Kaletra: Indications, Dosage, Precautions, Adverse Effects
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Kaletra - Product Information

Manufacture: AbbVie
Country: Canada
Condition: HIV Infection, Nonoccupational Exposure
Class: Protease inhibitors
Form: Tablets
Ingredients: lopinavir, ritonavir, colloidal silicon dioxide, copovidone, polyethylene glycol 3350, polyvinyl alcohol, sodium stearyl fumarate, sorbitan monolaurate, talc, titanium dioxide, yellow ferric oxide E172

KALETRA

lopinavir/ritonavir

Summary Product Information

Route of
Administration
Dosage Form /
Strength
Clinically Relevant Non-medicinal Ingredients*
Oral film-coated tablets
/ 100 mg/25 mg,
200 mg/50 mg
sorbitan monolaurate
oral solution /
80/20 mg/mL
alcohol, fructose, polyoxyl 40 hydrogenated castor oil and propylene glycol

* For a complete listing of non-medicinal ingredients, see DOSAGE FORMS, COMPOSITION AND PACKAGING section.

Description

KALETRA (lopinavir/ritonavir) is a co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the Human Immunodeficiency Virus (HIV) protease. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

Indications and Clinical Use

KALETRA (lopinavir/ritonavir) is indicated in combination with other antiretroviral agents when therapy is warranted for:

  • treatment of HIV-1 infection.

This indication is based on analyses of plasma HIV RNA levels and CD4 cell counts in controlled KALETRA studies of 48 weeks duration, and in smaller uncontrolled KALETRA dose-ranging studies of 144 to 360 weeks duration. At present, there are no results from controlled trials evaluating the effect of KALETRA on clinical progression of HIV disease. A limited number of patients between 6 months and 2 years of age have been studied. No data are available on patients less than 6 months of age.

There are insufficient data to support the use of once daily administration of KALETRA for adult patients with three or more protease-inhibitor associated mutations (see ACTION AND CLINICAL PHARMACOLOGY).

Geriatrics (≥ 65 years of age)

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.

Pediatrics (6 months to 18 years of age)

The safety and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 6 months have not been established. For pediatric use of KALETRA oral solution, see (WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics), (DOSAGE AND ADMINISTRATION), and (OVERDOSAGE). In HIV-infected patients age 6 months to 18 years, the adverse event profile seen during clinical trials was similar to that for adult patients (see CLINICAL TRIALS, Pediatric Use). KALETRA should not be administered once daily to pediatric patients less than 18 years of age.

Contraindications

  • KALETRA (lopinavir/ritonavir) is contraindicated in patients with known hypersensitivity to any of its ingredients, including ritonavir. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
  • Co-administration of KALETRA is contraindicated with drugs that are highly dependent on CYP3A (cytochrome P450 3A) for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. These drugs are listed in Table 1.
  • 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 1.
Table 1. Drugs that are Contraindicated with KALETRA
Drug Class Drugs Within Class That Are
Contraindicated with
KALETRA
Clinical Comment
Alpha 1-adrenoreceptor antagonist alfuzosin CONTRAINDICATED due to potential for serious reactions such as hypotension.
Antibiotic fusidic acid CONTRAINDICATED due to potential of increased fusidic acid-associated adverse events such as hepatitis or bone marrow suppression.
Antihistamines astemizole1, terfenadine1 CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Antimycobacterial rifampin CONTRAINDICATED due to potential loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents. See (DETAILED PHARMACOLOGY) for further details.
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.
Gastrointestinal (GI) Motility Agent cisapride1 CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
Herbal Products St. John’s Wort
(Hypericum perforatum)
CONTRAINDICATED due to potential loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors (see also DRUG INTERACTIONS, Drug-Herb Interactions).
HMG-CoA Reductase Inhibitors lovastatin, simvastatin CONTRAINDICATED due to potential for serious reactions such as risk of myopathy including rhabdomyolysis [see also (WARNINGS AND PRECAUTIONS) and (DRUG INTERACTIONS, Serious Drug Interactions)].
Long Acting Beta-Adrenoceptor Agonist salmeterol CONTRAINDICATED due to the potential for increased risk of cardiovascular adverse events associated with salmeterol.
Neuroleptic pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
PDE5 Inhibitors sildenafil2, only when used for the treatment of pulmonary arterial hypertension [PAH] CONTRAINDICATED due to potential increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
vardenafil CONTRAINDICATED due to potential increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
Sedatives/Hypnotics midazolam, triazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

1. Product not marketed in Canada.

2. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 8 for administration of sildenafil in patients with erectile dysfunction.

Warnings and Precautions

Serious Warnings and Precautions

  • 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 should occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

General

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 the area under the plasma concentration-time curve (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. Additionally, KALETRA induces glucuronidation [see (CONTRAINDICATIONS), (DRUG INTERACTIONS) and (DETAILED PHARMACOLOGY)].

The presence of fructose in KALETRA oral solution may be unsuitable in Hereditary Fructose Intolerance (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

The presence of high level alcohol in KALETRA oral solution is potentially harmful for those suffering from liver disease, alcoholism, epilepsy, brain injury or disease, as well as for pregnant women and children. It may modify or increase the effects of the other medicines (see DOSAGE FORMS, COMPOSITION AND PACKAGING).

Patients taking KALETRA oral solution, particularly those with renal impairment or with decreased ability to metabolize propylene glycol (e.g. those of Asian origin), should be monitored for adverse reactions potentially related to propylene glycol toxicity (i.e. seizures, stupor, tachycardia, hyperosmolarity, lactic acidosis, renal toxicity, haemolysis).

Antimycobacterial

KALETRA should not be co-administered with rifampin as it may significantly decrease lopinavir’s therapeutic effect (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Co-administration of KALETRA with rifabutin substantially increases concentration of rifabutin and its active metabolite by > 5-fold which may result in an increase in rifabutin-associated adverse events, including fever, neutropenia and uveitis (see DRUG INTERACTIONS).

Antipsychotics

Due to inhibition of CYP3A by KALETRA, co-administration of KALETRA with quetiapine results in increased quetiapine concentrations. Serious and life-threatening quetiapine-related adverse reactions have been reported. KALETRA should not be used in combination with quetiapine (see DRUG INTERACTIONS).

HMG-CoA Reductase Inhibitors

HMG-CoA reductase inhibitors (statins) may interact with protease inhibitors and increase the risk of myopathy including rhabdomyolysis. The long-term safety when co-administering HMG-CoA reductase inhibitors with KALETRA has not been established. Concomitant use of protease inhibitors with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS and DRUG INTERACTIONS).

Co-Administration with Tipranavir

The concomitant administration of KALETRA and tipranavir co-administered with low-dose ritonavir is not recommended. Tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily), co-administered with lopinavir/ritonavir (400/100 mg twice daily), resulted in a 55 and 70% reduction in lopinavir AUC and Cmin, respectively (see DRUG INTERACTIONS).

Carcinogenesis and Mutagenesis

For a brief discussion of pre-clinical animal data, (see TOXICOLOGY, Mutagenicity and Carcinogenicity).

Cardiovascular

PR Interval Prolongation

In a Phase 1 study in healthy volunteers, mean change from baseline in PR interval of 11.6 to 31.2 msec was noted in subjects receiving KALETRA on Study Day 3 when exposures were up to 3-fold higher than observed with recommended once daily or twice daily KALETRA doses at steady state. Maximum PR interval was 286 msec and no second- or third-degree heart block was observed.

There have been post-marketing reports of asymptomatic prolongation of the PR interval in some patients receiving combination antiretroviral therapy containing lopinavir/ritonavir. Reports of second- or third-degree atrioventricular block in patients with underlying structural heart disease and pre-existing conduction system abnormalities or in patients receiving drugs known to prolong the PR interval (such as verapamil, calcium blockers, beta-adrenergic blockers, digoxin and atazanavir) have been reported in patients receiving KALETRA. KALETRA should be used with caution in such patients, particularly with those drugs metabolized by CYP3A (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacodynamics, Effects on the Electrocardiogram).

QT Interval Prolongation

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 QT interval (see ACTION AND CLINICAL PHARMACOLOGY).

Endocrine and Metabolism

Corticosteroids

The concomitant use of KALETRA and fluticasone or other glucocorticoids, such as budesonide, that are metabolized by CYP3A4 significantly increases the plasma concentration of fluticasone or budesonide, leading to significant decreases in the plasma concentration of cortisol. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during post-marketing administration of KALETRA with inhaled or intranasal fluticasone or budesonide.

Co-administration of KALETRA and fluticasone or budesonide, therefore, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects (see DRUG INTERACTIONS).

Diabetes Mellitus/Hyperglycemia

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 (PI) 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 PI 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 PI therapy and these events has not been established.

Fat Redistribution

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.

Hematologic

There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors (PIs). In some patients additional factor VIII was given. In more than half of the reported cases, treatment with PIs was continued or reintroduced. A causal relationship between PI therapy and these events has not been established; however, the frequency of bleeding episodes should be closely monitored in patients on KALETRA.

Hepatic/Biliary/Pancreatic

Hepatic

KALETRA is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment. KALETRA has not been studied in patients with severe hepatic impairment. Pharmacokinetic data suggests increases in lopinavir plasma concentrations of approximately 30% as well as decreases in plasma protein binding in HIV and hepatitis C virus (HCV) co-infected patients with mild to moderate hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics). Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for developing or worsening of transaminases elevations or hepatic decompensation with use of KALETRA.

There have been post-marketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA 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 in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with KALETRA therapy has not been established.

Increased aspartate transaminase (AST) and alanine transaminase (ALT) monitoring should be considered in these patients, especially during the first several months of KALETRA treatment.

Pancreatic

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 elevation is a risk factor for development of pancreatitis (see WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests, Lipid Elevations). Patients with advanced HIV 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.

Immune

Immune Reconstitution Inflammatory Syndrome

Immune reconstitution inflammatory syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of treatment, patients responding to antiretroviral therapy may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium-complex (MAC), cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia (PCP), and tuberculosis (TB)], which may necessitate further evaluation and treatment.

Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.

Sexual Function/Reproduction

PDE5 inhibitors

Particular caution should be used when prescribing PDE5 inhibitors for the treatment of erectile dysfunction in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in increase in associated adverse events such as hypotension, syncope, visual changes, and prolonged erection.

Concomitant use of sildenafil with KALETRA is contraindicated in pulmonary arterial hypertension patients. Concomitant use of vardenafil with KALETRA is contraindicated. See (CONTRAINDICATIONS) and (DRUG INTERACTIONS).

Sensitivity/Resistance

Resistance/Cross-resistance

Various degrees of cross-resistance among protease inhibitors have been observed. The effect of KALETRA therapy on the efficacy of subsequently-administered PIs is under investigation. HIV-1 isolates with reduced susceptibility to lopinavir have been selected in vitro. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in vitro. The selection of resistance to KALETRA therapy in antiretroviral treatment-naïve patients has not yet been characterized in vivo (see ACTION AND CLINICAL PHARMACOLOGY, Resistance and Cross-resistance).

Special Populations

Pregnant Women

There are no adequate and well-controlled studies in pregnant women.

KALETRA, twice daily only, may be used during pregnancy only if the potential benefits justify the potential risk to the fetus.

