GERIATRIC USE SECTION.


8.5 Geriatric Use. Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING. KALETRA (R) (lopinavir and ritonavir) tablets and oral solution are available in the following strengths and package sizes: 200 mg lopinavir/50 mg ritonavirYellow film-coated ovaloid tablets debossed with the logo and the code KA Store KALETRA tablets at 20- 25C (68- 77F); excursions permitted to 15- 30C (59- 86F) [see USP controlled room temperature]. Dispense in original container or USP equivalent tight container. For patient use: exposure of this product to high humidity outside the original container or USP equivalent tight container for longer than weeks is not recommended. Recommended Storage:.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. KALETRA is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 14 days and older.Limitations of Use:Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA [see Microbiology 12.4)] . Genotypic or phenotypic testing and/or treatment history should guide the use of KALETRA. The number of baseline lopinavir resistance-associated substitutions affects the virologic response to KALETRA [see Microbiology 12.4)] . KALETRA is an HIV-1 protease inhibitor indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients (14 days and older). 1).

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide)General Administration Information [see Dosage and Administration 2)] Advise patients to pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of KALETRA. Advise patients and caregivers that the oral solution should be administered using the calibrated dosing cup (supplied) or oral dosing syringe.Advise caregivers to inform their healthcare provider if the childs weight changes in order to make sure that the childs KALETRA dose is adjusted as needed. Inform patients and caregivers that KALETRA tablets may be taken with or without food but KALETRA oral solution should be taken with food to enhance absorption. Advise patients to remain under the care of healthcare provider while using KALETRA and to take KALETRA in combination with other antiretroviral drugs as prescribed. Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider. If dose of KALETRA is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if dose is skipped the patient should not double the next dose.Inform patients that it is important to take KALETRA on regular dosing schedule as directed and to avoid missing doses as that can result in development of resistance.Inform patients that there may be greater chance of developing diarrhea with the once daily regimen as compared with the twice daily regimen. Inform patients that Kaletra is not cure for HIV-1 infection and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections. Drug InteractionsInform patients that KALETRA may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any prescription, non-prescription medication or herbal products such as St. Johns Wort [see Contraindications 4), Warnings and Precautions 5.1) and Drug Interactions 7)] PancreatitisAdvise patients that pancreatitis has been observed in patients receiving KALETRA and to alert their healthcare provider if they experience symptoms such as nausea, vomiting or abdominal pain [see Warnings and Precautions 5.3)] Skin RashInform patients that skin rash ranging in severity from mild to toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, erythema multiforme, urticaria, and angioedema have been reported in patients receiving KALETRA or its components lopinavir and/or ritonavir. Advise patients to contact their healthcare provider if they develop rash while taking KALETRA [see Adverse Reactions 6.1)] HepatotoxicityPre-existing liver disease including Hepatitis or can worsen with use of KALETRA. This can be seen as worsening of transaminase elevations or hepatic decompensation. Advise patients that their liver function tests will need to be monitored closely especially during the first several months of KALETRA treatment and that they should notify their healthcare provider if they develop the signs and symptoms of worsening liver disease including loss of appetite, abdominal pain, jaundice, and itchy skin [see Warnings and Precautions 5.4)] QT and PR Interval ProlongationAdvise patients that KALETRA may produce changes in the electrocardiogram (e.g., PR and/or QT prolongation) and to consult their healthcare provider if they experience symptoms such as dizziness, lightheadedness, abnormal heart rhythm or loss of consciousness [see Warnings and Precautions 5.5, 5.6)] Diabetes Mellitus/HyperglycemiaAdvise patients that new onset of diabetes or exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during KALETRA use. Advise patients to notify their healthcare provider if they develop the signs and symptoms of diabetes mellitus including frequent urination, excessive thirst, extreme hunger or unusual weight loss and/or an increased blood sugar while on KALETRA as they may require change in their diabetes treatment or new treatment [see Warnings and Precautions 5.7)] Immune Reconstitution SyndromeAdvise patients that immune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including KALETRA [see Warnings and Precautions 5.8)] Lipid DisordersAdvise patients that treatment with KALETRA therapy can result in substantial increases in the concentration of total cholesterol and triglycerides [see Warnings and Precautions 5.9)] Fat RedistributionAdvise patients that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long term health effects of these conditions are not known at this time [see Warnings and Precautions 5.10)] Patients with HemophiliaAdvise patients with hemophilia that they may experience increased bleeding when treated with protease inhibitors such as KALETRA [see Warnings and Precautions 5.11)] Pregnancy Exposure RegistryInform patients that there is an antiretroviral pregnancy registry that monitors fetal outcomes of pregnant women exposed to KALETRA [see Use in Specific Populations 8.1)] LactationInstruct women with HIV-1 infection not to breastfeed because HIV-1 can be passed to the baby in breast milk [see Use in Specific Populations 8.2)] Manufactured by AbbVie Inc., North Chicago, IL 60064 USAKALETRA is trademark of AbbVie Inc.The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. (C) 2020 AbbVie Inc. All rights reserved. 20065455. Advise patients to pay special attention to accurate administration of their dose to minimize the risk of accidental overdose or underdose of KALETRA. Advise patients and caregivers that the oral solution should be administered using the calibrated dosing cup (supplied) or oral dosing syringe.. Advise caregivers to inform their healthcare provider if the childs weight changes in order to make sure that the childs KALETRA dose is adjusted as needed. Inform patients and caregivers that KALETRA tablets may be taken with or without food but KALETRA oral solution should be taken with food to enhance absorption. Advise patients to remain under the care of healthcare provider while using KALETRA and to take KALETRA in combination with other antiretroviral drugs as prescribed. Advise patients not to alter the dose or discontinue therapy without consulting with their healthcare provider. If dose of KALETRA is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if dose is skipped the patient should not double the next dose.. Inform patients that it is important to take KALETRA on regular dosing schedule as directed and to avoid missing doses as that can result in development of resistance.. Inform patients that there may be greater chance of developing diarrhea with the once daily regimen as compared with the twice daily regimen. Inform patients that Kaletra is not cure for HIV-1 infection and that they may continue to experience illnesses associated with HIV-1 infection, including opportunistic infections.

