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 (12.3) 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 non-nucleoside 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:Among patients 14 days to 6 months of age receiving 300/75 mg/m2 twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children.
This dose resulted in HIV-1 RNA < 400 copies/mL in 55% of patients (70% in those initiating treatment at <6 weeks of age).
Among patients 6 months to 12 years of age, 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).
These doses resulted in treatment benefit (proportion of patients with HIV-1 RNA < 400 copies/mL) similar to that seen in the adult clinical trials.Among patients 12 to 18 years of age receiving 400/100 mg/m2 or 480/120 mg/m2 (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among 6 to 12 year old patients receiving 230/57.5 mg/m2.
Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients 6 to 12 years of age.
Although changes in HIV-1 RNA in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients 6 to 12 years of age, not to exceed the recommended adult dose.For all age groups, the body surface area dosing was converted to body weight dosing using the actual patient dose.
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:The use of other active agents with KALETRA is associated with a greater likelihood of treatment response [see Clinical Pharmacology (12.4) and Clinical Studies (14)].Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA [see Clinical Pharmacology (12.4)].The number of baseline primary protease inhibitor mutations affects the virologic response to KALETRA [see Clinical Pharmacology (12.4)].Once-daily administration of KALETRA is not recommended for therapy-experienced adult patients or any pediatric patients.
? KALETRA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., Stevens-Johnson syndrome, erythema multiforme) to any of its ingredients, including ritonavir.? Co-administration of KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions.? Co-administration of KALETRA is contraindicated with potent CYP3A inducers where significantly reduced lopinavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance and cross-resistance.
These drugs are listed in Table 3.Table 3.
Drugs That Are Contraindicated With KALETRA Drug ClassDrugs Within Class That Are Contraindicated With KALETRAClinical comments: aSee Drug Interactions, Table 9 for parenterally administered midazolam AntimycobacterialRifampinMay 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 (7)] Ergot DerivativesDihydroergotamine, ergonovine, ergotamine, methylergonovinePotential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agentCisapridePotential 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 InhibitorsLovastatin, simvastatinPotential for myopathy including rhabdomyolysis. NeurolepticPimozidePotential for cardiac arrhythmias. Sedative/HypnoticsTriazolam;orally administered midazolamaProlonged or increased sedation or respiratory depression.