† |
| Tipranavir/ritonavir3 | 500/200 mgBID (28 doses) | 400/100 capsule BID(27 doses) | 21 | 0.53 | 0.45 | 0.30 (0.17, 0.51)8 |
| 69 | (0.40,0.69)8 | (0.32, 0.63)8 | 0.48 (0.40, 0.58)9 | |||
| All interaction studies conducted in healthy, HIV-1 negative subjects unless otherwise indicated. 1 The pharmacokinetics of ritonavir are unaffected by concurrent efavirenz. 2 Data extracted from the fosamprenavir package insert. 3 Study conducted in HIV-1 positive adult subjects. 4 Study conducted in HIV-1 positive pediatric subjects ranging in age from 6 months to 12 years. 5 Titrated to 800/200 BID as 533/133 BID x 1 d, 667/167 BID x 1 d, then 800/200 BID x 7 d, compared to 400/100 BID x 10 days alone. 6 Titrated to 400/400 BID as 400/200 BID x 1 d, 400/300 BID x 1 d, then 400/400 BID x 7 d, compared to 400/100 BID x 10 days alone. 7 Data extracted from the tenofovir package insert. 8 Intensive PK analysis. 9 Drug levels obtained at 8-16 hrs post-dose. 10 Reference for comparison is lopinavir/ritonavir 400/100 mg BID without efavirenz. * Parallel group design; n for KALETRA + co-administered drug, n for KALETRA alone. † NC = No change. |
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Table 11. Drug Interactions: Pharmacokinetic Parameters for
co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or Regimen
| Co-administered Drug | Dose of Co-administered Drug (mg) | Dose of KALETRA (mg) | n | Ratio (in combination with KALETRA/alone) of co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | ||
| Cmax | AUC | Cmin | ||||
| Amprenavir1 | 750 BID, 10 d combo vs. 1200 BID, 14 d alone | 400/100 capsule BID,21 d | 11 | 1.12 | 1.72 | 4.57 |
| (0.91, 1.39) | (1.41, 2.09) | (3.51, 5.95) | ||||
| Desipramine2 | 100 single dose | 400/100 capsule BID,10 d | 15 | 0.91 | 1.05 | N/A |
| (0.84, 0.97) | (0.96, 1.16) | |||||
| Efavirenz | 600 QHS, 9 d | 400/100 capsule BID, 9d | 11,12* | 0.91 | 0.84 | 0.84 |
| (0.72, 1.15) | (0.62, 1.15) | (0.58, 1.20) | ||||
| Ethinyl Estradiol | 35 μg QD, 21 d (OrthoNovum®) | 400/100 capsule BID,14 d | 12 | 0.59 | 0.58 | 0.42 |
| (0.52, 0.66) | (0.54, 0.62) | (0.36, 0.49) | ||||
| Fosamprenavir3 | 700 BID plus ritonavir 100 BID, 14 d | 400/100 capsule BID,14 d | 0.42 | 0.37 | 0.35 | |
| (0.30, 0.58) | (0.28, 0.49) | (0.27, 0.46) | ||||
| Indinavir1 | 600 BID, 10 d combo nonfasting vs. 800 TID, 5d alone fasting | 400/100 capsule BID,15 d | 0.71 | 0.91 | 3.47 | |
| (0.63, 0.81) | (0.75, 1.10) | (2.60, 4.64) | ||||
| Ketoconazole | 200 single dose | 400/100 capsule BID,16 d | 1.13 | 3.04 | N/A | |
| (0.91, 1.40) | (2.44, 3.79) | |||||
| Methadone | 5 single dose | 400/100 capsule BID,10 d | 0.55 | 0.47 | N/A | |
| (0.48, 0.64) | (0.42, 0.53) | |||||
| Nelfinavir1 | 1000 BID, 10 d combo vs. 1250 BID, 14 d alone | 400/100 capsule BID,21 d | 0.93 | 1.07 | 1.86 | |
| (0.82, 1.05) | (0.95, 1.19) | (1.57, 2.22) | ||||
| M8 metabolite | 2.36 | 3.46 | 7.49 | |||
| (1.91, 2.91) | (2.78, 4.31) | (5.85, 9.58) | ||||
| Nevirapine | 200 QD, 14 d; BID, 6 d | 400/100 capsule BID,20 d | 1.05 | 1.08 | 1.15 | |
| (0.72, 1.52) | (0.72, 1.64) | (0.71, 1.86) | ||||
| Norethindrone | 1 QD, 21 d (Ortho Novum®) | 400/100 capsule BID,14 d | 0.84 | 0.83 | 0.68 | |
| (0.75, 0.94) | (0.73, 0.94) | (0.54, 0.85) | ||||
| Pravastatin | 20 QD, 4 d | 400/100 capsule BID,14 d | 1.26 | 1.33 | N/A | |