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. KALETRA is fixed-dose combination of HIV-1 antiviral drugs lopinavir [see Microbiology 12.4)] and ritonavir. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. The following adverse reactions are discussed in greater detail in other sections of the labeling.QT Interval Prolongation, PR Interval Prolongation [see Warnings and Precautions 5.5, 5.6)] Drug Interactions [see Warnings and Precautions 5.1)] Pancreatitis [see Warnings and Precautions 5.3)] Hepatotoxicity [see Warnings and Precautions 5.4)] QT Interval Prolongation, PR Interval Prolongation [see Warnings and Precautions 5.5, 5.6)] Drug Interactions [see Warnings and Precautions 5.1)] Pancreatitis [see Warnings and Precautions 5.3)] Hepatotoxicity [see Warnings and Precautions 5.4)] Commonly reported adverse reactions to KALETRA included diarrhea, nausea, vomiting, hypertriglyceridemia and hypercholesterolemia. 6.1) To report SUSPECTED ADVERSE REACTIONS, contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Adverse Reactions in AdultsThe safety of KALETRA has been investigated in about 2,600 patients in Phase II-IV clinical trials, of which about 700 have received dose of 800/200 mg (6 capsules or tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine.In clinical studies the incidence of diarrhea in patients treated with either KALETRA capsules or tablets was greater in those patients treated once daily than in those patients treated twice daily. Any grade of diarrhea was reported by at least half of patients taking once daily Kaletra capsules or tablets. At the time of treatment discontinuation, 4.2-6.3% of patients taking once daily Kaletra and 1.8-3.7% of those taking twice daily Kaletra reported ongoing diarrhea.Commonly reported adverse reactions to KALETRA 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. The following have been identified as adverse reactions of moderate or severe intensity (Table 8):Table 8. Adverse Reactions of Moderate or Severe Intensity Occurring in at Least 0.1% of Adult Patients Receiving KALETRA in Combined Phase II/IV Studies (N=2,612)System Organ Class (SOC) and Adverse Reactionn%BLOOD AND LYMPHATIC SYSTEM DISORDERS anemia542.1 leukopenia and neutropenia441.7 lymphadenopathy351.3CARDIAC DISORDERS atherosclerosis such as myocardial infarction100.4 atrioventricular block30.1 tricuspid valve incompetence30.1EAR AND LABYRINTH DISORDERS vertigo70.3 tinnitus60.2ENDOCRINE DISORDERS hypogonadism160.8 EYE DISORDERS visual impairment80.3GASTROINTESTINULLL DISORDERS diarrhea51019.5 nausea26910.3 vomiting1776.8 abdominal pain (upper and lower)1606.1 gastroenteritis and colitis662.5 dyspepsia532.0 pancreatitis451.7 Gastroesophageal Reflux Disease (GERD)401.5 hemorrhoids391.5 flatulence361.4 abdominal distension341.3 constipation261.0 stomatitis and oral ulcers240.9 duodenitis and gastritis200.8 gastrointestinal hemorrhage including rectal hemorrhage130.5 dry mouth90.3 gastrointestinal ulcer 60.2 fecal incontinence50.2GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS fatigue including asthenia1987.6HEPATOBILIARY DISORDERS hepatitis including AST, ALT, and GGT increases913.5 hepatomegaly50.2 cholangitis30.1 hepatic steatosis30.1IMMUNE SYSTEM DISORDERS hypersensitivity including urticaria and angioedema702.7 immune reconstitution syndrome30.1INFECTIONS AND INFESTATIONS upper respiratory tract infection36313.9 lower respiratory tract infection2027.7 skin infections including cellulitis, folliculitis, and furuncle863.3METABOLISM AND NUTRITION DISORDERS hypercholesterolemia 1927.4 hypertriglyceridemia1616.2 weight decreased612.3 decreased appetite522.0 blood glucose disorders including diabetes mellitus301.1 weight increased200.8 lactic acidosis110.4 increased appetite50.2MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS musculoskeletal pain including arthralgia and back pain1666.4 myalgia461.8 muscle disorders such as weakness and spasms341.3 rhabdomyolysis180.7 osteonecrosis30.1NERVOUS SYSTEM DISORDERS headache including migraine1656.3 insomnia993.8 neuropathy and peripheral neuropathy512.0 dizziness451.7 ageusia190.7 convulsion90.3 tremor90.3 cerebral vascular event60.2PSYCHIATRIC DISORDERS anxiety1013.9 abnormal dreams190.7 libido decreased190.7RENULLL AND URINULLRY DISORDERS renal failure311.2 hematuria200.8 nephritis30.1REPRODUCTIVE SYSTEM AND BREAST DISORDERS erectile dysfunction341.7 menstrual disorders amenorrhea, menorrhagia101.7 SKIN AND SUBCUTANEOUS TISSUE DISORDERS rash including maculopapular rash993.8 lipodystrophy acquired including facial wasting582.2 dermatitis/rash including eczema and seborrheic dermatitis501.9 night sweats421.6 pruritus291.1 alopecia100.4 capillaritis and vasculitis30.1VASCULAR DISORDERS hypertension471.8 deep vein thrombosis170.7Represents medical concept including several similar MedDRA PTs 1. Percentage of male population (N=2,038) 2. Percentage of female population (N=574) Laboratory Abnormalities in AdultsThe percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table (treatment-naive patients) and Table 10 (treatment-experienced patients).Table 9. Grade 3-4 Laboratory Abnormalities Reported in >= 2% of Adult Antiretroviral-Naive Patients Study 863(48 Weeks)Study 720(360 Weeks) Study 730(48 Weeks)VariableLimit KALETRA400/100 mg Twice Daily d4T +3TC(N 326)Nelfinavir 750 mg Three Times Daily d4T 3TC(N 327)KALETRATwice Daily d4T 3TC(N 100)KALETRAOnce Daily TDF +FTC(N=333)KALETRA Twice Daily TDF +FTC(N=331)ChemistryHigh Glucose 250 mg/dL 2%2%4%0%<1% Uric Acid 12 mg/dL 2%2%5%<1%1% SGOT/ AST > 180 U/L 2%4%10%1%2% SGPT/ ALT >215 U/L4%4%11%1%1%GGT>300 U/LN/AN/A10%N/AN/ATotal Cholesterol >300 mg/dL9%5%27%4%3%Triglycerides>750 mg/dL9%1%29%3%6%Amylase>2 ULN3%2%4%N/AN/ALipase>2 ULNN/AN/AN/A3%5%ChemistryLow Calculated Creatinine Clearance<50 mL/minN/AN/AN/A2%2%HematologyLow Neutrophils<0.75 10 9/L 1%3%5%2%1%1 ULN upper limit of the normal range; N/A Not Applicable. Criterion for Study 730 was >5x ULN (AST/ALT). Table 10. Grade 3-4 Laboratory Abnormalities Reported in >= 2% of Adult Protease Inhibitor-Experienced Patients Study 888(48 Weeks)Study 957 and Study 765 (84-144 Weeks) Study 802(48 Weeks)VariableLimit KALETRA 400/100 mg Twice Daily NVP NRTIs (N 148) Investigator-Selected Protease Inhibitor(s) NVP NRTIs(N 140)KALETRATwice Daily NNRTI NRTIs(N 127)KALETRA800/200 mg Once Daily +NRTIs(N=300)KALETRA 400/100 mg Twice Daily +NRTIs(N=299)ChemistryHigh Glucose>250 mg/dL1%2%5%2%2% Total Bilirubin>3.48 mg/dL1%3%1%1%1% SGOT/AST >180 U/L5%11%8%3%2% SGPT/ALT >215 U/L6%13%10%2%2% GGT>300 U/LN/AN/A29%N/AN/A Total Cholesterol >300 mg/dL20%21%39%6%7% Triglycerides>750 mg/dL25%21%36%5%6% Amylase>2 ULN4%8%8%4%4% Lipase>2 ULNN/AN/AN/A4%1% Creatine Phosphokinase >4 ULNN/AN/AN/A4%5%ChemistryLow Calculated Creatinine Clearance <50 mL/minN/AN/AN/A3%3% Inorganic Phosphorus <1.5 mg/dL1%0%2%1%<1%HematologyLow Neutrophils<0.75 10 9/L 1%2%4%3%4% Hemoglobin<80 g/L1%1%1%1%2%1 ULN upper limit of the normal range; N/A Not Applicable. Includes clinical laboratory 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. Includes clinical laboratory 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. Criterion for Study 802 was >5x ULN (AST/ALT). Adverse Reactions in Pediatric PatientsKALETRA oral solution dosed up to 300/75 mg/m has been studied in 100 pediatric patients months to 12 years of age. The adverse reaction profile seen during Study 940 was similar to that for adult patients. Dysgeusia (22%), vomiting (21%), and diarrhea (12%) were the most common adverse reactions of any severity reported in pediatric patients treated with combination therapy for up to 48 weeks in Study 940. total of patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the subjects include: hypersensitivity (characterized by fever, rash and jaundice), pyrexia, viral infection, constipation, hepatomegaly, pancreatitis, vomiting, alanine aminotransferase increased, dry skin, rash, and dysgeusia. Rash was the only event of those listed that occurred in or more subjects (N 3).KALETRA oral solution dosed at 300/75 mg/m has been studied in 31 pediatric patients 14 days to months of age. The adverse reaction profile in Study 1030 was similar to that observed in older children and adults. No adverse reaction was reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in or more subjects included decreased neutrophil count (N=3), anemia (N=2), high potassium (N=2), and low sodium (N=2). KALETRA oral solution and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg/m (without concomitant NNRTI) and 480/120 mg/m (with concomitant NNRTI) have been studied in 26 pediatric patients to 18 years of age in Study 1038. Patients also had saquinavir mesylate added to their regimen at Week 4. Rash (12%), blood cholesterol abnormal (12%) and blood triglycerides abnormal (12%) were the only adverse reactions reported in greater than 10% of subjects. Adverse drug reactions of moderate to severe intensity occurring in or more subjects included rash (N=3), blood triglycerides abnormal (N=3), and electrocardiogram QT prolonged (N=2). Both subjects with QT prolongation had additional predisposing conditions such as electrolyte abnormalities, concomitant medications, or pre-existing cardiac abnormalities. Laboratory Abnormalities in Pediatric PatientsThe percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 11.Table 11. Grade 3-4 Laboratory Abnormalities Reported in >= 2% Pediatric Patients in Study 940VariableLimit KALETRA Twice Daily RTIs(N 100)ChemistryHigh Sodium> 149 mEq/L3% Total Bilirubin>= 3.0 ULN3% SGOT/AST> 180 U/L8% SGPT/ALT> 215 U/L7% Total Cholesterol> 300 mg/dL3% Amylase> 2.5 ULN7% ChemistryLow Sodium< 130 mEq/L3%HematologyLow Platelet Count< 50 10 9/L 4% Neutrophils< 0.40 10 9/L 2%1 ULN upper limit of the normal range. Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase. 6.2 Postmarketing Experience. The following adverse reactions have been reported during postmarketing use of KALETRA. Because these reactions are reported voluntarily from population of unknown size, it is not possible to reliably estimate their frequency or establish causal relationship to KALETRA exposure.Body as Whole Redistribution/accumulation of body fat has been reported [see Warnings and Precautions 5.10)] Cardiovascular Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes [see Warnings and Precautions 5.5, 5.6)] Renal and Urinary DisordersNephrolithiasis Skin and AppendagesToxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC 0-24hr measurement) at the recommended dose of 400/100 mg KALETRA twice daily. Administration of lopinavir/ritonavir did not cause statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, there was dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg KALETRA twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 9-fold for the females that of the exposure in humans. There were no carcinogenic effects in rats. In this study, the exposure at the high dose was approximately 0.7-fold that of the exposure in humans with the 400/100 mg KALETRA twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. MutagenesisNeither lopinavir nor ritonavir was found to be mutagenic or clastogenic in battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes. Impairment of FertilityLopinavir in combination with ritonavir at 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. KALETRA is fixed-dose combination of HIV-1 antiviral drugs lopinavir [see Microbiology 12.4)] and ritonavir. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of KALETRA on QTcF interval was evaluated in placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in Day mean max approximately 2-fold higher than the mean max observed with the approved once daily and twice daily KALETRA doses at steady state. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively [see Warnings and Precautions 5.5, 5.6)] . 12.3 Pharmacokinetics. The pharmacokinetic properties of lopinavir are summarized in Table 13. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 14. Under fed conditions, lopinavir concentrations were similar following administration of KALETRA tablets to capsules with less pharmacokinetic variability. Under fed conditions (500 kcal, 25% from fat), lopinavir concentrations were similar following administration of KALETRA capsules and oral solution. Table 13. Pharmacokinetic Properties of LopinavirAbsorption max (hr) 4.4 +- 0.8Effect of meal (relative to fasting) Tablet Oral solution 19% 130% Distribution Bound to human plasma proteins> 98V d/F (L) 16.9Metabolism MetabolismCYP3AElimination Major route of eliminationhepatict 1/2 (h) 6.9 +- 2.2% of dose excreted in urine10.4 +- 2.3% of dose excreted in feces82.6 +- 2.5a. Kaletra tablet b. Changes in AUC values Table 14. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean +- SDPharmacokinetic ParameterTwice DailyaOnce DailybC max (ug/mL) 9.8 +- 3.711.8 +- 3.7C min (ug/mL) 5.5 +- 2.71.7 +- 1.6AUC tau (ugoh/mL) 92.6 +- 36.7154.1 +- 61.419 HIV-1 subjects, Kaletra 400/100 mg twice daily24 HIV-1 subjects, Kaletra 800/200 mg emtricitabine 200 mg tenofovir DF 300 mgSpecific PopulationsGender, Race and AgeNo gender or race related pharmacokinetic differences have been observed in adult patients. Lopinavir pharmacokinetics have not been studied in elderly patients. Pediatric PatientsThe 230/57.5 mg/m twice daily regimen without nevirapine and the 300/75 mg/m 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. Table 15. Lopinavir Pharmacokinetic Data from Pediatric Clinical Trials, Mean +- SDC max (ug/mL) min (ug/mL) AUC 12 (ugohr/m Age >= 14 Days to 6 Weeks Cohort (N 9):5.17 +- 1.84 1.40 +- 0.48 43.39 +- 14.80 Age >= Weeks to 6 Months Cohort (N 18):9.39 +- 4.91 1.95 +- 1.80 74.50 +- 37.87 Age >= Months to <= 12 years Cohort (N 24):8.2 +- 2.9 3.4 +- 2.1 72.6 +- 31.1 10.0 +- 3.3 3.6 +- 3.5 85.8 +- 36.9 KALETRA oral solution300/75 mg/m twice daily without concomitant NNRTI therapy KALETRA oral solution 230/57.5 mg/m twice daily without nevirapine (n=12) KALETRA oral solution 300/75 mg/m twice daily with nevirapine (n=12) PregnancyThe 12h values of lopinavir were lower during the second and third trimester by approximately 40% as compared to post-partum in 12 HIV-infected pregnant women received KALETRA 400 mg/100 mg twice daily. Yet this decrease is not considered clinically relevant in patients with no documented KALETRA-associated resistance substitutions receiving 400 mg/100 mg twice daily [see Use in Specific Populations 8.1)] Renal ImpairmentLopinavir pharmacokinetics have not been studied in patients with renal impairment; however, since the renal clearance of lopinavir is negligible, decrease in total body clearance is not expected in patients with renal impairment. Hepatic ImpairmentMultiple dosing of KALETRA 400/100 mg twice daily to HIV-1 and HCV co-infected patients with mild to moderate hepatic impairment (n 12) resulted in 30% increase in lopinavir AUC and 20% increase in max compared to HIV-1 infected subjects with normal hepatic function (n 12). Additionally, the plasma protein binding of lopinavir was statistically significantly lower in both mild and moderate hepatic impairment compared to controls (99.09 vs. 99.31%, respectively). KALETRA has not been studied in patients with severe hepatic impairment [see Warnings and Precautions 5.4) and Use in Specific Populations 8.6)] Drug InteractionsKALETRA is an inhibitor of the P450 isoform CYP3A in vitro. 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. The effects of co-administration of KALETRA on the AUC, max and min are summarized in Table 16 (effect of other drugs on lopinavir) and Table 17 (effect of KALETRA on other drugs). For information regarding clinical recommendations, see Table 12 in Drug Interactions 7) Table 16. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug for Recommended Alterations in Dose or Regimen Co- administered Drug Dose of Co- administered Drug (mg) Dose of KALETRA (mg) nRatio (in combination with Co-administered drug/alone) of Lopinavir Pharmacokinetic Parameters (90% CI); No Effect 1.00 max AUCC min Efavirenz 600 at bedtime 400/100 capsule twice daily 11, 3 0.97 (0.78, 1.22) 0.81 (0.64, 1.03) 0.61 (0.38, 0.97) 600 at bedtime 500/125 tablet twice daily 191.12 (1.02, 1.23) 1.06 (0.96, 1.17) 0.90 (0.78, 1.04) 600 at bedtime 600/150 tablet twice daily 231.36 (1.28, 1.44) 1.36 (1.28, 1.44) 1.32 (1.21, 1.44) Etravirine200 twice daily 400/100 mg twice day (tablets) 160.89 (0.82-0.96) 0.87 (0.83-0.92) 0.80 (0.73-0.88) Fosamprenavir 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 181.30 (0.85, 1.47) 1.37 (0.80, 1.55) 1.52 (0.72, 1.82) Ketoconazole200 single dose400/100 capsule twice daily 120.89 (0.80, 0.99) 0.87 (0.75, 1.00) 0.75 (0.55, 1.00) Nelfinavir1000 twice daily400/100 capsule twice daily 130.79 (0.70, 0.89) 0.73 (0.63, 0.85) 0.62 (0.49, 0.78) Nevirapine200 twice daily steady-state 400/100 capsule twice daily 22, 19 0.81 (0.62, 1.05) 0.73 (0.53, 0.98) 0.49 (0.28, 0.74) mg/kg or mg/kg once daily; twice daily wk (> yr) 300/ 75 mg/m oral solution twice daily 12, 15 0.86 (0.64, 1.16) 0.78 (0.56, 1.09) 0.45 (0.25, 0.81) Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir 25/150/100 dasabuvir 400 400/100 tablet twice daily 60.87 (0.76, 0.99) 0.94 (0.81, 1.10) 1.15 (0.93, 1.42) Omeprazole40 once daily, d 400/100 tablet twice daily, 10 121.08 (0.99, 1.17) 1.07 (0.99, 1.15) 1.03 (0.90, 1.18) 40 once daily, d 800/200 tablet once daily, 10 120.94 (0.88, 1.00) 0.92 (0.86, 0.99) 0.71 (0.57, 0.89) Pravastatin20 once daily, d 400/100 capsule twice daily, 14 120.98 (0.89, 1.08) 0.95 (0.85, 1.05) 0.88 (0.77, 1.02) Ranitidine150 single dose 400/100 tablet twice daily, 10 120.99 (0.95, 1.03) 0.97 (0.93, 1.01) 0.90 (0.85, 0.95) 150 single dose800/200 tablet once daily, 10 100.97 (0.95, 1.00) 0.95 (0.91, 0.99) 0.82 (0.74, 0.91) Rifabutin150 once daily400/100 capsule twice daily 141.08 (0.97, 1.19) 1.17 (1.04, 1.31) 1.20 (0.96, 1.65) Rifampin600 once daily400/100 capsule twice daily 220.45 (0.40, 0.51) 0.25 (0.21, 0.29) 0.01 (0.01, 0.02) 600 once daily800/200 capsule twice daily 101.02 (0.85, 1.23) 0.84 (0.64, 1.10) 0.43 (0.19, 0.96) 600 once daily400/400 capsule twice daily 90.93 (0.81, 1.07) 0.98 (0.81, 1.17) 1.03 (0.68, 1.56) Rilpivirine150 once daily 400/100 twice daily (capsules) 150.96 (0.88-1.05) 0.99 (0.89-1.10) 0.89 (0.73-1.08) Ritonavir100 twice daily400/100 capsule twice daily 8, 21 1.28 (0.94, 1.76) 1.46 (1.04, 2.06) 2.16 (1.29, 3.62) Tipranavir/ ritonavir 500/200 twice daily 400/100 capsule twice daily 21 69 0.53 (0.40, 0.69) 0.45 (0.32, 0.63) 0.30 (0.17, 0.51) 0.48 (0.40, 0.58) Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. Data extracted from the U.S. prescribing information of co-administered drugs. Parallel group design Drug levels obtained at 8-16 hours post dose N/A Not available. Table 17. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or RegimenCo- administered Drug Dose of Co- administered Drug (mg) Dose of KALETRA (mg) Ratio (in combination with KALETRA/alone) of Co- administered Drug Pharmacokinetic Parameters (90% CI); No Effect 1.00 max AUCC min Bedaquiline 400 single dose400/100 twice daily N/AN/A1.22 (1.11, 1.34) N/AEfavirenz600 at bedtime400/100 capsule twice daily 11, 12 0.91 (0.72, 1.15) 0.84 (0.62, 1.15) 0.84 (0.58, 1.20) Elbasvir/ grazoprevir 50 once daily400/100 twice daily 102.87 (2.29, 3.58) 3.71 (3.05, 4.53) 4.58 (3.72, 5.64) 200 once daily137.31 (5.65, 9.45) 12.86 (10.25, 16.13) 21.70 (12.99, 36.25) Ethinyl Estradiol 35 ug once daily (Ortho Novum (R)) 400/100 capsule twice daily 120.59 (0.52, 0.66) 0.58 (0.54, 0.62) 0.42 (0.36, 0.49) Etravirine200 twice daily400/100 tablet twice day 160.70 (0.64-0.78) 0.65 (0.59-0.71) 0.55 (0.49-0.62) Fosamprenavir 700 twice daily plus ritonavir 100 twice daily 400/100 capsule twice daily 180.42 (0.30, 0.58) 0.37 (0.28, 0.49) 0.35 (0.27, 0.46) Indinavir600 twice daily combo nonfasting vs. 800 three times daily alone fasting 400/100 capsule twice daily 130.71 (0.63, 0.81) 0.91 (0.75, 1.10) 3.47 (2.60, 4.64) Ketoconazole200 single dose400/100 capsule twice daily 121.13 (0.91, 1.40) 3.04 (2.44, 3.79) N/AMaraviroc 300 twice daily400/100 twice daily 111.97 (1.66, 2.34) 3.95 (3.43, 4.56) 9.24 (7.98, 10.7) Methadone5 single dose400/100 capsule twice daily 110.55 (0.48, 0.64) 0.47 (0.42, 0.53) N/ANelfinavir1000 twice daily combo vs. 1250 twice daily alone 400/100 capsule twice daily 130.93 (0.82, 1.05) 1.07 (0.95, 1.19) 1.86 (1.57, 2.22) M8 metabolite 2.36 (1.91, 2.91) 3.46 (2.78, 4.31) 7.49 (5.85, 9.58) Nevirapine200 once daily twice daily 400/100 capsule twice daily 5, 3 1.05 (0.72, 1.52) 1.08 (0.72, 1.64) 1.15 (0.71, 1.86) Norethindrone1 once daily (Ortho Novum (R)) 400/100 capsule twice daily 120.84 (0.75, 0.94) 0.83 (0.73, 0.94) 0.68 (0.54, 0.85) Ombitasvir/ paritaprevir/ ritonavir+ dasabuvir 25/150/100 dasabuvir 400 400/100 tablet twice daily 61.14 (1.01, 1.28) 1.17 (1.07, 1.28) 1.24 (1.14, 1.34) 2.04 (1.30, 3.20) 2.17 (1.63, 2.89) 2.36 (1.00, 5.55) 1.55 (1.16, 2.09) 2.05 (1.49, 2.81) 5.25 (3.33, 8.28) 0.99 (0.75, 1.31) 0.93 (0.75, 1.15) 0.68 (0.57, 0.80) Pitavastatin 4 once daily400/100 tablet twice daily 230.96 (0.84-1.10) 0.80 (0.73-0.87) N/APravastatin20 once daily400/100 capsule twice daily 121.26 (0.87, 1.83) 1.33 (0.91, 1.94) N/ARifabutin150 once daily combo vs. 300 once daily alone 400/100 capsule twice daily 122.12 (1.89, 2.38) 3.03 (2.79, 3.30) 4.90 (3.18, 5.76) 25- O-desacetyl rifabutin 23.6 (13.7, 25.3) 47.5 (29.3, 51.8) 94.9 (74.0, 122) Rifabutin 25- O-desacetyl rifabutin 3.46 (3.07, 3.91) 5.73 (5.08, 6.46) 9.53 (7.56, 12.01) Rilpivirine150 once daily400/100 capsules twice daily 151.29 (1.18-1.40) 1.52 (1.36-1.70) 1.74 (1.46-2.08) Rosuvastatin 20 once daily400/100 tablet twice daily 154.66 (3.4, 6.4) 2.08 (1.66, 2.6) 1.04 (0.9, 1.2) Tenofovir alafenamide 10 once daily800/200 tablet once daily 102.19 (1.72, 2.79) 1.47 (1.17, 1.85) N/ATenofovir disoproxil fumarate 300 once daily400/100 capsule twice daily 24No Change 1.32 (1.26, 1.38) 1.51 (1.32, 1.66) Data extracted from the U.S. prescribing information of co-administered drugs. Kiser, et al. Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8. Parallel group design N/A Not available. 19 HIV-1 subjects, Kaletra 400/100 mg twice daily. 