Based on limited pharmacokinetics data from a published literature, 12 HIV-infected pregnant women received KALETRA 400 mg/100 mg (two 200/50 mg tablets) twice daily as part of an antiretroviral regimen. Plasma concentrations of lopinavir were measured over 12-hour periods during the second trimester (20-24 weeks gestation), the third trimester (30 weeks gestation) and at 8 weeks post-partum. The C12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum.

Once daily KALETRA dosing is not recommended in pregnancy.

There are insufficient data to recommend KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions.

Avoid use of KALETRA oral solution during pregnancy due to the alcohol content. KALETRA oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v).

No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits. Embryonic and fetal developmental toxicities occurred in rats at a maternally toxic dose (see TOXICOLOGY, Reproduction and Teratology, Reproduction).

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).

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.

In post-marketing surveillance through the Antiretroviral Pregnancy Registry, established since January 1989, based on prospective reports of over 3000 exposures to lopinavir containing regimens (including over 1000 exposed in the first trimester), there was no difference between lopinavir and overall birth defects compared with the background birth defect rate of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). Based on prospective reports from the APR of over 5000 exposures to ritonavir containing regimens (including over 2000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems. The prevalence of birth defects after any trimester exposure to KALETRA is comparable to the prevalence observed in the general population. The population exposed and monitored to date is only sufficient to detect major teratogenicity, and cannot detect an increase in the risk of relatively rare defects, however no pattern of birth defects suggestive of a common etiology was seen.

Nursing Women

HIV-infected mothers should 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.

Pediatrics (6 months to 18 years of age)

KALETRA should not be administered once daily to pediatric patients less than 18 years of age (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Pediatrics).

Toxicity in Preterm Neonates

A safe and effective dose of KALETRA oral solution in the preterm neonate population has not been established. KALETRA oral solution contains the excipients alcohol (42.4% v/v) and propylene glycol (15.3% w/v). KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities (see OVERDOSAGE). 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 an increased risk of propylene glycolassociated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. 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. Infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to 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. 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 oral solution.

Geriatrics (≥ 65 years of age)

For a brief discussion, see INDICATIONS AND CLINICAL USE.

Monitoring and Laboratory Tests

Lipid Elevations

Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides (see ADVERSE REACTIONS, Abnormal Hematologic and Clinical Chemistry Findings, and Table 6). 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 consideration any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors [see (CONTRAINDICATIONS) and (DRUG INTERACTIONS)].

Adverse Reactions

Overview

Adults

The safety of KALETRA (lopinavir/ritonavir) has been investigated in 2,612 patients in Phase 2 to 4 clinical trials, of which more than 700 have received a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine.

Commonly reported adverse reactions to KALETRA during clinical trials included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. Diarrhea, nausea and vomiting may occur at the beginning of the treatment while hypertriglyceridemia and hypercholesterolemia may occur later.

Cumulative treatment-emergent adverse reactions of moderate or severe intensity are identified in Table 4.

Pediatrics

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.

Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity and of probable, possible or unknown relationship to KALETRA oral solution in pediatric patients treated with combination therapy for up to 48 weeks in Study M98-940. A total of eight subjects experienced adverse events of moderate to severe intensity and of possible, probable, or unknown relationship to KALETRA, which include: allergic reaction (characterized by fever, rash, and jaundice), fever, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, serum glutamic pyruvic transaminase (SGPT) increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in two or more subjects (n=3).

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Adults

Drug-related clinical adverse events of moderate or severe intensity in ≥ 2% of patients treated with combination therapy including KALETRA for up to 48 weeks (Phase 3) and for up to 360 weeks (Phase 1/2) are presented in Table 2. For other information regarding observed or potentially serious adverse events, see WARNINGS AND PRECAUTIONS.

Percentages of patients with selected treatment-emergent adverse events of moderate or severe intensity reported in ≥ 2% of adult PI-experienced patients are listed in Table 3. The incidence of diarrhea during 48 weeks of therapy was similar for KALETRA tablets dosed once daily compared to KALETRA tablets dosed twice daily in Study M05-730.

Table 2. Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients
Study M98-863
(48 Weeks)
Study M02-418
(48 Weeks)
Study
M97-720
(360 Weeks)
Study M05-730
(48 Weeks)
KALETRA capsules 400/100 mg b.i.d. + d4T + 3TC nelfinavir 750 mg t.i.d. + d4T + 3TC KALETRA capsules 800/200 mg daily + TDF + FTC KALETRA capsules 400/100 mg b.i.d. + TDF + FTC KALETRA capsules b.i.d.2 + d4T + 3TC KALETRA tablets3 800/200 mg daily + TDF + FTC KALETRA tablets3 400/100 mg b.i.d. + TDF + FTC
(N=326) (N=327) (N=115) (N=75) (N=100) (N=333) (N=331)
Endocrine Disorders
Hypogonadism Male 0% 0% 0% 0% 2% 0% 0%
Gastrointestinal Disorders
Diarrhea 16% 17% 16% 5% 28% 17% 15%
Nausea 7% 5% 9% 8% 16% 7% 5%
Vomiting 2% 2% 3% 4% 6% 3% 4%
Abdominal Pain 4% 3% 3% 3% 11% 1% 1%
Dyspepsia 2% < 1% 0% 1% 6% 0% 0%
Flatulence 2% 1% 2% 1% 4% 1% 1%
Abdominal Distension < 1% 1% 1% 0% 4% < 1% < 1%
Abnormal Feces 0% < 1% 0% 0% 8% 0% 0%
General Disorders and Administration Site Conditions
Asthenia 4% 3% 0% 0% 9% < 1% < 1%
Pain 1% 0% 0% 0% 3% 0% 0%
Infections and Infestations
Bronchitis 0% 0% 0% 0% 2% 0% < 1%
Investigations
Weight decreased 1% < 1% 0% 0% 2% 0% < 1%
Metabolism and Nutrition Disorders
Anorexia 1% < 1% 1% 1% 2% < 1% 1%
Musculoskeletal and Connective Tissue Disorders
Myalgia 1% 1% 0% 0% 2% 0% 0%
Nervous System Disorders
Headache 2% 2% 3% 3% 6% 2% 1%
Paresthesia 1% 1% 0% 0% 2% 0% 0%
Psychiatric Disorders
Insomnia 2% 1% 0% 0% 3% 1% 0%
Depression 1% 2% 1% 0% 0% 0% 0%
Libido decreased < 1% < 1% 0% 1% 2% 0% < 1%
Reproductive System and Breast Disorders
Amenorrhea 0% 0% 5% 0% 0% 0% 0%
Skin and Subcutaneous Tissue Disorders
Lipodystrophy Acquired 1% 1% 0% 0% 12% 0% 0%
Rash 1% 2% 1% 0% 5% < 1% 1%
Vascular Disorders
Vasodilatation 0% 0% 0% 0% 3% 0% 0%

1: Includes adverse events of possible or probable relationship to study drug.

2: Includes adverse event data from dose group I (200/100 mg twice daily [N=16] and 400/100 mg twice daily only [N=16]) and dose group II (400/100 mg twice daily [N=35] and 400/200 mg twice daily [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.

3: In the first 8 weeks of the study, 166 and 165 of the patients received KALETRA capsule once daily and twice daily, respectively. After that period, all patients received KALETRA tablet.

Definitions: b.i.d. = twice daily; t.i.d. = three times daily; d4T = stavudine; 3TC = lamivudine; FTC = emtricitabine; TDF = tenofovir DF

Table 3. Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients
Study M98-888
(48 Weeks)
Study M98-9572
and Study M97-7653
(84 to 144
Weeks)
Study M06-802
(48 Weeks)
KALETRA
capsules
400/100 mg
b.i.d. + NVP +
NRTIs
Investigator-selected PI(s) +
NVP + NRTIs
KALETRA
capsules b.i.d. +
NNRTI + NRTIs
KALETRA
tablets
800/200 mg
daily + NRTIs
KALETRA
tablets
400/100 mg
b.i.d. + NRTIs
(N=148) (N=140) (N=127) (N=300) (N=299)
Gastrointestinal Disorders
Diarrhea 7% 9% 23% 14% 11%
Nausea 7% 16% 5% 3% 7%
Vomiting 4% 12% 2% 2% 3%
Abdominal Pain 2% 2% 4% 2% <1%
Abdominal Pain Upper N/A N/A N/A 1% 2%
Flatulence 1% 2% 2% 1% 1%
Dysphagia 2% 1% 0% 0% 0%
Abnormal Feces 0% 2% 0% 0% 0%
General Disorders and Administration Site Conditions
Asthenia 3% 6% 9% <1% <1%
Pyrexia 2% 1% 2% 0% <1%
Pain 0% 0% 4% 0% 0%
Chills 2% 0% 0% 0% 0%
Investigations
Weight decreased 0% 1% 3% <1% <1%
Metabolism and Nutrition Disorders
Anorexia 1% 3% 0% 0% 1%
Nervous System Disorders
Headache 2% 3% 2% <1% 0%
Paresthesia 0% 1% 2% 0% 0%
Psychiatric Disorders
Depression 1% 2% 3% <1% 0%
Insomnia 0% 2% 2% 0% <1%
Skin and Subcutaneous Tissue Disorders
Lipodystrophy Acquired 1% 1% 6% 1% 1%
Rash 2% 1% 2% 0% 0%
Vascular Disorders
Hypertension 0% 0% 2% 0% 0%

1: Includes adverse events of possible or probable relationship to study drug.

2: Includes adverse event data from patients receiving 400/100 mg twice daily (n=29) or 533/133 mg twice daily (n=28) for 84 weeks. Patients received KALETRA in combination with NRTIs and efavirenz.

3: Includes adverse event data from patients receiving 400/100 mg twice daily (n=36) or 400/200 mg twice daily (n=34) for 144 weeks. Patients received KALETRA in combination with NRTIs and nevirapine.

2, 3: Average of Studies M98-957 and M97-765; both studies have subjects dosed with KALETRA + NNRTI + NRTIs.

Definitions: b.i.d. = twice daily; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; N/A = not applicable.

Cummulative Common Clinical Trial Adverse Drug Reactions

The following have been identified as cumulative treatment-emergent adverse reactions of moderate to severe intensity (Table 4).