| (0.87, 1.83) | (0.91, 1.94) | |||||
| Rifabutin | 150 QD, 10 d; combo vs. 300 QD, 10 d; alone | 400/100 capsule BID,10 d | 2.12 | 3.03 | 4.90 | |
| (1.89, 2.38) | (2.79, 3.30) | (3.18, 5.76) | ||||
| 25-O-desacetyl rifabutin | 23.6 | 47.5 | 94.9 | |||
| (13.7, 25.3) | (29.3, 51.8) | (74.0, 122) | ||||
| Rifabutin + 25-Odesacetyl rifabutin4 | 3.46 | 5.73 | 9.53 | |||
| (3.07, 3.91) | (5.08, 6.46) | (7.56, 12.01) | ||||
| Rosuvastatin5 | 20 mg QD, 7 d | 400/100 tabletBID, 7 d | 4.66 | 2.08 | 1.04 | |
| (3.4, 6.4) | (1.66, 2.6) | (0.9, 1.2) | ||||
| Tenofovir6 | 300 mg QD, 14 d | 400/100 capsule BID,14 d | NC† | 1.32 | 1.51 | |
| (1.26, 1.38) | (1.32, 1.66) | |||||
| All interaction studies conducted in healthy, HIV-1 negative subjects unless otherwise indicated. 1 Ratio of parameters for amprenavir, indinavir, and nelfinavir, are not normalized for dose. 2 Desipramine is a probe substrate for assessing effects on CYP2D6-mediated metabolism. 3 Data extracted from the fosamprenavir package insert. 4 Effect on the dose-normalized sum of rifabutin parent and 25-O -desacetyl rifabutin active metabolite. 5 Data extracted from the rosuvastatin package insert and results presented at the 2007 Conference on Retroviruses and Opportunistic Infection (Hoody, et al, abstract L-107, poster #564 ). 6 Data extracted from the tenofovir package insert. * Parallel group design; n for KALETRA + co-administered drug, n for co-administered drug alone. N/A = Not available. † NC = No change. |
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Lopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.
The antiviral activity of lopinavir against laboratory HIV strains and clinical HIV-1 isolates was evaluated in acutely infected lymphoblastic cell lines and peripheral blood lymphocytes, respectively. In the absence of human serum, the mean 50% effective concentration (EC50) values of lopinavir against five different HIV-1 subtype B laboratory strains ranged from 10-27 nM (0.006-0.017 μg/mL, 1 μg/mL = 1.6 μM) and ranged from 4-11 nM (0.003-0.007 μg/mL) against several HIV-1 subtype B clinical isolates (n = 6). In the presence of 50% human serum, the mean EC50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 μg/mL), representing a 7- to 11-fold attenuation. Combination antiviral drug activity studies with lopinavir in cell cultures demonstrated additive to antagonistic activity with nelfinavir and additive to synergistic activity with amprenavir, atazanavir, indinavir, saquinavir and tipranavir. The EC50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/mL).
HIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture.
The selection of resistance to KALETRA in antiretroviral treatment naïve patients has not yet been characterized. In a study of 653 antiretroviral treatment naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA > 400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No evidence of resistance to KALETRA was observed in 37 evaluable KALETRA-treated patients (0%). Evidence of genotypic resistance to nelfinavir, defined as the presence of the D30N and/or L90M substitution in HIV-1 protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to KALETRA in antiretroviral treatment naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).
Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA therapy. In studies of 227 antiretroviral treatment naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable ( > 400 copies/mL) viral RNA following treatment with KALETRA for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. Three of these patients had previously received treatment with a single protease inhibitor (indinavir, nelfinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, ritonavir, and saquinavir). All four of these patients had at least 4 substitutions associated with protease inhibitor resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance. However, there are insufficient data at this time to identify patterns of lopinavir-associated substitutions in isolates from patients on KALETRA therapy. The assessment of these patterns is under study.
Varying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during KALETRA therapy.
The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with a single protease inhibitor was determined. Isolates that displayed > 4-fold reduced susceptibility to nelfinavir (n = 13) and saquinavir (n = 4), displayed < 4-fold reduced susceptibility to lopinavir. Isolates with > 4-fold reduced susceptibility to indinavir (n = 16) and ritonavir (n = 3) displayed a mean of 5.7- and 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following paragraph.
The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.
Virologic response to KALETRA has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 12 shows the 48-week virologic response (HIV-1 RNA < 400 copies/mL) according to the number of the above protease inhibitor resistance mutations at baseline in studies 888 and 765 [see Clinical Studies] and study 957 (see below).
Table 12. Virologic Response (HIV-1 RNA < 400 copies/mL)
at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Substitutions
Associated with Reduced Response to KALETRA1
| Number of protease inhibitor substitutions at baseline1 | Study 888 (Single protease inhibitor-experienced2, NNRTI-naïve) n=130 |
Study 765 (Single protease inhibitor-experienced3, NNRTI-naïve) n=56 |
Study 957 (Multiple protease inhibitor-experienced4, NNRTI-naïve) n=50 |
| 0-2 | 76/103 (74%) | 34/45 (76%) | 19/20 (95%) |
| 3-5 | 13/26 (50%) | 8/11 (73%) | 18/26 (69%) |
| 6 or more | 0/1 (0%) | n/a | 1/4 (25%) |
| 1 Substitutions considered in the analysis included L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 2 43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 3 41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir. 4 86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir. |
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Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA > 1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC50 value. Fifty-five percent (31/56) of these baseline isolates displayed > 4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 13.
Table 13. HIV-1 RNA Response at Week 48 by Baseline
Lopinavir Susceptibility1
| Lopinavir susceptibility2 at baseline | HIV-1 RNA < 400 copies/mL (%) | HIV-1 RNA < 50 copies/mL (%) |
| < 10 fold | 25/27 (93%) | 22/27 (81%) |
| > 10 and < 40 fold | 11/15 (73%) | 9/15 (60%) |
| ≥ 40 fold | 2/8 (25%) | 2/8 (25%) |
| 1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. 2 Fold change in susceptibility from wild type. |
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Study 863 was a randomized, double-blind, multicenter trial comparing treatment with KALETRA (400/100 mg twice-daily) plus stavudine and lamivudine versus nelfinavir (750 mg three-times-daily) plus stavudine and lamivudine in 653 antiretroviral treatment naïve patients. Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD4+ cell count was 259 cells/mm³ (range: 2 to 949 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL (range: 2.6 to 6.8 log10 copies/mL).
Treatment response and outcomes of randomized treatment are presented in Table 14.
Table 14. Outcomes of Randomized Treatment Through Week 48
(Study 863)
| Outcome | KALETRA+d4T+3TC (N = 326) |
Nelfinavir+d4T+3TC (N = 327) |
| Responder1 | 75% | 62% |
| Virologic failure2 | 9% | 25% |
| Rebound | 7% | 15% |
| Never suppressed through Week 48 | 2% | 9% |
| Death | 2% | 1% |
| Discontinued due to adverse events | 4% | 4% |
| Discontinued for other reasons3 | 10% | 8% |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48. 2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48. 3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the KALETRA arm and 24% in the nelfinavir arm. |
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Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the KALETRA arm compared to the nelfinavir arm with HIV-1 RNA < 400 copies/mL (75% vs. 62%, respectively) and HIV-1 RNA < 50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV-1 RNA level subgroups is presented in Table 15.