24 HIV-1 subjects, Kaletra 800/200 mg emtricitabine 200 mg tenofovir DF 300 mg. KALETRA oral solution300/75 mg/m twice daily without concomitant NNRTI therapy KALETRA oral solution 230/57.5 mg/m twice daily without nevirapine (n=12) KALETRA oral solution 300/75 mg/m twice daily with nevirapine (n=12) 12.4 Microbiology. Mechanism of ActionLopinavir, an inhibitor of the HIV-1 protease, prevents cleavage of the viral Gag-Pol polyprotein, resulting in the production of immature, non-infectious viral particles.Antiviral ActivityIn the absence of human serum, the mean 50% effective concentration (EC 50) values of lopinavir against five different HIV-1 subtype laboratory strains in lymphoblastic cell lines ranged from 10-27 nM (0.006-0.017 ug/mL, ug/mL 1.6 uM), and ranged from 4-11 nM (0.003-0.007 ug/mL) against several HIV-1 subtype clinical isolates in peripheral blood lymphocytes (n 6). In the presence of 50% human serum, the mean EC 50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 ug/mL), representing 7 to 11-fold attenuation. The EC 50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 ug/mL). ResistanceHIV-1 isolates with reduced susceptibility to lopinavir have been selected in cell culture. The presence of ritonavir does not appear to influence the selection of lopinavir-resistant viruses in cell culture. In study of 653 antiretroviral treatment-naive patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNULL >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No specific amino acid substitutions could be associated with resistance to KALETRA in the virus from 37 evaluable KALETRA-treated patients. The selection of resistance to KALETRA in antiretroviral treatment-naive pediatric patients (Study 940) appears to be consistent with that seen in adult patients (Study 863).Resistance to KALETRA has been noted to emerge in patients treated with other protease inhibitors prior to KALETRA therapy. In studies of 227 antiretroviral treatment-naive and protease inhibitor experienced patients, isolates from of 23 patients with quantifiable (>400 copies/mL) viral RNULL following treatment with KALETRA for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. All four of these patients had previously received treatment with at least one protease inhibitor and had at least substitutions associated with protease inhibitor resistance immediately prior to KALETRA therapy. Following viral rebound, isolates from these patients all contained additional substitutions, some of which are recognized to be associated with protease inhibitor resistance. Cross-resistance Nonclinical StudiesVarying degrees of cross-resistance have been observed among HIV-1 protease inhibitors. The antiviral activity in cell culture of lopinavir against clinical isolates from patients previously treated with single protease inhibitor was determined (Table 18). Table 18. Susceptibility Reduction to Lopinavir Against Isolates from Patients Previously Treated With Single Protease InhibitorSusceptibility reduced by >4 foldSusceptibility reduced to LPVIndinavir (n=16)5.7 foldNelfinavir (n=13)<4 fold Ritonavir (n=3)8.32 foldSaquinavir (n=4)<4 foldIsolates from patients previously treated with two or more protease inhibitors showed greater reductions in susceptibility to lopinavir, as described in the following section.Clinical Studies Antiviral Activity of KALETRA in Patients with Previous Protease Inhibitor TherapiesThe clinical relevance of reduced susceptibility in cell culture to lopinavir has been examined by assessing the virologic response to KALETRA therapy in treatment-experienced patients, with respect to baseline viral genotype in three studies and baseline viral phenotype in one study.Virologic response to KALETRA has been shown to be affected by the presence of three or more of the following amino acid substitutions in protease at baseline: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. Table 19 shows the 48-week virologic response (HIV-1 RNULL <400 copies/mL) according to the number of the above protease inhibitor resistance-associated substitutions at baseline in studies 888 and 765 [see Clinical Studies 14.2) and 14.3)] and study 957 (see below). Once daily administration of KALETRA for adult patients with three or more of the above substitutions is not recommended. Table 19. Virologic Response (HIV-1 RNULL <400 copies/mL) at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA Number of protease inhibitor substitutions at baseline Study 888 (Single protease inhibitor-experienced 2, NNRTI-naive) n=130 Study 765 (Single protease inhibitor-experienced 3, NNRTI-naive) n=56 Study 957 (Multiple protease inhibitor-experienced 4, NNRTI-naive) n=50 0-276/103 (74%)34/45 (76%)19/20 (95%)3-513/26 (50%)8/11 (73%)18/26 (69%)6 or more0/1 (0%)N/A1/4 (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. 43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir. 41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir. 86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir. Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naive patients with HIV-1 RNULL >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC 50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC 50 value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 20. Table 20. HIV-1 RNULL Response at Week 48 by Baseline Lopinavir Susceptibility Lopinavir susceptibility at baseline HIV-1 RNULL <400 copies/mL (%)HIV-1 RNULL <50 copies/mL (%)< 10 fold 25/27 (93%)22/27 (81%)> 10 and 40 fold11/15 (73%)9/15 (60%)>= 40 fold2/8 (25%)2/8 (25%)1 Lopinavir susceptibility was determined by recombinant phenotypic technology performed by Virologic. Fold change in susceptibility from wild type.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. 14.1 Adult Patients without Prior Antiretroviral Therapy. Study 863: KALETRA Capsules twice daily stavudine lamivudine compared to nelfinavir three times daily stavudine lamivudineStudy 863 was randomized, double-blind, multicenter trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus stavudine and lamivudine versus nelfinavir (750 mg three times daily) plus stavudine and lamivudine in 653 antiretroviral treatment naive patients. Patients had mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD4+ cell count was 259 cells/mm (range: to 949 cells/mm 3) and mean baseline plasma HIV-1 RNULL was 4.9 log 10 copies/mL (range: 2.6 to 6.8 log 10 copies/mL). Treatment response and outcomes of randomized treatment are presented in Table 21.Table 21. Outcomes of Randomized Treatment Through Week 48 (Study 863)OutcomeKALETRA+d4T+3TC(N 326)Nelfinavir+d4T+3TC(N 327)Responder 75%62%Virologic failure Rebound Never suppressed through Week 48 9% 7% 2% 25% 15% 9% Death2%1%Discontinued due to adverse events4%4%Discontinued for other reasons 10%8%1 Patients achieved and maintained confirmed HIV-1 RNULL 400 copies/mL through Week 48. Includes confirmed viral rebound and failure to achieve confirmed 400 copies/mL through Week 48. Includes lost to follow-up, patients withdrawal, non-compliance, protocol violation and other reasons. Overall discontinuation through Week 48, including patients who discontinued subsequent to virologic failure, was 17% in the KALETRA arm and 24% in the nelfinavir arm. Through 48 weeks of therapy, there was statistically significantly higher proportion of patients in the KALETRA arm compared to the nelfinavir arm with HIV-1 RNULL 400 copies/mL (75% vs. 62%, respectively) and HIV-1 RNULL 50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV-1 RNULL level subgroups is presented in Table 22.Table 22. Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863)Baseline Viral Load (HIV-1 RNULL copies/mL)KALETRA +d4T+3TCNelfinavir +d4T+3TC <400 copies/mL <50 copies/mL n <400 copies/mL <50 copies/mL n 30,00074%71%8279%72%87>= 30,000 to 100,00081%73%7967%54%79>= 100,000 to 250,00075%64%8360%47%72>= 250,00072%60%8244%33%891 Patients achieved and maintained confirmed HIV-1 RNULL 400 copies/mL through Week 48. Patients achieved HIV-1 RNULL 50 copies/mL at Week 48. Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 207 cells/mm for the KALETRA arm and 195 cells/mm for the nelfinavir arm. Study 730: KALETRA Tablets once daily tenofovir DF emtricitabine compared to KALETRA Tablets twice daily tenofovir DF emtricitabineStudy 730 was randomized, open-label, multicenter trial comparing treatment with KALETRA 800/200 mg once daily plus tenofovir DF and emtricitabine versus KALETRA 400/100 mg twice daily plus tenofovir DF and emtricitabine in 664 antiretroviral treatment-naive patients. Patients were randomized in 1:1 ratio to receive either KALETRA 800/200 mg once daily (n 333) or KALETRA 400/100 mg twice daily (n 331). Further stratification within each group was 1:1 (tablet vs. capsule). Patients administered the capsule were switched to the tablet formulation at Week and maintained on their randomized dosing schedule. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ cell count was 216 cells/mm (range: 20 to 775 cells/mm 3) and mean baseline plasma HIV-1 RNULL was 5.0 log 10 copies/mL (range: 1.7 to 7.0 log 10 copies/mL). Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 23. Table 23. Outcomes of Randomized Treatment Through Week 48 (Study 730)OutcomeKALETRA Once Daily TDF FTC(n 333)KALETRA Twice Daily TDF FTC(n 331)Responder 78%77%Virologic failure Rebound Never suppressed through Week 48 10% 5% 5% 8% 5% 3% Death1%<1%Discontinued due to adverse events4%3%Discontinued for other reasons 8%11%1 Patients achieved and maintained confirmed HIV-1 RNULL 50 copies/mL through Week 48. Includes confirmed viral rebound and failure to achieve confirmed 50 copies/mL through Week 48. Includes lost to follow-up, patients withdrawal, non-compliance, protocol violation and other reasons. Through 48 weeks of therapy, 78% in the KALETRA once daily arm and 77% in the KALETRA twice daily arm achieved and maintained HIV-1 RNULL 50 copies/mL (95% confidence interval for the difference, -5.9% to 6.8%). Mean CD4+ cell count increases at Week 48 were 186 cells/mm for the KALETRA once daily arm and 198 cells/mm for the KALETRA twice daily arm. 14.2 Adult Patients with Prior Antiretroviral Therapy. Study 888: KALETRA Capsules twice daily nevirapine NRTIs compared to investigator-selected protease inhibitor(s) nevirapine NRTIs Study 888 was randomized, open-label, multicenter trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naive patients. Patients had mean age of 40 years (range: 18 to 74), 68% were Caucasian, and 86% were male. Mean baseline CD4+ cell count was 322 cells/mm (range: 10 to 1059 cells/mm 3) and mean baseline plasma HIV-1 RNULL was 4.1 log 10 copies/mL (range: 2.6 to 6.0 log 10 copies/mL). Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 24. Table 24. Outcomes of Randomized Treatment Through Week 48 (Study 888)OutcomeKALETRA nevirapine NRTIs (n 148)Investigator-Selected Protease Inhibitor(s) nevirapine NRTIs (n 140)Responder 57%33%Virologic failure Rebound Never suppressed through Week 48 24% 11% 13% 41% 19% 23% Death1%2%Discontinued due to adverse events 5%11%Discontinued for other reasons 14%13%1 Patients achieved and maintained confirmed HIV-1 RNULL 400 copies/mL through Week 48. Includes confirmed viral rebound and failure to achieve confirmed 400 copies/mL through Week 48. Includes lost to follow-up, patients withdrawal, non-compliance, protocol violation and other reasons. Through 48 weeks of therapy, there was statistically significantly higher proportion of patients in the KALETRA arm compared to the investigator-selected protease inhibitor(s) arm with HIV-1 RNULL 400 copies/mL (57% vs. 33%, respectively).Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells/mm for the KALETRA arm and 112 cells/mm for the investigator-selected protease inhibitor(s) arm. Study 802: KALETRA Tablets 800/200 mg Once Daily Versus 400/100 mg Twice Daily when Co-administered with Nucleoside/Nucleotide Reverse Transcriptase Inhibitors in Antiretroviral-Experienced, HIV-1 Infected Subjects M06-802 was randomized open-label study comparing the safety, tolerability, and antiviral activity of once daily and twice daily dosing of KALETRA tablets in 599 subjects with detectable viral loads while receiving their current antiviral therapy. Of the enrolled subjects, 55% on both treatment arms had not been previously treated with protease inhibitor and 81 88% had received prior NNRTIs as part of their anti-HIV treatment regimen. Patients were randomized in 1:1 ratio to receive either KALETRA 800/200 mg once daily (n 300) or KALETRA 400/100 mg twice daily (n 299). Patients were administered at least two nucleoside/nucleotide reverse transcriptase inhibitors selected by the investigator. Mean age of patients enrolled was 41 years (range: 21 to 73); 51% were Caucasian, and 66% were male. Mean baseline CD4+ cell count was 254 cells/mm (range: to 952 cells/mm 3) and mean baseline plasma HIV-1 RNULL was 4.3 log 10 copies/mL (range: 1.7 to 6.6 log 10 copies/mL). Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 25.Table 25. Outcomes of Randomized Treatment Through Week 48 (Study 802) OutcomeKALETRA Once Daily NRTIs (n 300)KALETRA Twice Daily NRTIs(n 299)Virologic Success (HIV-1 RNULL <50 copies/mL) 57%54%Virologic failure 22%24%No virologic data in Week 48 window Discontinued study due to adverse event or death 5%7%Discontinued study for other reasons 13%12%Missing data during window but on study3%3%1 Includes patients who discontinued prior to Week 48 for lack or loss of efficacy and patients with HIV-1 RNULL >= 50 copies/mL at Week 48. Includes patients who discontinued due to adverse events or death at any time from Day through Week 48 if this resulted in no virologic data on treatment at Week 48. Includes withdrawal of consent, loss to follow-up, non-compliance, protocol violation and other reasons. Through 48 weeks of treatment, the mean change from baseline for CD4 cell count was 135 cells/mm for the once daily group and 122 cells/mm for the twice daily group. 14.3 Other Studies Supporting Approval in Adult Patients. Study 720: KALETRA twice daily stavudine lamivudineStudy 765: KALETRA twice daily nevirapine NRTIsStudy 720 (patients without prior antiretroviral therapy) and study 765 (patients with prior protease inhibitor therapy) were randomized, blinded, multi-center trials evaluating treatment with KALETRA at up to three dose levels (200/100 mg twice daily [720 only], 400/100 mg twice daily, and 400/200 mg twice daily). In Study 720, all patients switched to 400/100 mg twice daily between Weeks 48-72. Patients in study 720 had mean age of 35 years, 70% were Caucasian, and 96% were male, while patients in study 765 had mean age of 40 years, 73% were Caucasian, and 90% were male. Mean (range) baseline CD4+ cell counts for patients in study 720 and study 765 were 338 (3-918) and 372 (72-807) cells/mm 3, respectively. Mean (range) baseline plasma HIV-1 RNULL levels for patients in study 720 and study 765 were 4.9 (3.3 to 6.3) and 4.0 (2.9 to 5.8) log 10 copies/mL, respectively. Through 360 weeks of treatment in study 720, the proportion of patients with HIV-1 RNULL 400 (< 50) copies/mL was 61% (59%) [n 100]. Among patients completing 360 weeks of treatment with CD4+ cell count measurements [n=60], the mean (median) increase in CD4+ cell count was 501 (457) cells/mm 3. Thirty-nine patients (39%) discontinued the study, including 13 (13%) discontinuations due to adverse reactions and (1%) death. Through 144 weeks of treatment in study 765, the proportion of patients with HIV-1 RNULL 400 (< 50) copies/mL was 54% (50%) [n 70], and the corresponding mean increase in CD4+ cell count was 212 cells/mm 3. Twenty-seven patients (39%) discontinued the study, including (7%) discontinuations secondary to adverse reactions and (3%) deaths. 14.4 Pediatric Studies Study 1030 was an open-label, multicenter, dose-finding trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at dose of 300/75 mg/m twice daily plus NRTIs in HIV-1 infected infants >=14 days and <6 months of age. Ten infants, >=14 days and <6 wks of age, were enrolled at median (range) age of 5.7 (3.6-6.0) weeks and all completed 24 weeks. At entry, median (range) HIV-1 RNULL was 6.0 (4.7-7.2) log 10 copies/mL. Seven of 10 infants had HIV-1 RNULL <400 copies/mL at Week 24. At entry, median (range) CD4+ percentage was 41 (16-59) with median decrease of 1% (95% CI: -10, 18) from baseline to week 24 in infants with available data. Twenty-one infants, between weeks and months of age, were enrolled at median (range) age of 14.7 (6.9-25.7) weeks and 19 of 21 infants completed 24 weeks. At entry, median (range) HIV RNULL level was 5.8 (3.7-6.9) log 10 copies/mL. Ten of 21 infants had HIV RNULL <400 copies/mL at Week 24. At entry, the median (range) CD4+ percentage was 32 (11-54) with median increase of 4% (95% CI: -1, 9) from baseline to week 24 in 19 infants with available data [see Clinical Pharmacology 12.3) for pharmacokinetic results] Study 940 was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naive (44%) and experienced (56%) pediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naive. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per 2 or 300 mg lopinavir/75 mg ritonavir per 2. Naive patients also received lamivudine and stavudine. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors. Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after three weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300 mg lopinavir/75 mg ritonavir per 2 dose. Patients had mean age of years (range months to 12 years) with 14% less than years. Mean baseline CD4+ cell count was 838 cells/mm and mean baseline plasma HIV-1 RNULL was 4.7 log 10 copies/mL. Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV-1 RNULL 400 copies/mL was 80% for antiretroviral naive patients and 71% for antiretroviral experienced patients. The mean increase from baseline in CD4+ cell count was 404 cells/mm for antiretroviral naive and 284 cells/mm for antiretroviral experienced patients treated through 48 weeks. At 48 weeks, two patients (2%) had prematurely discontinued the study. One antiretroviral naive patient prematurely discontinued secondary to an adverse reaction, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-1 related event. Dose selection in pediatric patients was based on the following:Among patients 14 days to months of age receiving 300/75 mg/m twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children. This dose resulted in HIV-1 RNULL 400 copies/mL in 55% of patients (70% in those initiating treatment at <6 weeks of age). Among patients months to 12 years of age, the 230/57.5 mg/m oral solution twice daily regimen without nevirapine and the 300/75 mg/m oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine). These doses resulted in treatment benefit (proportion of patients with HIV-1 RNULL 400 copies/mL) similar to that seen in the adult clinical trials. Among patients 12 to 18 years of age receiving 400/100 mg/m or 480/120 mg/m (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among to 12 year old patients receiving 230/57.5 mg/m 2. Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients to 12 years of age. Although changes in HIV-1 RNULL in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients to 12 years of age, not to exceed the recommended adult dose. For all age groups, the body surface area dosing was converted to body weight dosing using the patients prescribed lopinavir dose.. Among patients 14 days to months of age receiving 300/75 mg/m twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children. This dose resulted in HIV-1 RNULL 400 copies/mL in 55% of patients (70% in those initiating treatment at <6 weeks of age). Among patients months to 12 years of age, the 230/57.5 mg/m oral solution twice daily regimen without nevirapine and the 300/75 mg/m oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine). These doses resulted in treatment benefit (proportion of patients with HIV-1 RNULL 400 copies/mL) similar to that seen in the adult clinical trials. Among patients 12 to 18 years of age receiving 400/100 mg/m or 480/120 mg/m (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among to 12 year old patients receiving 230/57.5 mg/m 2. Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients to 12 years of age. Although changes in HIV-1 RNULL in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients to 12 years of age, not to exceed the recommended adult dose. For all age groups, the body surface area dosing was converted to body weight dosing using the patients prescribed lopinavir dose.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. KALETRA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions 7.1) and Clinical Pharmacology 12.3)] Alpha 1- Adrenoreceptor Antagonist: alfuzosinAntianginal: ranolazineAntiarrhythmic: dronedaroneAnti-gout: colchicineAntipsychotics: lurasidone, pimozide Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovineGI Motility Agent: cisaprideHepatitis direct acting antiviral: elbasvir/grazoprevirHMG-CoA Reductase Inhibitors: lovastatin, simvastatinMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapideMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapidePDE5 Inhibitor: sildenafil (Revatio (R)) when used for the treatment of pulmonary arterial hypertension Sedative/Hypnotics: triazolam, orally administered midazolam KALETRA is contraindicated with drugs that are 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 [see Drug Interactions 7.2) and Clinical Pharmacology 12.3)] Anticancer Agents: apalutamideAntimycobacterial: rifampinHerbal Products: St. Johns Wort (hypericum perforatum) KALETRA is contraindicated in patients with previously demonstrated clinically significant hypersensitivity (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) to any of its ingredients, including ritonavir.. KALETRA is contraindicated with drugs that are highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening reactions [see Drug Interactions 7.1) and Clinical Pharmacology 12.3)] Alpha 1- Adrenoreceptor Antagonist: alfuzosinAntianginal: ranolazineAntiarrhythmic: dronedaroneAnti-gout: colchicineAntipsychotics: lurasidone, pimozide Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovineGI Motility Agent: cisaprideHepatitis direct acting antiviral: elbasvir/grazoprevirHMG-CoA Reductase Inhibitors: lovastatin, simvastatinMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapideMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapidePDE5 Inhibitor: sildenafil (Revatio (R)) when used for the treatment of pulmonary arterial hypertension Sedative/Hypnotics: triazolam, orally administered midazolam Alpha 1- Adrenoreceptor Antagonist: alfuzosin. Antianginal: ranolazine. Antiarrhythmic: dronedarone. Anti-gout: colchicine. Antipsychotics: lurasidone, pimozide Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine. GI Motility Agent: cisapride. Hepatitis direct acting antiviral: elbasvir/grazoprevir. HMG-CoA Reductase Inhibitors: lovastatin, simvastatin. Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapideMicrosomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide. PDE5 Inhibitor: sildenafil (Revatio (R)) when used for the treatment of pulmonary arterial hypertension Sedative/Hypnotics: triazolam, orally administered midazolam. KALETRA is contraindicated with drugs that are 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 [see Drug Interactions 7.2) and Clinical Pharmacology 12.3)] Anticancer Agents: apalutamideAntimycobacterial: rifampinHerbal Products: St. Johns Wort (hypericum perforatum) Anticancer Agents: apalutamide. Antimycobacterial: rifampin. Herbal Products: St. Johns Wort (hypericum perforatum). Hypersensitivity to KALETRA (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of its ingredients, including ritonavir. 4) Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. 4) Co-administration 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. 4) Hypersensitivity to KALETRA (e.g., toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, urticaria, angioedema) or any of its ingredients, including ritonavir. 4) Co-administration with drugs highly dependent on CYP3A for clearance and for which elevated plasma levels may result in serious and/or life-threatening events. 4) Co-administration 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. 4).

