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Kaletra Side Effects, and Drug Interactions - Lopinavir/ritonavir

SIDE EFFECTS

Adults:

Treatment-Emergent Adverse Events: KALETRA has been studied in 701 patients as combination therapy in Phase I/II and Phase III clinical trials. The most common adverse event associated with KALETRA therapy was diarrhea, which was generally of mild to moderate severity. Rates of discontinuation of randomized therapy due to adverse events were 5.8% in KALETRA-treated and 4.9% in nelfinavir-treated patients in Study 863.

Drug related clinical adverse events of moderate or severe intensity in > 2% of patients treated with combination therapy for up to 48 weeks (Phase III) and for up to 72 weeks (Phase I/II) are presented in Table 10. For other information regarding observed or potentially serious adverse events, please see WARNINGS and PRECAUTIONS.

Table 10: Percentage of Patients with Selected Treatment-Emergent¹ Adverse Events of Moderate or Severe Intensity Reported in > 2% of Adult Patients
	Study 863		Study 888		Other Studies
	Antiretroviral-Naive Patients 48 Weeks		Protease Inhibitor-Experien-ced Patients 48 Weeks		Study 720 (72 Weeks)	Study 957³and Study 765⁴(48-72 Weeks)
	KALETRA 400/100 mg BID+d4T + 3TC(N=326)	Nelfinavir 750 mg TID + d4T + 3TC (N=327)	KALETRA 400/100 mg BID+ NVP + NRTIs (N=148)	Investigator-Selected protease inhibitor(s)+ NVP+ NRTIs (N=140)	KALETRA BID²+ d4T + 3TC (N= 84)	KALETRA BID + NNRTI + NRTIs (N= 127)
Body as a Whole
Abdominal Pain	4%	3%	2%	2%	5%	2%
Asthenia	4%	3%	3%	6%	7%	8%
Chills	0%	<1%	2%	0%	1%	0%
Fever	<1%	<1%	2%	1%	0%	2%
Headache	2%	2%	2%	3%	7%	2%
Digestive System
Anorexia	1%	<1%	1%	3%	0%	0%
Diarrhea	16%	17%	7%	9%	24%	18%
Dyspepsia	2%	<1%	1%	1%	1%	0%
Dysphagia	0%	0%	2%	1%	1%	0%
Flatulence	2%	1%	1%	2%	1%	2%
Nausea	7%	5%	7%	16%	15%	4%
Vomiting	2%	2%	4%	12%	5%	2%
Nervous System
Depression	1%	2%	1%	2%	0%	2%
Insomnia	2%	1%	0%	2%	2%	2%
Skin and Appendages
Rash	1%	2%	2%	1%	4%	2%
¹mg BID [N=33]). Within dosing groups, moderate to severe nausea of probable/possible relationship to KALETRA occurred at a higher
²rate in the 400/200 mg dose arm compared to the 400/100 mg dose arm in group II.
³Includes adverse event data from patients receiving 400/100 mg BID (n=29) or 533/133 mg BID (n=28) for 48 weeks. Patients received KALETRA in combination with NRTIs and efavirenz.
⁴Includes adverse event data from patients receiving 400/100 mg BID (n=36) or 400/200 mg BID (n=34) for 72 weeks. Patients received KALETRA in combination with NRTIs and nevirapine.

Treatment-emergent adverse events occurring in less than 2% of adult patients receiving KALETRA in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment with KALETRA and of at least moderate intensity are listed below by body system.

Body as a Whole: Abdomen enlarged, allergic reaction, back pain, chest pain, chest pain substernal, cyst, drug interaction, drug level increased, face edema, flu syndrome, hypertrophy, infection bacterial, malaise, and viral infection.

Cardiovascular System: Atrial fibrillation, deep vein thrombosis, hypertension, migraine, palpitation, thrombophlebitis, varicose vein, and vasculitis.

Digestive System: Cholangitis, cholecystitis, constipation, dry mouth, enteritis, enterocolitis, eructation, esophagitis, fecal incontinence, gastritis, gastroenteritis, hemorrhagic colitis, increased appetite, jaundice, mouth ulceration, pancreatitis, sialadenitis, stomatitis, and ulcerative stomatitis.

