Kaletra Information
Kaletra (Lopinavir + ritonavir) Indications And Usage
Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) :
Kaletra (Lopinavir + ritonavir) Warnings And Precautions
Kaletra (Lopinavir + ritonavir) is a CYP3A inhibitor. Initiating treatment with Kaletra (Lopinavir + ritonavir) in patients receiving medications metabolized by CYP3A or initiating medications metabolized by CYP3A in patients already maintained on Kaletra (Lopinavir + ritonavir) may result in increased plasma concentrations of concomitant medications. Higher plasma concentrations of concomitant medications can result in increased or prolonged therapeutic or adverse effects, potentially leading to severe, life-threatening or fatal events. The potential for drug-drug interactions must be considered prior to and during therapy with Kaletra (Lopinavir + ritonavir) . Review of other medications taken by patients and monitoring of patients for adverse effects is recommended during therapy with Kaletra (Lopinavir + ritonavir) .
See Tables and for listing of drugs that are contraindicated for use with Kaletra (Lopinavir + ritonavir) due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity.
Kaletra (Lopinavir + ritonavir) oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving Kaletra (Lopinavir + ritonavir) oral solution.
Kaletra (Lopinavir + ritonavir) oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. A safe and effective dose of Kaletra (Lopinavir + ritonavir) oral solution in this patient population has not been established. However, if the benefit of using Kaletra (Lopinavir + ritonavir) oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to Kaletra (Lopinavir + ritonavir) oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of alcohol and propylene glycol from all medicines that are to be given to infants should be taken into account in order to avoid toxicity from these excipients
Pancreatitis has been observed in patients receiving Kaletra (Lopinavir + ritonavir) therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) .
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 (Lopinavir + ritonavir) therapy has not been established.
Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of Kaletra (Lopinavir + ritonavir) in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with Kaletra (Lopinavir + ritonavir) therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) treatment
Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. Kaletra (Lopinavir + ritonavir) should be used with caution in patients with underlying structural heart disease, pre-existing 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 (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended.
Kaletra (Lopinavir + ritonavir) Adverse Reactions
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.
Kaletra (Lopinavir + ritonavir) Drug Interactions
See also Contraindications (), Warnings and Precautions (), Clinical Pharmacology ()
Kaletra (Lopinavir + ritonavir) Use In Specific Populations
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. 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 well-controlled studies in pregnant women. Kaletra (Lopinavir + ritonavir) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
p269131408
The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV-1
not to breast-feed if they are receiving Kaletra (Lopinavir + ritonavir)
The safety, efficacy, and pharmacokinetic profiles of Kaletra (Lopinavir + ritonavir) in pediatric patients below the age of 14 days have not been established. Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of with 300/75 mg/m twice daily plus two NRTIs in HIV-infected infants ≥14 days and
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 (Lopinavir + ritonavir) 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/m oral solution twice daily regimen without nevirapine and the 300/75 mg/m 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) .
A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose Kaletra (Lopinavir + ritonavir) with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m twice daily + ≥ 1 NRTI + 1 NNRTI) in children and adolescents ≥ 2 years to
Kaletra (Lopinavir + ritonavir) Overdosage
Overdoses with Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) oral solution (520 mg lopinavir, approximately 10-fold above the recommended lopinavir dose) nine days prior. The following events have been reported in association with unintended overdoses in preterm neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure . Healthcare professionals should be aware that Kaletra (Lopinavir + ritonavir) oral solution is highly concentrated and therefore, should pay special attention to accurate calculation of the dose of Kaletra (Lopinavir + ritonavir) , 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 (Lopinavir + ritonavir) oral solution contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v). Ingestion of the product over the recommended dose by an infant or a young child could result in significant toxicity and could potentially be lethal.
Human experience of acute overdosage with Kaletra (Lopinavir + ritonavir) is limited. Treatment of overdose with Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) . If indicated, elimination of unabsorbed drug should be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since lopinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with Kaletra (Lopinavir + ritonavir) oral solution.
Kaletra (Lopinavir + ritonavir) Description
Kaletra (Lopinavir + ritonavir) (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV-1 protease. As co-formulated in Kaletra (Lopinavir + ritonavir) , ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.
Lopinavir is chemically designated as [1-[1*,(*), 3*, 4*]]--[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2)-pyrimidineacetamide. Its molecular formula is CHNO, 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:
Ritonavir is chemically designated as 10-hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5-(5*,8*,10*,11*)]. Its molecular formula is CHNOS, 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:
Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) Clinical Pharmacology
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 (Lopinavir + ritonavir) 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 antiviral EC of lopinavir is approximately 10-fold lower than that of ritonavir. Therefore, the antiviral activity of Kaletra (Lopinavir + ritonavir) is due to lopinavir.
Figure 1 displays the mean steady-state plasma concentrations of lopinavir and ritonavir after Kaletra (Lopinavir + ritonavir) 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)
Plasma concentrations of lopinavir and ritonavir after administration of two 200/50 mg Kaletra (Lopinavir + ritonavir) tablets are similar to three 133.3/33.3 mg Kaletra (Lopinavir + ritonavir) capsules under fed conditions with less pharmacokinetic variability.