DESCRIPTION SECTION.


11 DESCRIPTION. KALETRA is co-formulation of lopinavir and ritonavir. Lopinavir is an inhibitor of the HIV-1 protease. As co-formulated in KALETRA, ritonavir inhibits the CYP3A-mediated metabolism of lopinavir, thereby providing increased plasma levels of lopinavir.Lopinavir is chemically designated as [1 S-[1 R,( R), R, R]]- N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2 H)-pyrimidineacetamide. Its molecular formula is 37H 48N 4O 5, and its molecular weight is 628.80. Lopinavir is white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Lopinavir has the following structural formula: Ritonavir is chemically designated as 10-hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5 S-(5 R,8 R,10 R,11 R)]. Its molecular formula is 37H 48N 6O 5S 2, and its molecular weight is 720.95. Ritonavir is white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Ritonavir has the following structural formula: KALETRA tablets are available for oral administration in two strengths: Yellow or red tablets containing 200 mg of lopinavir and 50 mg of ritonavirPale yellow or pink tablets containing 100 mg of lopinavir and 25 mg of ritonavir.The yellow, 200 mg lopinavir and 50 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and yellow ferric oxide E172. The red, 200 mg lopinavir and 50 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate and sorbitan monolaurate. The following are the ingredients in the film coating: colloidal silicon dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and red ferric oxide E172.The pale yellow, 100 mg lopinavir and 25 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow ferric oxide E172. The pink, 100 mg lopinavir and 25 mg ritonavir, tablets contain the following inactive ingredients: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The following are the ingredients in the film coating: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and red ferric oxide E172.KALETRA oral solution is available for oral administration as 80 mg lopinavir and 20 mg ritonavir per milliliter with the following inactive ingredients: acesulfame potassium, artificial cotton candy flavor, citric acid, ethanol, glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water. KALETRA oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Yellow or red tablets containing 200 mg of lopinavir and 50 mg of ritonavir. Pale yellow or pink tablets containing 100 mg of lopinavir and 25 mg of ritonavir.. lopinavir-chem-structure. ritonavir-chem-structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Tablets: May be taken with or without food, swallowed whole and not chewed, broken, or crushed. 2.1) Oral solution: must be taken with food. 2.1) KALETRA oral solution is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes composed of silicone or polyvinyl chloride (PVC) can be used. (2.2) Adults 2.3): Total recommended daily dosage is 800/200 mg given once or twice daily.KALETRA can be given as once daily or twice daily regimen. See Full Prescribing Information for details. KALETRA once daily dosing regimen is not recommended in: Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 12.4) In combination with carbamazepine, phenobarbital, or phenytoin. 7.3) In combination with efavirenz, nevirapine, or nelfinavir. 12.3) In pregnant women. 2.5, 8.1, 12.3) Pediatric Patients (14 days and older) 2.4): KALETRA once daily dosing regimen is not recommended in pediatric patients.Twice daily dose is based on body weight or body surface area. Concomitant Therapy in Adults and Pediatric Patients:Dose adjustments of KALETRA may be needed when co-administering with efavirenz, nevirapine, or nelfinavir. 2.3, 2.4, 7.3) KALETRA oral solution should not be administered to neonates before postmenstrual age (first day of the mothers last menstrual period to birth plus the time elapsed after birth) of 42 weeks and postnatal age of at least 14 days has been attained 2.4, 5.2) Pregnancy 2.5): 400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.There are insufficient data to recommend KALETRA dose for pregnant patients with any documented KALETRA-associated resistance substitutions.No dose adjustment of KALETRA is required for patients during the postpartum period.. Total recommended daily dosage is 800/200 mg given once or twice daily.. KALETRA can be given as once daily or twice daily regimen. See Full Prescribing Information for details. KALETRA once daily dosing regimen is not recommended in: Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 12.4) In combination with carbamazepine, phenobarbital, or phenytoin. 7.3) In combination with efavirenz, nevirapine, or nelfinavir. 12.3) In pregnant women. 2.5, 8.1, 12.3) Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V. 12.4) In combination with carbamazepine, phenobarbital, or phenytoin. 7.3) In combination with efavirenz, nevirapine, or nelfinavir. 12.3) In pregnant women. 2.5, 8.1, 12.3) KALETRA once daily dosing regimen is not recommended in pediatric patients.. Twice daily dose is based on body weight or body surface area. Dose adjustments of KALETRA may be needed when co-administering with efavirenz, nevirapine, or nelfinavir. 2.3, 2.4, 7.3) KALETRA oral solution should not be administered to neonates before postmenstrual age (first day of the mothers last menstrual period to birth plus the time elapsed after birth) of 42 weeks and postnatal age of at least 14 days has been attained 2.4, 5.2) 400/100 mg twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.. There are insufficient data to recommend KALETRA dose for pregnant patients with any documented KALETRA-associated resistance substitutions.. No dose adjustment of KALETRA is required for patients during the postpartum period.. 2.1 General Administration Recommendations. KALETRA tablets may be taken with or without food. The tablets should be swallowed whole and not chewed, broken, or crushed. KALETRA oral solution must be taken with food. 2.2 Administering Oral Solution by Feeding Tube. Because KALETRA oral solution contains ethanol and propylene glycol, it is not recommended for use with polyurethane feeding tubes due to potential incompatibility. Feeding tubes that are compatible with ethanol and propylene glycol, such as silicone and polyvinyl chloride (PVC) feeding tubes, can be used for administration of KALETRA oral solution. Follow instructions for use of the feeding tube to administer the medicine.. 2.3 Dosage Recommendations in Adults. KALETRA can be given in once daily or twice daily dosing regimen at dosages noted in Tables and 2. KALETRA once daily dosing regimen is not recommended in: Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V [see Microbiology 12.4)] In combination with carbamazepine, phenobarbital, or phenytoin [see Drug Interactions 7.3)] In combination with efavirenz, nevirapine, or nelfinavir [see Drug Interactions 7.3) and Clinical Pharmacology 12.3)] In pediatric patients younger than 18 years of age [see Dosage and Administration 2.4)] In pregnant women [see Dosage and Administration 2.5), Use in Specific Populations 8.1) and Clinical Pharmacology 12.3)] Table 1. Recommended Dosage in Adults KALETRA Once Daily Regimen KALETRA Dosage FormRecommended Dosage200 mg/50 mg Tablets800 mg/200 mg (4 tablets) once daily80 mg/20 mg per mL Oral Solution800 mg/200 mg (10 mL) once dailyTable 2. Recommended Dosage in Adults KALETRA Twice Daily Regimen KALETRA Dosage FormRecommended Dosage200 mg/50 mg Tablets400 mg/100 mg (2 tablets) twice daily80 mg/20 mg per mL Oral Solution400 mg/100 mg (5 mL) twice dailyThe dose of KALETRA must be increased when administered in combination with efavirenz, nevirapine or nelfinavir. Table outlines the dosage recommendations for twice daily dosing when KALETRA is taken in combination with these agents. Table 3. Recommended Dosage in Adults KALETRA Twice Daily Regimen in Combination with Efavirenz, Nevirapine, or NelfinavirKALETRA Dosage FormRecommended Dosage200 mg/50 mg Tablets and 100 mg/25 mg Tablets 500 mg/125 mg (2 tablets of 200 mg/50 mg 1 tablet of 100 mg/25 mg) twice daily 80 mg/20 mg per mL Oral Solution520 mg/130 mg (6.5 mL) twice daily. Adult patients with three or more of the following lopinavir resistance-associated substitutions: L10F/I/R/V, K20M/N/R, L24I, L33F, M36I, I47V, G48V, I54L/T/V, V82A/C/F/S/T, and I84V [see Microbiology 12.4)] . In combination with carbamazepine, phenobarbital, or phenytoin [see Drug Interactions 7.3)] . In combination with efavirenz, nevirapine, or nelfinavir [see Drug Interactions 7.3) and Clinical Pharmacology 12.3)] . In pediatric patients younger than 18 years of age [see Dosage and Administration 2.4)] . In pregnant women [see Dosage and Administration 2.5), Use in Specific Populations 8.1) and Clinical Pharmacology 12.3)] . 2.4 Dosage Recommendations in Pediatric Patients. KALETRA tablets and oral solution are not recommended for once daily dosing in pediatric patients younger than 18 years of age. The dose of the oral solution should be administered using the calibrated cup (supplied) or oral dosing syringe. KALETRA 100/25 mg tablets should be considered only in children who have reliably demonstrated the ability to swallow the intact tablet. KALETRA oral solution is not recommended in neonates before postmenstrual age (first day of the mothers last menstrual period to birth plus the time elapsed after birth) of 42 weeks and postnatal age of at least 14 days has been attained [see Warnings and Precautions 5.2)] KALETRA oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Total amounts of ethanol and propylene glycol from all medicines that are to be given to pediatric patients 14 days to months of age should be taken into account in order to avoid toxicity from these excipients [see Warnings and Precautions 5.2) and Overdosage 10)]. Pediatric Dosage CalculationsCalculate the appropriate dose of KALETRA for each individual pediatric patient based on body weight (kg) or body surface area (BSA) to avoid underdosing or exceeding the recommended adult dose.Body surface area (BSA) can be calculated as follows: The KALETRA dose can be calculated based on weight or BSA:Based on Weight:Patient Weight (kg) Prescribed lopinavir dose (mg/kg) Administered lopinavir dose (mg) Based on BSA:Patient BSA (m 2) Prescribed lopinavir dose (mg/m 2) Administered lopinavir dose (mg) If KALETRA oral solution is used, the volume (mL) of KALETRA solution can be determined as follows:Volume of KALETRA solution (mL) Administered lopinavir dose (mg) 80 (mg/mL)Oral Solution Dosage Recommendation in Pediatric Patients 14 Days to Less Than 18 Years:Table summarizes the recommended daily dosing regimen for pediatric patients 14 days to less than 18 years of age using the oral solution. KALETRA administered in combination with efavirenz, nevirapine, or nelfinavir in patients younger than months of age is not recommended. Total dose of KALETRA oral solution in pediatric patients should not exceed the recommended adult daily dose of 400/100 mg (5mL) twice daily.Table 4. KALETRA Oral Solution Daily Dosage Recommendations in Pediatric Patients 14 days to Less Than 18 Years Without Concomitant Efavirenz, Nevirapine, or NelfinavirPatient AgeBased on Weight (mg/kg) Based on BSA (mg/m 2) Frequency14 days to months16/4300/75Given twice daily Older than months to less than 18 yearsLess than15 kg12/3230/57.5Given twice daily 15 kg to 40 kg10/2.5Tablet Dosage Recommendation in Pediatric Patients Older than Months to Less than 18 Years:Table provides the dosing recommendations for pediatric patients older than months to less than 18 years of age based on body weight or body surface area for KALETRA tablets.Table 5. KALETRA Tablet Daily Dosage Recommendations in Pediatric Patients 6 Months to 18 Years of Age Without Concomitant Efavirenz, Nevirapine, or Nelfinavir Body Weight (kg)Body Surface Area (m 2) Recommended number of 100/25 mg Tablets Twice Daily >=15 to 25>=0.6 to 0.92 >25 to 35>=0.9 to 1.43 >35>=1.44 KALETRA oral solution is available for children with BSA less than 0.6 2 or those who are unable to reliably swallow tablet. Concomitant Therapy: Efavirenz, Nevirapine, or NelfinavirDosing recommendations using oral solutionTable provides the dosing recommendations for pediatric patients older than months to less than 18 years of age based on body weight or body surface area for KALETRA Oral Solution when given in combination with efavirenz, nevirapine, or nelfinavir:Table 6. KALETRA Oral Solution Daily Dosage Recommendations for Pediatric Patients 6 Months to 18 Years of Age With Concomitant Efavirenz, Nevirapine, or Nelfinavir Patient AgeBased on Weight (mg/kg) Based on BSA (mg/m 2) Frequency> months to 18 years <15 kg 13/3.25300/75Given twice daily >=15 kg to 45 kg11/2.75Dosing recommendations using tabletsTable provides the dosing recommendations for pediatric patients older than months to less than 18 years of age based on body weight or body surface area for KALETRA tablets when given in combination with efavirenz, nevirapine, or nelfinavir. Table 7. KALETRA Tablet Daily Dosage Recommendations for Pediatric Patients 6 Months to 18 Years of Age With Concomitant Efavirenz +, Nevirapine, or Nelfinavir Body Weight (kg)Body Surface Area (m 2) Recommended number of100/25 mg Tablets Twice Daily>=15 to 20>=0.6 to 0.82 >20 to 30>=0.8 to 1.23 >30 to 45>=1.2 to <1.74>45>=1.75 [see Dosage and Administration 2.4)] KALETRA oral solution is available for children with BSA less than 0.6 2 or those who are unable to reliably swallow tablet. Please refer to the individual product labels for appropriate dosing in children. Body surface area equation.. 2.5 Dosage Recommendations in Pregnancy. Administer 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions.Once daily KALETRA dosing is not recommended in pregnancy [see Use in Specific Populations 8.1) and Clinical Pharmacology 12.3)] There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions. No dosage adjustment of KALETRA is required for patients during the postpartum period.Avoid use of KALETRA oral solution in pregnant women [see Use in Specific Populations 8.1)] . Once daily KALETRA dosing is not recommended in pregnancy [see Use in Specific Populations 8.1) and Clinical Pharmacology 12.3)] . There are insufficient data to recommend dosing in pregnant women with any documented lopinavir-associated resistance substitutions. No dosage adjustment of KALETRA is required for patients during the postpartum period.. Avoid use of KALETRA oral solution in pregnant women [see Use in Specific Populations 8.1)].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. Tablets: 200 mg lopinavir, 50 mg ritonavir: Yellow, film-coated, ovaloid, debossed with the a logo and the code KA containing 200 mg lopinavir and 50 mg ritonavir.100 mg lopinavir, 25 mg ritonavir: Pale yellow, film-coated, ovaloid, debossed with the a logo and the code KC containing 100 mg lopinavir and 25 mg ritonavir.200 mg lopinavir, 50 mg ritonavir: Red, film-coated, ovaloid, debossed with the a logo and the code AL containing 200 mg lopinavir and 50 mg ritonavir. 100 mg lopinavir, 25 mg ritonavir: Pink, film-coated, ovaloid, debossed with the a logo and the code AC containing 100 mg lopinavir and 25 mg ritonavir. Oral Solution: Light yellow to orange colored liquid containing 400 mg lopinavir and 100 mg ritonavir per mL (80 mg lopinavir and 20 mg ritonavir per mL). Tablets: 200 mg lopinavir, 50 mg ritonavir: Yellow, film-coated, ovaloid, debossed with the a logo and the code KA containing 200 mg lopinavir and 50 mg ritonavir.100 mg lopinavir, 25 mg ritonavir: Pale yellow, film-coated, ovaloid, debossed with the a logo and the code KC containing 100 mg lopinavir and 25 mg ritonavir.200 mg lopinavir, 50 mg ritonavir: Red, film-coated, ovaloid, debossed with the a logo and the code AL containing 200 mg lopinavir and 50 mg ritonavir. 100 mg lopinavir, 25 mg ritonavir: Pink, film-coated, ovaloid, debossed with the a logo and the code AC containing 100 mg lopinavir and 25 mg ritonavir. 200 mg lopinavir, 50 mg ritonavir: Yellow, film-coated, ovaloid, debossed with the a logo and the code KA containing 200 mg lopinavir and 50 mg ritonavir.. 100 mg lopinavir, 25 mg ritonavir: Pale yellow, film-coated, ovaloid, debossed with the a logo and the code KC containing 100 mg lopinavir and 25 mg ritonavir.. 200 mg lopinavir, 50 mg ritonavir: Red, film-coated, ovaloid, debossed with the a logo and the code AL containing 200 mg lopinavir and 50 mg ritonavir. 100 mg lopinavir, 25 mg ritonavir: Pink, film-coated, ovaloid, debossed with the a logo and the code AC containing 100 mg lopinavir and 25 mg ritonavir.. Oral Solution: Light yellow to orange colored liquid containing 400 mg lopinavir and 100 mg ritonavir per mL (80 mg lopinavir and 20 mg ritonavir per mL). Light yellow to orange colored liquid containing 400 mg lopinavir and 100 mg ritonavir per mL (80 mg lopinavir and 20 mg ritonavir per mL).. Tablets: 200 mg lopinavir and 50 mg ritonavir 3) Tablets: 100 mg lopinavir and 25 mg ritonavir 3) Oral solution: 80 mg lopinavir and 20 mg ritonavir per milliliter 3) Tablets: 200 mg lopinavir and 50 mg ritonavir 3) Tablets: 100 mg lopinavir and 25 mg ritonavir 3) Oral solution: 80 mg lopinavir and 20 mg ritonavir per milliliter 3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Co-administration of KALETRA can alter the plasma concentrations of other drugs and other drugs may alter the plasma concentrations of lopinavir. The potential for drug-drug interactions must be considered prior to and during therapy. 