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Kaletra (Lopinavir / Ritonavir) - Side Effects and Adverse Reactions

 
 



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 ]
  • Pancreatitis [see Warnings and Precautions]
  • Hepatotoxicity [see Warnings and Precautions ]

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.

Adult Clinical Trial Experience

The safety profile of KALETRA in adults is primarily based on 1,964 HIV-1 infected patients in clinical trials.

The most common adverse reaction was diarrhea, which was generally of mild to moderate severity.

In study 730, the incidence of diarrhea of any severity during 48 weeks of therapy was 60% in patients receiving KALETRA tablets once daily compared to 57% in patients receiving KALETRA tablets twice daily. More patients receiving KALETRA tablets once daily (14, 4.2%) had ongoing diarrhea at the time of discontinuation as compared to patients receiving KALETRA tablets twice daily (6, 1.8%). In study 730, discontinuations due to any adverse reaction were 4.8% in patients receiving KALETRA tablets once daily as compared to 3% in patients receiving KALETRA tablets twice daily. In study 802, the incidence of diarrhea of any severity during 48 weeks of therapy was 50% in patients receiving KALETRA tablets once daily compared to 39% in patients receiving KALETRA tablets twice daily. Moderate or severe drug-related diarrhea occurred in 14% of patients receiving KALETRA tablets once daily as compared to 11% in patients receiving KALETRA tablets twice daily. At the time of discontinuation, 19 (6.3%) patients receiving KALETRA tablets once daily had ongoing diarrhea, as compared to 11 (3.7%) patients receiving KALETRA tablets twice daily. Discontinuations due to any adverse reaction occurred in 4.3% of patients receiving KALETRA tablets once daily compared to 7.0% in patients receiving KALETRA tablets twice daily. In study 863, discontinuations of randomized therapy due to adverse reactions were 3.4% in KALETRA-treated and 3.7% in nelfinavir-treated patients.

Treatment-emergent clinical adverse reactions of moderate or severe intensity in ≥ 2% of patients treated with combination therapy for up to 48 weeks (Studies 863 and 730) and for up to 360 weeks (Study 720) are presented in Table 4 (treatment-naïve patients); and for up to 48 weeks (Studies 888 and 802), 84 weeks (Study 957) and 144 weeks (Study 765) in Table 5 (protease inhibitor-experienced patients).

Table 4. Percentage of Adult Patients with Selected Treatment-Emergent1 Adverse Reactions of Moderate or Severe Intensity Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients
  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 Daily2 + d4T + 3TC
(N = 100)
KALETRA 800/200 mg Once Daily + TDF +FTC (N=333) KALETRA 400/100 mg Twice Daily + TDF +FTC (N=331)
Endocrine Disorders        
Hypogonadism 0% 0% 2% 0% 0%
Gastrointestinal Disorders          
Diarrhea 16% 17% 28% 17% 15%
Nausea 7% 5% 16% 7% 5%
Vomiting 2% 2% 6% 3% 4%
Abdominal Pain 4% 3% 11% 1% 1%
Dyspepsia 2% <1% 6% 0% 0%
Flatulence 2% 1% 4% 1% 1%
General Disorders and Administration Site Conditions        
Asthenia 4% 3% 9% <1% <1%
Infections and Infestations        
Bronchitis 0% 0% 2% 0% <1%
Investigations        
Weight Decreased 1% <1% 2% 0% <1%
Metabolism and Nutrition Disorders          
Anorexia 1% <1% 2% <1% 1%
Musculoskeletal and Connective Tissue Disorders          
Myalgia 1% 1% 2% 0% 0%
Nervous System Disorders          
Headache 2% 2% 6% 2% 2%
Paresthesia 1% 1% 2% 0% 0%
Psychiatric Disorders        
Insomnia 2% 1% 3% 1% 0%
Depression 1% 2% 0% 0% 0%
Libido Decreased <1% <1% 2% 0% <1%
Skin and Subcutaneous Tissue Disorders          
Rash 1% 2% 5% <1% 1%
Vascular Disorders          
Vasodilation 0% 0% 3% 0% 0%
1   Includes adverse reactions of possible or probable relationship to study drug.
2   Includes adverse reaction data from dose group I (200/100 mg twice daily [N = 16] and 400/100 mg twice daily [N = 16]) and dose group II (400/100 mg twice daily [N = 35] and 400/200 mg twice daily [N = 33]). Within dosing groups, moderate to severe nausea of probable/possible relationship to KALETRA occurred at a higher rate in the 400/200 mg dose arm compared to the 400/100 mg dose arm in group II.
Definitions: d4T = Stavudine; 3TC = Lamivudine; TDF = Tenofovir Disoproxil Fumarate; FTC = Emtricitabine
Table 5. Percentage of Adult Patients with Selected Treatment-Emergent1 Adverse Reactions of Moderate or Severe Intensity 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)
  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)
Gastrointestinal Disorders          
Diarrhea 7% 9% 23% 14% 11%
Nausea 7% 16% 5% 3% 7%
Vomiting 4% 12% 2% 2% 3%
Abdominal Pain 2% 2% 4% 2% <1%
Abdominal Pain Upper N/A N/A N/A 1% 2%
Dyspepsia 1% 1% 2% 1% <1%
Flatulence 1% 2% 2% 1% 1%
Dysphasia 2% 1% 0% 0% 0%
General Disorders and Administration Site Conditions          
Asthenia 3% 6% 9% <1% <1%
Pyrexia 2% 1% 2% 0% <1%
Chills 2% 0% 0% 0% 0%
Investigations          
Weight Decreased 0% 1% 3% <1% <1%
Metabolism and Nutrition Disorders          
Anorexia 1% 3% 0% 0% 1%
Musculoskeletal and Connective Tissue Disorders          
Myalgia 1% 1% 2% 0% 0%
Nervous System Disorders          
Headache 2% 3% 2% <1% 0%
Paresthesia 0% 1% 2% 0% 0%
Psychiatric Disorders          
Depression 1% 2% 3% <1% 0%
Insomnia 0% 2% 2% 0% <1%
Skin and Subcutaneous Tissue Disorders          
Rash 2% 1% 2% 0% 0%
Vascular Disorders          
Hypertension 0% 0% 2% 0% 0%
1   Includes adverse reactions of possible or probable relationship to study drug.
2   Includes adverse reaction data from patients receiving 400/100 mg twice daily (n = 29) or 533/133 mg twice daily (n = 28) for 84 weeks. Patients received KALETRA in combination with NRTIs and efavirenz.
3   Includes adverse reaction 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.
Definitions: NVP = Nevirapine; NRTI = Nucleoside Reverse Transcriptase Inhibitors; NNRTI = Non-nucleoside Reverse Transcriptase Inhibitors

