The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.
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)].
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 1 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 3 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 and100 mg/25 mg Tablets 500 mg/125 mg (2 tablets of 200 mg/50 mg + 1 tablet of 100 mg/25 mg) twice daily80 mg/20 mg per mL Oral Solution520 mg/130 mg (6.5 mL) twice daily
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 a postmenstrual age (first day of the mother’s last menstrual period to birth plus the time elapsed after birth) of 42 weeks and a 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 6 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 (m2) × Prescribed lopinavir dose (mg/m2) = 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 4 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 6 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/m2)Frequency14 days to 6 months16/4300/75Given twicedailyOlder than 6 months to less than 18 yearsLess than15 kg12/3230/57.5Given twicedaily15 kg to 40 kg10/2.5Tablet Dosage Recommendation in Pediatric Patients Older than 6 Months to Less than 18 Years:Table 5 provides the dosing recommendations for pediatric patients older than 6 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 (m2)*Recommended numberof 100/25 mg TabletsTwice 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 a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet. Concomitant Therapy: Efavirenz, Nevirapine, or NelfinavirDosing recommendations using oral solutionTable 6 provides the dosing recommendations for pediatric patients older than 6 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/m2)Frequency> 6 months to< 18 years<15 kg 13/3.25300/75Given twicedaily≥15 kg to 45 kg11/2.75Dosing recommendations using tabletsTable 7 provides the dosing recommendations for pediatric patients older than 6 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 (m2)*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 a BSA less than 0.6 m2 or those who are unable to reliably swallow a tablet.† Please refer to the individual product labels for appropriate dosing in children.
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)].
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.Tablets, 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.Oral Solution: Light yellow to orange colored liquid containing 400 mg lopinavir and 100 mg ritonavir per 5 mL (80 mg lopinavir and 20 mg ritonavir per mL).
- 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.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.Table 8. Drugs That Are Contraindicated With KALETRADrug ClassDrugs Within ClassThat AreContraindicatedWith KALETRAClinical CommentsAlpha 1- Adrenoreceptor AntagonistAlfuzosinPotentially increased alfuzosin concentrations can result in hypotension.AntianginalRanolazinePotential for serious and/or life-threatening reactions.AntiarrhythmicDronedaronePotential for cardiac arrhythmias.Anti-goutColchicineaPotential for serious and/or life-threatening reactions in patients with renal and/or hepatic impairment.AntimycobacterialRifampinMay lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other co-administered antiretroviral agents.AntipsychoticsLurasidonePimozidePotential for serious and/or life-threatening reactions.Potential for serious and/or life‑threatening reactions such as cardiac arrhythmias.Ergot DerivativesDihydroergotamine, ergotamine, methylergonovinePotential for acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues.GI Motility AgentCisapridePotential for cardiac arrhythmias.Hepatitis C direct acting antiviralElbasvir/grazoprevirPotential for the increased risk of alanine transaminase (ALT) elevations. Herbal Products St. John's Wort (hypericum perforatum)May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors.HMG-CoA Reductase InhibitorsLovastatin, simvastatinPotential for myopathy including rhabdomyolysis.PDE5 InhibitorSildenafilb (Revatio®) when used for the treatment of pulmonary arterial hypertensionPotential for sildenafil-associated adverse events, including visual abnormalities, hypotension, prolonged erection, and syncope.Sedative/HypnoticsTriazolam;orally administered midazolamcProlonged or increased sedation or respiratory depression.a see Drug Interactions (7), Table 13 for colchicine doses in patients with normal hepatic and renal function. b see Drug Interactions (7), Table 13 for co-administration of sildenafil in patients with erectile dysfunction.c see Drug Interactions (7), Table 13 for parenterally administered midazolam.
5.1 Risk Of Serious Adverse Reactions Due To Drug Interactions
- Initiation of KALETRA, a 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 13 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)].
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. A 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)].
Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a 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 a 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.
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA.There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established. Elevated transaminases with or without elevated bilirubin levels have been reported in HIV-1 mono-infected and uninfected patients as early as 7 days after the initiation of KALETRA in conjunction with other antiretroviral agents. In some cases, the hepatic dysfunction was serious; however, a definitive causal relationship with KALETRA therapy has not been established. 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 a 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 a 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-Barré syndrome) have also been reported to occur in the setting of immune reconstitution, however, the time to onset is more variable, and can occur many months after initiation of treatment.
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. A 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 A and B 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. A causal relationship between protease inhibitor therapy and these events has not been established.
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)].