Table 15. Proportion of Responders Through Week 48 by
Baseline Viral Load (Study 863)
| Baseline Viral Load (HIV-1 RNA copies/mL) | KALETRA +d4T+3TC | n | Nelfinavir +d4T+3TC | n | ||
| < 400 copies/mL1 | < 50 copies/mL2 | < 400 copies/mL1 | < 50 copies/mL2 | |||
| < 30,000 | 74% | 71% | 82 | 79% | 72% | 87 |
| ≥ 30,000 to < 100,000 | 81% | 73% | 79 | 67% | 54% | 79 |
| ≥ 100,000 to < 250,000 | 75% | 64% | 83 | 60% | 47% | 72 |
| ≥ 250,000 | 72% | 60% | 82 | 44% | 33% | 89 |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48. 2 Patients achieved HIV-1 RNA < 50 copies/mL at Week 48. |
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Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 207 cells/mm³ for the KALETRA arm and 195 cells/mm³ for the nelfinavir arm.
Study 418 was a randomized, open-label, multicenter trial comparing treatment with KALETRA 800/200 mg once-daily plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg twice-daily plus tenofovir DF and emtricitabine in 190 antiretroviral treatment naïve patients. Patients had a mean age of 39 years (range: 19 to 75), 54% were Caucasian, and 78% were male. Mean baseline CD4+ cell count was 260 cells/mm³ (range: 3 to 1006 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.8 log10 copies/mL (range: 2.6 to 6.4 log10 copies/mL).
Treatment response and outcomes of randomized treatment are presented in Table 16.
Table 16. Outcomes of Randomized Treatment Through Week 48
(Study 418)
| Outcome | KALETRA QD + TDF + FTC (n = 115) |
KALETRA BID + TDF + FTC (n = 75) |
| Responder1 | 71% | 65% |
| Virologic failure2 | 10% | 9% |
| Rebound | 6% | 5% |
| Never suppressed through Week 48 | 3% | 4% |
| Death | 0% | 1% |
| Discontinued due to adverse events | 12% | 7% |
| Discontinued for other reasons3 | 7% | 17% |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48. 2 Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48. 3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. |
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Through 48 weeks of therapy, 71% in the KALETRA once-daily arm and 65% in the KALETRA twicedaily arm achieved and maintained HIV-1 RNA < 50 copies/mL (95% confidence interval for the difference, -7.6% to 19.5%). Mean CD4+cell count increases at Week 48 were 185 cells/mm³ for the KALETRA once-daily arm and 196 cells/mm³ for the KALETRA twice-daily arm.
Study 888 was a randomized, open-label, multicenter trial comparing treatment with KALETRA (400/100 mg twice-daily) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve patients. Patients had a mean age of 40 years (range: 18 to 74), 68% were Caucasian, and 86% were male. Mean baseline CD4+cell count was 322 cells/mm³ (range: 10 to 1059 cells/mm³) and mean baseline plasma HIV-1 RNA was 4.1 log10 copies/mL (range: 2.6 to 6.0 log10 copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 17.
Table 17. Outcomes of Randomized Treatment Through Week 48
(Study 888)
| Outcome | KALETRA + nevirapine + NRTIs (n = 148) |
Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs (n = 140) |
| Responder1 | 57% | 33% |
| Virologic failure2 | 24% | 41% |
| Rebound | 11% | 19% |
| Never suppressed through | 13% | 23% |
| Week 48 | ||
| Death | 1% | 2% |
| Discontinued due to adverse events | 5% | 11% |
| Discontinued for other reasons3 | 14% | 13% |
| 1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48. 2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48. 3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons. |
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Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the KALETRA arm compared to the investigator-selected protease inhibitor(s) arm with HIV-1 RNA < 400 copies/mL (57% vs. 33%, respectively).
Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells/mm³ for the KALETRA arm and 112 cells/mm³ for the investigator-selected protease inhibitor(s) arm.
Study 720 (patients without prior antiretroviral therapy) and study 765 (patients with prior protease inhibitor therapy) were randomized, blinded, multi-center trials evaluating treatment with KALETRA at up to three dose levels (200/100 mg twice-daily [720 only], 400/100 mg twice-daily, and 400/200 mg twice-daily). In Study 720, all patients switched to 400/100 mg twice-daily between Weeks 48-72. Patients in study 720 had a mean age of 35 years, 70% were Caucasian, and 96% were male, while patients in study 765 had a mean age of 40 years, 73% were Caucasian, and 90% were male. Mean (range) baseline CD4+ cell counts for patients in study 720 and study 765 were 338 (3-918) and 372 (72-807) cells/mm³, respectively. Mean (range) baseline plasma HIV-1 RNA levels for patients in study 720 and study 765 were 4.9 (3.3 to 6.3) and 4.0 (2.9 to 5.8) log10 copies/mL, respectively.
Through 360 weeks of treatment in study 720, the proportion of patients with HIV-1 RNA < 400 ( < 50) copies/mL was 61% (59%) [n = 100]. Among patients completing 360 weeks of treatment with CD4+ cell count measurements [n=60], the mean (median) increase in CD4+cell count was 501 (457) cells/mm³. Thirty-nine patients (39%) discontinued the study, including 13 (13%) discontinuations due to adverse reactions and 1 (1%) death.
Through 144 weeks of treatment in study 765, the proportion of patients with HIV-1 RNA < 400 ( < 50) copies/mL was 54% (50%) [n = 70], and the corresponding mean increase in CD4+cell count was 212 cells/mm³. Twenty-seven patients (39%) discontinued the study, including 5 (7%) discontinuations secondary to adverse reactions and 2 (3%) deaths.
Study 1030 was an open-label, multicenter, dose-finding trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m² twice daily plus 2 NRTIs in HIV-1 infected infants ≥ 14 days and < 6 months of age.
Ten infants, ≥ 14 days and < 6 wks of age, were enrolled at a median (range) age of 5.7 (3.6-6.0) weeks and all completed 24 weeks. At entry, median (range) HIV-1 RNA was 6.0 (4.7-7.2) log10 copies/mL. Seven of 10 infants had HIV-1 RNA < 400 copies/mL at Week 24. At entry, median (range) CD4+ percentage was 41 (16-59) with a median decrease of 1% (95% CI: -10, 18) from baseline to week 24 in 6 infants with available data.
Twenty-one infants, between 6 weeks and 6 months of age, were enrolled at a median (range) age of 14.7 (6.9-25.7) weeks and 19 of 21 infants completed 24 weeks. At entry, median (range) HIV RNA level was 5.8 (3.7-6.9) log10 copies/mL. Ten of 21 infants had HIV RNA < 400 copies/mL at Week 24. At entry, the median (range) CD4+ percentage was 32 (11-54) with a median increase of 4% (95% CI: -1, 9) from baseline to week 24 in 19 infants with available data.
See CLINICAL PHARMACOLOGY for pharmacokinetic results .
Study 940 was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve (44%) and experienced (56%) pediatric patients. All patients were nonnucleoside reverse transcriptase inhibitor naïve. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m² or 300 mg lopinavir/75 mg ritonavir per m². Naïve patients also received lamivudine and stavudine. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors.
Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after three weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300 mg lopinavir/75 mg ritonavir per m² dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14% less than 2 years. Mean baseline CD4+ cell count was 838 cells/mm³ and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/mL.
Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV-1 RNA < 400 copies/mL was 80% for antiretroviral naïve patients and 71% for antiretroviral experienced patients. The mean increase from baseline in CD4+cell count was 404 cells/mm³ for antiretroviral naïve and 284 cells/mm³ for antiretroviral experienced patients treated through 48 weeks. At 48 weeks, two patients (2%) had prematurely discontinued the study. One antiretroviral naïve patient prematurely discontinued secondary to an adverse reaction, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-1 related event.