Less Common Adverse Reactions

Treatment-emergent adverse reactions occurring in less than 2% of adult patients receiving KALETRA in the clinical trials supporting approval and of at least moderate intensity are listed below by system organ class.

Blood and Lymphatic System Disorders

Anemia, leukopenia, lymphadenopathy, neutropenia, and splenomegaly.

Cardiac Disorders

Angina pectoris, atrial fibrillation, atrioventricular block, myocardial infarction, palpitations, and tricuspid valve incompetence.

Ear and Labyrinth Disorders

Hyperacusis, tinnitus, and vertigo.

Endocrine Disorders

Cushing's syndrome and hypothyroidism.

Eye Disorders

Eye disorder and visual disturbance.

Gastrointestinal Disorders

Abdominal discomfort, abdominal distension, abdomen pain lower, constipation, duodenitis, dry mouth, enteritis, enterocolitis, enterocolitis hemorrhagic, eructation, esophagitis, fecal incontinence, gastric disorder, gastric ulcer, gastritis, gastroesophageal reflux disease, hemorrhoids, mouth ulceration, pancreatitis, periodontitis, rectal hemorrhage, stomach discomfort, and stomatitis.

General Disorders and Administration Site Conditions

Chest pain, cyst, drug interaction, edema, edema peripheral, face edema, fatigue, hypertrophy, and malaise.

Hepatobiliary Disorders

Cholangitis, cholecystitis, cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly, jaundice, and liver tenderness.

Immune System Disorders

Drug hypersensitivity, hypersensitivity, and immune reconstitution syndrome.

Infections and Infestations

Bacterial infection, bronchopneumonia, cellulitis, folliculitis, furuncle, gastroenteritis, influenza, otitis media, perineal abscess, pharyngitis, rhinitis, sialoadenitis, sinusitis, and viral infection.

Investigations

Drug level increased, glucose tolerance decreased, and weight increased.

Metabolism and Nutrition Disorders

Decreased appetite, dehydration, diabetes mellitus, hypovitaminosis, increased appetite, lactic acidosis, lipomatosis, and obesity.

Musculoskeletal and Connective Tissue Disorders

Arthralgia, arthropathy, back pain, muscular weakness, osteoarthritis, osteonecrosis, and pain in extremity.

Neoplasms Benign, Malignant and Unspecified (incl Cysts and Polyps)

Benign neoplasm of skin, lipoma, and neoplasm.