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)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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 a dose of 800/200 mg (6 capsules or 4 tablets) once daily. Along with nucleoside reverse transcriptase inhibitors (NRTIs), in some studies, KALETRA was used in combination with efavirenz or nevirapine.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 9):Table 9. 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 anemia*542.1 leukopenia and neutropenia*441.7 lymphadenopathy*351.3CARDIAC DISORDERS atherosclerosis such as myocardial infarction*100.4 atrioventricular block*30.1 tricuspid valve incompetence*30.1EAR AND LABYRINTH DISORDERS vertigo*70.3 tinnitus60.2ENDOCRINE DISORDERS hypogonadism*160.81EYE DISORDERS visual impairment*80.3GASTROINTESTINAL DISORDERS diarrhea*51019.5 nausea26910.3 vomiting*1776.8 abdominal pain (upper and lower)*1606.1 gastroenteritis and colitis*662.5 dyspepsia532.0 pancreatitis*451.7 Gastroesophageal Reflux Disease (GERD)*401.5 hemorrhoids391.5 flatulence361.4 abdominal distension341.3 constipation*261.0 stomatitis and oral ulcers*240.9 duodenitis and gastritis*200.8 gastrointestinal hemorrhage including rectal hemorrhage*130.5 dry mouth90.3 gastrointestinal ulcer* 60.2 fecal incontinence50.2GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS fatigue including asthenia*1987.6HEPATOBILIARY DISORDERS hepatitis including AST, ALT, and GGT increases*913.5 hepatomegaly50.2 cholangitis30.1 hepatic steatosis30.1IMMUNE SYSTEM DISORDERS hypersensitivity including urticaria and angioedema*702.7 immune reconstitution syndrome30.1INFECTIONS AND INFESTATIONS upper respiratory tract infection*36313.9 lower respiratory tract infection*2027.7 skin infections including cellulitis, folliculitis, and furuncle*863.3METABOLISM AND NUTRITION DISORDERS hypercholesterolemia* 1927.4 hypertriglyceridemia*1616.2 weight decreased*612.3 decreased appetite522.0 blood glucose disorders including diabetes mellitus*301.1 weight increased*200.8 lactic acidosis*110.4 increased appetite50.2MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS musculoskeletal pain including arthralgia and back pain*1666.4 myalgia*461.8 muscle disorders such as weakness and spasms*341.3 rhabdomyolysis*180.7 osteonecrosis30.1NERVOUS SYSTEM DISORDERS headache including migraine*1656.3 insomnia*993.8 neuropathy and peripheral neuropathy*512.0 dizziness*451.7 ageusia*190.7 convulsion*90.3 tremor*90.3 cerebral vascular event*60.2PSYCHIATRIC DISORDERS anxiety*1013.9 abnormal dreams*190.7 libido decreased190.7RENAL AND URINARY DISORDERS renal failure*311.2 hematuria*200.8 nephritis*30.1REPRODUCTIVE SYSTEM AND BREAST DISORDERS erectile dysfunction*341.71 menstrual disorders - amenorrhea, menorrhagia*101.72SKIN AND SUBCUTANEOUS TISSUE DISORDERS rash including maculopapular rash*993.8 lipodystrophy acquired including facial wasting*582.2 dermatitis/rash including eczema and seborrheic dermatitis*501.9 night sweats*421.6 pruritus*291.1 alopecia100.4 capillaritis and vasculitis*30.1VASCULAR DISORDERS hypertension*471.8 deep vein thrombosis*170.7*Represents a 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 10 (treatment-naïve patients) and Table 11 (treatment-experienced patients).Table 10. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients Study 863(48 Weeks)Study 720(360 Weeks) Study 730(48 Weeks)VariableLimit1KALETRA400/100 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/AST2 > 180 U/L 2%4%10%1%2% SGPT/ALT2 >215 U/L4%4%11%1%1%GGT>300 U/LN/AN/A10%N/AN/ATotalCholesterol>300 mg/dL9%5%27%4%3%Triglycerides>750 mg/dL9%1%29%3%6%Amylase>2 x ULN3%2%4%N/AN/ALipase>2 x ULNN/AN/AN/A3%5%ChemistryLow Calculated Creatinine Clearance<50 mL/minN/AN/AN/A2%2%HematologyLow Neutrophils<0.75 x 109/L1%3%5%2%1%1 ULN = upper limit of the normal range; N/A = Not Applicable.2 Criterion for Study 730 was >5x ULN (AST/ALT). Table 11. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Protease Inhibitor-Experienced Patients Study 888(48 Weeks)Study 9572 and Study 7653(84-144 Weeks)Study 802(48 Weeks)VariableLimit1KALETRA400/100 mgTwice 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/AST4>180 U/L5%11%8%3%2% SGPT/ALT4>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 x ULN4%8%8%4%4% Lipase>2 x ULNN/AN/AN/A4%1% Creatine Phosphokinase>4 x ULNN/AN/AN/A4%5%ChemistryLow CalculatedCreatinine Clearance<50 mL/minN/AN/AN/A3%3% Inorganic Phosphorus<1.5 mg/dL1%0%2%1%<1%HematologyLow Neutrophils<0.75 x 109/L1%2%4%3%4% Hemoglobin<80 g/L1%1%1%1%2%1 ULN = upper limit of the normal range; N/A = Not Applicable.2 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.3 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.4 Criterion for Study 802 was >5x ULN (AST/ALT). Adverse Reactions in Pediatric PatientsKALETRA oral solution dosed up to 300/75 mg/m2 has been studied in 100 pediatric patients 6 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. A total of 8 patients experienced adverse reactions of moderate to severe intensity. The adverse reactions meeting these criteria and reported for the 8 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 2 or more subjects (N = 3).KALETRA oral solution dosed at 300/75 mg/m2 has been studied in 31 pediatric patients 14 days to 6 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 2 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/m2 (without concomitant NNRTI) and 480/120 mg/m2 (with concomitant NNRTI) have been studied in 26 pediatric patients 7 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 2 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 12.Table 12. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients in Study 940VariableLimit1KALETRA Twice Daily + RTIs(N = 100)ChemistryHigh Sodium> 149 mEq/L3% Total Bilirubin≥ 3.0 x ULN3% SGOT/AST> 180 U/L8% SGPT/ALT> 215 U/L7% Total Cholesterol> 300 mg/dL3% Amylase> 2.5 x ULN7%2ChemistryLow Sodium< 130 mEq/L3%HematologyLow Platelet Count< 50 x 109/L4% Neutrophils< 0.40 x 109/L2%1 ULN = upper limit of the normal range.2 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 a population of unknown size, it is not possible to reliably estimate their frequency or establish a causal relationship to KALETRA exposure.Body as a Whole Redistribution/accumulation of body fat has been reported [see 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)].Skin and AppendagesToxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.
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 a dose adjustment or additional monitoring as shown in Table 13.Additionally, KALETRA induces glucuronidation.Published data suggest that lopinavir is an inhibitor of OATP1B1.