Dose selection in pediatric patients was based on the following:
Last updated on RxList: 4/27/2009
MEDICATION GUIDE
KALETRA® (kuh-LEE-tra)
(lopinavir/ritonavir) Tablets
KALETRA® (kuh-LEE-tra)
(lopinavir/ritonavir) Oral Solution
Read the Medication Guide that comes with KALETRA before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or treatment. You and your doctor should talk about your treatment with KALETRA before you start taking it and at regular check-ups. You should stay under your doctor's care when taking KALETRA.
What is the most important information I should know about KALETRA?
KALETRA may cause serious side effects, including:
Tell your doctor right away if you have any of these symptoms while taking KALETRA:
See the section below “What are the possible side effects of KALETRA?” for more information about serious side effects.
What is KALETRA?
KALETRA is a prescription anti-HIV medicine that contains two medicines: lopinavir and ritonavir. KALETRA is called a protease inhibitor that is used with other anti-HIV-1 medicines to treat people with human immunodeficiency virus (HIV-1) infection. HIV-1 is the virus that causes AIDS (Acquired Immune Deficiency Syndrome).
It is not known if KALETRA is safe and effective in children under 14 days old.
Who should not take KALETRA?
What should I tell my doctor before taking KALETRA?
Kaletra may not be right for you. Tell your doctor about all your medical conditions, including if you:
Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Many medicines interact with KALETRA. Do not start taking a new medicine without telling your doctor or pharmacist. Your doctor can tell you if it is safe to take KALETRA with other medicines. Your doctor may need to change the dose of other medicines while you take KALETRA.
Medicines you should not take with KALETRA.
Serious problems or death can happen if you take these medicines with KALETRA:
Medicines that you should not take with KALETRA since they may make KALETRA not work as well:
Medicines that may need changes:
If you are not sure if you are taking a medicine above, ask your doctor.
How should I take KALETRA?
Avoid doing things that can spread HIV infection. KALETRA does not stop you from passing HIV infection to others. Do not share needles, other injection equipment or personal items that can have blood or body fluids on them, like toothbrushes and razor blades. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
What are the possible side effects of KALETRA?
KALETRA can cause serious side effects.
Common side effects of KALETRA include:
These are not all of the possible side effects of KALETRA. For more information, ask your doctor or pharmacist. Tell your doctor about any side effect that bothers you or that does not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store KALETRA?
KALETRA tablets:
KALETRA oral solution:
Throw away any medicine that is out of date or that you no longer need.
Keep KALETRA and all medicines out of the reach of children.
General information about KALETRA
KALETRA does not cure HIV-1 or AIDS. The long-term effects of KALETRA are not known at this time. People taking KALETRA may still get opportunistic infections or other conditions that happen with HIV-1 infection. Some of these conditions are pneumonia, herpes virus infections, and Mycobacterium avium complex (MAC) infections.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use KALETRA for a condition for which it was not prescribed. Do not give KALETRA to other people, even if they have the same condition you have. It may harm them.
This Medication Guide summarizes the most important information about KALETRA. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about KALETRA that is written for health professionals. For more information about KALETRA call 1-800-633-9110 or go to www.KALETRA.com.
What are the ingredients in KALETRA?
Active ingredient: lopinavir and ritonavir
Inactive ingredients:
KALETRA 200 mg lopinavir and 50 mg ritonavir tablets: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating contains: hypromellose, titanium dioxide, polyethylene glycol 400, hydroxypropyl cellulose, talc, colloidal silicon dioxide, polyethylene glycol 3350, yellow ferric oxide 172, and polysorbate 80.
KALETRA 100 mg lopinavir and 25 mg ritonavir tablets: copovidone, sorbitan monolaurate, colloidal silicon dioxide, and sodium stearyl fumarate. The film coating contains: polyvinyl alcohol, titanium dioxide, talc, polytheylene glycol 3350, and yellow ferric oxide E172.