Endocrine System: Cushing�s syndrome, diabetes mellitus, and hypothyroidism.

Hemic and Lymphatic System: Anemia, leukopenia, and lymphadenopathy.

Metabolic and Nutritional Disorders: Avitaminosis, dehydration, edema, glucose tolerance decreased, lactic acidosis, obesity, peripheral edema, weight gain, and weight loss.

Musculoskeletal System: Arthralgia, arthrosis and myalgia.

Nervous System: Abnormal dreams, agitation, amnesia, anxiety, apathy, ataxia, confusion, convulsion, dizziness, dyskinesia, emotional lability, encephalopathy, facial paralysis, hypertonia, libido decreased, neuropathy, paresthesia, peripheral neuritis, somnolence, thinking abnormal, and tremor.

Respiratory System: Asthma, bronchitis, dyspnea, lung edema, pharyngitis, rhinitis, and sinusitis.

Skin and Appendages: Acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, maculopapular rash, nail disorder, pruritis, seborrhea, skin benign neoplasm, skin discoloration, skin ulcer, and sweating.

Special Senses: Abnormal vision, eye disorder, otitis media, and taste perversion, and tinnitus.

Urogenital System: Abnormal ejaculation, gynecomastia, hypogonadism male, kidney calculus, and urine abnormality.

Post-Marketing Experience: The following adverse reactions have been reported during post-marketing use of KALETRA. Because these reactions are reported voluntarily from a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to KALETRA exposure.

Body as a whole: Redistribution/accumulation of body fat has been reported (see PRECAUTIONS, Fat Redistribution).

Cardiovascular: Bradyarrhythmias.

Laboratory Abnormalities: The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 11.

Table 11: Grade 3-4 Laboratory Abnormalities Reported in > 2% of Adult Patients
		Study 863		Study 888		Other Studies
		Antiretroviral-Naive Patients 48 Weeks		Protease Inhibitor-Experienced Patients 48 Weeks		Study 720 (72Weeks)	Study 957³and Study 765⁴(48-72 Weeks)
Variable	Limit¹	KALETRA 400/100mg BID + d4T + 3TC (N=326)	Nelfinavir 750 mg TID + d4T + 3TC (N=327)	KALETRA 400/100 mg BID + NVP + NRTIs (N=148)	Investigator- selected Protease In-hibitor(s)+ NVP+NRTIs (N=140)	KALETRA BID²+ d4T + 3TC (N= 84)	KALETRA BID + NNRTI + NRTIs (N= 127)
Chemistry	High
Glucose	>250 mg/dL	2%	2%	1%	2%	2%	5%
Uric Acid	>12 mg/dL	2%	2%	0%	1%	4%	1%
Total Bilirubin	>3.48mg/dL	<1%	0%	1%	3%	1%	0%
SGOT/AST	>180 U/L	2%	4%	5%	11%	10%	6%
SGPT/ALT	>215 U/L	4%	4%	6%	13%	8%	10%
GGT	>300 U/L	N/A	N/A	N/A	N/A	4%	28%
Total Cholesterol	>300 mg/dL	9%	5%	20%	21%	14%	33%
Triglycerides	>750 mg/dL	9%	1%	25%	21%	11%	32%
Amylase	>2 x ULN	3%	2%	4%	8%	5%	6%
Chemistry	Low
Inorganic	<1.5 mg/dL	0%	0%	1%	0%	0%	2%
Phosphorus
Hematology	Low
Neutrophils	0.75 x 10⁹/L	1%	3%	1%	2%	2%	4%
₁ULN = upper limit of the normal range; N/A = Not Applicable.
₂Includes clinical laboratory data from dose group I (400/100 mg BID only [N=16]) and dose group II (400/100 mg BID [N=35] and 400/200 mg BID [N=33]).
₃Includes clinical laboratory data from patients receiving 400/100 mg BID (n=29) or 533/133 mg BID (n=28) for 48 weeks. Patients received KALETRA in combination with NRTIs and efavirenz.
₄Includes clinical laboratory data from patients receiving 400/100 mg BID (n=36) or 400/200 mg BID (n=34) for 72 weeks. Patients received KALETRA in combination with NRTIs and nevirapine.