Lopinavir/ritonavir is a CYP3A substrate; therefore, drugs that induce CYP3A may decrease lopinavir plasma concentrations and reduce KALETRA’s 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 13 provides a listing of established or potentially clinically significant drug interactions. Alteration in dose or regimen may be recommended based on drug interaction studies or predicted interaction [see Contraindications (4), Warnings and Precautions (5.1), Clinical Pharmacology (12.3)] for magnitude of interaction.Table 13. 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 ↓ lopinavirAn 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↓ lopinavirKALETRA 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:abacavirzidovudine↓ abacavir↓ zidovudineThe clinical significance of this potential interaction is unknown. Other AgentsAntiarrhythmics e.g.amiodarone,bepridil,lidocaine (systemic),quinidine↑ antiarrhythmicsFor contraindicated antiarrhythmics, [see Contraindications (4)].Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. Anticancer Agents: vincristine,vinblastine,dasatinib, nilotinib,venetoclax↑ anticancer agentsFor 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 a prolonged period, consideration should be given to initiating a revised regimen that does not include a CYP3A or P-gp inhibitor.A 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.Coadministration of venetoclax and KALETRA may increase the risk of tumor lysis syndrome. Refer to the venetoclax prescribing information for dosing instructions. Anticoagulants:warfarin,rivaroxaban↑↓ warfarin↑ rivaroxabanConcentrations 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↓ phenytoinKALETRA 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 ↔ valproateA 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, hydroxybupropionPatients 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. A 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 CLCR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%.For patients on KALETRA with CLCR < 30 mL/min the dose of clarithromycin should be decreased by 75%.No dose adjustment for patients with normal renal function is necessary.Antifungals:ketoconazole*,itraconazole,voriconazoleisavuconazonium sulfate*↑ ketoconazole↑ itraconazole↓ voriconazole↑ isavuconazoniumHigh 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↑ colchicineConcomitant administration with colchicine is contraindicated 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) x 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Dose to be repeated no earlier than 3 days.Prophylaxis of gout flares-co-administration of colchicine in patients on KALETRA:If the original colchicine regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original colchicine regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day.Treatment of familial Mediterranean fever (FMF)-co-administration of colchicine in patients on KALETRA:Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).Antimycobacterial:bedaquiline↑ bedaquilineFor contraindicated antimycobacterials, [see Contraindications (4)].Bedaquiline 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., a 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: 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.Sedative/hypnotics: parenterally administered midazolam↑ midazolamFor contraindicated sedative/hypnotics,[see Contraindications (4)]. If 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. 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.Systemic/Inhaled/Nasal/OphthalmicCorticosteroids: e.g.,betamethasonebudesonideciclesonidedexamethasonefluticasonemethylprednisolonemometasoneprednisonetriamcinolone ↓ lopinavir↑ glucocorticoidsCoadministration 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 Cushing’s 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. Dihydropyridine CalciumChannel Blockers: e.g.felodipine,nifedipine,nicardipine↑ dihydropyridine calcium channel blockersClinical monitoring of patients is recommended and a 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.Hepatitis C direct acting antivirals:boceprevir*simeprevirombitasvir/paritaprevir/ritonavir and dasabuvir*↓ lopinavir↓ boceprevir↓ ritonavir↑ simeprevir↑ ombitasvir↑ paritaprevir↑ ritonavir↔ dasabuvirFor contraindicated hepatitis C direct acting antivirals, [see Contraindications (4)].It is not recommended to co-administer KALETRA and boceprevir, simeprevir, or ombitasvir/paritaprevir/ritonavir and dasabuvir. HMG-CoA Reductase Inhibitors:atorvastatinrosuvastatin↑ atorvastatin↑ rosuvastatinFor contraindicated HMG-CoA reductase inhibitors, [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. Immunosuppressants: e.g.cyclosporine,tacrolimus,sirolimus↑ immunosuppressantsTherapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.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↑ fentanylDosage 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 For contraindicated PDE5 inhibitors, [see Contraindications (4)].Do not use KALETRA with avanafil because a 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®) is contraindicated [see Contraindications (4)].The following dose adjustments are recommended for use of tadalafil (Adcirca®) 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 hoursUse with increased monitoring for adverse events.* see Clinical Pharmacology (12.3) for magnitude of interaction.
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.
Pregnancy Exposure Registry There is a 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 a 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 a 1.5 fold increase in risk of overall birth defects and a 2 fold increase in risk of birth defects in the cardiovascular and genitourinary systems. 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 a 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 a pre- and post-natal study in rats, a developmental toxicity (a decrease in survival in pups between birth and postnatal Day 21) occurred. No embryonic and fetal developmental toxicities were observed in rabbits administered lopinavir in combination with ritonavir (on gestation days 6-18) at a 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).
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 a dose of 300/75 mg/m2 twice daily plus two NRTIs in HIV-infected infants ≥14 days and < 6 months of age. Results revealed that infants younger than 6 months of age generally had lower lopinavir AUC12 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 RNA <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 a clinical trial in 100 patients. The clinical trial was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety, and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve and experienced pediatric patients ages 6 months to 12 years. Dose selection for patients 6 months to 12 years of age was based on the following results. The 230/57.5 mg/m2 oral solution twice daily regimen without nevirapine and the 300/75 mg/m2 oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine) [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/m2 twice daily + ≥ 2 NRTIs; Group 2: 480/120 mg/m2 twice daily + ≥ 1 NRTI + 1 NNRTI) in 26 children and adolescents ≥ 2 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 a safety profile similar to those observed in previous trials; changes in HIV-1 RNA were less than anticipated; three patients had HIV-1 RNA <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 (RNA) < 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 RNA 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 a 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)].
Overdoses with KALETRA oral solution have been reported. One of these reports described fatal cardiogenic shock in a 2.1 kg infant who received a single dose of 6.5 mL of KALETRA oral solution (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 a 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.
- KALETRA is a 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 [1S-[1R*,(R*), 3R*, 4R*]]-N-[4-[[(2,6-dimethylphenoxy)acetyl]amino]-3-hydroxy-5-phenyl-1-(phenylmethyl)pentyl]tetrahydro-alpha-(1-methylethyl)-2-oxo-1(2H)-pyrimidineacetamide. Its molecular formula is C37H48N4O5, and its molecular weight is 628.80. Lopinavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Lopinavir has the following structural formula: Ritonavir is chemically designated as 10-hydroxy-2-methyl-5-(1-methylethyl)-1- [2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid, 5-thiazolylmethyl ester, [5S-(5R*,8R*,10R*,11R*)]. Its molecular formula is C37H48N6O5S2, and its molecular weight is 720.95. Ritonavir is a white to light tan powder. It is freely soluble in methanol and ethanol, soluble in isopropanol and practically insoluble in water. Ritonavir has the following structural formula: KALETRA tablets are available for oral administration in two strengths: Yellow tablets containing 200 mg of lopinavir and 50 mg of ritonavirPale yellow 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 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. 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.
12.1 Mechanism Of Action
KALETRA is a 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.
Cardiac ElectrophysiologyThe effect of KALETRA on QTcF interval was evaluated in a 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 a Day 3 mean Cmax approximately 2-fold higher than the mean Cmax 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)].
