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]
- Drug Interactions [see WARNINGS AND PRECAUTIONS]
- Pancreatitis [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
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 Adults
The 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 Reaction||n||%|
|BLOOD AND LYMPHATIC SYSTEM DISORDERS|
|leukopenia and neutropenia*||44||1.7|
|atherosclerosis such as myocardial infarction*||10||0.4|
|tricuspid valve incompetence*||3||0.1|
|EAR AND LABYRINTH DISORDERS|
|abdominal pain (upper and lower)*||160||6.1|
|gastroenteritis and colitis*||66||2.5|
|Gastroesophageal Reflux Disease (GERD)*||40||1.5|
|stomatitis and oral ulcers*||24||0.9|
|duodenitis and gastritis*||20||0.8|
|gastrointestinal hemorrhage including rectal hemorrhage*||13||0.5|
|GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS|
|fatigue including asthenia*||198||7.6|
|hepatitis including AST, ALT, and GGT increases*||91||3.5|
|IMMUNE SYSTEM DISORDERS|
|hypersensitivity including urticaria and angioedema*||70||2.7|
|immune reconstitution syndrome||3||0.1|
|INFECTIONS AND INFESTATIONS|
|upper respiratory tract infection*||363||13.9|
|lower respiratory tract infection*||202||7.7|
|skin infections including cellulitis, folliculitis, and furuncle*||86||3.3|
|METABOLISM AND NUTRITION DISORDERS|
|blood glucose disorders including diabetes mellitus*||30||1.1|
|MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS|
|musculoskeletal pain including arthralgia and back pain*||166||6.4|
|muscle disorders such as weakness and spasms*||34||1.3|
|NERVOUS SYSTEM DISORDERS|
|headache including migraine*||165||6.3|
|neuropathy and peripheral neuropathy*||51||2.0|
|cerebral vascular event*||6||0.2|
|RENAL AND URINARY DISORDERS|
|REPRODUCTIVE SYSTEM AND BREAST DISORDERS|
|menstrual disorders - amenorrhea, menorrhagia*||10||1.72|
|SKIN AND SUBCUTANEOUS TISSUE DISORDERS|
|rash including maculopapular rash*||99||3.8|
|lipodystrophy acquired including facial wasting*||58||2.2|
|dermatitis/rash including eczema and seborrheic dermatitis*||50||1.9|
|capillaritis and vasculitis*||3||0.1|
|deep vein thrombosis*||17||0.7|
|*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 Adults
The 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 (treatmentexperienced patients).
Table 10: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients
|Variable||Limit1||Study 863 (48 Weeks)||Study 720 (360 Weeks)||Study 730 (48 Weeks)|
|KALETRA 400/100 mg Twice Daily + d4T +3TC
(N = 326)
|Nelfinavir 750 mg Three Times Daily + d4T + 3TC
(N = 327)
|KALETRA Twice Daily + d4T + 3TC
(N = 100)
|KALETRA Once Daily + TDF +FTC
|KALETRA Twice Daily + TDF +FTC
|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/L||4%||4%||11%||1%||1%|
|GGT||> 300 U/L||N/A||N/A||10%||N/A||N/A|
|Total Cholesterol||> 300 mg/dL||9%||5%||27%||4%||3%|
|Triglycerides||> 750 mg/dL||9%||1%||29%||3%||6%|
|Amylase||> 2 x ULN||3%||2%||4%||N/A||N/A|
|Lipase||> 2 x ULN||N/A||N/A||N/A||3%||5%|
|Calculated Creatinine Clearance||< 50 mL/min||N/A||N/A||N/A||2%||2%|
|Neutrophils||< 0.75 x 109/L||1%||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
|Variable||Limit1||Study 888 (48 Weeks)||Study 9572 and Study 7653 (84-144 Weeks)||Study 802 (48 Weeks)|
|KALETRA 400/100 mg Twice Daily + NVP + NRTIs
(N = 148)
|Investigator-Selected Protease Inhibitor(s) + NVP + NRTIs
(N = 140)
|KALETRA Twice Daily + NNRTI + NRTIs
(N = 127)
|KALETRA 800/200 mg Once Daily +NRTIs
|KALETRA 400/100 mg Twice Daily +NRTIs
|Glucose||> 250 mg/dL||1%||2%||5%||2%||2%|
|Total Bilirubin||> 3.48 mg/dL||1%||3%||1%||1%||1%|
|SGOT/AST4||> 180 U/L||5%||11%||8%||3%||2%|
|SGPT/ALT4||> 215 U/L||6%||13%||10%||2%||2%|
|GGT||> 300 U/L||N/A||N/A||29%||N/A||N/A|
|Total Cholesterol||> 300 mg/dL||20%||21%||39%||6%||7%|
|Triglycerides||> 750 mg/dL||25%||21%||36%||5%||6%|
|Amylase||> 2 x ULN||4%||8%||8%||4%||4%|
|Lipase||> 2 x ULN||N/A||N/A||N/A||4%||1%|
|Creatine Phosphokinase||> 4 x ULN||N/A||N/A||N/A||4%||5%|
|Calculated Creatinine Clearance||< 50 mL/min||N/A||N/A||N/A||3%||3%|
|Inorganic Phosphorus||< 1.5 mg/dL||1%||0%||2%||1%||< 1%|
|Neutrophils||< 0.75 x 109/L||1%||2%||4%||3%||4%|
|Hemoglobin||< 80 g/L||1%||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 Patients
KALETRA 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 preexisting cardiac abnormalities.
Laboratory Abnormalities in Pediatric Patients
The 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 940
|Variable||Limit1||KALETRA Twice Daily + RTIs
(N = 100)
|Sodium||> 149 mEq/L||3%|
|Total Bilirubin||≥ 3.0 x ULN||3%|
|SGOT/AST||> 180 U/L||8%|
|Total Cholesterol||> 300 mg/dL||3%|
|Amylase||> 2.5 x ULN||7%2|
|Sodium||< 130 mEq/L||3%|
|Platelet Count||< 50 x 109/L||4%|
|Neutrophils||< 0.40 x 109/L||2%|
|1 ULN = upper limit of the normal range.
2 Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase.
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].
Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes [see WARNINGS AND PRECAUTIONS].
Skin and Appendages
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.