Distribution
14
Elimination
Once Daily Dosing
max
The pharmacokinetics of once daily Kaletra (Lopinavir + ritonavir) has also been evaluated in treatment experienced HIV-1 infected subjects. Lopinavir exposure (C, AUC, C) with once daily Kaletra (Lopinavir + ritonavir) administration in treatment experienced subjects is comparable to the once daily lopinavir exposure in treatment naïve subjects.
Effects on Electrocardiogram
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 (Lopinavir + ritonavir) , respectively. Kaletra (Lopinavir + ritonavir) 800/200 mg twice daily resulted in a Day 3 mean C approximately 2-fold higher than the mean Cobserved with the approved once daily and twice daily Kaletra (Lopinavir + ritonavir) doses at steady state.
PR interval prolongation was also noted in subjects receiving Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) , respectively .
Special Populations
Gender, Race and Age
The mean steady-state lopinavir AUC, C, and C were 72.6 ± 31.1 µgh/mL, 8.2 ± 2.9 and 3.4 ± 2.1 µg/mL, respectively after Kaletra (Lopinavir + ritonavir) oral solution 230/57.5 mg/m twice daily without nevirapine (n = 12), and were 85.8 ± 36.9 µg h/mL, 10.0 ± 3.3 and 3.6 ± 3.5 µg/mL, respectively, after 300/75 mg/m 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 (Lopinavir + ritonavir) oral solution at approximately 300/75 mg/m 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 AUC, C, and C were 43.4 ± 14.8 µg• h/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 µg• h/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 (Lopinavir + ritonavir) oral solution was administered at approximately 300/75 mg/m twice daily without concomitant NNRTI therapy.
The pharmacokinetics of Kaletra (Lopinavir + ritonavir) soft gelatin capsule and oral solution (Group 1: 400/100 mg/m twice daily + 2 NRTIs; Group 2: 480/120 mg/m twice daily + ≥ 1 NRTI + 1 NNRTI) have been evaluated in children and adolescents age ≥ 2 years to
Kaletra (Lopinavir + ritonavir) once daily has not been evaluated in pediatric patients.
Renal Impairment
max
Drug Interactions
Kaletra (Lopinavir + ritonavir) is an inhibitor of the P450 isoform CYP3A . Co-administration of Kaletra (Lopinavir + ritonavir) 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 .
Kaletra (Lopinavir + ritonavir) does not inhibit CYP2D6, CYP2C9, CYP2C19, CYP2E1, CYP2B6 or CYP1A2 at clinically relevant concentrations.
Kaletra (Lopinavir + ritonavir) has been shown to induce its own metabolism and to increase the biotransformation of some drugs metabolized by cytochrome P450 enzymes and by glucuronidation.
Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.
Drug interaction studies were performed with Kaletra (Lopinavir + ritonavir) and other drugs likely to be co-administered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of co-administration of Kaletra (Lopinavir + ritonavir) on the AUC, C and C are summarized in Table 10 (effect of other drugs on lopinavir) and Table 11 (effect of Kaletra (Lopinavir + ritonavir) 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 .
Mechanism of Action
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.
Antiviral Activity
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 (EC) 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 EC 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 EC values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/mL).
Resistance
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 (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) was observed in 37 evaluable Kaletra (Lopinavir + ritonavir) -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 (Lopinavir + ritonavir) in antiretroviral treatment naïve pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).
Resistance to Kaletra (Lopinavir + ritonavir) has been noted to emerge in patients treated with other protease inhibitors prior to Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) 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 resistance-associated substitutions in isolates from patients on Kaletra (Lopinavir + ritonavir) therapy. The assessment of these patterns is under study.
Cross-resistance - Preclinical Studies
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 (Lopinavir + ritonavir) 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 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.
Clinical Studies - Antiviral Activity of Kaletra (Lopinavir + ritonavir) in Patients with Previous Protease Inhibitor Therapies
The clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) 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
Virologic response to Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC 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.
Kaletra (Lopinavir + ritonavir) Clinical Studies
Study 863: Kaletra (Lopinavir + ritonavir) Capsules twice daily + stavudine + lamivudine compared to nelfinavir three times daily + stavudine + lamivudine
Study 863 was a randomized, double-blind, multicenter trial comparing treatment with Kaletra (Lopinavir + ritonavir) capsules (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/mm (range: 2 to 949 cells/mm) and mean baseline plasma HIV-1 RNA was 4.9 log copies/mL (range: 2.6 to 6.8 log copies/mL).
Treatment response and outcomes of randomized treatment are presented in Table 14.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the Kaletra (Lopinavir + ritonavir) arm compared to the nelfinavir arm with HIV-1 RNA
Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 207 cells/mm for the Kaletra (Lopinavir + ritonavir) arm and 195 cells/mm for the nelfinavir arm.