- The pharmacokinetic properties of lopinavir are summarized in Table 14. The steady-state pharmacokinetic parameters of lopinavir are summarized in Table 15. 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 14. Pharmacokinetic Properties of LopinavirAbsorption Tmax (hr)a4.4 ± 0.8Effect of meal(relative to fasting)TabletOral solution↑ 19%b↑ 130%bDistribution % Bound to human plasma proteins> 98Vd/Fa (L)16.9Metabolism MetabolismCYP3AElimination Major route of eliminationhepatict1/2 (h)a6.9 ± 2.2% of dose excreted in urine10.4 ± 2.3% of dose excreted in feces82.6 ± 2.5a. Kaletra tabletb. Changes in AUC valuesTable 15. Steady-State Pharmacokinetic Parameters of Lopinavir, Mean ± SDPharmacokinetic ParameterTwice DailyaOnce DailybCmax (µg/mL)9.8 ± 3.711.8 ± 3.7Cmin (µg/mL)5.5 ± 2.71.7 ± 1.6AUCtau (µg •h/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/m2 twice daily regimen without nevirapine and the 300/75 mg/m2 twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen without nevirapine. Table 16. Lopinavir Pharmacokinetic Data from Pediatric Clinical Trials, Mean ± SDCmax (μg/mL)Cmin (μg/mL)AUC12 (μg •hr/m)Age ≥ 14 Days to < 6 Weeks Cohort (N = 9):5.17 ± 1.84a1.40 ± 0.48a43.39 ± 14.80aAge ≥ 6 Weeks to < 6 Months Cohort (N = 18):9.39 ± 4.91a1.95 ± 1.80a74.50 ± 37.87aAge ≥ 6 Months to ≤ 12 years Cohort (N = 24):8.2 ± 2.9b3.4 ± 2.1b72.6 ± 31.1b10.0 ± 3.3c3.6 ± 3.5c85.8 ± 36.9cKALETRA oral solution300/75 mg/m2 twice daily without concomitant NNRTI therapyKALETRA oral solution 230/57.5 mg/m2 twice daily without nevirapine (n=12)KALETRA oral solution 300/75 mg/m2 twice daily with nevirapine (n=12)PregnancyThe C12h 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, a 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 a 30% increase in lopinavir AUC and 20% increase in Cmax 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, Cmax and Cmin are summarized in Table 17 (effect of other drugs on lopinavir) and Table 18 (effect of KALETRA on other drugs). For information regarding clinical recommendations, see Table 13 in Drug Interactions (7).Table 17. Drug Interactions: Pharmacokinetic Parameters for Lopinavir in the Presence of the Co-administered Drug for Recommended Alterations in Dose or Regimen Co-administeredDrugDose of Co-administeredDrug(mg)Dose ofKALETRA(mg)nRatio (in combination withCo-administered drug/alone) ofLopinavir PharmacokineticParameters (90% CI);No Effect = 1.00 CmaxAUCCminEfavirenz1600 atbedtime400/100 capsuletwice daily11,730.97(0.78, 1.22)0.81(0.64, 1.03)0.61(0.38, 0.97) 600 atbedtime500/125 tablettwice daily191.12(1.02, 1.23)1.06(0.96, 1.17)0.90(0.78, 1.04) 600 atbedtime600/150 tablettwice daily231.36(1.28, 1.44)1.36(1.28, 1.44)1.32(1.21, 1.44)Etravirine200 twicedaily400/100 mgtwice day(tablets) 160.89(0.82-0.96) 0.87(0.83-0.92)0.80(0.73-0.88)Fosamprenavir2700 twice dailyplus ritonavir100 twice daily400/100 capsuletwice daily181.30(0.85, 1.47)1.37(0.80, 1.55)1.52(0.72, 1.82)Ketoconazole200 single dose400/100 capsuletwice daily120.89(0.80, 0.99)0.87(0.75, 1.00)0.75(0.55, 1.00)Nelfinavir1000 twice daily400/100 capsuletwice daily130.79 (0.70, 0.89)0.73 (0.63, 0.85)0.62(0.49, 0.78)Nevirapine200 twice dailysteady-state400/100 capsuletwice daily22,1930.81(0.62, 1.05) 0.73(0.53, 0.98)0.49(0.28, 0.74)7 mg/kg or4 mg/kg once daily;twice daily1 wk5(> 1 yr) 300/75 mg/m2oral solutiontwice daily12,1530.86(0.64, 1.16) 0.78(0.56, 1.09)0.45(0.25, 0.81)Ombitasvir/paritaprevir/ritonavir+dasabuvir225/150/100 +dasabuvir 400400/100 tablettwice daily60.87(0.76, 0.99)0.94(0.81, 1.10)1.15(0.93, 1.42)Omeprazole40 oncedaily,5 d400/100 tablettwice daily,10 d121.08(0.99, 1.17)1.07(0.99, 1.15)1.03(0.90, 1.18)40 oncedaily,5 d800/200 tabletonce daily,10 d120.94(0.88, 1.00)0.92(0.86, 0.99)0.71(0.57, 0.89)Pravastatin20 oncedaily,4 d 400/100 capsuletwice daily,14 d120.98(0.89, 1.08)0.95(0.85, 1.05)0.88(0.77, 1.02)Ranitidine150 singledose400/100 tablettwice daily,10 d 120.99(0.95, 1.03)0.97(0.93, 1.01)0.90(0.85, 0.95)150 single dose800/200 tabletonce daily,10 d 100.97(0.95, 1.00)0.95(0.91, 0.99)0.82(0.74, 0.91)Rifabutin150 once daily400/100 capsuletwice daily141.08(0.97, 1.19)1.17(1.04, 1.31)1.20(0.96, 1.65)Rifampin600 once daily400/100 capsuletwice daily220.45(0.40, 0.51)0.25(0.21, 0.29)0.01(0.01, 0.02) 600 once daily800/200 capsuletwice daily101.02(0.85, 1.23)0.84(0.64, 1.10)0.43(0.19, 0.96) 600 once daily400/400 capsuletwice daily90.93(0.81, 1.07)0.98(0.81, 1.17)1.03(0.68, 1.56)Rilpivirine150 oncedaily400/100 twicedaily (capsules)150.96(0.88-1.05)0.99(0.89-1.10)0.89(0.73-1.08)Ritonavir100 twice daily400/100 capsuletwice daily8,2131.28(0.94, 1.76)1.46(1.04, 2.06)2.16(1.29, 3.62)Tipranavir/ritonavir500/200 twicedaily400/100 capsuletwice daily216930.53(0.40, 0.69)0.45(0.32, 0.63)0.30(0.17, 0.51) 0.484(0.40, 0.58)1 Reference for comparison is lopinavir/ritonavir 400/100 mg twice daily without efavirenz. 2 Data extracted from the U.S. prescribing information of co-administered drugs.3 Parallel group design4 Drug levels obtained at 8-16 hours post dose N/A = Not available. Table 18. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drug in the Presence of KALETRA for Recommended Alterations in Dose or RegimenCo-administeredDrugDose of Co-administeredDrug (mg)Dose ofKALETRA(mg) nRatio (in combination withKALETRA/alone) of Co-administered DrugPharmacokinetic Parameters(90% CI); No Effect = 1.00 CmaxAUCCminBedaquiline1400 single dose400/100 twicedailyN/AN/A1.22(1.11, 1.34)N/AEfavirenz600 at bedtime400/100capsule twicedaily11,1230.91(0.72, 1.15)0.84(0.62, 1.15)0.84(0.58, 1.20)Elbasvir/grazoprevir150 once daily400/100 twicedaily102.87(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)EthinylEstradiol35 µg oncedaily(Ortho Novum®)400/100capsule twicedaily120.59(0.52, 0.66)0.58(0.54, 0.62)0.42(0.36, 0.49)Etravirine200 twice daily400/100 tablettwice day160.70(0.64-0.78)0.65(0.59-0.71)0.55(0.49-0.62)Fosamprenavir1700 twice dailyplus ritonavir100 twicedaily400/100capsule twicedaily180.42(0.30, 0.58)0.37(0.28, 0.49)0.35(0.27, 0.46)Indinavir600 twicedaily combononfasting vs.800 three timesdaily alonefasting400/100 capsule twicedaily130.71(0.63, 0.81)0.91(0.75, 1.10)3.47(2.60, 4.64)Ketoconazole200 single dose400/100capsule twicedaily121.13(0.91, 1.40)3.04(2.44, 3.79)N/AMaraviroc1300 twice daily400/100twice daily111.97(1.66, 2.34)3.95(3.43, 4.56)9.24(7.98, 10.7)Methadone5 single dose400/100capsule twicedaily110.55(0.48, 0.64)0.47(0.42, 0.53)N/ANelfinavir1000 twicedailycombo vs.1250 twicedaily alone400/100capsule twicedaily130.93(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 dailytwice daily400/100capsule twicedaily5,631.05(0.72, 1.52)1.08(0.72, 1.64)1.15(0.71, 1.86)Norethindrone1 once daily(Ortho Novum®)400/100capsule twicedaily120.84(0.75, 0.94)0.83(0.73, 0.94)0.68(0.54, 0.85)Ombitasvir/paritaprevir/ritonavir+dasabuvir125/150/100 +dasabuvir 400400/100tablet twicedaily61.14(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)Pitavastatin14 once daily400/100 tablettwice daily230.96(0.84-1.10)0.80(0.73-0.87) N/APravastatin20 once daily400/100 capsuletwice daily121.26(0.87, 1.83)1.33(0.91, 1.94)N/ARifabutin150 once dailycombo vs. 300once dailyalone400/100 capsuletwice daily122.12(1.89, 2.38)3.03(2.79, 3.30)4.90(3.18, 5.76)25-O-desacetylrifabutin 23.6(13.7, 25.3)47.5(29.3, 51.8)94.9(74.0, 122)Rifabutin + 25-O-desacetylrifabutin 3.46(3.07, 3.91)5.73(5.08, 6.46)9.53(7.56, 12.01)Rilpivirine150 once daily400/100 capsulestwice daily151.29(1.18-1.40)1.52(1.36-1.70)1.74(1.46-2.08)Rosuvastatin220 once daily400/100 tablettwice daily154.66(3.4, 6.4)2.08(1.66, 2.6)1.04(0.9, 1.2)Tenofoviralafenamide110 once daily800/200tablet oncedaily102.19(1.72, 2.79)1.47(1.17, 1.85)N/ATenofovirdisoproxilfumarate1300 once daily400/100 capsuletwice daily24NoChange1.32(1.26, 1.38)1.51(1.32, 1.66)1 Data extracted from the U.S. prescribing information of co-administered drugs.2 Kiser, et al. J Acquir Immune Defic Syndr. 2008 Apr 15; 47(5):570-8.3 Parallel group designN/A = Not available.
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 (EC50) values of lopinavir against five different HIV-1 subtype B laboratory strains in lymphoblastic cell lines ranged from 10-27 nM (0.006-0.017 µg/mL, 1 µg/mL = 1.6 µM), and ranged from 4-11 nM (0.003-0.007 µg/mL) against several HIV-1 subtype B clinical isolates in peripheral blood lymphocytes (n = 6). In the presence of 50% human serum, the mean EC50 values of lopinavir against these five HIV-1 laboratory strains ranged from 65-289 nM (0.04-0.18 µg/mL), representing a 7 to 11-fold attenuation. The EC50 values of lopinavir against three different HIV-2 strains ranged from 12-180 nM (0.008-113 μg/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 a study of 653 antiretroviral treatment-naïve patients (Study 863), plasma viral isolates from each patient on treatment with plasma HIV-1 RNA >400 copies/mL at Week 24, 32, 40 and/or 48 were analyzed. No 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-naïve 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-naïve and protease inhibitor experienced patients, isolates from 4 of 23 patients with quantifiable (>400 copies/mL) viral RNA following treatment with KALETRA for 12 to 100 weeks displayed significantly reduced susceptibility to lopinavir compared to the corresponding baseline viral isolates. All four of these patients had previously received treatment with at least one protease inhibitor and had at least 4 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 a single protease inhibitor was determined (Table 19). Table 19. Susceptibility Reduction to Lopinavir Against Isolates from Patients Previously Treated With a 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 20 shows the 48-week virologic response (HIV-1 RNA <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 20. Virologic Response (HIV-1 RNA <400 copies/mL) at Week 48 by Baseline KALETRA Susceptibility and by Number of Protease Substitutions Associated with Reduced Response to KALETRA1Number of protease inhibitor substitutions at baseline1Study 888 (Single protease inhibitor-experienced2, NNRTI-naïve) n=130Study 765 (Single protease inhibitor-experienced3, NNRTI-naïve) n=56Study 957 (Multiple protease inhibitor-experienced4, NNRTI-naïve) n=500-276/103 (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.2 43% indinavir, 42% nelfinavir, 10% ritonavir, 15% saquinavir.3 41% indinavir, 38% nelfinavir, 4% ritonavir, 16% saquinavir.4 86% indinavir, 54% nelfinavir, 80% ritonavir, 70% saquinavir.Virologic response to KALETRA therapy with respect to phenotypic susceptibility to lopinavir at baseline was examined in Study 957. In this study 56 NNRTI-naïve patients with HIV-1 RNA >1,000 copies/mL despite previous therapy with at least two protease inhibitors selected from indinavir, nelfinavir, ritonavir, and saquinavir were randomized to receive one of two doses of KALETRA in combination with efavirenz and nucleoside reverse transcriptase inhibitors (NRTIs). The EC50 values of lopinavir against the 56 baseline viral isolates ranged from 0.5- to 96-fold the wild-type EC50 value. Fifty-five percent (31/56) of these baseline isolates displayed >4-fold reduced susceptibility to lopinavir. These 31 isolates had a median reduction in lopinavir susceptibility of 18-fold. Response to therapy by baseline lopinavir susceptibility is shown in Table 21.Table 21. HIV-1 RNA Response at Week 48 by Baseline Lopinavir Susceptibility1Lopinavir susceptibility2 at baselineHIV-1 RNA <400 copies/mL (%)HIV-1 RNA <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.2 Fold change in susceptibility from wild type.
