Kaletra Side Effects

Please note - some side effects for Kaletra may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Kaletra - for the Consumer

Kaletra

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Kaletra:

Diarrhea; headache; mild stomach pain or upset; nausea; tiredness; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Kaletra:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; dizziness or light-headedness; fainting; fast, slow, or irregular heartbeat; fever, chills, or sore throat; loss of consciousness; red, swollen, blistered, or peeling skin; severe or persistent nausea, vomiting, or stomach pain; symptoms of high blood sugar (eg, confusion; flushed face; fruit-like breath odor; increased thirst, hunger, or urination; unusual drowsiness); symptoms of liver problems (eg, yellowing of the skin or eyes, dark urine, pale stools, loss of appetite, unusual fatigue); unusual bleeding or bruising.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Kaletra Capsules

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Kaletra Capsules:

Abnormal stools; chills; depression; diarrhea; fever; gas; headache; indigestion; loss of appetite; muscle pain; nausea; pain; prickling or tingling sensation on the skin; shift in body fat to stomach and upper body; sleeplessness; stomach pain; tiredness; vomiting; weakness; weight loss.

Seek medical attention right away if any of these SEVERE side effects occur when using Kaletra Capsules:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blood in stool; dark urine; drowsiness; fatigue; flushed face; increased blood sugar; increased thirst or urination; persistent fever; severe stomach pain with nausea and vomiting; unusual bleeding or bruising; unusual hunger; vision changes; yellowing of the skin or eyes.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

Kaletra Solution

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Kaletra Solution:

Diarrhea; headache; mild stomach pain or upset; nausea; tiredness; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur when using Kaletra Solution:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); chest pain; dizziness or light-headedness; fainting; fast, slow, or irregular heartbeat; fever, chills, or sore throat; loss of consciousness; red, swollen, blistered, or peeling skin; severe or persistent nausea, vomiting, or stomach pain; symptoms of high blood sugar (eg, confusion; flushed face; fruit-like breath odor; increased thirst, hunger, or urination; unusual drowsiness); symptoms of liver problems (eg, yellowing of the skin or eyes, dark urine, pale stools, loss of appetite, unusual fatigue); unusual bleeding or bruising.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Kaletra Side Effects - for the Professional

Kaletra

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

• PR Interval Prolongation, QT Interval Prolongation [see Warnings and Precautions (5.6, 5.7)]
• Drug Interactions [see Warnings and Precautions (5.1)]
• Pancreatitis [see Warnings and Precautions (5.3)]
• Hepatotoxicity [see Warnings and Precautions (5.4)]

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 practice.

Adults - Clinical Trials Experience

The safety profile of Kaletra in adults is primarily based on 1964 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 Patients - Clinical Trials 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 (5.9)].

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 (5.6,5.7)].

Skin and Appendages
Toxic epidermal necrolysis (TEN), Stevens Johnson Syndrome and erythema multiforme.

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Kaletra Oral Solution

Adults

Treatment-Emergent Adverse Events

Kaletra has been studied in 891 patients as combination therapy in Phase I/II and Phase III clinical trials. The most common adverse event associated with Kaletra therapy was diarrhea, which was generally of mild to moderate severity. Rates of discontinuation of randomized therapy due to adverse events were 5.8% in Kaletra-treated and 4.9% in nelfinavir-treated patients in Study 863. The incidence of diarrhea was greater for Kaletra once-daily compared to Kaletra twice-daily in Study 418.

Treatment-Emergent clinical adverse events of moderate or severe intensity in ≥ 2% of patients treated with combination therapy for up to 48 weeks (Phase III) and for up to 360 weeks (Phase I/II) are presented in Table 12. For other information regarding observed or potentially serious adverse events, please see WARNINGS and PRECAUTIONS.

Table 12. Percentage of Patients with Selected Treatment-Emergent1 Adverse Events of Moderate or Severe Intensity Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients

	Study 863 (48 Weeks)		Study 418 (48 Weeks)		Study 720 (360 Weeks)
	Kaletra 400/100 mg BID + d4T + 3TC (N=326)	Nelfinavir 750 mg TID + d4T + 3TC (N=327)	Kaletra 800/200 mg QD + TDF + FTC (N=115)	Kaletra 400/100 mg BID + TDF + FTC (N=75)	Kaletra BID2 + d4T + 3TC (N=100)
1   Includes adverse events of possible, probable, or unknown relationship to study drug. 2   Includes adverse event data from dose group I (200/100 mg BID [N=16] and 400/100 mg BID [N=16]) and dose group II (400/100 mg BID [N=35] and 400/200 mg BID [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.
Body as a Whole
Abdominal Pain	4%	3%	3%	3%	11%
Asthenia	4%	3%	0%	0%	9%
Headache	2%	2%	3%	3%	6%
Cardiovascular System
Vein distended	0%	0%	0%	0%	3%
Digestive System
Anorexia	1%	<1%	<1%	1%	2%
Diarrhea	16%	17%	16%	5%	28%
Dyspepsia	2%	<1%	0%	1%	6%
Flatulence	2%	1%	2%	1%	4%
Nausea	7%	5%	9%	8%	16%
Vomiting	2%	2%	3%	4%	6%
Metabolic and Nutritional
Weight Loss	1%	<1%	0%	0%	2%
Musculoskeletal
Myalgia	1%	1%	0%	0%	2%
Nervous System
Depression	1%	2%	1%	0%	0%
Insomnia	2%	1%	0%	0%	3%
Libido decreased	<1%	<1%	0%	1%	2%
Paresthesia	1%	1%	0%	0%	2%
Respiratory
Bronchitis	0%	0%	0%	0%	2%
Skin and Appendages
Rash	1%	2%	1%	0%	5%
Urogenital
Hypogonadism male	0%	0%	0%	0%	2%

Table 13. Percentage of Patients with Selected Treatment-Emergent1 Adverse Events 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)
	Kaletra 400/100 mg BID + NVP + NRTIs (N=148)	Investigator-selected protease inhibitor(s) + NVP + NRTIs (N=140)	Kaletra BID + NNRTI + NRTIs (N=127)
1   Includes adverse events of possible,probable, or unknown relationship to study drug. 2  Includes adverse event data from patients receiving 400/100 mg BID (n=29) or 533/133 mg BID (n=28) for 84 weeks. Patients receiving Kaletra in combination with NRTIs and efavirenz. 3   Includes adverse event data from patients receiving 400/100 mg BID (n=36) or 400/200 mg BID (n=34) for 144 weeks. Patients received Kaletra in combination with NRTIs and nevirapine.
Body as a Whole
Abdominal Pain	2%	2%	4%
Asthenia	3%	6%	9%
Chills	2%	0%	0%
Fever	2%	1%	2%
Headache	2%	3%	2%
Cardiovascular
Hypertension	0%	0%	2%
Digestive System
Anorexia	1%	3%	0%
Diarrhea	7%	9%	23%
Dyspepsia	1%	1%	2%
Dysphagia	2%	1%	0%
Flatulence	1%	2%	2%
Nausea	7%	16%	5%
Vomiting	4%	12%	2%
Metabolic and Nutritional
Weight loss	0%	1%	3%
Musculoskeletal
Myalgia	1%	1%	2%
Nervous System
Depression	1%	2%	2%
Insomnia	0%	2%	2%
Paresthesia	1%	0%	2%
Skin and Appendages
Rash	2%	1%	2%

Treatment-emergent adverse events occurring in less than 2% of adult patients receiving Kaletra in all phase II/III clinical trials and considered at least possibly related or of unknown relationship to treatment with Kaletra and of at least moderate intensity are listed below by body system.

Body as a Whole

Allergic reaction, back pain, chest pain, chest pain substernal, cyst, drug interaction, drug level increased, face edema, flu syndrome, hypertrophy, infection bacterial, malaise, neoplasm, and viral infection.

Cardiovascular System

Atrial fibrillation, cerebral infarct, deep thrombophlebitis, deep vein thrombosis, migraine, myocardial infarct, palpitation, postural hypotension, thrombophlebitis, varicose vein, and vasculitis.

Digestive System

Cholangitis, cholecystitis, constipation, dry mouth, enteritis, enterocolitis, eructation, esophagitis, fecal incontinence, gastritis, gastroenteritis, hemorrhagic colitis, hepatitis, hepatomegaly, increased appetite, jaundice, liver fatty deposit, liver tenderness, mouth ulceration, pancreatitis, periodontitis, sialadenitis, stomatitis, and ulcerative stomatitis.

Endocrine System

Cushing's syndrome, diabetes mellitus, and hypothyroidism.

Hemic and Lymphatic System

Anemia, leukopenia, and lymphadenopathy.