Table 4. Treatment-Emergent Adverse Reactions of Moderate or Severe Intensity Occurring in ≥ 2% of Adult Patients Receiving KALETRA in Combined Phase 2 to 4 Studies (N= 2,612)
System Organ Class / Adverse Drug Reactions* n %
Blood and Lymphatic System Disorders
Anemia* 54 2.1
Gastrointestinal Disorders
Abdominal pain (upper and lower) * 160 6.1
Diarrhea* 510 19.5
Dyspepsia 53 2.0
Gastroenteritis and colitis* 66 2.5
Nausea 269 10.3
Vomitting* 177 6.8
General Disorders and Administration Site
Conditions
Fatigue including asthenia* 198 7.6
Hepatobiliary Disorders
Hepatitis including AST, ALT, and GGT increases* 91 3.5
Immune System Disorders
Hypersensivity including urticaria and angioedema* 70 2.7
Infections and Infestations
Lower respiratory tract infection* 202 7.7
Skin infections including cellulitis, folliculitis, and furuncle* 86 3.3
Upper respiratory tract infection* 363 13.9
Metabolism and Nutrition Disorders
Decreased appetite 52 2.0
Hypercholesterolemia* 192 7.4
Hypertriglyceridemia* 161 6.2
Weight decreased* 61 2.3
Musculoskeletal and Connective Tissue Disorders
Musculoskeletal pain including arthralgia and back pain* 166 6.4
Nervous System Disorders
Headache including migraine* 165 6.3
Insomnia* 99 3.8
Neuropathy and peripheral neuropathy* 51 2.0
Psychiatric Disorders
Anxiety* 101 3.9
Renal and Urinary Disorders
Reproductive System and Breast Disorders
Skin and Subcutaneous Tissue Disorders
Lipodystrophy acquired including facial wasting* 58 2.2
Rash including maculopapular rash* 99 3.8
Vascular Disorders

* Represents a medical concept including several similar MedDRA Preferred Terms (PTs)

Less Common Clinical Trial Adverse Drug Reactions (< 2%)

Treatment-emergent adverse events occurring in less than 2% of adult patients receiving KALETRA in all Phase 2 to 4 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 system organ class.

Blood and Lymphatic System Disorders: Leukopenia and neutropenia*, lymphadenopathy*, splenomegaly.
Cardiac Disorders: Angina pectoris, atherosclerosis such as myocardial infarction*, atrial fibrillation, atrioventricular block*, palpitations, tricuspid valve incompetence*.
Ear and Labyrinth Disorders: Hyperacusis, tinnitus, vertigo*.
Endocrine Disorders: Cushing’s syndrome, hypogonadism*, hypothyroidism.
Eye Disorders: Eye disorder, visual disturbance, visual impairment*.
Gastrointestinal Disorders: Abdominal discomfort, abdominal distension, constipation*, dry mouth, duodenitis and gastritis*, enteritis, enterocolitis, enterocolitis hemorrhagic, eructation, esophagitis, fecal incontinence, flatulence, gastroesophageal reflux disease (GERD)*, gastric disorder, gastric ulcer, gastrointestinal hemorrhage including rectal hemorrhage*, hemorrhoids, gastrointestinal ulcer*, pancreatitis*, periodontitis, rectal hemorrhage, stomach discomfort, stomatitis and oral ulcers*.
General Disorders and Administration Site Conditions: Chest pain, cyst, drug interaction, edema, edema peripheral, face edema, hypertrophy, malaise.
Hepatobiliary Disorders: Cholangitis, cholecystitis, cytolytic hepatitis, hepatic steatosis, hepatomegaly, jaundice, liver tenderness.
Immune System Disorders: Drug hypersensitivity, immune reconstitution inflammatory syndrome.
Infection and Infestations: Bacterial infection, bronchopneumonia, influenza, otitis media, perineal abscess, pharyngitis, rhinitis, sialoadenitis, sinusitis, viral infections.
Investigations: Drug level increased, glucose tolerance decreased.
Metabolism and Nutrition Disorders: Blood glucose disorders including diabetes mellitus*, dehydration, dislipidaemia, hypovitaminosis, increased appetite, lactic acidosis*, lipomatosis, obesity, weight increased*.
Musculoskeletal and Connective Tissue Disorders: Arthropathy, muscle disorders such as weakness and spasms*, myalgia*, osteoarthritis, osteonecrosis, pain in extremity, rhabdomyolisis*.
Neoplasms Benign, Malignant and Unspecified (incl. Cysts and Polyps): Benign neoplasm of skin, lipoma, neoplasm.
Nervous System Disorders: Ageusia*, amnesia, ataxia, balance disorder, cerebral infarction, cerebral vascular event*, convulsion*, dizziness*, dysgeusia, dyskinesia, encephalopathy, extrapyramidal disorder, facial palsy, hypertonia, somnolence, tremor*.
Psychiatric Disorders: Abnormal dreams*, affect lability, agitation, apathy, confusional state, disorientation, libido decreased, mood swings, nervousness, thinking abnormal.
Renal and Urinary Disorders: Hematuria*, nephritis*, nephrolithiasis, renal disorder, renal failure*, urine abnormality, and urine odor abnormal.
Reproductive System and Breast Disorders: Breast enlargement, menstrual disorders including amenorrhea, menorrhagia*, ejaculation disorder, erectile dysfunction*, gynecomastia.
Respiratory, Thoracic and Mediastinal Disorders: Asthma, cough, dyspnea, pulmonary edema.
Skin and Subcutaneous Tissue Disorders: Acne, alopecia, capillaritis and vasculitis*, dermatitis acneiform, dermatitis allergic, dermatitis exfoliative, dermatitis/rash including eczema and seborrheic dermatitis*, dry skin, hyperhidrosis, idiopathic capillaritis, nail disorder, night sweats*, pruritus*, rash generalized, seborrhea, skin discoloration, skin hypertrophy, skin striae, skin ulcer, swelling face.
Vascular Disorders: Deep vein thrombophlebitis, deep vein thrombosis*, orthostatic hypertension*, hypotension, thrombophlebitis, varicose vein, vasculitis.

*Represents a medical concept including several similar MedDRA Preferred Terms (PTs)

Abnormal Hematologic and Clinical Chemistry Findings

The percentages of adult antiretroviral-naïve and PI-experienced patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 5 and Table 6.

Table 5 Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients
Variable Limit Study M98-863
(48 Weeks)
Study M02-418
(48 Weeks)
Study M97-720
(360 Weeks)
Study M05-730
(48 Weeks)
KALETRA
capsules
400/100 mg
b.i.d. + d4T
+ 3TC
Nelfinavir
750 mg
t.i.d. +
d4T +
3TC
KALETRA
capsules
800/200 mg
daily + TDF
+ FTC
KALETRA
capsules
400/100 mg b.i.d. + TDF
+ FTC
KALETRA
capsules
b.i.d.1 + d4T +
3TC
KALETRA
tablets2
800/200 mg
daily + TDF +
FTC
KALETRA
tablets2
400/100 mg
b.i.d. + TDF +
FTC
(N=326) (N=327) (N=115) (N=75) (N=100) (N=333) (N=331)
Chemistry High
Glucose > 13.8 mmol/L 2% 2% 3% 1% 4% 0% < 1%
Uric Acid > 0.71 mmol/L 2% 2% 0% 3% 5% < 1% 1%
SGOT/AST 3 > 5 x ULN 2% 4% 5% 3% 10% 1% 2%
SGPT/ALT 3 > 5 x ULN 4% 4% 4% 3% 11% 1% 1%
GGT > 5 x ULN N/A N/A N/A N/A 10% N/A N/A
Total Cholesterol > 7.77 mmol/L 9% 5% 3% 3% 27% 4% 3%
Triglycerides > 8.25 mmol/L 9% 1% 5% 4% 29% 3% 6%
Amylase > 2 x ULN 3% 2% 7% 5% 4% N/A N/A
Lipase > 2 x ULN N/A N/A N/A N/A N/A 3% 5%
Chemistry Low
Calculated Creatinine Clearance4 <50 mL/min N/A N/A N/A N/A N/A 2% 2%
Hematology Low
Neutrophils 0.75 x 109/L 1% 3% 5% 1% 5% 2% 1%

1: Includes adverse event data from dose group I (200/100 mg twice daily [N=16] and 400/100 mg twice daily only [N=16]) and dose group II (400/100 mg twice daily [N=35] and 400/200 mg twice daily [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.

2: In the first 8 weeks of the study, 166 and 165 of the patients received KALETRA capsule once daily and twice daily, respectively. After that period, all patients received KALETRA tablet.

3: Criterion for Study M05-730 was >5 x ULN (AST/ALT).

4: The Cockcroft-Gault formula was used to calculate creatinine clearance.

Definitions: b.i.d. = twice daily; t.i.d. = three times daily; d4T = stavudine; 3TC = lamivudine; FTC = emtricitabine; TDF = tenofovir DF; ULN = upper limit of the normal range; N/A = Not Applicable; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase; GGT = gamma-glutamyl transpeptidase.

Table 6. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients
Variable Limit Study M98-888
(48 Weeks)
Studies
M98-957 1 and
M97-7652
(84 to 144
Weeks)
Study M06-802
(48 Weeks)
KALETRA
capsules
400/100 mg
b.i.d. + NVP +
NRTIs
Investigator-
elected PI(s)
+ NVP +
NRTIs
KALETRA
capsules b.i.d.
+ NNRTI +
NRTIs
KALETRA
tablets
800/200 mg
daily +
NRTIs
KALETRA
tablets
400/100 mg
b.i.d. +
NRTIs
(N=148) (N=140) (N=127) (N=300) (N=299)
Chemistry High
Glucose > 13.8 mmol/L 1% 2% 5% 2% 2%
Total Bilirubin > 59.5 micromol/L 1% 3% 1% 1% 1%
SGOT/AST3 > 5 x ULN 5% 11% 8% 3% 2%
SGPT/ALT3 > 5 x ULN 6% 13% 10% 2% 2%
GGT > 5 x ULN N/A N/A 29% N/A N/A
Total
Cholesterol
> 7.77 mmol/L 20% 21% 39% 6% 7%
Triglycerides > 8.25 mmol/L 25% 21% 36% 5% 6%
Amylase > 2 x ULN 4% 8% 8% 4% 4%
Lipase > 2 x ULN N/A N/A N/A 4% 1%
Creatinine
Phosphokinase
> 4 x ULN N/A N/A N/A 4% 5%
Chemistry Low
Calculated
Creatinine
Clearance4
< 50
mL/min
N/A N/A N/A 3% 3%
Inorganic
Phosphorous
< 0.48
mmol/L
1% 0% 2% 1% <1%
Hematology Low
Neutrophils 0.75 x 109/L 1% 2% 4% 3% 4%
Hemoglobin < 80 g/L 1% 1% 1% 1% 2%

1: Includes clinical laboratory data from patients receiving 400/100 mg capsules twice daily (n=29) or 533/133 mg capsules twice daily (n=28) for 84 weeks. Patients received KALETRA capsules in combination with NRTIs and efavirenz.

2: Includes clinical laboratory data from patients receiving 400/100 mg capsules twice daily (n=36) or 400/200 mg capsules twice daily (n=34) for 144 weeks. Patients received KALETRA capsules in combination with NRTIs and nevirapine.

3: Criterion for Study M06-802 was > 5 x ULN (AST/ALT).

4: The Cockcroft-Gault formula was used to calculate creatinine clearance.

Definitions: b.i.d. = twice daily; NRTI = nucleoside reverse transcriptase inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; ULN = upper limit of the normal range; N/A = Not Applicable; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase; GGT = gamma-glutamyl transpeptidase.

The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 7.

Table 7. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients
Variable Limit KALETRA oral solution b.i.d.1 + NRTIs
(N=100)
Chemistry High
Sodium > 149 mmol/L 3%
Total Bilirubin > 2.9 x ULN 4%
SGOT/AST > 180 U/L 8%
SGPT/ALT > 215 U/L 7%
Total Cholesterol > 7.77 mmol/L 4%
Amylase > 2.5 x ULN 6%
Chemistry Low
Sodium < 130 mmol/L 3%
Calcium < 1.75 mmol/dL 2%
Hematology Low
Hemoglobin < 70 g/L 2%
Platelet Count < 50 x 109/L 4%
Neutrophils < 0.40 x 109/L 2%

1: Includes clinical laboratory data from the 230/57.5 mg/m2 (n=49) and 300/75 mg/m2 (n=51) dose arms.

