KALETRA CAPSULES SIDE EFFECTS

  • Generic Name: lopinavir, ritonavir capsules
  • Brand Name: Kaletra Capsules
Last updated on MDtodate: 10/6/2022

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling.

  • QT Interval Prolongation, PR Interval Prolongation
  • Drug Interactions
  • Pancreatitis
  • Hepatotoxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction 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, nauseavomiting, 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 (Table1):

Table 1: Treatment-Emergent 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
  anemia* 54 2.1
  leukopenia and neutropenia* 44 1.7
  lymphadenop athy * 35 1.3
CARDIAC DISORDERS
  atherosclerosis such as myocardial infarction* 10 0.4
  atrioventricular block* 3 0.1
  tricuspid valve incompetence* 3 0.1
EAR AND LABYRINTH DISORDERS
  vertigo* 7 0.3
  tinnitus 6 0.2
ENDOCRINE DISORDERS
  hypogonadism* 16 0.81
EYE DISORDERS
  visual impairment* 8 0.3
GASTROINTESTINAL DISORDERS
  diarrhea* 510 19.5
  nausea 269 10.3
  vomiting* 177 6.8
  abdominal pain (upper and lower)* 160 6.1
  gastroenteritis and colitis* 66 2.5
  dyspepsia 53 2.0
  pancreatitis* 45 1.7
  Gastroesophageal Reflux Disease (GERD)* 40 1.5
  hemorrhoids 39 1.5
  flatulence 36 1.4
  abdominal distension 34 1.3
  constipation* 26 1.0
  stomatitis and oral ulcers* 24 0.9
  duodenitis and gastritis* 20 0.8
  gastrointestinal hemorrhage including rectal hemorrhage* 13 0.5
  dry mouth 9 0.3
  gastrointestinal ulcer* 6 0.2
  fecal incontinence 5 0.2
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS
  fatigue including asthenia* 198 7.6
HEPATOBILIARY DISORDERS
  hepatitis including AST, ALT, and GGT increases* 91 3.5
  hepatomegaly 5 0.2
  cholangitis 3 0.1
  hepatic steatosis 3 0.1
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
  hypercholesterol emia* 192 7.4
  hypertriglyceridemia* 161 6.2
  weight decreased* 61 2.3
  decreased appetite 52 2.0
  blood glucose disorders including diabetes mellitus* 30 1.1
  weight increased* 20 0.8
  lactic acidosis* 11 0.4
  increased appetite 5 0.2
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS
  musculoskeletal pain including arthralgia and back pain* 166 6.4
  myalgia* 46 1.8
  muscle disorders such as weakness and spasms* 34 1.3
  rhabdomyolysis* 18 0.7
  osteonecrosis 3 0.1
NERVOUS SYSTEM DISORDERS
  headache including migraine* 165 6.3
  insomnia* 99 3.8
  neuropathy and peripheral neuropathy* 51 2.0
  dizziness* 45 1.7
  ageusia* 19 0.7
  convulsion* 9 0.3
  tremor* 9 0.3
  cerebral vascular event* 6 0.2
PSYCHIATRIC DISORDERS
  anxiety* 101 3.9
  abnormal dreams* 19 0.7
  libido decreased 19 0.7
RENAL AND URINARY DISORDERS
  renal failure* 31 1.2
  hematuria* 20 0.8
  nephritis* 3 0.1
REPRODUCTIVE SYSTEM AND BREAST DISORDERS
  erectile dysfunction* 34 1.71
  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
  night sweats* 42 1.6
  pruritus* 29 1.1
  alopecia 10 0.4
  capillaritis and vasculitis* 3 0.1
VASCULAR DISORDERS
  hypertension* 47 1.8
  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 3 (treatment-naïve patients) and Table 4 (treatmentexperienced patients).

Table 2: Grade 3-4 Laboratory Abnormalities Reported in greater than or equal to 2% of Adult Antiretroviral-Naïve Patients

Variable Limit1 Study 863 (48 Weeks) Study 720 (360 Weeks) Study 418 (48 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 800/200 mg Once Daily + TDF + FTC
(N=115)
KALETRA 400/100 mg Twice Daily + TDF + FTC
(N=75)
KALETRA Once Daily + TDF +FTC
(N=333)
KALETRA Twice Daily + TDF +FTC
(N=331)
Chemistry High
Glucose > 250 mg/dL 2% 2% 4% 3% 1% 0% < 1%
Uric Acid > 12 mg/dL 2% 2% 5% 0% 3% < 1% 1%
SGOT/ AST2 > 180 U/L 2% 4% 10% 5% 3% 1% 2%
SGPT/ ALT2 > 215U/L 4% 4% 11% 4% 3% 1% 1%
GGT > 300 U/L N/A N/A 10% N/A N/A N/A N/A
Total Cholesterol > 300 mg/dL 9% 5% 27% 3% 3% 4% 3%
Triglycerid es > 750 mg/dL 9% 1% 29% 5% 4% 3% 6%
Amylase > 2 x ULN 3% 2% 4% 7% 5% N/A N/A
Lipase > 2 x ULN N/A N/A N/A N/A N/A 3% 5%
Chemistry Low
Calculated Creatinine Clearance < 50 mL/min N/A N/A N/A N/A N/A 2% 2%
Hematology Low
Neutrophils < 0.75 x 109/L 1% 3% 5% 5% 1% 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 3: Grade 3-4 Laboratory Abnormalities Reported in greater than or equal to 2% of Adult Protease Inhibitor-Experienced Patients

Variable Limit1 Study 888 (48 Weeks) Study 957and 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
(N=300)
KALETRA 400/100 mg Twice Daily +NRTIs
(N=299)
Chemistry High
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%
Chemistry Low
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%
Hematology Low
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 per 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 and soft gelatin capsules dosed at higher than recommended doses including 400/100 mg per m² (without concomitant NNRTI) and 480/120 mg per 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 Patients

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

Table 4: Grade 3-4 Laboratory Abnormalities Reported in greater than or equal to 2% Pediatric Patients in Study 940

Variable Limit1 KALETRA Twice Daily + RTIs
(N = 100)
Chemistry High
Sodium > 149 mEq/L 3%
Total Bilirubin ≥ 3.0 x ULN 3%
SGOT/AST > 180U/L 8%
SGPT/ALT > 215 U/L 7%
Total Cholesterol > 300 mg/dL 3%
Amylase > 2.5 x ULN 7%2
Chemistry Low
Sodium < 130 mEq/L 3%
Hematology Low
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.

 

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 always 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.

Cardiovascular

Bradyarrhythmias. First-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, torsades (torsade) de pointes.

Skin and Appendages

Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.

 

SRC: NLM .