4, 5.1, 7, 12.3) 7.1 Potential for KALETRA to Affect Other Drugs. Lopinavir/ritonavir is an inhibitor of CYP3A and may increase plasma concentrations of agents that are primarily metabolized by CYP3A. Agents that are extensively metabolized by CYP3A and have high first pass metabolism appear to be the most susceptible to large increases in AUC (> 3-fold) when co-administered with KALETRA. Thus, co-administration of KALETRA with drugs highly dependent on CYP3A for clearance and for which elevated plasma concentrations are associated with serious and/or life-threatening events is contraindicated. Co-administration with other CYP3A substrates may require dose adjustment or additional monitoring as shown in Table 12.Additionally, KALETRA induces glucuronidation.Published data suggest that lopinavir is an inhibitor of OATP1B1.These examples are guide and not considered comprehensive list of all possible drugs that may interact with lopinavir/ritonavir. The healthcare provider should consult appropriate references for comprehensive information. 7.2 Potential for Other Drugs to Affect Lopinavir. Lopinavir/ritonavir is CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRAs therapeutic effect. Although not observed in the KALETRA/ketoconazole drug interaction study, co-administration of KALETRA and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations.. 7.3 Established and Other Potentially Significant Drug Interactions. Table 12 provides listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications 4), Warnings and Precautions 5.1), Clinical Pharmacology 12.3)] for magnitude of interaction. Table 12. Established and Other Potentially Significant Drug InteractionsConcomitant Drug Class:Drug NameEffect on Concentration of Lopinavir or Concomitant DrugClinical CommentsHIV-1 Antiviral AgentsHIV-1 Protease Inhibitor: fosamprenavir/ritonavir amprenavir lopinavir An increased rate of adverse reactions has been observed with co-administration of these medications. Appropriate doses of the combinations with respect to safety and efficacy have not been established.HIV-1 Protease Inhibitor: indinavir indinavir Decrease indinavir dose to 600 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with indinavir.HIV-1 Protease Inhibitor: nelfinavir nelfinavir M8 metabolite of nelfinavir lopinavir KALETRA once daily in combination with nelfinavir is not recommended [see Dosage and Administration 2)] HIV-1 Protease Inhibitor: ritonavir lopinavirAppropriate doses of additional ritonavir in combination with KALETRA with respect to safety and efficacy have not been established.HIV-1 Protease Inhibitor: saquinavir saquinavir The saquinavir dose is 1000 mg twice daily, when co-administered with KALETRA 400/100 mg twice daily. KALETRA once daily has not been studied in combination with saquinavir. HIV-1 Protease Inhibitor: tipranavir lopinavirCo-administration with tipranavir (500 mg twice daily) and ritonavir (200 mg twice daily) is not recommended.HIV CCR5 Antagonist: maraviroc maravirocWhen co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for maraviroc. Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz, nevirapine lopinavirIncrease the dose of KALETRA tablets to 500/125 mg when KALETRA tablet is co-administered with efavirenz or nevirapine. KALETRA once daily in combination with efavirenz or nevirapine is not recommended [see Dosage and Administration 2)] Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine lopinavirAppropriate doses of the combination with respect to safety and efficacy have not been established.Nucleoside Reverse Transcriptase Inhibitor: didanosine KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (given with food). Nucleoside Reverse Transcriptase Inhibitor: tenofovir disoproxil fumarate tenofovirPatients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir. Nucleoside Reverse Transcriptase Inhibitors: abacavir zidovudine abacavir zidovudine The clinical significance of this potential interaction is unknown. Other AgentsAlpha 1- Adrenoreceptor Antagonist: alfuzosin alfuzosinContraindicated due to potential hypotension [see Contraindications 4)] Antianginal: ranolazine ranolazineContraindicated due to potential for serious and/or life-threatening reactions [see Contraindications 4)] Antiarrhythmics: dronedarone dronedaroneContraindicated due to potential for cardiac arrhythmias [see Contraindications 4)] Antiarrhythmics e.g. amiodarone, bepridil, lidocaine (systemic), quinidine antiarrhythmicsCaution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. Anticancer Agents: abemaciclib, apalutamide, encorafenib, ibrutinib, ivosidenib, dasatinib, neratinib, nilotinib, venetoclax, vinblastine, vincristine anticancer agents lopinavir/ritonavir Apalutamide is contraindicated due to potential for loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors [see Contraindications 4)] Avoid co-administration of encorafenib or ivosidenib with KALETRA due to potential risk of serious adverse events such as QT interval prolongation. If co-administration of encorafenib with KALETRA cannot be avoided, modify dose as recommended in encorafenib USPI. If co-administration of ivosidenib with KALETRA cannot be avoided, reduce ivosidenib dose to 250 mg once daily. Avoid use of neratinib, venetoclax or ibrutinib with KALETRA. For vincristine and vinblastine, consideration should be given to temporarily withholding the ritonavir-containing antiretroviral regimen in patients who develop significant hematologic or gastrointestinal side effects when KALETRA is administered concurrently with vincristine or vinblastine. If the antiretroviral regimen must be withheld for prolonged period, consideration should be given to initiating revised regimen that does not include CYP3A or P-gp inhibitor. decrease in the dosage or an adjustment of the dosing interval of nilotinib and dasatinib may be necessary for patients requiring co-administration with strong CYP3A inhibitors such as KALETRA. Please refer to the nilotinib and dasatinib prescribing information for dosing instructions. Anticoagulants: warfarin, rivaroxaban warfarin rivaroxaban Concentrations of warfarin may be affected. Initial frequent monitoring of the INR during KALETRA and warfarin co-administration is recommended. Avoid concomitant use of rivaroxaban and KALETRA. Co-administration of KALETRA and rivaroxaban may lead to increased risk of bleeding. Anticonvulsants: carbamazepine, phenobarbital, phenytoin lopinavir phenytoin KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA once daily in combination with carbamazepine, phenobarbital, or phenytoin is not recommended. In addition, co-administration of phenytoin and KALETRA may cause decreases in steady-state phenytoin concentrations. Phenytoin levels should be monitored when co-administering with KALETRA. Anticonvulsants: lamotrigine, valproate lamotrigine or <-> valproate dose increase of lamotrigine or valproate may be needed when co-administered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments. Antidepressant: bupropion bupropion active metabolite, hydroxybupropion Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion. Antidepressant: trazodone trazodoneAdverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. lower dose of trazodone should be considered. Anti-infective: clarithromycin clarithromycinFor patients with renal impairment, adjust clarithromycin dose as follows: For patients on KALETRA with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CL CR 30 mL/min the dose of clarithromycin should be decreased by 75%. No dose adjustment for patients with normal renal function is necessary. Antifungals: ketoconazole, itraconazole, voriconazole isavuconazonium sulfate ketoconazole itraconazole voriconazole isavuconazonium High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended. The coadministration of voriconazole and KALETRA should be avoided unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Isavuconazonium and Kaletra should be coadministered with caution. Alternative antifungal therapies should be considered in these patients. Anti-gout: colchicine colchicineContraindicated due to potential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment [see Contraindications 4)] For patients with normal renal or hepatic function: Treatment of gout flares-co-administration of colchicine in patients on KALETRA: 0.6 mg (1 tablet) 1 dose, followed by 0.3 mg (half tablet) hour later. Dose to be repeated no earlier than days. Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA: If the original colchicine regimen was 0.6 mg twice day, the regimen should be adjusted to 0.3 mg once day. If the original colchicine regimen was 0.6 mg once 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 day). Antimycobacterial: rifampin lopinavirContraindicated 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 Contraindications 4)] Antimycobacterial: bedaquiline bedaquilineBedaquiline should only be used with KALETRA if the benefit of co-administration outweighs the risk. Antimycobacterial: rifabutin rifabutin and rifabutin metaboliteDosage reduction of rifabutin by at least 75% of the usual dose of 300 mg/day is recommended (i.e., maximum dose of 150 mg every other day or three times per week). Increased monitoring for adverse reactions is warranted in patients receiving the combination. Further dosage reduction of rifabutin may be necessary.Antiparasitic: atovaquone atovaquoneClinical significance is unknown; however, increase in atovaquone doses may be needed.Antipsychotics: lurasidone pimozide lurasidone pimozide Contraindicated due to potential for serious and/or life-threatening reactions [see Contraindications 4)] Contraindicated due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications 4)] Antipsychotics: quetiapine quetiapineInitiation of KALETRA in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking KALETRA: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. Contraceptive: ethinyl estradiol ethinyl estradiolBecause contraceptive steroid concentrations may be altered when KALETRA is co-administered with oral contraceptives or with the contraceptive patch, alternative methods of nonhormonal contraception are recommended.Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine dihydropyridine calcium channel blockersClinical monitoring of patients is recommended and dose reduction of the dihydropyridine calcium channel blocker may be considered. Disulfiram/metronidazole KALETRA oral solution contains ethanol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). Endothelin Receptor Antagonists: bosentan bosentanCo-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. Ergot Derivatives: dihydroergotamine, ergotamine, methylergonovine ergot derivativesContraindicated due to potential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications 4)] GI Motility Agent: cisapride cisaprideContraindicated due to potential for cardiac arrhythmias [see Contraindications 4)] GnRH Receptor Antagonists: elagolix elagolix lopinavir/ritonavir Concomitant use of elagolix 200 mg twice daily and KALETRA for more than month is not recommended due to potential risk of adverse events such as bone loss and hepatic transaminase elevations. Limit concomitant use of elagolix 150 mg once daily and KALETRA to months. Hepatitis direct acting antiviral: elbasvir/grazoprevir elbasvir/grazoprevirContraindicated due to increased risk of alanine transaminase (ALT) elevations [see Contraindications 4)] Hepatitis direct acting antivirals: boceprevir glecaprevir/pibrentasvir simeprevir sofosbuvir/velpatasvir/voxilaprevir ombitasvir/paritaprevir/ ritonavir and dasabuvir lopinavir boceprevir ritonavir glecaprevir pibrentasvir simeprevir sofosbuvir velpatasvir voxilaprevir ombitasvir paritaprevir ritonavir <-> dasabuvir It is not recommended to co-administer KALETRA and boceprevir, glecaprevir/pibrentasvir, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir. Herbal Products: St. Johns Wort (hypericum perforatum) lopinavirContraindicated due to potential for loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors [see Contraindications 4)] Lipid-modifying agents HMG-CoA Reductase Inhibitors: lovastatin simvastatin atorvastatin rosuvastatin Microsomal triglyceride transfer protein (MTTP) Inhibitor: lomitapide lovastatin simvastatin atorvastatin rosuvastatin lomitapide Contraindicated due to potential for myopathy including rhabdomyolysis [see Contraindications 4)] Use atorvastatin with caution and at the lowest necessary dose. Titrate rosuvastatin dose carefully and use the lowest necessary dose; do not exceed rosuvastatin 10 mg/day. Lomitapide is sensitive substrate for CYP3A4 metabolism. CYP3A4 inhibitors increase the exposure of lomitapide, with strong inhibitors increasing exposure approximately 27-fold. Concomitant use of moderate or strong CYP3A4 inhibitors with lomitapide is contraindicated due to potential for hepatotoxicity [see Contraindications 4)] Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus immunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.Kinase Inhibitors: fostamatinib (also see anticancer agents above) fostamatinib metabolite R406 Monitor for toxicities of R406 such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required.Long-acting beta-adrenoceptor Agonist: salmeterol salmeterolConcurrent administration of salmeterol and KALETRA is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia.Narcotic Analgesics: methadone, fentanyl methadone fentanyl Dosage of methadone may need to be increased when co-administered with KALETRA. Careful monitoring of therapeutic and adverse effects (including potentially fatal respiratory depression) is recommended when fentanyl is concomitantly administered with KALETRA. PDE5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil avanafil sildenafil tadalafil vardenafil Sildenafil when used for the treatment of pulmonary arterial hypertension (Revatio (R)) is contraindicated due to the potential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope [see Contraindications 4)] Do not use KALETRA with avanafil because safe and effective avanafil dosage regimen has not been established. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving KALETRA. Co-administration of KALETRA with these drugs may result in an increase in PDE5 inhibitor associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Sildenafil (Revatio (R)) is contraindicated [see Contraindications 4)] The following dose adjustments are recommended for use of tadalafil (Adcirca (R)) with KALETRA: Co-administration of ADCIRCA in patients on KALETRA: In patients receiving KALETRA for at least one week, start ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Co-administration of KALETRA in patients on ADCIRCA: Avoid use of ADCIRCA during the initiation of KALETRA. Stop ADCIRCA at least 24 hours prior to starting KALETRA. After at least one week following the initiation of KALETRA, resume ADCIRCA at 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: It is recommended not to exceed the following doses: Sildenafil: 25 mg every 48 hours Tadalafil: 10 mg every 72 hours Vardenafil: 2.5 mg every 72 hours Use with increased monitoring for adverse events. Sedative/Hypnotics: triazolam, orally administered midazolam triazolam midazolam Contraindicated due to potential for prolonged or increased sedation or respiratory depression [see Contraindications 4)] Sedative/Hypnotics: parenterally administered midazolam midazolamIf KALETRA is co-administered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. Systemic/Inhaled/ Nasal/Ophthalmic Corticosteroids: e.g., betamethasone budesonide ciclesonide dexamethasone fluticasone methylprednisolone mometasone prednisone triamcinolone lopinavir glucocorticoids Coadministration with oral dexamethasone or other systemic corticosteroids that induce CYP3A may result in loss of therapeutic effect and development of resistance to lopinavir. Consider alternative corticosteroids. Coadministration with corticosteroids whose exposures are significantly increased by strong CYP3A inhibitors can increase the risk for Cushings syndrome and adrenal suppression. Alternative corticosteroids including beclomethasone and prednisolone (whose PK and/or PD are less affected by strong CYP3A inhibitors relative to other studied steroids) should be considered, particularly for long-term use. see Clinical Pharmacology 12.3) for magnitude of interaction. refers to interaction with apalutamide. For patients on KALETRA with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CL CR 30 mL/min the dose of clarithromycin should be decreased by 75%. 7.4 Drugs with No Observed or Predicted Interactions with KALETRA Drug interaction or clinical studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), etravirine, pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir, ranitidine, or rilpivirine.Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisLopinavir/ritonavir combination was evaluated for carcinogenic potential by oral gavage administration to mice and rats for up to 104 weeks. Results showed an increase in the incidence of benign hepatocellular adenomas and an increase in the combined incidence of hepatocellular adenomas plus carcinoma in both males and females in mice and males in rats at doses that produced approximately 1.6-2.2 times (mice) and 0.5 times (rats) the human exposure (based on AUC 0-24hr measurement) at the recommended dose of 400/100 mg KALETRA twice daily. Administration of lopinavir/ritonavir did not cause statistically significant increase in the incidence of any other benign or malignant neoplasm in mice or rats. Carcinogenicity studies in mice and rats have been carried out on ritonavir. In male mice, there was dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg KALETRA twice daily). There were no carcinogenic effects seen in females at the dosages tested. The exposure at the high dose was approximately 9-fold for the females that of the exposure in humans. There were no carcinogenic effects in rats. In this study, the exposure at the high dose was approximately 0.7-fold that of the exposure in humans with the 400/100 mg KALETRA twice daily regimen. Based on the exposures achieved in the animal studies, the significance of the observed effects is not known. MutagenesisNeither lopinavir nor ritonavir was found to be mutagenic or clastogenic in battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes. Impairment of FertilityLopinavir in combination with ritonavir at 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