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 AUC0-24hr measurement) at the recommended dose of 400/100 mg KALETRA twice daily. Administration of lopinavir/ritonavir did not cause a 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 a dose dependent increase in the incidence of both adenomas and combined adenomas and carcinomas in the liver. Based on AUC measurements, the exposure at the high dose was approximately 4-fold for males that of the exposure in humans with the recommended therapeutic dose (400/100 mg KALETRA 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 a battery of in vitro and in vivo assays including the Ames bacterial reverse mutation assay using S. typhimurium and E. coli, the mouse lymphoma assay, the mouse micronucleus test and chromosomal aberration assays in human lymphocytes.Impairment of FertilityLopinavir in combination with ritonavir at a 2:1 ratio produced no effects on fertility in male and female rats at levels of 10/5, 30/15 or 100/50 mg/kg/day. Based on AUC measurements, the exposures in rats at the high doses were approximately 0.7-fold for lopinavir and 1.8-fold for ritonavir of the exposures in humans at the recommended therapeutic dose (400/100 mg twice daily).
Study 863: KALETRA Capsules twice daily + stavudine + lamivudine compared to nelfinavir three times daily + stavudine + lamivudineStudy 863 was a 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 naïve patients. Patients had a mean age of 38 years (range: 19 to 84), 57% were Caucasian, and 80% were male. Mean baseline CD4+ cell count was 259 cells/mm3 (range: 2 to 949 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.9 log10 copies/mL (range: 2.6 to 6.8 log10 copies/mL).Treatment response and outcomes of randomized treatment are presented in Table 22.Table 22. Outcomes of Randomized Treatment Through Week 48 (Study 863)OutcomeKALETRA+d4T+3TC(N = 326)Nelfinavir+d4T+3TC(N = 327)Responder175%62%Virologic failure2 Rebound Never suppressed through Week 489%7%2%25%15%9%Death2%1%Discontinued due to adverse events4%4%Discontinued for other reasons310%8%1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.3 Includes lost to follow-up, patient's 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 a statistically significantly higher proportion of patients in the KALETRA arm compared to the nelfinavir arm with HIV-1 RNA < 400 copies/mL (75% vs. 62%, respectively) and HIV-1 RNA < 50 copies/mL (67% vs. 52%, respectively). Treatment response by baseline HIV-1 RNA level subgroups is presented in Table 23.Table 23. Proportion of Responders Through Week 48 by Baseline Viral Load (Study 863)Baseline Viral Load (HIV-1 RNA copies/mL)KALETRA +d4T+3TCNelfinavir +d4T+3TC <400 copies/mL 1<50 copies/mL 2n <400 copies/mL 1<50 copies/mL 2n < 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 RNA < 400 copies/mL through Week 48.2 Patients achieved HIV-1 RNA < 50 copies/mL at Week 48.Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 207 cells/mm3 for the KALETRA arm and 195 cells/mm3 for the nelfinavir arm.Study 730: KALETRA Tablets once daily + tenofovir DF + emtricitabine compared to KALETRA Tablets twice daily + tenofovir DF + emtricitabineStudy 730 was a 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-naïve patients. Patients were randomized in a 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 8 and maintained on their randomized dosing schedule. Patients were administered emtricitabine 200 mg once daily and tenofovir DF 300 mg once daily. Mean age of patients enrolled was 39 years (range: 19 to 71); 75% were Caucasian, and 78% were male. Mean baseline CD4+ cell count was 216 cells/mm3 (range: 20 to 775 cells/mm3) and mean baseline plasma HIV-1 RNA was 5.0 log10 copies/mL (range: 1.7 to 7.0 log10 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 730)OutcomeKALETRA Once Daily + TDF + FTC(n = 333)KALETRA Twice Daily + TDF + FTC(n = 331)Responder178%77%Virologic failure2 Rebound Never suppressed through Week 4810%5%5%8%5%3%Death1%<1%Discontinued due to adverse events4%3%Discontinued for other reasons38%11%1 Patients achieved and maintained confirmed HIV-1 RNA < 50 copies/mL through Week 48.2 Includes confirmed viral rebound and failure to achieve confirmed < 50 copies/mL through Week 48.3 Includes lost to follow-up, patient's 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 RNA < 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/mm3 for the KALETRA once daily arm and 198 cells/mm3 for the KALETRA twice daily arm.
Study 888: KALETRA Capsules twice daily + nevirapine + NRTIs compared to investigator-selected protease inhibitor(s) + nevirapine + NRTIs Study 888 was a randomized, open-label, multicenter trial comparing treatment with KALETRA capsules (400/100 mg twice daily) plus nevirapine and nucleoside reverse transcriptase inhibitors versus investigator-selected protease inhibitor(s) plus nevirapine and nucleoside reverse transcriptase inhibitors in 288 single protease inhibitor-experienced, non-nucleoside reverse transcriptase inhibitor (NNRTI)-naïve patients. Patients had a mean age of 40 years (range: 18 to 74), 68% were Caucasian, and 86% were male. Mean baseline CD4+ cell count was 322 cells/mm3 (range: 10 to 1059 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.1 log10 copies/mL (range: 2.6 to 6.0 log10 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 888)OutcomeKALETRA + nevirapine + NRTIs (n = 148)Investigator-Selected Protease Inhibitor(s) + nevirapine + NRTIs (n = 140)Responder157%33%Virologic failure2 Rebound Never suppressed through Week 4824%11%13%41%19%23%Death1%2%Discontinued due to adverse events 5%11%Discontinued for other reasons314%13%1 Patients achieved and maintained confirmed HIV-1 RNA < 400 copies/mL through Week 48.2 Includes confirmed viral rebound and failure to achieve confirmed < 400 copies/mL through Week 48.3 Includes lost to follow-up, patient's withdrawal, non-compliance, protocol violation and other reasons.Through 48 weeks of therapy, there was a statistically significantly higher proportion of patients in the KALETRA arm compared to the investigator-selected protease inhibitor(s) arm with HIV-1 RNA < 400 copies/mL (57% vs. 33%, respectively).Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 111 cells/mm3 for the KALETRA arm and 112 cells/mm3 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 a 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 a protease inhibitor and 81 – 88% had received prior NNRTIs as part of their anti-HIV treatment regimen. Patients were randomized in a 1:1 ratio to receive either KALETRA 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/mm3 (range: 4 to 952 cells/mm3) and mean baseline plasma HIV-1 RNA was 4.3 log10 copies/mL (range: 1.7 to 6.6 log10 copies/mL).Treatment response and outcomes of randomized treatment through Week 48 are presented in Table 26.Table 26. 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 RNA <50 copies/mL) 57%54%Virologic failure122%24%No virologic data in Week 48 window Discontinued study due to adverse event or death25%7%Discontinued study for other reasons313%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 RNA ≥ 50 copies/mL at Week 48.2 Includes patients who discontinued due to adverse events or death at any time from Day 1 through Week 48 if this resulted in no virologic data on treatment at Week 48. 3 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/mm3 for the once daily group and 122 cells/mm3 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 a mean age of 35 years, 70% were Caucasian, and 96% were male, while patients in study 765 had a mean age of 40 years, 73% were Caucasian, and 90% were male. Mean (range) baseline CD4+ cell counts for patients in study 720 and study 765 were 338 (3-918) and 372 (72-807) cells/mm3, respectively. Mean (range) baseline plasma HIV-1 RNA levels for patients in study 720 and study 765 were 4.9 (3.3 to 6.3) and 4.0 (2.9 to 5.8) log10 copies/mL, respectively.Through 360 weeks of treatment in study 720, the proportion of patients with HIV-1 RNA < 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/mm3. Thirty-nine patients (39%) discontinued the study, including 13 (13%) discontinuations due to adverse reactions and 1 (1%) death. Through 144 weeks of treatment in study 765, the proportion of patients with HIV-1 RNA < 400 (< 50) copies/mL was 54% (50%) [n = 70], and the corresponding mean increase in CD4+ cell count was 212 cells/mm3. Twenty-seven patients (39%) discontinued the study, including 5 (7%) discontinuations secondary to adverse reactions and 2 (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 a dose of 300/75 mg/m2 twice daily plus 2 NRTIs in HIV-1 infected infants ≥14 days and <6 months of age.Ten infants, ≥14 days and <6 wks of age, were enrolled at a median (range) age of 5.7 (3.6-6.0) weeks and all completed 24 weeks. At entry, median (range) HIV-1 RNA was 6.0 (4.7-7.2) log10 copies/mL. Seven of 10 infants had HIV-1 RNA <400 copies/mL at Week 24. At entry, median (range) CD4+ percentage was 41 (16-59) with a median decrease of 1% (95% CI: -10, 18) from baseline to week 24 in 6 infants with available data.Twenty-one infants, between 6 weeks and 6 months of age, were enrolled at a median (range) age of 14.7 (6.9-25.7) weeks and 19 of 21 infants completed 24 weeks. At entry, median (range) HIV RNA level was 5.8 (3.7-6.9) log10 copies/mL. Ten of 21 infants had HIV RNA <400 copies/mL at Week 24. At entry, the median (range) CD4+ percentage was 32 (11-54) with a median increase of 4% (95% CI: -1, 9) from baseline to week 24 in 19 infants with available data [see Clinical Pharmacology (12.3) for pharmacokinetic results].Study 940 was an open-label, multicenter trial evaluating the pharmacokinetic profile, tolerability, safety and efficacy of KALETRA oral solution containing lopinavir 80 mg/mL and ritonavir 20 mg/mL in 100 antiretroviral naïve (44%) and experienced (56%) pediatric patients. All patients were non-nucleoside reverse transcriptase inhibitor naïve. Patients were randomized to either 230 mg lopinavir/57.5 mg ritonavir per m2 or 300 mg lopinavir/75 mg ritonavir per m2. Naïve patients also received lamivudine and stavudine. Experienced patients received nevirapine plus up to two nucleoside reverse transcriptase inhibitors.Safety, efficacy and pharmacokinetic profiles of the two dose regimens were assessed after three weeks of therapy in each patient. After analysis of these data, all patients were continued on the 300 mg lopinavir/75 mg ritonavir per m2 dose. Patients had a mean age of 5 years (range 6 months to 12 years) with 14% less than 2 years. Mean baseline CD4+ cell count was 838 cells/mm3 and mean baseline plasma HIV-1 RNA was 4.7 log10 copies/mL. Through 48 weeks of therapy, the proportion of patients who achieved and sustained an HIV-1 RNA < 400 copies/mL was 80% for antiretroviral naïve patients and 71% for antiretroviral experienced patients. The mean increase from baseline in CD4+ cell count was 404 cells/mm3 for antiretroviral naïve and 284 cells/mm3 for antiretroviral experienced patients treated through 48 weeks. At 48 weeks, two patients (2%) had prematurely discontinued the study. One antiretroviral naïve patient prematurely discontinued secondary to an adverse reaction, while one antiretroviral experienced patient prematurely discontinued secondary to an HIV-1 related event. Dose selection in pediatric patients was based on the following:Among patients 14 days to 6 months of age receiving 300/75 mg/m2 twice daily without nevirapine, plasma concentrations were lower than those observed in adults or in older children. This dose resulted in HIV-1 RNA < 400 copies/mL in 55% of patients (70% in those initiating treatment at <6 weeks of age). Among patients 6 months to 12 years of age, the 230/57.5 mg/m2 oral solution twice daily regimen without nevirapine and the 300/75 mg/m2 oral solution twice daily regimen with nevirapine provided lopinavir plasma concentrations similar to those obtained in adult patients receiving the 400/100 mg twice daily regimen (without nevirapine). These doses resulted in treatment benefit (proportion of patients with HIV-1 RNA < 400 copies/mL) similar to that seen in the adult clinical trials.Among patients 12 to 18 years of age receiving 400/100 mg/m2 or 480/120 mg/m2 (with efavirenz) twice daily, plasma concentrations were 60-100% higher than among 6 to 12 year old patients receiving 230/57.5 mg/m2. Mean apparent clearance was similar to that observed in adult patients receiving standard dose and in patients 6 to 12 years of age. Although changes in HIV-1 RNA in patients with prior treatment failure were less than anticipated, the pharmacokinetic data supports use of similar dosing as in patients 6 to 12 years of age, not to exceed the recommended adult dose. For all age groups, the body surface area dosing was converted to body weight dosing using the patient’s prescribed lopinavir dose.