Pediatrics:

Treatment-Emergent Adverse Events: KALETRA has been studied in 100 pediatric patients 6 months to 12 years of age. The adverse event profile seen during a clinical trial was similar to that for adult patients.

Taste aversion, vomiting, and diarrhea were the most commonly reported drug related adverse events of any severity in pediatric patients treated with combination therapy including KALETRA for up to 48 weeks in Study 940. A total of 8 children experienced moderate or severe adverse events at least possibly related to KALETRA. Rash (reported in 3%) was the only drug-related clinical adverse event of moderate to severe intensity observed in � 2% of children enrolled.

Laboratory Abnormalities: The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 12.

Table 12: Grade 3-4 Laboratory Abnormalities Reported in � 2% Pediatric Patients
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.

DRUG INTERACTIONS

KALETRA is an inhibitor of CYP3A (cytochrome P450 3A) both in vitro and in vivo. Co-administration of KALETRA and drugs primarily metabolized by CYP3A (e.g., dihydropyridine calcium channel blockers, HMG-CoA reductase inhibitors, immunosuppressants and sildenafil) may result in increased plasma concentrations of the other drugs that could increase or prolong their therapeutic and adverse effects (see Table 9: Established and Other Potentially Significant Drug Interactions). 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.

KALETRA inhibits CYP2D6 in vitro, but to a lesser extent than CYP3A. Clinically significant drug interactions with drugs metabolized by CYP2D6 are possible with KALETRA at the recommended dose, but the magnitude is not known. KALETRA does not inhibit 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. Co-administration of KALETRA and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see Table 9: Established and Other Potentially Significant Drug Interactions). Although not noted with concurrent ketoconazole, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drugs that are contraindicated and not recommended for co-administration with KALETRA are included in Table 8: Drugs That Should Not Be Co-administered With KALETRA. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 8: Drugs That Should Not Be Co-administered With KALETRA
Drug Class: Drug Name	Clinical Comment
Antiarrhythmics: flecainide, propafenone	CONTRAINDICATED due to potential for serious and/or life threatening reactions such as cardiac arrhythmias.
Antihistamines: astemizole, terfenadine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
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.
Ergot Derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.
GI Motility Agent: cisapride	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products: St. John�s 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 serious reactions such as risk of myopathy including rhabdomyolysis.
Neuroleptic: pimozide	CONTRAINDICATED due to the potential for serious and/or life- threatening reactions such as cardiac arrhythmias.
Sedative/Hypnotics: midazolam, triazolam	CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