NURSING MOTHERS SECTION.


8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Because of the potential for: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV- positive infants), and 3) adverse reactions in the breastfed infant, instruct mothers not to breastfeed if they are receiving KALETRA.

OVERDOSAGE SECTION.


10 OVERDOSAGE. Overdoses with KALETRA oral solution have been reported. One of these reports described fatal cardiogenic shock in 2.1 kg infant who received single dose of 6.5 mL of KALETRA oral solution (520 mg lopinavir, approximately 10-fold above the recommended lopinavir dose) nine days prior. The following events have been reported in association with unintended overdoses in preterm neonates: complete AV block, cardiomyopathy, lactic acidosis, and acute renal failure [see Warnings and Precautions 5.2)] Healthcare professionals should be aware that KALETRA oral solution is highly concentrated and therefore, should pay special attention to accurate calculation of the dose of KALETRA, transcription of the medication order, dispensing information and dosing instructions to minimize the risk for medication errors and overdose. This is especially important for infants and young children. KALETRA oral solution contains approximately 42% (v/v) ethanol and approximately 15% (w/v) propylene glycol. Ingestion of the product over the recommended dose by an infant or young child could result in significant toxicity and could potentially be lethal.Human experience of acute overdosage with KALETRA is limited. Treatment of overdose with KALETRA should consist of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient. There is no specific antidote for overdose with KALETRA. If indicated, elimination of unabsorbed drug should be achieved by gastric lavage. Administration of activated charcoal may also be used to aid in removal of unabsorbed drug. Since lopinavir is highly protein bound, dialysis is unlikely to be beneficial in significant removal of the drug. However, dialysis can remove both ethanol and propylene glycol in the case of overdose with KALETRA oral solution.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA should not be administered once daily in pediatric patients.An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at dose of 300/75 mg/m twice daily plus two NRTIs in HIV-infected infants >=14 days and 6 months of age. Results revealed that infants younger than months of age generally had lower lopinavir AUC 12 than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIV-1 RNULL <400 copies/mL at Week 24 [see Adverse Reactions 6.2), Clinical Pharmacology 12.3), Clinical Studies 14.4)] Safety and efficacy in pediatric patients 6 months of age was demonstrated in clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naive and experienced pediatric patients ages months to 12 years. Dose selection for patients months to 12 years of age was based on the following results. The 230/57.5 mg/m oral solution twice daily regimen without nevirapine and the 300/75 mg/m oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine) [see Adverse Reactions 6.2), Clinical Pharmacology 12.3), Clinical Studies 14.4)] A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m twice daily >= NRTIs; Group 2: 480/120 mg/m twice daily >= NRTI 1 NNRTI) in 26 children and adolescents >= years to 18 years of age who had failed prior therapy. Patients also had saquinavir mesylate added to their regimen. This strategy was intended to assess whether higher than approved doses of KALETRA could overcome protease inhibitor cross-resistance. High doses of KALETRA exhibited safety profile similar to those observed in previous trials; changes in HIV-1 RNULL were less than anticipated; three patients had HIV-1 RNULL <400 copies/mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks [see Adverse Reactions 6.2), Clinical Pharmacology 12.3)] A prospective multicenter, randomized, open-label study evaluated the efficacy and safety of twice-daily versus once-daily dosing of KALETRA tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible when they were aged 18 years, >= 15 kg in weight, receiving cART that included KALETRA, HIV-1 ribonucleic acid (RNULL) 50 copies/mL for at least 24 weeks and able to swallow tablets. At week 24, efficacy (defined as the proportion of subjects with plasma HIV-1 RNULL less than 50 copies per mL) was significantly higher in subjects receiving twice daily dosing compared to subjects receiving once daily dosing. The safety profile was similar between the two treatment arms although there was greater incidence of diarrhea in the once daily treated subjects.

PHARMACODYNULLMICS SECTION.


12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of KALETRA on QTcF interval was evaluated in placebo and active (moxifloxacin 400 mg once daily) controlled crossover study in 39 healthy adults. The maximum mean time-matched (95% upper confidence bound) differences in QTcF interval from placebo after baseline-correction were 5.3 (8.1) and 15.2 (18.0) mseconds (msec) for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively. KALETRA 800/200 mg twice daily resulted in Day mean max approximately 2-fold higher than the mean max observed with the approved once daily and twice daily KALETRA doses at steady state. The maximum mean (95% upper confidence bound) difference from placebo in the PR interval after baseline-correction were 24.9 (21.5, 28.3) and 31.9 (28.5, 35.3) msec for 400/100 mg twice daily and supratherapeutic 800/200 mg twice daily KALETRA, respectively [see Warnings and Precautions 5.5, 5.6)].

PREGNULLNCY SECTION.


8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.Risk SummaryAvailable data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation (see Data). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses. Clinical ConsiderationsDose Adjustments During Pregnancy and the Postpartum PeriodAdminister 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions [see Dosage and Administration 2.5) and Clinical Pharmacology 12.3)] There are insufficient data to recommend KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of KALETRA is required for patients during the postpartum period. Once daily KALETRA dosing is not recommended in pregnancy.Avoid use of KALETRA oral solution during pregnancy due to the ethanol content. KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%.DataHuman Data KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial [see Clinical Pharmacology 12.3)] No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data. Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 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. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir-containing regimens. For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least 1.5 fold increase in risk of overall birth defects and 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems. Animal DataEmbryonic 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 administered lopinavir in combination with ritonavir (on gestation days 6-17) at maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In pre- and post-natal study in rats, 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 administered lopinavir in combination with ritonavir (on gestation days 6-18) at maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).

RECENT MAJOR CHANGES SECTION.


Contraindications 4) 12/2019.

SPL MEDGUIDE SECTION.