Definitions: b.i.d. = twice daily; NRTI = nucleoside reverse transcriptase inhibitor; ULN = upper limit of the normal range; SGPT/ALT = serum glutamic-pyruvic transaminase/alanine aminotransferase; SGOT/AST = serum glutamic-oxaloacetic transaminase/aspartate aminotransferase.

Post-Market Adverse Drug Reactions

Hepatobiliary
Disorders:
Hepatitis
Metabolism and
Nutrition Disorders:
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia.
Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events.
Skin and Subcutaneous
Tissue Disorders:
Toxic epidermal necrolysis, Stevens Johnson Syndrome and erythema multiforme.
Vascular Disorders: Bradyarrhythmia.

Drug Interactions

Serious Drug Interactions

  • Alpha 1-adrenoreceptor antagonist (alfuzosin): CONTRAINDICATED due to potential for serious reactions such as hypotension.
  • Antibiotic (fusidic acid): CONTRAINDICATED due to potential of increased fusidic acid-associated adverse events such as hepatitis or bone marrow suppression.
  • Analgesics (fentanyl): Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when KALETRA is co-administered with fentanyl, including extended-release, transdermal or transmucosal preparations.
  • Antihistamines (astemizole*, terfenadine*): CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • Antimycobacterial (rifampin): CONTRAINDICATED due to potential loss of virologic response and possible resistance to KALETRA (lopinavir/ritonavir) or to the class of protease inhibitors or other co-administered antiretroviral agents. KALETRA should not be co-administered with rifampin.
  • 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 (Gastrointestinal) Motility Agent (cisapride*): CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • Herbal Products (St. John’s Wort): CONTRAINDICATED due to potential loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors.
  • HMG-CoA Reductase Inhibitors (lovastatin, simvastatin): CONTRAINDICATED due to potential for serious reactions such as risk of myopathy including rhabdomyolysis. KALETRA should not be co-administered with these drugs.
  • Long Acting Beta-Adrenoceptor Agonist (salmeterol): CONTRAINDICATED due to the potential for increased risk of cardiovascular adverse events associated with salmeterol.
  • Neuroleptic (pimozide): CONTRAINDICATED due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias.
  • PDE5 Inhibitors (sildenafil [only when used for the treatment of pulmonary arterial hypertension], vardenafil): CONTRAINDICATED due to potential increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection.
  • Sedatives/Hypnotics (midazolam, triazolam): CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression.

* Product not marketed in Canada.

Overview

No drug interaction studies were performed with the once daily regimen of KALETRA (lopinavir/ritonavir).

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 PDE5 inhibitors) may result in increased plasma concentrations of the other drugs that could increase or prolong their therapeutic and adverse effects (see DRUG INTERACTIONS, Table 8). 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 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. Co-administration of KALETRA and drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce its therapeutic effect (see DRUG INTERACTIONS, Table 8). Co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.

Drug-Drug Interactions

Possible Dose Adjustments Based on Drug-Drug Interactions

Table 8 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. The effects of other drugs on ritonavir are not shown since they generally correlate with those observed with lopinavir. See (DETAILED PHARMACOLOGY) for magnitude of interaction.

Table 8. Established and Other Potentially Significant Drug Interactions with Lopinavir: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction.
Concomitant Drug
Class: Drug Name
Effect on Concentration
of Lopinavir or
Concomitant Druga
Clinical Comment
HCV-Antiviral Agents
HCV Protease Inhibitors:
boceprevir
↓ boceprevir
↓ lopinavir
Concomitant administration of boceprevir and KALETRA resulted in reduced boceprevir and lopinavir steady-state exposure. It is not recommended to co-administer KALETRA and boceprevir.
HCV Protease Inhibitors:
simeprevir
↑ simeprevir Concomitant use of KALETRA and simeprevir may result in significantly increased plasma concentrations of simeprevir. It is not recommended to co-administer KALETRA and simeprevir.
HCV Protease Inhibitors:
telaprevir
↓ telaprevir
↔ lopinavirb
Concomitant administration of telaprevir and KALETRA resulted in reduced telaprevir steady-state exposure, while the lopinavir steadystate exposure was not affected.
HIV-Antiviral Agents
HIV CCR5 – Antagonist:
maraviroc
↑ maraviroc
lopinavir (not studied)
Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. The dose of maraviroc should be decreased during co-administration with KALETRA 400/100 mg b.i.d. For further details, see complete prescribing information for maraviroc.
Non-nucleoside Reverse Transcriptase Inhibitors:
efavirenz, nevirapine
↓ lopinavir
↔ efavirenzb
↔ nevirapineb
KALETRA dose increase is recommended in all patients.
A dose increase of KALETRA tablets to 500/125 mg twice daily (given as two 200/50 mg tablets and one 100/25 mg tablet) when used in combination with efavirenz resulted in similar lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg twice daily without efavirenz (see DOSAGE AND ADMINISTRATION).
A dose increase of KALETRA oral solution to 533/133 mg (6.5 mL) twice daily taken with food may be considered when used in combination with efavirenz or nevirapine in patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).
KALETRA should not be administered once daily in combination with efavirenz or nevirapine (see DOSAGE AND ADMINISTRATION).
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.
Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily when co-administered with efavirenz significantly increased the lopinavir plasma concentrations approximately 35%, and ritonavir concentrations approximately 56 to 92%, compared to KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz (see DETAILED PHARMACOLOGY).
Non-nucleoside Reverse Transcriptase Inhibitor:
delavirdine
↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Non-nucleoside Reverse Transcriptase Inhibitor:
etravirine
↓ etravirine
Non-nucleoside Reverse Transcriptase Inhibitor:
rilpivirine
↑ rilpivirine Concomitant use of KALETRA with rilpivirine causes an increase in the plasma concentrations of rilpivirine, but no dose adjustment is required. Refer to the rilpivirine Product Monograph for more information.
Nucleoside Reverse Transcriptase Inhibitor:
didanosine
↔ didanosine Dosage adjustment is not required.
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
↔ lopinavirb
KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for tenofovir-associated adverse events.
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 Protease Inhibitor:
amprenavirc
↑ amprenavir
↓ lopinavir
KALETRA at a twice daily dose of 400/100 mg, when co-administered with amprenavir, is not recommended. Safety and efficacy of increased doses of KALETRA in combination with amprenavir have not been established (see DETAILED PHARMACOLOGY).
KALETRA should not be administered once daily in combination with amprenavir.
Amprenavir induces the activity of CYP3A and thus has the potential to decrease plasma concentrations of other protease inhibitors when used in combination with KALETRA (see DOSAGE AND ADMINISTRATION).
fosamprenavir ↓ amprenavir
↓ lopinavir
An increased rate of adverse events has been observed with the co-administration of KALETRA twice daily and fosamprenavir. The safety and efficacy of this combination have not been established. The concomitant use of fosamprenavir/ritonavir and KALETRA is not recommended because of significant pharmacokinetic interactions (see DETAILED PHARMACOLOGY).
fosamprenavir/ritonavir ↓ amprenavir
↑ lopinavir
HIV Protease Inhibitors:
indinavir
↑ indinavir
↔ lopinavirb
Decrease indinavir dose to 600 mg twice daily when co-administered with KALETRA 400/100 mg twice daily.
KALETRA tablets once daily has not been studied in combination with indinavir.
HIV Protease Inhibitors:
nelfinavir
↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
A dose increase of KALETRA to 533/133 mg (6.5 mL of oral solution) or 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) twice daily may be considered in patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence).
The safety and efficacy of this combination have not been established. KALETRA should not be administered once daily in combination with nelfinavir.
Nelfinavir induces the activity of CYP3A and thus has the potential to decrease plasma concentrations of other protease inhibitors when used in combination with KALETRA (see DOSAGE AND ADMINISTRATION).
HIV Protease Inhibitors:
ritonavir
↑ lopinavir The safety and efficacy of this combination have not been established.
HIV Protease Inhibitors:
saquinavir
↑ saquinavir
↔ lopinavirb
Saquinavir 1000 mg twice daily may be considered when co-administered with KALETRA 400/100 mg twice daily.
KALETRA tablets once daily has not been studied in combination with saquinavir.
HIV Protease Inhibitors:
tipranavir/ritonavir
↓ lopinavir The concomitant administration of KALETRA and tipranavir co-administered with low-dose ritonavir is not recommended. Tipranavir (500 mg twice daily) with ritonavir (200 mg twice daily), co-administered with lopinavir/ritonavir (400/100 mg twice daily), resulted in a 55 and 70% reduction in lopinavir AUC and Cmin, respectively.
Other Agents
Analgesic:
fentanyl
↑ fentanyl The CYP3A inhibitor activity of KALETRA is expected to increase the plasma concentrations of fentanyl. Careful monitoring of therapeutic and adverse effects (including respiratory depression) is recommended when KALETRA is co-administered with fentanyl, including extended-release, transdermal or transmucosal preparations.
Antiarrhythmics:
amiodarone, bepridilc, lidocaine (systemic), and quinidine
↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when co-administered with KALETRA, if available.
Anticancer Agents:
dasatinib, nilotinib,
vinblastine, vincristine
↑ anticancer agents Potentially life-threatening adverse events associated with these anticancer agents have occurred as a result of having their serum concentrations increased when co-administered with KALETRA. Concomitant administration of KALETRA and nilotinib or dasatinib should be avoided where possible. Where co-administration is unavoidable, refer to the drug’s Product Monograph for dosing instructions and relevant warnings and precautions.
Anticoagulant:
rivaroxaban
↑ rivaroxaban Co-adminstration of rivaroxaban and KALETRA may result in significant changes in rivaroxaban exposures and may increase the risk of bleeding; therefore the combination should be avoided. For more detailed information please refer to the rivaroxaban Product Monograph.
Anticoagulant:
warfarin
↓ warfarin Concentrations of warfarin may be affected. It is recommended that INR (International Normalized Ratio) be monitored.
Anticonvulsants:
carbamazepine,
phenobarbital, phenytoin
↓ lopinavir
↓ phenytoin
Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. In addition, co-administration of phenytoin and KALETRA resulted in moderate decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA.
Anticonvulsants:
lamotrigine, valproate
↓ lamotrigine
↓ valproate
Co-administration of KALETRA and either lamotrigine or valproate was associated with reduction in exposure of the anticonvulsant; 50% reduction in lamotrigine exposure has been reported. Use with caution. A dose increase of the anticonvulsant may be needed when coadministered with KALETRA and therapeutic concentration monitoring for the anticonvulsant may be indicated, particularly during dosage adjustments.
Antidepressants:
bupropion
↓ bupropion
↓ hydroxybupropion
↔ lopinavirb
Concurrent administration of bupropion with KALETRA will decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion).
trazodone ↑ trazodone Adverse events of nausea, dizziness, hypotension and syncope have been observed. If trazodone is used with a CYP3A4 inhibitor such as KALETRA, the combination should be used with caution and a lower dose of trazodone should be considered.
Antigout Agents:
colchicine
↑ colchicine Concentrations of colchicine are expected to increase when co-administered with KALETRA.
Treatment of gout flares
Co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.
Prophylaxis of gout flares
Co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.
Treatment of familial Mediterranean fever (FMF)
Co-administration of colchicine in patients on KALETRA: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Co-administration in renal and hepatic impairment patients
Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
Anti-infective:
clarithromycin
↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
• For patients with CLCR 30 to 60 mL/min, the dose of clarithromycin should be reduced by 50%.
• For patients with CLCR < 30 mL/min, the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals:
itraconazole,
ketoconazole,
voriconazole
↑ itraconazole
↑ ketoconazole
↔ lopinavirb
↓ voriconazole
High doses of ketoconazole or itraconazole (> 200 mg/day) are not recommended. Careful monitoring for adverse events and cautious use of ketoconazole or itraconazole is warranted at doses > 200 mg/day when administered with KALETRA.
Administration of a single 200 mg dose of ketoconazole did not increase the Cmax, AUC or Cmin of lopinavir during KALETRA 400/100 mg twice daily administration. However, it is possible that with multiple administration or higher doses of ketoconazole, lopinavir concentrations could be moderately increased.
A study has shown that co-administration of ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of lopinavir/ritonavir and voriconazole should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole.
Antimycobacterial:
rifabutin,
↑ rifabutin and rifabutin metabolite
↔ lopinavirb
Co-administration of KALETRA with rifabutin substantially increases concentration of rifabutin and its active metabolite by > 5-fold which may result in an increase in rifabutin-associated adverse events, including fever, neutropenia and uveitis.
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. Large reductions in lopinavir plasma concentrations were observed in a study evaluating the combination of rifampin 600 mg once daily with KALETRA 400/100 mg twice daily. KALETRA should not be co-administered with rifampin as it may significantly decrease lopinavir's therapeutic effect. Results from studies using higher doses of KALETRA co-administered with rifampin indicated higher incidences of liver and gastrointestinal toxicity (see CONTRAINDICATIONS).
rifampin ↓ lopinavir
Antiparasitic:
atovaquone
↓ atovaquone Clinical significance is unknown; however an increase in atovaquone doses may be needed.
Antipsychotics:
quetiapine
↑ quetiapine KALETRA should not be used in combination with quetiapine. Due to CYP3A inhibition by KALETRA, concentrations of quetiapine are expected to increase, which can result in serious and/or life-threatening adverse reactions.
Calcium Channel Blockers, Dihydropyridine:
e.g., felodipine, nicardipinec, nifedipine
↑ dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Cardiotonic Glycoside:
digoxin
↑ digoxin Co-administration of ritonavir (300 mg every 12 hours) and digoxin resulted in significantly increased digoxin levels. Caution should be exercised when co-administering KALETRA with digoxin, with appropriate monitoring of serum digoxin levels.
Corticosteroid:
Systemic:
dexamethasone
↓ lopinavir Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Corticosteroid:
Inhaled/Nasal:
budesonide, fluticasone propionate
↑ budesonide
↑ fluticasone
The concomitant use of KALETRA and fluticasone or other glucocorticoids, such as budesonide, that are metabolized by CYP3A4 significantly increases the plasma concentration of fluticasone or budesonide, leading to significant decreases in the plasma concentration of cortisol. Systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during post-marketing administration of KALETRA with inhaled or intranasal fluticasone or budesonide.
Co-administration of KALETRA and fluticasone or budesonide, therefore, is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. A dose reduction of glucocorticoid should be considered with close monitoring of local and systemic effects or consider alternatives (e.g. beclomethasone) to glucocorticoids which are not substrates of CYP3A4, particularly for long term use.
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).
Endothelin Receptor Antagonist:
bosentan
↑ bosentan Co-administration of bosentan and KALETRA increased steadystate bosentan maximum concentrations (Cmax) and area-under-the-curve (AUC) by 6-fold and 5-fold, respectively.
Co-administration of bosentan in patients on KALETRA:
In patients who have been receiving KALETRA for at least 10 days, start bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
Co-administration of KALETRA in patients on bosentan:
Discontinue use of bosentan at least 36 hours prior to initiation of KALETRA. After at least 10 days following the initiation of KALETRA, resume bosentan at 62.5 mg once daily or every other day based upon individual tolerability.
HMG-CoA Reductase
Inhibitors:

atorvastatin, rosuvastatind, pravastatin
↑ atorvastatin
↔ lopinavirb
↑ rosuvastatin
↔ lopinavirb
↑ pravastatin
↔ lopinavirb
HMG-CoA reductase inhibitors (statins) may interact with protease inhibitors and increase the risk of myopathy including rhabdomyolysis. The long-term safety when co-administering HMG-CoA reductase inhibitors with KALETRA has not been established. Concomitant use of protease inhibitors with lovastatin or simvastatin is contraindicated (see CONTRAINDICATIONS). Other HMG-CoA reductase inhibitors (statins) may also interact with protease inhibitors. This warning is based on clinical reports and on indirect evidence from studies on the cytochrome P450 CYP3A4 metabolism pathway. Use the lowest possible dose of atorvastatin or rosuvastatin with careful monitoring. Consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. Note that an approximate 30% increase in pravastatin concentrations was observed and careful monitoring is warranted (see DETAILED PHARMACOLOGY).
Immunosuppressants:
cyclosporine, rapamycin, tacrolimus
↑ 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 or Patch
Contraceptive:

ethinyl estradiol,
norethindrone
↓ ethinyl estradiol
↓ norethindrone
Alternative or additional contraceptive measures should be used when estrogen-progesterone-based oral or patch contraceptives and KALETRA are co-administered.
PDE5 inhibitors:
sildenafil, tadalafil,
vardenafil
↑ sildenafil
↑ tadalafil
↑ vardenafil
lopinavir (not studied)
Particular caution should be used when prescribing PDE5 inhibitors for the treatment of erectile dysfunction in patients receiving KALETRA. Co-administration of KALETRA with these drugs is expected to substantially increase their concentrations and may result in increase in associated adverse events such as hypotension, syncope, visual changes, and prolonged erection.
Use of PDE-5 Inhibitors for Erectile Dysfunction
Sildenafil may be used with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events.
Tadalafil may be used with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events.
Vardenafil should not be used with KALETRA (see CONTRAINDICATIONS).
Use of PDE-5 Inhibitors for Pulmonary Arterial Hypertension
Tadalafil may be used with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. When tadalafil is administered for the treatment of pulmonary arterial hypertension (PAH) to patients who are receiving KALETRA, refer to the tadalafil label for prescribing information.
The use of sildenafil or vardenafil are CONTRAINDICATED with KALETRA (see CONTRAINDICATIONS).

a The maginitude (geometric mean ratio estimates) and direction (↑increase; ↓, decrease or ↔, no effect) of the interaction are reported in DETAILED PHARMACOLOGY.

b The “no effect” (↔) of geometric mean estimates are not considered clinically significant.

c Product not marketed in Canada

d See Reference 8.

Definitions: b.i.d. = twice daily; t.i.d. = three times a day.

Drugs with No Observed or Predicted Interactions with KALETRA

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.

Flecainide and Propafenone

Based on results of a desipramine interaction study, KALETRA does not inhibit CYP2D6-mediated metabolism at clinically relevant concentrations. However, caution should be used when co-administering either flecainide or propafenone with KALETRA.

Raltegravir

Clinical studies showed no clinically significant interaction between KALETRA and raltegravir.

Drug-Food Interactions

The bioavailability of KALETRA tablets is not significantly affected when administered with a high or moderate fat meal (see CLINCAL STUDIES, Pivotal Comparative Bioavailability Studies). KALETRA tablets can be taken with or without food.

The bioavailability of KALETRA oral solution is affected when administered with a high or moderate fat meal (see CLINCAL STUDIES, Pivotal Comparative Bioavailability Studies). KALETRA oral solution must be taken with food.

Drug-Herb Interactions

St. John’s Wort (Hypericum perforatum)

Concomitant use of KALETRA and St. John’s Wort (Hypericum perforatum), or products containing St. John’s Wort, is contraindictated (see CONTRAINDICATIONS). Co-administration of protease inhibitors, including KALETRA®, with St. John’s Wort is expected to substantially decrease protease inhibitor concentrations and may result in sub-optimal levels of lopinavir and lead to loss of virologic response and possible resistance to lopinavir or to the class of protease inhibitors.

Drug-Laboratory Interactions

The interactions of KALETRA with laboratory tests have not been established.

Dosage and Administration

Dosing Considerations

  • Do not use once daily administration of KALETRA (lopinavir/ritonavir) in:
    • combination with efavirenz, nevirapine or nelfinavir
    • combination with carbamazepine, phenobarbital or phenytoin
    • pediatric patients
  • Concomitant therapy may affect the dose of KALETRA [see (DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Adults, Concomitant Therapy) and (DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Pediatric Patients, Concomitant Therapy)].
  • For children 6 months to 18 years of age, the pediatric dose is based on body weight or body surface area calculations.
  • Total amounts of alcohol and propylene glycol from all medicines, including KALETRA oral solution, that are to be given to infants should be taken into account in order to avoid toxicity from these excipients [see (INDICATIONS AND CLINICAL USE), (WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics), and (OVERDOSAGE)].

Recommended Dose and Dosage adjustment

  • KALETRA tablets may be taken with or without food.
  • KALETRA oral solution must be taken with food.
  • KALETRA tablets should be swallowed whole and not chewed, broken, or crushed.

The recommended oral dose of KALETRA is as follows (please also refer to INDICATIONS AND CLINICAL USE and ADVERSE REACTIONS).

Adults

Twice Daily Administration
  • KALETRA tablets 400/100 mg (given as two 200/50 mg tablets) twice daily.
  • KALETRA oral solution 400/100 mg (given as 5.0 mL) twice daily.
Once Daily Administration
  • KALETRA tablets 800/200 mg (given as four 200/50 mg tablets) once daily in patients with less than three protease-inhibitor associated mutations.
  • KALETRA oral solution 800/200 mg (given as 10.0 mL) once daily in patients with less than three protease-inhibitor associated mutations.

There are insufficient data to support the use of once daily administration of KALETRA for adult patients with three or more protease-inhibitor associated mutations (see ACTION AND CLINICAL PHARMACOLOGY).

Concomitant Therapy

Omeprazole and Ranitidine:

  • KALETRA can be used in combination with acid-reducing agents (omeprazole and ranitidine) with no dose adjustment (see DETAILED PHARMACOLOGY).

Efavirenz, Nevirapine, Amprenavir or Nelfinavir:

KALETRA tablets and oral solution should not be administered as a once daily regimen in combination with efavirenz, nevirapine, amprenavir or nelfinavir.

  • A dose increase of KALETRA tablets to 500/125 mg twice daily (given as two 200/50 mg tablets and one 100/25 mg tablet) should be considered when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir in treatment experienced patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence) (see DRUG INTERACTIONS).
  • A dose increase of KALETRA oral solution to 533/133 mg (given as 6.5 mL oral solution) twice daily may be considered when used in combination with efavirenz, nevirapine, amprenavir or nelfinavir in the treatment of experienced patients where reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence) (see DRUG INTERACTIONS).