Table 9: Established and Other Potentially 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, Tables 2 and 3)
Concomitant Drug Class: Drug Name	Effect on Concentration of lopinavir or Concomitant Drug	Clinical Comment
HIV-Antiviral Agents
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine	� Lopinavir	A dose increase of KALETRA to 533/133 mg (4 capsules or 6.5 mL) twice daily taken with food is recommended when used in combination with efavirenz or nevirapine (see DOSAGE AND ADMINIST-RATION). NOTE: Efavirenz and nevirapine induce the activity of CYP3A and thus have the potential to decrease plasma concentrations of other protease inhibitors when used in combination with KALETRA.
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		It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA (given with food).
HIV-Protease Inhibitors: amprenavir, indinavir, saquinavir*	When co-administered with reduced doses of concomitant protease inhibitors: � Amprenavir (Similar AUC, � C_max,� C_min⁾� Indinavir (Similar AUC, � C_max^,� C_min⁾� Saquinavir (Similar AUC, � C_min⁾	Alterations in concentrations (e.g., AUC, C_maxand C_min) are noted when reduced doses of concomitant protease inhibitors are co- administered with KALETRA. Appropriate doses of the combination with respect to safety and efficacy have not been established (see CLINICAL PHARMACO-LOGY: Table 3 and Effect of KALETRA on other Protease Inhibitors (PIs)).
HIV-Protease Inhibitor: ritonavir*	� Lopinavir	Appropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.
Other Agents
Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine	� Antiarrhythmics	Caution is warranted and therapeutic concentration moni-toring is recommended for antiarrhythmics when co-administered with KALETRA, if available.
Anticoagulant: warfarin		Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin	� Lopinavir	Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Anti-infective: clarithromycin	� Clarithromycin	For patients with renal impair-ment, the following dosage ad-justments should be considered:
		� For patients with CLCR 30 to 60 mL/min the dose of clari-thromycin should be reduced by 50%. � For patients with CLCR <30 mL/min the dose of clarithro-mycin should be decreased by 75%.
		No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole	� Ketoconazole � Itraconazole	High doses of ketoconazole or itraconazole (>200 mg/day) are not recommended.
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 events is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.
Antiparasitic: atovaquone	� Atovaquone	Clinical significance is unknown; however, increase in atovaquone doses may be needed.
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/metronid-azole		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).
Erectile Dysfunction Agent: sildenafil	� Sildenafil	Use with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
HMG-CoA Reductase Inhibitors: atorvastatin*	� Atorvastatin	Use lowest possible dose of atorvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA.
Immunosuppresants: cyclosporine, tacrolimus, rapamycin	� Immunosuppressants	Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Narcotic Analgesic: Methadone*	� Methadone	Dosage of methadone may need to be increased when co-administered with KALETRA.
Oral Contraceptive: ethinyl estradiol*	� Ethinyl estradiol	Alternative or additional contraceptive measures should be used when estrogen-based oral contraceptives and KALETRA are co- administered.
* See CLINICAL PHARMACOLGY for Magnitude of Interaction, Tables 2 and 3

Other Drugs:

Drug interaction studies reveal no clinically significant interaction between KALETRA and pravastatin, stavudine or lamivudine.

Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

Zidovudine and Abacavir: KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.

Carcinogenesis, Mutagenesis and Impairment of Fertility

Long-term carcinogenicity studies of KALETRA in animal systems have not been completed. Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, at levels of 50, 100 or 200 mg/kg/day, 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 BID). 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. In rats dosed at levels of 7, 15 or 30 mg/kg/day there were no carcinogenic effects. 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 BID 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 BID).

Pregnancy

Pregnancy Category C: 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 (100/50 mg/kg/day). Based on AUC measurements, the drug exposures in rats at 100/50 mg/kg/day 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 BID). In a peri- and postnatal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal day 21) occurred at 40/20 mg/kg/day and greater.

No embryonic and fetal developmental toxicities were observed in rabbits at a maternally toxic dosage (80/40 mg/kg/day). Based on AUC measurements, the drug exposures in rabbits at 80/40 mg/kg/day 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 BID). There are, however, no adequate and well-controlled studies in pregnant women. KALETRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Antiretroviral Pregnancy Registry: 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.

Nursing Mothers: The Centers for Disease Control and Prevention recommend that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV. 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 transmission and the potential for serious adverse reactions in nursing infants, mothers should be instructed not to breast-feed if they are receiving KALETRA.

Geriatric Use

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.

Pediatric Use

The safety and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 6 months have not been established. In HIV-infected patients age 6 months to 12 years, the adverse event profile seen during a clinical trial was similar to that for adult patients. The evaluation of the antiviral activity of KALETRA in pediatric patients in clinical trials is ongoing.

Study 940 is an ongoing 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 naive (44%) and experienced (56%) pediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naive. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m² or 300 mg lopinavir/75 mg ritonavir per m². Naive 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 RNA < 400 copies/mL was 80% for antiretroviral naive patients and 71% for antiretroviral experienced patients. The mean increase from baseline in CD4 cell count was 404 cells/mm³ for antiretroviral naive 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 naive patient prematurely discontinued secondary to an adverse event attributed to KALETRA, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-related event.

Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m² BID regimen without nevirapine and the 300/75 mg/m² BID regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg BID regimen (without nevirapine).

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