16 How Supplied/Storage And Handling
KALETRA® (lopinavir and ritonavir) tablets and oral solution are available in the following strengths and package sizes: KALETRA Tablets,200 mg lopinavirand 50 mg ritonavirKALETRA Tablets,100 mg lopinavir and25 mg ritonavirKALETRA Oral Solution,80 mg lopinavir and 20 mg ritonavir per mLPresentationYellow film-coated ovaloid tablets debossed with the “a” logo and the code KAPale yellow film-coated ovaloid tablets debossed with the “a” logo and the code KCLight yellow to orange colored liquid supplied in amber-colored multiple-dose bottles containing 400 mg lopinavir and 100 mg ritonavir per 5 mL packaged with a marked dosing cupBottle Sizeand NDCNumberBottles of 120 tablets(NDC 0074-6799-22)Bottles of 60 tablets(NDC 0074-0522-60) 160 mL bottle(NDC 0074-3956-46)Recommended Storage:Store KALETRA tablets at 20°- 25°C (68°- 77°F); excursions permitted to 15°- 30°C (59°- 86°F) [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 2 weeks is not recommended.Store KALETRA oral solution at 2°- 8°C (36°- 46°F) until dispensed. Avoid exposure to excessive heat. For patient use: refrigerated KALETRA oral solution remains stable until the expiration date printed on the label. If stored at room temperature up to 25°C (77°F), oral solution should be used within 2 months.
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 child’s weight changes in order to make sure that the child’s 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 a 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 a dose of KALETRA is missed patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.Inform patients that it is important to take KALETRA on a regular dosing schedule as directed and to avoid missing doses as that can result in development of resistance.Inform patients that there may be a greater chance of developing diarrhea with the once daily regimen as compared with the twice daily regimen. Inform patients that Kaletra is not a 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. John’s 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 a rash while taking KALETRA [see Adverse Reactions (6.1)].HepatotoxicityPre-existing liver disease including Hepatitis B or C 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 a 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)]. KALETRA Tablets, 200 mg lopinavir and 50 mg ritonavirManufactured by AbbVie LTD, Barceloneta, PR 00617for AbbVie Inc., North Chicago, IL 60064 USAKALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir and KALETRA Oral SolutionAbbVie Inc., North Chicago, IL 60064 USAThe 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. © 2017 AbbVie Inc. All rights reserved. 03-B593
- MEDICATION GUIDEKALETRA® (kuh-LEE-tra)(lopinavir and ritonavir)tabletsKALETRA® (kuh-LEE-tra)(lopinavir and ritonavir)oral solutionWhat is the most important information I should know about KALETRA?KALETRA 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 a certain fat (triglycerides) have a 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 a 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 B 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 a 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 KALETRA?KALETRA is a prescription medicine that is used with other antiviral 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 KALETRA?Do 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 a complete list of ingredients in KALETRA.Do not take KALETRA if you take any of the following medicines:alfuzosin (Uroxatral®)cisapride (Propulsid®, Propulsid Quicksolv®)colchicine (Colcrys®, Col-Probenecid®, Mitigare®), if you have kidney or liver problems.dronedarone (Multaq®)elbasvir/grazoprevir (Zepatier®)ergot containing medicines including:ergotamine tartrate (Cafergot®, Ergomar®, Ergostat®, Ergotamine®, Medihaler®, Migergot®, Wigraine®, Wigrettes®)dihydroergotamine mesylate (D.H.E. 45®, Migranal®)methylergonovine (Methergine®)lovastatin (Altoprev®, Mevacor®) midazolam when taken by mouthlurasidone (Latuda®)pimozide (Orap®) ranolazine (Ranexa®)rifampin (Rifadin®, Rifamate®, Rifater®, Rimactane®) sildenafil (Revatio®), when used for the treatment of pulmonary arterial hypertensionsimvastatin (Zocor®, Vytorin®) St. John’s Wort (Hypericum perforatum®)triazolam (Halcion®)Serious problems can happen if you or your child take 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 any heart problems, including if you have a condition called Congenital Long QT Syndrome.have or had pancreas problems.have liver problems, including Hepatitis B or Hepatitis C.have diabetes.have hemophilia. KALETRA may cause increased bleeding.have low potassium in your blood.are pregnant or plan to become pregnant.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 a 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 a list of your medicines to show your healthcare provider and pharmacist.You can ask your healthcare provider or pharmacist for a list of medicines that interact with KALETRA.Do not start taking a 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.You should not take KALETRA on a 1 time each day dosing schedule if you also take carbamazepine (Carbatrol®, Epitol®, Equetro®, Tegretol®, Tegretol-XR®, Teril®), phenobarbital, or phenytoin (Dilantin®, Phenytek®), efavirenz (Atripla®, Sustiva®), nevirapine (Viramune®, Viramune XR®), or nelfinavir (Viracept®). How should I take KALETRA?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 a 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 (Videx®) and KALETRA:Didanosine can be taken at the same time as KALETRA tablets, without food.Take didanosine either 1 hour before or 2 hours after taking KALETRA oral solution.If you are pregnant:You should not take KALETRA tablets on a 1 time each day dose schedule. Avoid use of KALETRA oral solution.If your child is prescribed KALETRA:Tell your healthcare provider if your child’s weight changes.KALETRA should not be given to children on a 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 a 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 a feeding tube. KALETRA oral solution contains propylene glycol and alcohol (ethanol), and should not be used with certain feeding tubes.You may have a greater chance of getting diarrhea if you take KALETRA 1 time each day than if you take it 2 times each day.Do not miss a 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 KALETRA?KALETRA can cause serious side effects, including:See “What is the most important information I 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 a 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 a 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.Common 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 I store KALETRA?KALETRA tablets:Store KALETRA tablets at room temperature, between 68°F to 77°F (20°C to 25°C).Store KALETRA tablets in the original container.Do not keep KALETRA tablets out of the container it comes in for longer than 2 weeks, especially in areas where there is a lot of humidity.Keep the container closed tightly. KALETRA oral solution:Store KALETRA oral solution in a refrigerator, between 36°F to 46°F (2°C to 8°C). 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 77°F or 25°C) should be used within 2 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 a Medication Guide. Do not use KALETRA for a 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 KALETRA?Active ingredients: lopinavir and ritonavirInactive ingredients:KALETRA 200 mg lopinavir and 50 mg ritonavir 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 172. KALETRA 100 mg lopinavir and 25 mg ritonavir 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 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 I take KALETRA?”For more information about KALETRA call 1-800-633-9110 or go to www.KALETRA.comKALETRA Tablets, 200 mg lopinavir and 50 mg ritonavir Manufactured by AbbVie LTD, Barceloneta, PR 00617for AbbVie Inc., North Chicago, IL 60064 USAKALETRA Tablets, 100 mg lopinavir and 25 mg ritonavir and KALETRA Oral SolutionAbbVie Inc., North Chicago, IL 60064 USAThe 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.© 2017 AbbVie Inc. All rights reserved. 03-B593This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: October 2017
* Please review the disclaimer below.