KALETRA oral solution: acesulfame potassium, alcohol, 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, and water.
KALETRA oral solution contains 42.4% alcohol (v/v). “See How should I take KALETRA?”.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
Last updated on RxList: 4/27/2009
IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.
LOPINAVIR/RITONAVIR SOLUTION - ORAL
(low-PIN-uh-veer/rye-TAWN-uh-veer)
COMMON BRAND NAME(S): Kaletra
USES: This combination product contains two medications, lopinavir and ritonavir. This product is used in combination with other medications to help control your HIV infection, thereby improving your quality of life. It also lowers your risk of getting HIV disease complications (e.g., opportunistic infections, cancer). Both lopinavir and ritonavir belong to a class of drugs known as HIV protease inhibitors. The ritonavir in this product helps the lopinavir to stay in your body. This effect builds up the amount of lopinavir in your body, increasing its effectiveness.
This lopinavir/ritonavir product is not a cure for HIV infection, and it does not prevent the spread of HIV to others through sexual contact or blood contamination (e.g., sharing used needles).
HOW TO USE: Read the Patient Information Leaflet provided by your pharmacist before you start using lopinavir/ritonavir and each time you get a refill. If you have any questions regarding the information, consult your doctor or pharmacist.
Take this product by mouth, usually twice daily with food or as directed by your doctor. Carefully measure out the dose with a medication cup/spoon.
Dosage is based on your medical condition, weight (for children), response to therapy, and any other anti-HIV medications you may be taking.
Taking this product once a day is not recommended if you have previously taken other drugs to treat your HIV infection. Consult your doctor for more details.
If you are taking didanosine in addition to this product, take it one hour before or two hours after taking this product.
It is very important to continue taking this medication (and other anti-HIV medications) exactly as prescribed by your doctor.
This medication works best when the amount of drug in your body is kept at a constant level. Therefore, take this drug at evenly spaced intervals. Remember to use it at the same time(s) each day. Do not skip any doses.
Do not take more or less of this drug than prescribed, or stop taking it (or other HIV medicines) even for a short time, unless directed to do so by your doctor. Skipping or changing your dose without approval from your doctor may cause the amount of virus to increase, make the infection more difficult to treat (resistant), or worsen side effects.
Find out about other drugs that should not be taken with this product (see Drug Interactions section).
Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.
Tell your doctor immediately if any of these unlikely but serious side effects occur: joint/muscle pain, increased thirst, increased urination, blurred vision, confusion, rapid heartbeat.
Tell your doctor immediately if any of these rare but very serious side effects occur: persistent nausea/vomiting, severe stomach pain, yellowing of skin/eyes, dark urine, persistent fever, unusual tiredness.
Changes in body fat may occur while you are taking this medication (e.g., increased fat in the upper back and stomach areas, decreased fat in the arms and legs). The cause and long-term effects of these changes are unknown. Discuss the risks and benefits of therapy with your doctor, as well as the possible role of exercise to reduce this side effect.
This medication may cause an increase in blood fat levels (cholesterol and triglycerides). Cholesterol and triglyceride testing should be done before and occasionally during treatment with this medication. Consult your doctor or pharmacist for more information.
A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.
This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.
Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.
PRECAUTIONS: Before taking this product, tell your doctor or pharmacist if you are allergic to either lopinavir or ritonavir; or to other HIV protease inhibitors such as amprenavir, indinavir or saquinavir; or if you have any other allergies.
Before using this medication, tell your doctor or pharmacist your medical history, especially of: liver disease, diabetes, pancreatitis, high blood fat levels (cholesterol/triglycerides), bleeding problems (e.g., hemophilia), previous infection with certain diseases (e.g., hepatitis B infection, hepatitis C infection, tuberculosis).
This product contains a large amount of alcohol and may make you dizzy or drowsy. Use caution engaging in activities requiring alertness. Limit alcoholic beverages.
Because this product contains alcohol, severe nausea and vomiting may occur if you are also taking disulfiram or metronidazole with lopinavir/ritonavir solution. Consult your doctor or pharmacist before taking either of these medications.