Pediatrics (6 months to 18 years)

KALETRA tablets and oral solution should not be administered once daily in pediatric patients less than 18 years of age.

In children 6 months to 18 years of age, the recommended dosage of KALETRA should be calculated based on body weight (kg) or body surface area (BSA – m2) and should not exceed the recommended adult dose.

Body surface area (BSA) can be calculated with the following equation:



The KALETRA dose can be calculated based on weight or BSA as follows:

Based on Weight Patient’s weight (kg) x Prescribed lopinavir dose (mg/kg) = administered lopinavir dose (mg)
Based on BSA Patient’s BSA (m2) x Prescribed lopinavir dose (mg/m2) = administered lopinavir dose (mg)

If KALETRA oral solution is used, the volume (mL) of KALETRA oral solution can be determined as follows:

Volume of KALETRA oral solution (mL) = administered lopinavir dose (mg) ÷ 80 (mg/mL)/p>

The dose of the oral solution should be administered using a calibrated oral 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.

Healthcare professionals should pay special attention to the accurate calculation of the dose of KALETRA, transcription of the medication orders, dispensing information and dosing instructions to minimize the risk for medication errors, overdose (see OVERDOSAGE) and underdose. Prescribers should calculate the appropriate dose based on body weight or body surface area (BSA) recommendations outlined in Table 9, Table 10, Table 11, Table 12, Table 13, and Table 14 for each individual child and depending on concomitant therapy.

Without Concomitant Efavirenz, Nevirapine, Amprenavir or Nelfinavir

Dosing Recommendations Using Tablets

Table 9 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on weight for KALETRA 100/25 mg tablets.

Table 9. Pediatric Dosing Guidelines Based on Weight or BSA for KALETRA 100/25 mg Tablets – Without Concomitant Efavirenz, Nevirapine, Nelfinavir or Amprenavir
Weight (kg) Body Surface Area (m2)* Number of 100/25 mg Tablets
Twice Daily†
7 to < 15 kg 0.4 to < 0.6 Tablets are not recommended. Use oral solution.
15 to 25 kg ≥ 0.6 to < 0.9 2 tablets (200/50 mg)
> 25 to 35 kg ≥ 0.9 to < 1.4 3 tablets (300/75 mg)
> 35 kg ≥ 1.4 4 tablets (400/100 mg)
(or two 200/50 mg tablets)

* Body surface area can be calculated with the equation presented in DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Pediatrics.

† KALETRA tablets may be taken with or without food.

Dosing Recommendations Using Oral Solution

Table 10 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on weight for KALETRA oral solution.

Table 10. Pediatric Dosing Guidelines Based on Weight for KALETRA Oral Solution – Without Concomitant Efavirenz, Nevirapine, Nelfinavir or Amprenavir
Weight
(kg)
Twice Daily Dose
(mg/kg)*
Volume of Oral Solution Twice Daily
(80 mg lopinavir/20 mg ritonavir per mL)†
7 to < 15 kg 12 mg/kg
7 to 10 kg 1.25 mL
> 10 to < 15 kg 1.75 mL
15 to 40 kg 10 mg/kg
15 to 20 kg 2.25 mL
> 20 to 25 kg 2.75 mL
> 25 to 30 kg 3.50 mL
> 30 to 35 kg 4.00 mL
> 35 to 40 kg 4.75 mL
> 40 kg See adult dosage recommendation

* Dosing based on the lopinavir component of KALETRA oral solution (80 mg/20 mg per mL).

† KALETRA oral solution should be taken with food.

Table 11 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body surface area for KALETRA oral solution.

Table 11. Pediatric Dosing Guidelines Based on BSA for KALETRA Oral Solution - Without Concomitant Efavirenz, Nevirapine, Nelfinavir or Amprenavir
Body Surface Area (m2)* Volume of Oral Solution Twice Daily
(80 mg lopinavir/20 mg ritonavir per mL)†
(230/57.5 mg/m2)
0.25 0.7 mL (57.5/14.4 mg)
0.5 1.4 mL (115/28.8 mg)
0.75 2.2 mL (172.5/43.1 mg)
1.0 2.9 mL (230/57.5 mg)
1.25 3.6 mL (287.5/71.9 mg)
1.5 4.3 mL (345/86.3 mg)
1.75 5 mL (400/100 mg)

* Body surface area can be calculated with the equation presented in DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Pediatrics.

† KALETRA oral solution should be taken with food.

Concomitant Therapy: Efavirenz, Nevirapine, Amprenavir or Nelfinavir

A dose increase of KALETRA, should be considered when used in combination with efavirenz, nevirapine, amprenavir, or nelfinavir in the treatment of experienced children 6 months to 18 years of age in which reduced susceptibility to lopinavir is clinically suspected (by treatment history or laboratory evidence) (see DRUG INTERACTIONS). Refer to Table 12, Table 13 and Table 14 for dosing guidelines.

Dosing Recommendations Using Tablets

Table 12 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on weight or body surface area for KALETRA 100/25 mg tablets.

Table 12. Pediatric Dosing Guidelines Based on Weight or BSA for KALETRA 100/25 mg Tablets - With Concomitant Efavirenz, Nevirapine, Nelfinavir or Amprenavir
Body Weight
(kg)
Body Surface Area (m2)* Recommended Number of
100/25 mg Tablets Twice Daily†
7 to < 15 0.4 to < 0.6 Tablets are not recommended. Use oral solution.
15 to 20 ≥ 0.6 to < 0.8 2 tablets (200/50 mg)
> 20 to 30 ≥ 0.8 to < 1.2 3 tablets (300/75 mg)
> 30 to 45 ≥ 1.2 to < 1.4 4 tablets (400/100 mg)
(or two 200/50 mg tablets)
> 45 ≥ 1.4 5 tablets (500/125 mg)
(or two 200/50 mg tablets and one 100/25 mg tablets)

* Body surface area can be calculated with the equation presented in DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Pediatrics.

† KALETRA tablets may be taken with or without food.

Dosing Recommendations Using Oral Solution

Table 13 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on weight for KALETRA oral solution.

Table 13. Pediatric Dosing Guidelines Based on Weight for KALETRA Oral Solution and 100/25 mg Tablets – With Concomitant Efavirenz, Nevirapine, Nelfinavir or Amprenavir
Weight
(kg)
Twice Daily Dose
(mg/kg)*
Volume of Oral Solution Twice Daily
(80 mg lopinavir/20 mg ritonavir per mL)†
7 to < 15 kg 13 mg/kg
7 to 10 kg 1.50 mL
> 10 to < 15 kg 2.00 mL
15 to 45 kg 11 mg/kg
15 to 20 kg 2.50 mL
> 20 to 25 kg 3.25 mL
> 25 to 30 kg 4.00 mL
> 30 to 35 kg 4.50 mL
> 35 to 45 kg 5.00 mL
> 45 kg 6.5

* Dosing based on the lopinavir component of KALETRA oral solution (80 mg/20 mg per mL).

† KALETRA oral solution should be taken with food.

Table 14 provides the dosing recommendations for pediatric patients 6 months to 18 years of age based on body surface area for KALETRA oral solution.

Table 14. Pediatric Dosing Guidelines Based on BSA for KALETRA Oral Solution - With Concomitant Efavirenz, Nevirapine, Nelfinavir or Amprenavir
Body Surface Area (m2)* Twice Daily Dose
(300/75 mg/m2)
0.25 0.9 mL (75/18.8 mg)
0.5 1.9 mL (150/37.5 mg)
0.75 2.8 mL (225/56.3 mg)
1.0 3.8 mL (300/75 mg)
1.25 4.7 mL (375/93.8 mg)
1.5 5.6 mL (450/112.5 mg)
1.75 6.5 mL (525/131.3 mg)

* Body surface area can be calculated with the equation presented in DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Pediatrics.

† KALETRA oral solution should be taken with food.

Missed Dose

If a dose of this medication has been missed, it should be taken as soon as possible. However, if it is almost time for the next dose, skip the missed dose and go back to the regular dosing schedule. Do not double doses.

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

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 oral solution nine days prior. However, a causal relationship between the overdose and the outcome could not be established. 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 oral solution is highly concentrated and contains 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v), 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 [see (INDICATIONS AND CLINICAL USE), (DOSAGE AND ADMINISTRATION), and (WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics)].

Accidental ingestion of KALETRA oral solution by a young child could result in significant alcohol-related toxicity and could approach the potential lethal dose of alcohol [see (WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics) and (DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment, Pediatrics)].

  • There is no specific antidote for overdose with KALETRA.
  • 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.
  • Administration of activated charcoal should be used to aid in removal of unabsorbed drug.
  • Human experience of acute overdosage with KALETRA is limited.
  • Since KALETRA is highly protein bound, dialysis is unlikely to be beneficial. However, dialysis can remove both alcohol and propylene glycol in the case of overdose with KALETRA oral solution.

Action and Clinical Pharmacology

Mechanism of Action

Lopinavir, an inhibitor of the HIV protease, prevents cleavage of the Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles. Ritonavir inhibits the metabolism of lopinavir, thereby increasing the plasma levels of lopinavir. The antiviral activity of KALETRA (lopinavir/ritonavir) is due to lopinavir.

Antiviral activity in vitro

The in vitro antiviral activity of lopinavir against laboratory HIV strains and clinical HIV 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) of lopinavir against five different HIV-1 laboratory strains ranged from 10 to 27 nM (0.006 to 0.017 mcg/mL, 1 mcg/mL = 1.6 microM) and ranged from 4 to 11 nM (0.003 to 0.007 mcg/mL) against several HIV-1 subtype B clinical isolates (n=6). In the presence of 50% human serum, the mean EC50 of lopinavir against these five laboratory strains ranged from 65 to 289 nM (0.04 to 0.18 mcg/mL), representing a 7- to 11-fold attenuation.

Resistance

The selection of resistance to KALETRA therapy in antiretroviral treatment-naïve patients has not yet been characterized. In a Phase 3 study of 653 antiretroviral treatment naïve patients (Study M98-863), plasma viral isolates from each patient on treatment with plasma HIV > 400 copies/mL at Week 24, 32, 40 and/or 48 were analysed. 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 D30N and/or L90M mutation in HIV protease, was observed in 25/76 (33%) of evaluable nelfinavir-treated patients. The selection of resistance to KALETRA in antiretroviral-naïve pediatric patients (Study M98-940) appears to be consistent with that seen in adult patients (Study M98-863).

There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on KALETRA therapy. However, in Phase 2 studies of 227 antiretroviral treatment-naïve and PI-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 (nelfinavir, indinavir, or saquinavir) and one patient had received treatment with multiple protease inhibitors (indinavir, saquinavir and ritonavir). All four of these patients had at least four mutations associated with PI resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional mutations, some of which were recognized to be associated with PI resistance.

Cross-resistance

Preclinical Studies

Varying degrees of cross-resistance have been observed among HIV protease inhibitors. Little information is available on the cross-resistance of viruses that developed decreased susceptibility to lopinavir during KALETRA therapy.