MEDICATION GUIDEKALETRA (R) (kuh-LEE-tra) (lopinavir and ritonavir) tablets KALETRA (R) (kuh-LEE-tra) (lopinavir and ritonavir) oral solution What is the most important information should know about KALETRAKALETRA may cause serious side effects, including:Interactions with other medicines. It is important to know the medicines that should not be taken with KALETRA. For more information, see Who should not take KALETRA Side Effects in babies taking KALETRA oral solution. KALETRA oral solution contains alcohol (ethanol) and propylene glycol. Call your healthcare provider right away if your baby appears too sleepy or their breathing changes. Inflammation of your pancreas (pancreatitis). KALETRA can cause pancreatitis which may be serious and may lead to death. People who have high levels of certain fat (triglycerides) have risk for developing pancreatitis. If you have advanced HIV-1 disease, you may have an increased risk of high triglyceride levels in your blood, and pancreatitis. If you have history of pancreatitis, you may have an increased risk of it coming back again during treatment with KALETRA. Tell your healthcare provider if you have any signs or symptoms of pancreatitis including: nausea vomiting stomach-area (abdominal) painLiver problems. Liver problems, including death, can happen in people who take KALETRA. Your healthcare provider should do blood tests before and during your treatment with KALETRA to check your liver function. If you have Hepatitis or Hepatitis C, or other liver problems, you may have an increased risk for developing new or worsening of liver problems during treatment with KALETRA. Tell your healthcare provider right away if you have any signs and symptoms of liver problems including: loss of appetiteyellow skin and whites of eyes (jaundice)dark-colored urinepale colored stoolsitchy skinstomach area (abdominal) painChanges in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG (electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you: have history of abnormal heart rhythm or certain types of heart problems.take other medicines that can affect your heart rhythm during treatment with KALETRA. Tell your healthcare provider right away if you have any of these symptoms:dizzinesslightheadednessfaintingsensation of abnormal heartbeatsSee What are the possible side effects of KALETRA for more information about serious side effects. What is KALETRAKALETRA is prescription medicine that is used with other antiretroviral medicines to treat Human Immunodeficiency Virus-1 (HIV-1) infection in adults and children 14 days of age and older. HIV is the virus that causes AIDS (Acquired Immune Deficiency Syndrome). It is not known if KALETRA is safe and effective in children under 14 days old. Who should not take KALETRADo not take KALETRA if you:are allergic to lopinavir, ritonavir, or any of the ingredients in KALETRA. See the end of this Medication Guide for complete list of ingredients in KALETRA.if you take any of the following medicines: alfuzosinapalutamideranolazinedronedaronecolchicine, if you have kidney or liver problems.rifampinlurasidonepimozideergot containing medicines including: dihydroergotamine mesylateergotamine tartratemethylergonovine cisaprideelbasvir/grazoprevirlovastatinsimvastatinlomitapidesildenafil (Revatio (R)), when used for the treatment of pulmonary arterial hypertension triazolammidazolam when taken by mouthSt. Johns Wort (Hypericum perforatum (R)) Serious problems can happen if you or your child takes any of the medicines listed above with KALETRA.Before taking KALETRA, tell your healthcare provider about all of your medical conditions, including if you:have ever had serious skin rash or an allergic reaction to medicines that contain lopinavir or ritonavir.have or had pancreas problems.have liver problems, including Hepatitis or Hepatitis C.have any heart problems, including if you have condition called Congenital Long QT Syndrome.have low potassium in your blood.have diabetes.have high cholesterol in your blood.have hemophilia. KALETRA may cause increased bleeding.are pregnant or plan to become pregnant. It is not known if KALETRA will harm your unborn baby. KALETRA oral solution contains alcohol (ethanol) and propylene glycol. You should not take KALETRA oral solution during pregnancy because there is no safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with KALETRA.KALETRA may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with KALETRA.Pregnancy Registry: There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take KALETRA. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.Talk to your healthcare provider about the best way to feed your baby. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Many medicines interact with KALETRA. Keep list of your medicines to show your healthcare provider and pharmacist. You can ask your healthcare provider or pharmacist for list of medicines that interact with KALETRA. Do not start taking new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take KALETRA with other medicines. Your healthcare provider may need to change the dose of other medicines during treatment with KALETRA. How should take KALETRATake KALETRA every day exactly as prescribed by your healthcare provider.Stay under the care of your healthcare provider during treatment with KALETRA.It is important to set up dosing schedule and follow it every day.Do not change your treatment or stop treatment without first talking with your healthcare provider.Swallow KALETRA tablets whole. Do not chew, break, or crush KALETRA tablets.KALETRA tablets can be taken with or without food.KALETRA oral solution must be taken with food.If you are taking both didanosine and KALETRA: Didanosine can be taken at the same time as KALETRA tablets, without food.Take didanosine either hour before or hours after taking KALETRA oral solution. If you are pregnant: You should not take KALETRA tablets on 1 time each day dose schedule. Avoid use of KALETRA oral solution. If your child is prescribed KALETRA: Tell your healthcare provider if your childs weight changes. KALETRA should not be given to children on 1 time each day dose schedule. When giving KALETRA to your child, give KALETRA exactly as prescribed. Use the dosing cup (supplied) or an oral syringe with mL (milliliter) markings to give the prescribed dose of KALETRA oral solution to your child. Your pharmacist should provide an oral syringe to you.KALETRA oral solution contains propylene glycol and large amount of alcohol (ethanol). KALETRA oral solution should not be given to babies younger than 14 days of age unless your healthcare provider thinks it is right for your baby. Talk with your healthcare provider if you plan to take or give KALETRA oral solution through feeding tube. KALETRA oral solution contains propylene glycol and alcohol (ethanol), and should not be used with certain feeding tubes.You may have greater chance of getting diarrhea if you take KALETRA time each day than if you take it times each day.Do not miss dose of KALETRA. This could make the virus harder to treat. If you forget to take KALETRA, take the missed dose right away. If it is almost time for your next dose, do not take the missed dose. Instead, follow your regular dosing schedule by taking your next dose at its regular time. Do not take more than one dose of KALETRA at one time. If you or your child take more than the prescribed dose of KALETRA, call your healthcare provider or go to the nearest emergency room right away.What are the possible side effects of KALETRAKALETRA can cause serious side effects, including:See What is the most important information should know about KALETRA Diabetes and high blood sugar (hyperglycemia). You may develop new or worsening diabetes or high blood sugar during treatment with KALETRA. Tell your healthcare provider if you get any of the following signs or symptoms: urinate more often than usualincreased hunger or thirstunusual weight lossincrease in your blood sugar levelsYour healthcare provider may need to start you on medicine to treat high blood sugar or change your diabetes medicines. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. Increases in certain fat (triglycerides and cholesterol) levels in your blood. Large increases of triglycerides and cholesterol can be seen in blood test results of some people who take KALETRA. Your healthcare provider should do blood tests to check your cholesterol and triglyceride levels before you start taking KALETRA and during your treatment. Changes in body fat can happen in some people who take antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known at this time. Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with KALETRA or similar medicines. Skin rash, which can be severe, can happen in people who take KALETRA. Tell your healthcare provider if you have history of skin rash with other medicine used to treat your HIV-1 infection or if you get any skin rash during treatment with KALETRA. Kidney stonesCommon side effects of KALETRA include: diarrheanauseavomitingincreased fats in blood (triglycerides or cholesterol)These are not all of the possible side effects of KALETRA. For more information, ask your healthcare provider or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store KALETRAKALETRA tablets:Store KALETRA tablets at room temperature, between 68F to 77F (20C to 25C).Store KALETRA tablets in the original container.Do not keep KALETRA tablets out of the container it comes in for longer than weeks, especially in areas where there is lot of humidity.Keep the container closed tightly. KALETRA oral solution:Store KALETRA oral solution in refrigerator, between 36F to 46F (2C to 8C). KALETRA oral solution that is kept refrigerated may be used until the expiration date printed on the label.KALETRA oral solution that is stored at room temperature (less than 77F or 25C) should be used within months.Keep KALETRA oral solution away from high heat.Throw away any medicine that is out of date or that you no longer need.Keep KALETRA and all medicines out of the reach of children.General information about the safe and effective use of KALETRA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use KALETRA for condition for which it was not prescribed. Do not give KALETRA to other people, even if they have the same condition you have. It may harm them. You can ask your pharmacist or healthcare provider for information about KALETRA that is written for health professionals. What are the ingredients in KALETRAActive ingredients: lopinavir and ritonavir Inactive ingredients: KALETRA 200 mg lopinavir and 50 mg ritonavir yellow tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: colloidal silicone dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and yellow ferric oxide E172. KALETRA 200 mg lopinavir and 50 mg ritonavir red tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: colloidal silicone dioxide, hydroxypropyl cellulose, hypromellose, polyethylene glycol 400, polyethylene glycol 3350, polysorbate 80, talc, titanium dioxide, and red ferric oxide E172. KALETRA 100 mg lopinavir and 25 mg ritonavir pale yellow tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and yellow ferric oxide E172. KALETRA 100 mg lopinavir and 25 mg ritonavir pink tablets: colloidal silicon dioxide, copovidone, sodium stearyl fumarate, and sorbitan monolaurate. The film coating contains: polyethylene glycol 3350, polyvinyl alcohol, talc, titanium dioxide, and red ferric oxide E172. KALETRA oral solution: acesulfame potassium, artificial cotton candy flavor, citric acid, ethanol (a type of alcohol), glycerin, high fructose corn syrup, Magnasweet-110 flavor, menthol, natural and artificial vanilla flavor, peppermint oil, polyoxyl 40 hydrogenated castor oil, povidone, propylene glycol, saccharin sodium, sodium chloride, sodium citrate, and water. KALETRA oral solution contains approximately 42% ethanol (a type of alcohol) and approximately 15% propylene glycol. See How should take KALETRA For more information about KALETRA call 1-800-633-9110 or go to www.KALETRA.com Manufactured by AbbVie Inc., North Chicago, IL 60064 USA KALETRA is trademark of AbbVie Inc. (C) 2020 AbbVie Inc. All rights reserved. The brands listed are trademarks of their respective owners and are not trademarks of AbbVie Inc. The makers of these brands are not affiliated with and do not endorse AbbVie Inc. or its products. 20065455 This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: October 2020 Interactions with other medicines. It is important to know the medicines that should not be taken with KALETRA. For more information, see Who should not take KALETRA Side Effects in babies taking KALETRA oral solution. KALETRA oral solution contains alcohol (ethanol) and propylene glycol. Call your healthcare provider right away if your baby appears too sleepy or their breathing changes. Inflammation of your pancreas (pancreatitis). KALETRA can cause pancreatitis which may be serious and may lead to death. People who have high levels of certain fat (triglycerides) have risk for developing pancreatitis. If you have advanced HIV-1 disease, you may have an increased risk of high triglyceride levels in your blood, and pancreatitis. If you have history of pancreatitis, you may have an increased risk of it coming back again during treatment with KALETRA. Tell your healthcare provider if you have any signs or symptoms of pancreatitis including: Liver problems. Liver problems, including death, can happen in people who take KALETRA. Your healthcare provider should do blood tests before and during your treatment with KALETRA to check your liver function. If you have Hepatitis or Hepatitis C, or other liver problems, you may have an increased risk for developing new or worsening of liver problems during treatment with KALETRA. Tell your healthcare provider right away if you have any signs and symptoms of liver problems including: loss of appetite. yellow skin and whites of eyes (jaundice). dark-colored urine. pale colored stools. itchy skin. stomach area (abdominal) pain. Changes in your heart rhythm and the electrical activity of your heart. These changes may be seen on an EKG (electrocardiogram) and can lead to serious heart problems. Your risk for these problems may be higher if you: have history of abnormal heart rhythm or certain types of heart problems.take other medicines that can affect your heart rhythm during treatment with KALETRA. have history of abnormal heart rhythm or certain types of heart problems.. take other medicines that can affect your heart rhythm during treatment with KALETRA.. dizziness. lightheadedness. fainting. sensation of abnormal heartbeats. are allergic to lopinavir, ritonavir, or any of the ingredients in KALETRA. See the end of this Medication Guide for complete list of ingredients in KALETRA.. if you take any of the following medicines: alfuzosinapalutamideranolazinedronedaronecolchicine, if you have kidney or liver problems.rifampinlurasidonepimozideergot containing medicines including: dihydroergotamine mesylateergotamine tartratemethylergonovine cisaprideelbasvir/grazoprevirlovastatinsimvastatinlomitapidesildenafil (Revatio (R)), when used for the treatment of pulmonary arterial hypertension triazolammidazolam when taken by mouthSt. Johns Wort (Hypericum perforatum (R)) alfuzosin. apalutamide. ranolazine. dronedarone. colchicine, if you have kidney or liver problems.. rifampin. lurasidone. pimozide. ergot containing medicines including: dihydroergotamine mesylateergotamine tartratemethylergonovine dihydroergotamine mesylate. ergotamine tartrate. methylergonovine. cisapride. elbasvir/grazoprevir. lovastatin. simvastatin. lomitapide. sildenafil (Revatio (R)), when used for the treatment of pulmonary arterial hypertension triazolam. midazolam when taken by mouth. St. Johns Wort (Hypericum perforatum (R)) have ever had serious skin rash or an allergic reaction to medicines that contain lopinavir or ritonavir.. have or had pancreas problems.. have liver problems, including Hepatitis or Hepatitis C.. have any heart problems, including if you have condition called Congenital Long QT Syndrome.. have low potassium in your blood.. have diabetes.. have high cholesterol in your blood.. have hemophilia. KALETRA may cause increased bleeding.. are pregnant or plan to become pregnant. It is not known if KALETRA will harm your unborn baby. KALETRA oral solution contains alcohol (ethanol) and propylene glycol. You should not take KALETRA oral solution during pregnancy because there is no safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with KALETRA.KALETRA may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with KALETRA.Pregnancy Registry: There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. KALETRA oral solution contains alcohol (ethanol) and propylene glycol. You should not take KALETRA oral solution during pregnancy because there is no safe level of alcohol exposure during pregnancy. Tell your healthcare provider if you become pregnant during treatment with KALETRA.. KALETRA may reduce how well hormonal birth control works. Females who may become pregnant should use another effective form of birth control or an additional barrier method of birth control during treatment with KALETRA.. Pregnancy Registry: There is pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of the pregnancy registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry. are breastfeeding or plan to breastfeed. Do not breastfeed if you take KALETRA. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.Talk to your healthcare provider about the best way to feed your baby. You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby.. Talk to your healthcare provider about the best way to feed your baby.. Take KALETRA every day exactly as prescribed by your healthcare provider.. Stay under the care of your healthcare provider during treatment with KALETRA.. It is important to set up dosing schedule and follow it every day.. Do not change your treatment or stop treatment without first talking with your healthcare provider.. Swallow KALETRA tablets whole. Do not chew, break, or crush KALETRA tablets.. KALETRA tablets can be taken with or without food.. KALETRA oral solution must be taken with food.. If you are taking both didanosine and KALETRA: Didanosine can be taken at the same time as KALETRA tablets, without food.Take didanosine either hour before or hours after taking KALETRA oral solution. Didanosine can be taken at the same time as KALETRA tablets, without food.. Take didanosine either hour before or hours after taking KALETRA oral solution.. If you are pregnant: You should not take KALETRA tablets on 1 time each day dose schedule. Avoid use of KALETRA oral solution. You should not take KALETRA tablets on 1 time each day dose schedule. Avoid use of KALETRA oral solution. If your child is prescribed KALETRA: Tell your healthcare provider if your childs weight changes. Tell your healthcare provider if your childs weight changes.. KALETRA should not be given to children on 1 time each day dose schedule. When giving KALETRA to your child, give KALETRA exactly as prescribed. Use the dosing cup (supplied) or an oral syringe with mL (milliliter) markings to give the prescribed dose of KALETRA oral solution to your child. Your pharmacist should provide an oral syringe to you.KALETRA oral solution contains propylene glycol and large amount of alcohol (ethanol). KALETRA oral solution should not be given to babies younger than 14 days of age unless your healthcare provider thinks it is right for your baby. Use the dosing cup (supplied) or an oral syringe with mL (milliliter) markings to give the prescribed dose of KALETRA oral solution to your child. Your pharmacist should provide an oral syringe to you.. KALETRA oral solution contains propylene glycol and large amount of alcohol (ethanol). KALETRA oral solution should not be given to babies younger than 14 days of age unless your healthcare provider thinks it is right for your baby. Talk with your healthcare provider if you plan to take or give KALETRA oral solution through feeding tube. KALETRA oral solution contains propylene glycol and alcohol (ethanol), and should not be used with certain feeding tubes.. You may have greater chance of getting diarrhea if you take KALETRA time each day than if you take it times each day.. Do not miss dose of KALETRA. This could make the virus harder to treat. If you forget to take KALETRA, take the missed dose right away. If it is almost time for your next dose, do not take the missed dose. Instead, follow your regular dosing schedule by taking your next dose at its regular time. Do not take more than one dose of KALETRA at one time. If you or your child take more than the prescribed dose of KALETRA, call your healthcare provider or go to the nearest emergency room right away.. See What is the most important information should know about KALETRA Diabetes and high blood sugar (hyperglycemia). You may develop new or worsening diabetes or high blood sugar during treatment with KALETRA. Tell your healthcare provider if you get any of the following signs or symptoms: urinate more often than usual. increased hunger or thirst. unusual weight loss. increase in your blood sugar levels. Your healthcare provider may need to start you on medicine to treat high blood sugar or change your diabetes medicines. Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for long time. Call your healthcare provider right away if you start having new symptoms after starting your HIV-1 medicine. Increases in certain fat (triglycerides and cholesterol) levels in your blood. Large increases of triglycerides and cholesterol can be seen in blood test results of some people who take KALETRA. Your healthcare provider should do blood tests to check your cholesterol and triglyceride levels before you start taking KALETRA and during your treatment. Changes in body fat can happen in some people who take antiretroviral therapy. These changes may include increased amount of fat in the upper back and neck (buffalo hump), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms and face may also happen. The exact cause and long-term health effects of these conditions are not known at this time. Increased bleeding in people with hemophilia. Some people with hemophilia have increased bleeding with KALETRA or similar medicines. Skin rash, which can be severe, can happen in people who take KALETRA. Tell your healthcare provider if you have history of skin rash with other medicine used to treat your HIV-1 infection or if you get any skin rash during treatment with KALETRA. Kidney stones. diarrhea. nausea. vomiting. increased fats in blood (triglycerides or cholesterol). Store KALETRA tablets at room temperature, between 68F to 77F (20C to 25C).. Store KALETRA tablets in the original container.. Do not keep KALETRA tablets out of the container it comes in for longer than weeks, especially in areas where there is lot of humidity.. Keep the container closed tightly. Store KALETRA oral solution in refrigerator, between 36F to 46F (2C to 8C). KALETRA oral solution that is kept refrigerated may be used until the expiration date printed on the label.. KALETRA oral solution that is stored at room temperature (less than 77F or 25C) should be used within months.. Keep KALETRA oral solution away from high heat.. Throw away any medicine that is out of date or that you no longer need.