Caution is advised when using this product in children. The alcohol in this product may cause an accidental overdose that could be serious.
This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.
It is not known if this medication passes into breast milk. Because breast milk can transmit HIV, do not breast-feed.
Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.
This drug should not be used with the following medications because very serious interactions may occur: alfuzosin, certain non-drowsy antihistamines, cisapride, conivaptan, eletriptan, eplerenone, ergot drugs (e.g., dihydroergotamine, ergonovine, methylergonovine, ergotamine), ivabradine, pimozide, ranolazine, rifampin, certain sedatives (midazolam, triazolam), certain "statins" (lovastatin, simvastatin), St John's wort, voriconazole.
If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting lopinavir/ritonavir.
Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: other HIV drugs (e.g., efavirenz, amprenavir, zidovudine, abacavir, nevirapine, atazanavir, tipranavir/ritonavir), antidepressants (e.g., bupropion, trazodone), atovaquone, other azole antifungals (ketoconazole, itraconazole), "blood thinners" (e.g., warfarin), calcium channel blockers (e.g., felodipine, nifedipine, nicardipine), certain cancer drugs (dasatinib, lapatinib, sunitinib), dexamethasone, disulfiram, drugs for erectile dysfunction (e.g., sildenafil, tadalafil, vardenafil), fluticasone, garlic supplements, heart rhythm medication (e.g., amiodarone, bepridil, lidocaine, quinidine), drugs that suppress the immune system (e.g., cyclosporine, tacrolimus, rapamycin), macrolide antibiotics (e.g., clarithromycin), metronidazole, narcotic pain medications (e.g., methadone), rifabutin, other sedatives (alprazolam, zolpidem), seizure medication (e.g., phenytoin, carbamazepine, phenobarbital), solifenacin, certain other "statins" (atorvastatin, rosuvastatin), temsirolimus.
This medication may decrease the effectiveness of combination-type birth control pills. This can result in pregnancy. You may need to use an additional form of reliable birth control while using this medication. Consult your doctor or pharmacist for details.
Tell your doctor or pharmacist if you also take drugs that cause drowsiness such as: certain antihistamines (e.g., diphenhydramine), muscle relaxants, psychiatric medicines (e.g., chlorpromazine, risperidone, amitriptyline).
Check the labels on all your medicines (e.g., cough-and-cold products) because they may contain drowsiness-causing ingredients. Ask you pharmacist about the safe use of those products.
This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.
OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly. Symptoms of overdose may include numbness or tingling in the arms, hands, legs, or feet, a change in amount of urine, severe drowsiness/dizziness, loss of consciousness, or shallow breathing.
Due to the high alcohol content of lopinavir/ritonavir solution, children accidentally drinking the medication may have a serious, possibly fatal reaction. If a child accidentally drinks this product, contact your local poison control center or emergency room immediately.
NOTES: To decrease your risk of spreading HIV disease, always use an effective barrier method (e.g., latex condoms/dental dams) during sexual activity. Consult your doctor or pharmacist for more details.
Do not share this medication with others.
Keep all medical and laboratory appointments. Laboratory and/or medical tests (e.g., liver function, blood counts, blood cholesterol/triglyceride levels, blood sugar) should be performed from time to time to monitor your progress or check for side effects. Consult your doctor for more details.
Lopinavir/ritonavir is available in tablets, capsules and oral solution. Do not switch types of this medication without instructions on how to do so by your doctor.
MISSED DOSE: It is important not to miss doses of this drug. If you miss a dose, take it as soon as you remember. If it is within 2 hours of your next dose, skip the missed dose and resume your usual dosing schedule.
STORAGE: Refrigerate between 36-46 degrees F (2-8 degrees C) away from light and moisture. If stored at room temperature (77 degrees F or 25 degrees C), this product should be used within 2 months. Avoid exposure to high heat. Do not store in the bathroom. Keep all medicines away from children and pets.
Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.
MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA), or 1-800-668-1507 (Canada).
Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.
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