The in vitro activity of lopinavir against clinical isolates from patients previously treated with a single PI 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 to 8.3-fold reduced susceptibility to lopinavir, respectively. Isolates from patients previously treated with two or more PIs showed greater reductions in susceptibility to lopinavir, as described in the Clinical Studies section that follows.

Clinical Studies - Antiviral activity of KALETRA in patients with previous protease inhibitor (PI) therapy.

The clinical relevance of reduced in vitro susceptibility to lopinavir has been examined by assessing the virologic response to KALETRA therapy, with respect to baseline viral genotype and phenotype, in 56 NNRTI-naïve patients with HIV RNA > 1000 copies/mL despite previous therapy with at least two PIs selected from nelfinavir, indinavir, saquinavir and ritonavir (Study M98-957). In this study, patients were initially randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC50 of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold higher than the EC50 against wild type HIV. Fifty-five percent (31/56) of these baseline isolates displayed a > 4-fold reduced susceptibility to lopinavir with a mean reduction in lopinavir susceptibility of 27.9-fold.

Table 15 shows the 48-week virologic response (HIV RNA < 400 and < 50 copies/mL) according to susceptibility and number of genotypic mutations at baseline in 50 evaluable patients enrolled in the Study M98-957 described above. Because this was a select patient population and the sample size was small, the data depicted in Table 15 do not constitute definitive clinical susceptibility breakpoints. Additional data are needed to determine clinically significant breakpoints for KALETRA.

Table 15. HIV RNA Response at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Inhibitor-Associated Mutations1 - Study M98-957
Lopinavir Susceptibility2 at Baseline HIV RNA < 400 copies/mL (%) HIV 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)
Number of Protease Inhibitor Mutations at Baseline
Up to 5 21/23 (91)3 19/23 (83)
> 5 17/27 (63) 14/27 (52)

1: Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic; genotype also performed by Virologic

2: Fold change in susceptibility from wild type.

3: Thirteen of the 23 patient isolates contained PI mutations at positions 82, 84, and/or 90.

After 48 weeks of treatment with KALETRA, efavirenz and NRTIs, plasma HIV RNA ≤ 400 copies/mL was observed in 93% (25/27), 73% (11/15), and 25% (2/8) of patients with < 10-fold, 10- to 40-fold, and ≥ 40-fold reduced susceptibility to lopinavir at baseline, respectively.

There are insufficient data at this time to identify lopinavir-associated mutational patterns in isolates from patients on KALETRA therapy. Further studies are needed to assess the association between specific mutational patterns and virologic response rates.

Genotypic correlates of reduced virologic response in antiretroviral-experienced patients initiating a KALETRA-based combination regimen.

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 16 shows the 48-week virologic response (HIV RNA < 400 copies/mL) according to the number of the above PI resistance mutations at baseline in Studies M98-888, M97-765 and M98-957.

Table 16. Virologic Response (HIV RNA < 400 copies/mL) at Week 48 by Baseline Kaletra Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to Kaletra 1
Number of PI mutations
at baseline1
Study M98-888 Study M97-765 Study M98-957
Single PI-experienced2,
NNRTI-naïve

(n=130)
Single PI-experienced3,
NNRTI-naïve

(n=56)
Multiple PI-
experienced4,
NNRTI-naïve
(n=50)
0 to 2 76/103 (74%) 34/45 (76%) 19/20 (95%)
3 to 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.

Definitions: NNRTI = Non-nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; N/A=not applicable.

Table 17 shows the 48-week virologic response (HIV-1 RNA < 50 copies/mL) in Study M06-802 according to the number of protease-inhibitor resistance associated mutations listed in Table 16 present at baseline (see CLINICAL TRIALS). Based on data dervived from a limited number of patients (see Table 17), once daily administration of KALETRA is not recommended for adult patients with three or more lopinavir resistance-associated substitutions.

Table 17 Virologic Response (HIV RNA < 50 copies/mL) at Week 48 by Baseline Number of Protease Substitutions Associated with Reduced Response to KALETRA 1
Number of PI mutations
at baseline1
Study M06-802 (Treatment-
Experienced2)
KALETRA Once Daily + NRTIs
(n=268)
Study M06-802 (Treatment-
Experienced3)
KALETRA Twice Daily + NRTIs
(n=264)
0 to 2 167/255 (65%) 154/250 (62%)
3 to 5 4/13 (31%) 8/14 (57%)
6 or more N/A N/A

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: 88% NNRTI-experienced, 47% PI-experienced (24% nelfinavir, 19% indinavir, 13% atazanavir).

3: 81% NNRTI-experienced, 46% PI-experienced (20% nelfinavir, 17% indinavir, 13% atazanavir).

Definitions: NRTI = Nucleoside/Nucleotide reverse transcriptase inhibitor; PI = protease inhibitor; N/A = not applicable.

Pharmacodynamics

Viral Effects

Lopinavir is virologically ten-fold more active than ritonavir, with an EC50 of 0.07 mcg/mL against HIV-1IIIB activity in MT4 cells in a medium containing 50% human serum and 10% calf serum. The protein binding corrected EC50 against wild-type HIV for ritonavir under the same conditions is 0.9 mcg/mL. Against ritonavir-resistant HIV, lopinavir displays potency similar to that observed by ritonavir against wild-type HIV. In the Phase 2 and Phase 3 trials, lopinavir has been tested in HIV PI-naïve subjects, as well as HIV-infected subjects with single PI experience who have developed various degrees of genotypic and phenotypic resistance to PIs and to NRTIs. Pharmacokinetic/pharmacodynamic modelling of the antiviral effect of lopinavir in these studies has shown little relationship between exposure and virologic outcome. In a study that evaluated subjects who were multiple PI-experienced, the Ctrough to EC50 (of the pretreatment HIV viral isolate) ratio was determined to be an important factor for durable virologic suppression with lopinavir/ritonavir.

The incidence of diarrhea showed increased rates with increased dose within individual studies; however, no statistically significant dose group differences were observed. Also, no apparent difference was observed in the incidence of diarrhea between the antiretroviral-naïve and experienced groups. The incidence of nausea was higher for treatment-naïve subjects who received the KALETRA capsule 400/200 mg dose than subjects who received the 400/100 mg dose. In addition, across-study comparisons suggested that naïve subjects receiving a KALETRA capsule 400/200 mg dose tended to have higher incidence rates of nausea compared to experienced subjects receiving the same dose.

Effects on the 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 (95% upper confidence bound) differences in QTcF from placebo were 3.6 (6.3) msec and 13.1 (15.8) msec for the 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA regimen, respectively. The two regimens resulted in exposures on Day 3 which were approximately 1.5- and 3-fold higher than those observed with recommended once daily or twice daily KALETRA doses at steady state. No subject experienced an increase in QTcF of > 60 msec from baseline or a QTcF interval exceeding the potentially clinically relevant threshold of 500 msec.

Mean change from baseline in PR interval of 11.6 to 31.2 msec was also noted in subjects receiving KALETRA tablets in the same study on Day 3. Maximum PR interval was 286 msec and no second- or third-degree heart block was observed (see WARNINGS AND PRECAUTIONS).

Pharmacokinetics

The pharmacokinetic properties of lopinavir co-administered with ritonavir have been evaluated in healthy adult volunteers and in HIV-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 capsules 400/100 mg twice daily yields mean steady-state lopinavir plasma concentrations 15- to 20-fold higher than those of ritonavir in HIV-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.

At steady state, KALETRA capsules 400/100 mg twice daily taken without meal restrictions produced a mean ± SD (standard deviation) lopinavir Cmax of 9.6 ± 4.4 mcg/mL, occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 5.5 ± 4.0 mcg/mL. Lopinavir AUC over a 12-hour dosing interval averaged 82.8 ± 44.5 mcg•h/mL. Administration of a single 400/100 mg dose of KALETRA capsules with a moderate-fat meal (500 to 682 Kcal, 23 to 25% calories from fat) was associated with a mean increase of 48 and 23% in lopinavir AUC and Cmax, respectively, relative to fasting. To enhance bioavailability and minimize pharmacokinetic variability, KALETRA capsules should be taken with food.

Lopinavir is approximately 98 to 99% bound to plasma proteins. 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 capsule dose was due to parent drug. After multiple dosing, less than 3% of the lopinavir dose is excreted unchanged in the urine. The half-life (t½) of lopinavir over a 12-hour dosing interval averaged 5 to 6 hours, and the apparent oral clearance (CL/F) of lopinavir is 6 to 7 L/h.

Absorption

In a pharmacokinetic study in HIV-positive subjects (n=19), multiple dosing with 400/100 mg KALETRA capsules twice daily with food for 3 weeks produced a mean ± SD lopinavir Cmax of 9.8 ± 3.7 mcg/mL (95% CI: 8.0 to 11.6 mcg/mL), occurring approximately 4 hours after administration. The mean steady-state trough concentration prior to the morning dose was 7.1 ± 2.9 mcg/mL (95% CI: 5.7 to 8.5 mcg/mL) and minimum concentration within a dosing interval was 5.5 ± 2.7 mcg/mL (95% CI: 4.2 to 6.8 mcg/mL). Lopinavir AUC over a 12-hour dosing interval averaged 92.6 ± 36.7 mcg•h/mL (95% CI: 74.9 to 110.3 mcg•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.

The relative bioavailability of KALETRA 200/50 mg tablets compared to KALETRA capsules was assessed in two Phase 1, single-center, open-label, randomized, cross-over studies (Studies M03-616 and M04-703) in 111 healthy adults under fed conditions (moderate-fat meal, 490 to 560 Kcal, 20 to 30% of calories from fat) as a single 400/100 mg dose. 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 (see CLINICAL TRIALS, Pivotal Comparative Bioavailability Studies). Following a moderate-fat meal, relative to the KALETRA capsule, administration of KALETRA 200/50 mg tablets increased lopinavir AUCt and Cmax by 18 and 24%, respectively, and increased ritonavir AUCt and Cmax by 20 and 35%, respectively.

In a Phase 1, single-center, open-label, randomized, cross-over study (Study M03-616) in 63 healthy adults (46 males, 17 females), no clinically significant changes in Cmax and AUC were observed following the administration of a single 400/100 mg dose of KALETRA 200/50 mg tablets under fasting conditions or following a moderate-fat meal (558 Kcal, 24.1% from fat) or a high-fat meal (998 Kcal, 51.3% from fat) relative to the KALETRA capsule dose following a moderate-fat meal. Relative to the KALETRA capsule dose following a moderate-fat meal, administration of KALETRA 200/50 mg tablets under fasting conditions increased lopinavir Cmax by 10% with no change in AUCt, and increased ritonavir AUCt and Cmax by 10 and 33%, respectively. Relative to the KALETRA capsule dose following a moderate-fat meal, administration of KALETRA 200/50 mg tablets following a moderate-fat meal increased lopinavir AUCt and Cmax by 27 and 30%, respectively, and increased ritonavir AUCt and Cmax by 27 and 40%, respectively. Relative to the KALETRA capsule dose following a moderate-fat meal, administration of KALETRA 200/50 mg tablets following a high-fat meal showed no change in lopinavir AUCt and Cmax, and increased ritonavir AUCt and Cmax each by 15% (see CLINICAL TRIALS, Pivotal Comparative Bioavailability Studies).