Nervous System Disorders

Ageusia, amnesia, ataxia, balance disorder, cerebral infarction, convulsion, dizziness, dysgeusia, dyskinesia, encephalopathy, extrapyramidal disorder, facial palsy, hypertonia, migraine, neuropathy, neuropathy peripheral, somnolence, and tremor.

Psychiatric Disorders

Abnormal dreams, affect lability, agitation, anxiety, apathy, confusional state, disorientation, mood swings, nervousness, and thinking abnormal.

Renal and Urinary Disorders

Hematuria, nephritis, nephrolithiasis, renal disorder, urine abnormality, and urine odor abnormal.

Reproductive System and Breast Disorders

Breast enlargement, ejaculation disorder, erectile dysfunction, gynecomastia, and menorrhagia.

Respiratory, Thoracic and Mediastinal Disorders

Asthma, cough, dyspnea, and pulmonary edema.

Skin and Subcutaneous Tissue Disorders

Acne, alopecia, dermatitis acneiform, dermatitis allergic, dermatitis exfoliative, dry skin, eczema, hyperhidrosis, idiopathic capillaritis, nail disorder, pruritis, rash generalized, rash maculo-papular, seborrhea, skin discoloration, skin hypertrophy, skin striae, skin ulcer, and swelling face.

Vascular Disorders

Deep vein thrombosis, orthostatic hypotension, thrombophlebitis, varicose vein, and vasculitis.

Laboratory Abnormalities

The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 6 (treatment-naïve patients) and Table 7 (treatment-experienced patients).

Table 6. 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)
Variable Limit1 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
(N=333)
KALETRA
Twice Daily + TDF +FTC
(N=331)
Chemistry High        
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%
Chemistry Low          
Calculated Creatinine Clearance <50 mL/min N/A N/A N/A 2% 2%
Hematology Low        
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 7. 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)
Variable Limit1 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).

Pediatric Clinical Trial Experience

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 pre-existing cardiac abnormalities.

Laboratory Abnormalities

The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 8.

Table 8. Grade 3-4 Laboratory Abnormalities Reported in ≥ 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 > 180 U/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 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 ].

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



REPORTS OF SUSPECTED KALETRA SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Kaletra. The information is not vetted and should not be considered as verified clinical evidence.

Possible Kaletra side effects / adverse reactions in 61 year old female

Reported by a health professional (non-physician/pharmacist) from Switzerland on 2011-10-04

Patient: 61 year old female

Reactions: Dyspnoea, Hypersensitivity, Localised Oedema, Drug Interaction

Suspect drug(s):
Kaletra

Other drugs received by patient possibly interacting with the suspect drug:
Cinacalcet
    Indication: Parathyroid Disorder

Saquinavir Mesilate
    Administration route: Oral
    Indication: Asymptomatic HIV Infection

Kaletra
    Dosage: 533.2/133.3mg
    Administration route: Oral

Cinacalcet
    Dosage: 1 tablet at night for 3 nights
    Administration route: Oral
    Indication: Hyperparathyroidism
    Start date: 2009-01-01
    End date: 2009-01-01

Other drugs received by patient: Calcitriol; Moxifloxacin; Lamivudine (Epivir Hbv); Venofer; Erythropoietin Human



Possible Kaletra side effects / adverse reactions in 40 year old male

Reported by a physician from Japan on 2011-10-04

Patient: 40 year old male

Reactions: Rhabdomyolysis, Diarrhoea, Renal Failure Acute

Adverse event resulted in: hospitalization

Suspect drug(s):
Alcohol
    Indication: Product Used FOR Unknown Indication

Tenofovir Disoproxil Fumarate
    Indication: HIV Infection

Kaletra
    Indication: HIV Infection

Emtricitabine
    Indication: HIV Infection



Possible Kaletra side effects / adverse reactions in 39 year old female

Reported by a physician from United States on 2011-10-05

Patient: 39 year old female

Reactions: Thrombosis, Premature Separation of Placenta, Inflammation

Suspect drug(s):
Kaletra
    Dosage: 4 tablets daily, taken at conception
    Administration route: Oral
    Indication: Antiviral Treatment
    Start date: 2010-07-15

Epivir
    Dosage: 300 mg daily, taken at conception
    Administration route: Oral
    Indication: Antiviral Treatment
    Start date: 2010-07-15

Viread
    Dosage: 300 mg daily, taken at conception
    Administration route: Oral
    Indication: Antiviral Treatment
    Start date: 2010-07-15



See index of all Kaletra side effect reports >>

Drug label data at the top of this Page last updated: 2013-11-06

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