SPL UNCLASSIFIED SECTION.


5.1 Risk of Serious Adverse Reactions Due to Drug Interactions. Initiation of KALETRA, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving KALETRA, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of KALETRA, respectively. These interactions may lead to:Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.Clinically significant adverse reactions from greater exposures of KALETRA.Loss of therapeutic effect of KALETRA and possible development of resistance.See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions 7)] Consider the potential for drug interactions prior to and during KALETRA therapy; review concomitant medications during KALETRA therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications 4) and Drug Interactions 7)] . Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.. Clinically significant adverse reactions from greater exposures of KALETRA.. Loss of therapeutic effect of KALETRA and possible development of resistance.

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended. 8.2) 8.1 Pregnancy. Pregnancy Exposure Registry There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to KALETRA during pregnancy. Physicians are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.Risk SummaryAvailable data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation (see Data). No treatment-related malformations were observed when lopinavir in combination with ritonavir was administered to pregnant rats or rabbits; however embryonic and fetal developmental toxicities occurred in rats administered maternally toxic doses. Clinical ConsiderationsDose Adjustments During Pregnancy and the Postpartum PeriodAdminister 400/100 mg of KALETRA twice daily in pregnant patients with no documented lopinavir-associated resistance substitutions [see Dosage and Administration 2.5) and Clinical Pharmacology 12.3)] There are insufficient data to recommend KALETRA dosing for pregnant patients with any documented lopinavir-associated resistance substitutions. No dose adjustment of KALETRA is required for patients during the postpartum period. Once daily KALETRA dosing is not recommended in pregnancy.Avoid use of KALETRA oral solution during pregnancy due to the ethanol content. KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v and propylene glycol, approximately 15%.DataHuman Data KALETRA was evaluated in 12 HIV-infected pregnant women in an open-label pharmacokinetic trial [see Clinical Pharmacology 12.3)] No new trends in the safety profile were identified in pregnant women dosed with KALETRA compared to the safety described in non-pregnant adults, based on the review of these limited data. Antiretroviral Pregnancy Registry Data: Based on prospective reports from the Antiretroviral Pregnancy Registry (APR) of over 3,000 exposures to lopinavir containing regimens (including over 1,000 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. The prevalence of birth defects in live births was 2.1% (95% CI: 1.4%-3.0%) following first-trimester exposure to lopinavir-containing regimens and 3.0% (95% CI: 2.4%-3.8%) following second and third trimester exposure to lopinavir-containing regimens. Based on prospective reports from the APR of over 5,000 exposures to ritonavir containing regimens (including over 2,000 exposures in the first trimester) there was no difference between ritonavir and overall birth defects compared with the U.S. background rate (MACDP). The prevalence of birth defects in live births was 2.2% (95% CI: 1.7%-2.8%) following first-trimester exposure to ritonavir-containing regimens and 2.9% (95% CI: 2.4%-3.6%) following second and third trimester exposure to ritonavir-containing regimens. For both lopinavir and ritonavir, sufficient numbers of first trimester exposures have been monitored to detect at least 1.5 fold increase in risk of overall birth defects and 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems. Animal DataEmbryonic 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 administered lopinavir in combination with ritonavir (on gestation days 6-17) at maternally toxic dosage. Based on AUC measurements, the drug exposures in rats at the toxic doses were approximately 0.7 times (for lopinavir) and 1.8 times (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). In pre- and post-natal study in rats, 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 administered lopinavir in combination with ritonavir (on gestation days 6-18) at maternally toxic dosage. Based on AUC measurements, the drug exposures in rabbits at the toxic doses were approximately 0.6 times (for lopinavir) and similar to (for ritonavir) the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily). 8.2 Lactation. Risk SummaryThe Centers for Disease Control and Prevention recommend that HIV-1 infected mothers not breastfeed their infants to avoid risking postnatal transmission of HIV-1. Because of the potential for: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV- positive infants), and 3) adverse reactions in the breastfed infant, instruct mothers not to breastfeed if they are receiving KALETRA.. 8.3 Females and Males of Reproductive Potential. ContraceptionUse of KALETRA may reduce the efficacy of combined hormonal contraceptives. Advise patients using combined hormonal contraceptives to use an effective alternative contraceptive method or an additional barrier method of contraception [see Drug Interactions 7.3)] . 8.4 Pediatric Use. The safety, efficacy, and pharmacokinetic profiles of KALETRA in pediatric patients below the age of 14 days have not been established. KALETRA should not be administered once daily in pediatric patients.An open-label, multi-center, dose-finding trial was performed to evaluate the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL at dose of 300/75 mg/m twice daily plus two NRTIs in HIV-infected infants >=14 days and 6 months of age. Results revealed that infants younger than months of age generally had lower lopinavir AUC 12 than older children (6 months to 12 years of age), however, despite the lower lopinavir drug exposure observed, antiviral activity was demonstrated as reflected in the proportion of subjects who achieved HIV-1 RNULL <400 copies/mL at Week 24 [see Adverse Reactions 6.2), Clinical Pharmacology 12.3), Clinical Studies 14.4)] Safety and efficacy in pediatric patients 6 months of age was demonstrated in clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naive and experienced pediatric patients ages months to 12 years. Dose selection for patients months to 12 years of age was based on the following results. The 230/57.5 mg/m oral solution twice daily regimen without nevirapine and the 300/75 mg/m oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine) [see Adverse Reactions 6.2), Clinical Pharmacology 12.3), Clinical Studies 14.4)] A prospective multicenter, open-label trial evaluated the pharmacokinetic profile, tolerability, safety and efficacy of high-dose KALETRA with or without concurrent NNRTI therapy (Group 1: 400/100 mg/m twice daily >= NRTIs; Group 2: 480/120 mg/m twice daily >= NRTI 1 NNRTI) in 26 children and adolescents >= years to 18 years of age who had failed prior therapy. Patients also had saquinavir mesylate added to their regimen. This strategy was intended to assess whether higher than approved doses of KALETRA could overcome protease inhibitor cross-resistance. High doses of KALETRA exhibited safety profile similar to those observed in previous trials; changes in HIV-1 RNULL were less than anticipated; three patients had HIV-1 RNULL <400 copies/mL at Week 48. CD4+ cell count increases were noted in the eight patients who remained on treatment for 48 weeks [see Adverse Reactions 6.2), Clinical Pharmacology 12.3)] A prospective multicenter, randomized, open-label study evaluated the efficacy and safety of twice-daily versus once-daily dosing of KALETRA tablets dosed by weight as part of combination antiretroviral therapy (cART) in virologically suppressed HIV-1 infected children (n=173). Children were eligible when they were aged 18 years, >= 15 kg in weight, receiving cART that included KALETRA, HIV-1 ribonucleic acid (RNULL) 50 copies/mL for at least 24 weeks and able to swallow tablets. At week 24, efficacy (defined as the proportion of subjects with plasma HIV-1 RNULL less than 50 copies per mL) was significantly higher in subjects receiving twice daily dosing compared to subjects receiving once daily dosing. The safety profile was similar between the two treatment arms although there was greater incidence of diarrhea in the once daily treated subjects. 8.5 Geriatric Use. Clinical studies of KALETRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, appropriate caution should be exercised in the administration and monitoring of KALETRA in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.. 8.6 Hepatic Impairment. KALETRA is principally metabolized by the liver; therefore, caution should be exercised when administering this drug to patients with hepatic impairment, because lopinavir concentrations may be increased [see Warnings and Precautions 5.4) and Clinical Pharmacology 12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. The following have been observed in patients receiving KALETRA:The concomitant use of KALETRA and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. 5.1, 7.3) Toxicity in preterm neonates: KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. safe and effective dose of KALETRA oral solution in this patient population has not been established. 2.4, 5.2) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate. 5.3) Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis and hepatitis C, or marked transaminase elevations. 5.4, 8.6) QT interval prolongation and isolated cases of torsade de pointes have been reported although causality could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval. 5.1, 5.5, 12.3) PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution in patients with pre-existing conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval. 5.1, 5.6, 12.3) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia 5.7), immune reconstitution syndrome. 5.8), redistribution/accumulation of body fat. 5.10) Total cholesterol and triglycerides elevations. Monitor prior to therapy and periodically thereafter. 5.9) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. 5.11) The concomitant use of KALETRA and certain other drugs may result in known or potentially significant drug interactions. Consult the full prescribing information prior to and during treatment for potential drug interactions. 5.1, 7.3) Toxicity in preterm neonates: KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. safe and effective dose of KALETRA oral solution in this patient population has not been established. 2.4, 5.2) Pancreatitis: Fatalities have occurred; suspend therapy as clinically appropriate. 5.3) Hepatotoxicity: Fatalities have occurred. Monitor liver function before and during therapy, especially in patients with underlying hepatic disease, including hepatitis and hepatitis C, or marked transaminase elevations. 5.4, 8.6) QT interval prolongation and isolated cases of torsade de pointes have been reported although causality could not be established. Avoid use in patients with congenital long QT syndrome, those with hypokalemia, and with other drugs that prolong the QT interval. 5.1, 5.5, 12.3) PR interval prolongation may occur in some patients. Cases of second and third degree heart block have been reported. Use with caution in patients with pre-existing conduction system disease, ischemic heart disease, cardiomyopathy, underlying structural heart disease or when administering with other drugs that may prolong the PR interval. 5.1, 5.6, 12.3) Patients may develop new onset or exacerbations of diabetes mellitus, hyperglycemia 5.7), immune reconstitution syndrome. 5.8), redistribution/accumulation of body fat. 5.10) Total cholesterol and triglycerides elevations. Monitor prior to therapy and periodically thereafter. 5.9) Hemophilia: Spontaneous bleeding may occur, and additional factor VIII may be required. 5.11) 5.1 Risk of Serious Adverse Reactions Due to Drug Interactions. Initiation of KALETRA, CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving KALETRA, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of KALETRA, respectively. These interactions may lead to:Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.Clinically significant adverse reactions from greater exposures of KALETRA.Loss of therapeutic effect of KALETRA and possible development of resistance.See Table 12 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations [see Drug Interactions 7)] Consider the potential for drug interactions prior to and during KALETRA therapy; review concomitant medications during KALETRA therapy, and monitor for the adverse reactions associated with the concomitant medications [see Contraindications 4) and Drug Interactions 7)] . Clinically significant adverse reactions, potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications.. Clinically significant adverse reactions from greater exposures of KALETRA.. Loss of therapeutic effect of KALETRA and possible development of resistance.. 5.2 Toxicity in Preterm Neonates. KALETRA oral solution contains the excipients ethanol, approximately 42% (v/v) and propylene glycol, approximately 15% (w/v). When administered concomitantly with propylene glycol, ethanol competitively inhibits the metabolism of propylene glycol, which may lead to elevated concentrations. Preterm neonates may be at increased risk of propylene glycol-associated adverse events due to diminished ability to metabolize propylene glycol, thereby leading to accumulation and potential adverse events. Postmarketing life-threatening cases of cardiac toxicity (including complete AV block, bradycardia, and cardiomyopathy), lactic acidosis, acute renal failure, CNS depression and respiratory complications leading to death have been reported, predominantly in preterm neonates receiving KALETRA oral solution.KALETRA oral solution should not be used in preterm neonates in the immediate postnatal period because of possible toxicities. safe and effective dose of KALETRA oral solution in this patient population has not been established. However, if the benefit of using KALETRA oral solution to treat HIV infection in infants immediately after birth outweighs the potential risks, infants should be monitored closely for increases in serum osmolality and serum creatinine, and for toxicity related to KALETRA oral solution including: hyperosmolality, with or without lactic acidosis, renal toxicity, CNS depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias and ECG changes, and hemolysis. Total amounts of ethanol 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 [see Dosage and Administration 2.4) and Overdosage 10)] . 5.3 Pancreatitis. Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although causal relationship to KALETRA has not been established, marked triglyceride elevations are risk factor for development of pancreatitis [see Warnings and Precautions 5.9)] Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with history of pancreatitis may be at increased risk for recurrence during KALETRA therapy. Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.. 5.4 Hepatotoxicity. Patients with underlying hepatitis or or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA.There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. 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 days after the initiation of KALETRA in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, definitive causal relationship with KALETRA therapy has not been established. Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of KALETRA treatment [see Use in Specific Populations 8.6)]. 5.5 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 the QT interval [see Clinical Pharmacology 12.3)] . 5.6 PR Interval Prolongation. Lopinavir/ritonavir prolongs the PR interval in some patients. Cases of second or third degree atrioventricular block have been reported. KALETRA should be used with caution in patients with underlying structural heart disease, pre-existing conduction system abnormalities, ischemic heart disease or cardiomyopathies, as these patients may be at increased risk for developing cardiac conduction abnormalities. The impact on the PR interval of co-administration of KALETRA with other drugs that prolong the PR interval (including calcium channel blockers, beta-adrenergic blockers, digoxin and atazanavir) has not been evaluated. As result, co-administration of KALETRA with these drugs should be undertaken with caution, particularly with those drugs metabolized by CYP3A. Clinical monitoring is recommended [see Clinical Pharmacology 12.3)] . 5.7 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 therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and causal relationship between protease inhibitor therapy and these events has not been established. Consider monitoring for hyperglycemia, new onset diabetes mellitus or an exacerbation of diabetes mellitus in patients treated with KALETRA.. 5.8 Immune Reconstitution Syndrome. Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre 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.. 5.9 Lipid Elevations. Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides [see Adverse Reactions 6.1)] Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors [see Contraindications 4) and Drug Interactions 7.3)] . 5.10 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. causal relationship has not been established. 5.11 Patients with Hemophilia. Increased bleeding, including spontaneous skin hematomas and hemarthrosis have been reported in patients with hemophilia type and treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. causal relationship between protease inhibitor therapy and these events has not been established.. 5.12 Resistance/Cross-resistance. Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in KALETRA-treated patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors [see Microbiology 12.4)].