Study 730: Kaletra (Lopinavir + ritonavir) Tablets once daily + tenofovir DF + emtricitabine compared to Kaletra (Lopinavir + ritonavir) Tablets twice daily + tenofovir DF + emtricitabine
Study 730 was a randomized, open-label, multicenter trial comparing treatment with Kaletra (Lopinavir + ritonavir) 800/200 mg once daily plus tenofovir DF and emtricitabine versus Kaletra (Lopinavir + ritonavir) 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naïve patients. Patients were randomized in a 1:1 ratio to receive either Kaletra (Lopinavir + ritonavir) 800/200 mg once daily (n = 333) or Kaletra (Lopinavir + ritonavir) 400/100 mg twice daily (n = 331). Further stratification within each group was 1:1 (tablet vs. capsule). Patients administered the capsule were switched to the tablet formulation at Week 8 and maintained on their randomized dosing schedule. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ cell count was 216 cells/mm(range: 20 to 775 cells/mm) and mean baseline plasma HIV-1 RNA was 5.0 log copies/mL (range: 1.7 to 7.0 log copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 16.
Through 48 weeks of therapy, 78% in the Kaletra (Lopinavir + ritonavir) once daily arm and 77% in the Kaletra (Lopinavir + ritonavir) twice daily arm achieved and maintained HIV-1 RNA
Study 888: Kaletra (Lopinavir + ritonavir) Capsules twice daily + nevirapine + NRTIs compared to investigator-selected protease inhibitor(s) + nevirapine + NRTIs
Study 888 was a randomized, open-label, multicenter trial comparing treatment with Kaletra (Lopinavir + ritonavir) capsules (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/mm (range: 10 to 1059 cells/mm) and mean baseline plasma HIV-1 RNA was 4.1 log copies/mL (range: 2.6 to 6.0 log copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 17.
Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the Kaletra (Lopinavir + ritonavir) arm compared to the investigator-selected protease inhibitor(s) arm with HIV-1 RNA
Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells/mm for the Kaletra (Lopinavir + ritonavir) arm and 112 cells/mm for the investigator-selected protease inhibitor(s) arm.
Study 802: Kaletra (Lopinavir + ritonavir) Tablets 800/200 mg Once Daily Versus 400/100 mg Twice Daily when Coadministered with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects
M06-802 was a randomized open-label study comparing the safety, tolerability, and antiviral activity of once daily and twice daily dosing of Kaletra (Lopinavir + ritonavir) tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy. Of the enrolled subjects, 55% on both treatment arms had not been previously treated with a protease inhibitor and 81 – 88% had received prior NNRTIs as part of their anti-HIV treatment regimen. Patients were randomized in a 1:1 ratio to receive either Kaletra (Lopinavir + ritonavir) 800/200 mg once daily (n = 300) or Kaletra (Lopinavir + ritonavir) 400/100 mg twice daily (n = 299). Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian, and 66% were male. Mean baseline CD4+ cell count was 254 cells/mm (range: 4 to 952 cells/mm) and mean baseline plasma HIV-1 RNA was 4.3 log copies/mL (range: 1.7 to 6.6 log copies/mL).
Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 18.
Through 48 weeks of treatment, the mean change from baseline for CD4 + cell count was 135 cells/mm for the once daily group and 122 cells/mm for the twice daily group.
Study 720: Kaletra (Lopinavir + ritonavir) twice daily + stavudine + lamivudineStudy 765: Kaletra (Lopinavir + ritonavir) twice daily + nevirapine + NRTIs
Study 720 (patients prior antiretroviral therapy) and study 765 (patients prior protease inhibitor therapy) were randomized, blinded, multi-center trials evaluating treatment with Kaletra (Lopinavir + ritonavir) 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/mm, 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) log copies/mL, respectively.
Through 360 weeks of treatment in study 720, the proportion of patients with HIV-1 RNA
Through 144 weeks of treatment in study 765, the proportion of patients with HIV-1 RNA
Study 1030 was an open-label, multicenter, dose-finding trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of Kaletra (Lopinavir + ritonavir) oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at a dose of 300/75 mg/m twice daily plus 2 NRTIs in HIV-1 infected infants ≥14 days and
Ten infants, ≥14 days and
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) log copies/mL. Ten of 21 infants had HIV RNA
See Clinical Pharmacology () for pharmacokinetic results
Study 940 was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of Kaletra (Lopinavir + ritonavir) 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 m or 300 mg lopinavir/75 mg ritonavir per m. 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 m 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/mm and mean baseline plasma HIV-1 RNA was 4.7 log copies/mL.
Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV-1 RNA
Dose selection in pediatric patients was based on the following:
Kaletra (Lopinavir + ritonavir) How Supplied/storage And Handling
Kaletra (Lopinavir + ritonavir) (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 (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) 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) (lopinavir/ritonavir) oral solution is a light yellow to orange colored liquid supplied in amber-colored 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 (Lopinavir + ritonavir) oral solution at 2°-8°C (36°-46°F) until dispensed. Avoid exposure to excessive heat. For patient use, refrigerated Kaletra (Lopinavir + ritonavir) 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 (Lopinavir + ritonavir) Patient Counseling Information
Kaletra (Lopinavir + ritonavir)
Kaletra (Lopinavir + ritonavir)
Kaletra (Lopinavir + ritonavir)
Kaletra (Lopinavir + ritonavir)