In a Phase 1, single-center, open-label, randomized, cross-over study (Study M04-703) in 48 healthy adults (34 males, 14 females) following a moderate-fat meal (492 Kcal, 22.9% from fat) and a single 400/100 mg dose, the relative bioavailability of KALETRA 200/50 mg tablets from two production lots compared to KALETRA capsules was increased for lopinavir AUCt and Cmax by 10 to 13% and 17 to 23%, respectively and increased for ritonavir AUCt and Cmax by 15% and 29 to 38%, respectively (see CLINICAL TRIALS, Pivotal Comparative Bioavailability Studies).

In a Phase 3, multicenter, open-label, randomized study (Study M05-730) in 664 HIV-1 infected adult subjects (502 males, 144 females), following multiple-dose administration of KALETRA in a parallel group comparison of Week 2 data (n=18 for twice daily and n=17 for once daily), lopinavir concentrations are approximately 14 to 25% higher following twice daily administration of the tablet compared to the capsule and 19 to 38% higher following once daily administration of the tablet compared to the capsule. Ritonavir plasma levels were similarly increased 25 to 54% following twice daily and once daily dosing of the KALETRA tablet compared to the capsule. In a within-subject analysis comparing the tablet at Week 10 to the capsule at Week 2 (n=18 for twice daily and n=16 for once daily), lopinavir and ritonavir plasma levels did not appear to be clinically significantly increased. The maximum average changes following twice daily and once daily dosing were 4 and 16%, respectively, for lopinavir and 10 and 18%, respectively, for ritonavir.

The relative bioavailability of KALETRA 100/25 mg tablets compared to KALETRA 200/50 mg tablets was assessed in a Phase 1, single-center, open-label, randomized, cross-over study (Study M06-858) in 44 healthy adults (35 males, 9 females) under fasting conditions as a single 400/100 mg dose. Plasma concentrations of lopinavir and ritonavir after administration of four 100/25 mg KALETRA tablets are similar to two 200/50 mg KALETRA tablets under fasting conditions (see CLINICAL TRIALS, Pivotal Comparative Bioavailability Studies).

Effects of Food on Oral Absorption

KALETRA Tablets

The relative bioavailability of KALETRA 200/50 mg tablets under fasting conditions was compared to KALETRA 200/50 mg tablets following meals in a Phase 1, single-center, open-label, randomized, cross-over study (Study M03-616) in 63 healthy adults as a 400/100 mg dose. No clinically significant changes in Cmax and AUC were observed following administration of KALETRA 200/50 mg tablets under fed conditions compared to fasted conditions. Relative to fasting, administration of KALETRA 200/50 mg tablets with a moderate-fat meal (558 Kcal, 24.1% calories from fat) increased lopinavir AUCt and Cmax by 26.9 and 17.6%, respectively, and ritonavir AUCt and Cmax by 15.6 and 4.9%, respectively. Relative to fasting, administration of KALETRA 200/50 mg tablets with a high-fat meal (998 Kcal, 51.3% from fat) increased lopinavir AUCt by 18.7% but not Cmax, and ritonavir AUCt and Cmax were increased 24.7 and 10.3%, respectively. The average lopinavir Tmax for the 200/50 mg tablet under fasting conditions, following a moderate-fat meal and following a high-fat meal were 3.6, 4.0 and 5.4 hours, respectively. The average ritonavir Tmax for the 200/50 mg tablet under fasting conditions, following a moderate-fat meal and following a high-fat meal were 3.4, 4.0 and 5.4 hours, respectively. The lopinavir terminal phase half-lives were similar for all regimens and ranged, on average, from 2.6 to 2.7 hours. The ritonavir terminal phase half-lives were similar for all regimens and ranged, on average, from 4.2 to 4.7 hours. Additional details regarding the pharmacokinetics of the KALETRA capsule and 200/50 mg tablet formulations under various meal conditions may be found in ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics, Absorption and CLINICAL TRIALS, Pivotal Comparative Bioavailability Studies. KALETRA tablets may therefore be taken with or without food.

KALETRA Oral Solution

Relative to fasting, KALETRA oral solution dosed with a moderate-fat meal (500 to 683 Kcal, 23 to 25% calories from fat) in healthy adults was associated with increases in lopinavir AUC and Cmax of 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.

Distribution

At steady-state, lopinavir is approximately 98 to 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-positive patients.

After a single dose of [14C]lopinavir/ritonavir (10/5 mg/kg) in rats, the radioactivity was distributed well throughout the body. With the exception of the adrenal gland, thyroid gland, liver and gastrointestinal tract, at 4 hours the tissue to plasma ratios of the remaining tissues were less than one. The highest concentrations were found in the liver and the lowest concentrations in the brain. The brain concentrations were approximately equal to the free concentrations in the plasma (approximately 2%). Concentrations in the lymphatic system were 6 to 61% of those in the plasma.

Metabolism

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. Pre-dose lopinavir concentrations decline with time during multiple dosing, stabilizing after approximately 10 to 16 days.

Excretion

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).

Once Daily Dosing

The pharmacokinetics of once daily KALETRA have been evaluated in HIV-infected subjects naïve to antiretroviral treatment. KALETRA capsules 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 capsules once daily for 4 weeks with food (n=24) produced a mean ± SD lopinavir Cmax of 11.8 ± 3.7 mcg/mL, occurring approximately 6 hours after administration. The mean steady-state lopinavir trough concentration prior to the morning dose was 3.2 ± 2.1 mcg/mL and minimum concentration within a dosing interval was 1.7 ± 1.6 mcg/mL. Lopinavir AUC over a 24-hour dosing interval averaged 154.1 ± 61.4 mcg•h/mL.

Special Populations and Conditions

Pediatrics

The pharmacokinetics of KALETRA oral solution 300/75 mg/m2 twice daily and 230/57.5 mg/m2 twice daily have been studied in a total of 53 pediatric patients, ranging in age from 6 months to 12 years. 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) (see CLINICAL TRIALS, Study Results, Pediatric Use).

The following describes the KALETRA - nevirapine interaction. The nevirapine regimen was 7 mg/kg twice daily (6 months to 8 years) or 4 mg/kg twice daily (> 8 years). The lopinavir mean steady-state AUC, Cmax, and Cmin were 72.6 ± 31.1, 8.2 ± 2.9 and 3.4 ± 2.1 mcg/mL respectively, after KALETRA 230/57.5 mg/m2 twice daily without nevirapine (n=12), and were 85.8 ± 36.9, 10.0 ± 3.3 and 3.6 ± 3.5 mcg/mL respectively, after 300/75 mg/m2 twice daily with nevirapine (n=12).

The KONCERT/PENTA 18 study assessed pharmacokinetics, safety and efficacy of twice daily versus once daily KALETRA tablets dosed as part of combination therapy in HIV-1 infected children. The pharmacokinetic substudy of KONCERT/PENTA18 explored lopinavir exposure in patients randomized to KALETRA tablets dosed either twice daily or once daily for 4 weeks stratified by body weight band (≥ 15 to ≤ 25 kg, > 25 to ≤ 35 kg, > 35kg). At enrollment, participating children were on combination antiretroviral regimen that included KALETRA and had viral suppression (HIV-1 RNA < 50 copies/mL) for at least the prior 24 weeks. The lopinavir mean steady-state AUC24, Cmax, and Clast were 237.3 ± 86.4, 13.0 ± 4.1 and 6.5 ± 3.3 mcg/mL respectively, after KALETRA tablets dosed twice daily (n=26), and were 171.5 ± 60.2, 14.5 ± 3.5 and 1.9 ± 1.9 mcg/mL respectively, after KALETRA tablets dosed once daily (n=26).

Geriatrics

Lopinavir pharmacokinetics has not been studied in elderly patients.

Gender

No gender-related pharmacokinetic differences have been observed in adult patients. Population pharmacokinetic analysis of lopinavir in HIV-infected subjects indicated that gender had no apparent effect on the exposure to lopinavir.

Race

No clinically important pharmacokinetic differences due to race have been identified. Population pharmacokinetic analysis of lopinavir in HIV-infected subjects indicated that race had no apparent effect on the exposure to lopinavir.

Hepatic Insufficiency

Lopinavir is principally metabolized and eliminated by the liver. Multiple dosing of KALETRA capsules 400/100 mg twice daily to HIV 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-infected subjects with normal hepatic function (n=12). Additionally, the plasma protein binding of lopinavir was 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, Hepatic/Biliary/Pancreatic).

Renal Insufficiency

Lopinavir pharmacokinetics have not been studied in patients with renal insufficiency; however, since less than 3% of the dose of lopinavir is eliminated unchanged in the urine, a decrease in total body clearance is not expected in patients with renal insufficiency. Population pharmacokinetic analysis of lopinavir in HIV-infected subjects indicated that subjects with mild renal impairment (CLCR between 50 to 80 mL/min, n=79) had no apparent effect on the exposure to lopinavir.

Storage and Stability

KALETRA Film-Coated Tablets

Store KALETRA film-coated tablets between 15 and 30°C. It is recommended that the product be stored and dispensed in the original container.

KALETRA Oral Solution

Store KALETRA oral solution between 2 and 8°C until dispensed. Avoid exposure to excessive heat. Keep cap tightly closed. Product must be stored and dispensed in the original container. Refrigeration of KALETRA oral solution by the patient is not required if used within 42 days and stored below 25°C.

Dosage Forms, Composition and Packaging

KALETRA Film-Coated Tablets

KALETRA (lopinavir/ritonavir) tablets are available in two strengths: 100 mg lopinavir/25 mg ritonavir and 200 mg lopinavir/50 mg ritonavir.

KALETRA 100 mg lopinavir/25 mg ritonavir tablets are supplied as pale yellow film-coated tablets embossed with the Abbott logo and the Abbo-Code KC. Each bottle contains 60 tablets.

KALETRA 200 mg lopinavir/50 mg ritonavir tablets are supplied as yellow film-coated tablets embossed with the Abbott logo and the Abbo-Code KA. Each bottle contains 120 tablets.

Listing of Non-Medicinal Ingredients

Each 100/25 mg tablet contains 100 mg of lopinavir and 25 mg of ritonavir with the following non-medicinal ingredients: copovidone, colloidal silicon dioxide, sodium stearyl fumarate and sorbitan monolaurate. The film-coating ingredients include: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow ferric oxide E172.

Each 200/50 mg tablet contains 200 mg of lopinavir and 50 mg of ritonavir with the following non-medicinal ingredients: copovidone, colloidal silicon dioxide, sodium stearyl fumarate and sorbitan monolaurate. The film-coating ingredients include: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and yellow ferric oxide E172.

KALETRA Oral Solution

KALETRA (lopinavir/ritonavir) oral solution is a light yellow to orange-coloured liquid supplied in amber-coloured multiple-dose bottles. Each multi-dose bottle contains 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.

Listing of Non-Medicinal Ingredients

Each mL of oral solution contains 80 mg of lopinavir and 20 mg of ritonavir with the following non-medicinal ingredients: acesulfame potassium, alcohol, artificial cotton candy flavour, citric acid, glycerine, high fructose corn syrup, Magnasweet 110 flavour, menthol, natural and artificial vanilla flavour, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water. The oral solution contains about 42.4% alcohol (v/v) and 15.3% propylene glycol (w/v).