Metabolic and Nutritional Disorders

Avitaminosis, dehydration, edema, glucose tolerance decreased, lactic acidosis, obesity, peripheral edema, and weight gain.

Musculoskeletal System

Arthralgia, arthrosis, bone necrosis, joint disorder, and myasthenia.

Nervous System

Abnormal dreams, agitation, amnesia, anxiety, apathy, ataxia, confusion, convulsion, dizziness, dyskinesia, emotional lability, encephalopathy, extrapyramidal syndrome, facial paralysis, hypertonia, nervousness, neuropathy, peripheral neuritis, somnolence, thinking abnormal, tremor, and vertigo.

Respiratory System

Asthma, cough increased, dyspnea, lung edema, pharyngitis, rhinitis, and sinusitis.

Skin and Appendages

Acne, alopecia, dry skin, eczema, exfoliative dermatitis, furunculosis, maculopapular rash, nail disorder, pruritis, seborrhea, skin benign neoplasm, skin discoloration, skin striae, skin ulcer, and sweating.

Special Senses

Abnormal vision, eye disorder, otitis media, taste loss, taste perversion, and tinnitus.

Urogenital System

Abnormal ejaculation, amenorrhea, breast enlargement, gynecomastia, impotence, kidney calculus, nephritis, and urine abnormality.

Post-marketing Experience

The following adverse reactions have been reported during post-marketing 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.

Cardiovascular

Bradyarrhythmias.

Skin and Appendages

Stevens Johnson Syndrome and erythema multiforme.

Laboratory Abnormalities

The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 14 and Table 15.

Table 14. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Antiretroviral-Naïve Patients

		Study 863 (48 Weeks)		Study 418 (48 Weeks)		Study 720 (360 Weeks)
Variable	Limit1	Kaletra 400/100 mg BID + d4T +3TC (N=326)	Nelfinavir 750 mg TID + d4T + 3TC (N=327)	Kaletra 800/200 mg QD + TDF + FTC (N=115)	Kaletra 400/100 mg BID + TDF + FTC (N=75)	Kaletra BID + d4T + 3TC (N=100)
1   ULN = upper limit of the normal range; N/A = Not Applicable.
Chemistry	High
Glucose	>250 mg/dL	2%	2%	3%	1%	4%
Uric Acid	>12 mg/dL	2%	2%	0%	3%	5%
SGOT/ AST	>180 U/L	2%	4%	5%	3%	10%
SGPT/ ALT	>215 U/L	4%	4%	4%	3%	11%
GGT	>300 U/L	N/A	N/A	N/A	N/A	10%
Total Cholesterol	>300 mg/dL	9%	5%	3%	3%	27%
Triglycerides	>750 mg/dL	9%	1%	5%	4%	29%
Amylase	>2 x ULN	3%	2%	7%	5%	4%
Hematology	Low
Neutrophils	0.75 x 109/L	1%	3%	5%	1%	5%

Table 15. 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)
Variable	Limit1	Kaletra 400/100 mg BID + NVP + NRTIs (N=148)	Investigator-selected protease inhibitor(s) + NVP + NRTIs (N=140)	Kaletra BID + NNRTI + NRTIs (N=127)
1   ULN = upper limit of the normal range; N/A = Not Applicable. 2   Includes clinical laboratory data from patients receiving 400/100 mg BID (n=29) or 533/133 mg BID (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 BID (n=36) or 400/200 mg BID (n=34) for 144 weeks. Patients received Kaletra in combination with NRTIs and nevirapine.
Chemistry	High
Glucose	>250 mg/dL	1%	2%	5%
Total Bilirubin	>3.48 mg/dL	1%	3%	1%
SGOT/AST	>180 U/L	5%	11%	8%
SGPT/ALT	>215 U/L	6%	13%	10%
GGT	>300 U/L	N/A	N/A	29%
Total Cholesterol	>300 mg/dL	20%	21%	39%
Triglycerides	>750 mg/dL	25%	21%	36%
Amylase	>2 x ULN	4%	8%	8%
Chemistry	Low
Inorganic Phosphorus	<1.5 mg/dL	1%	0%	2%
Hematology	Low
Neutrophils	0.75 x 109/L	1%	2%	4%

Pediatrics

Treatment-Emergent Adverse Events

Kaletra has been studied in 100 pediatric patients 6 months to 12 years of age. The adverse event profile seen during a clinical trial was similar to that for adult patients.

Taste aversion, vomiting, and diarrhea were the most commonly reported drug related adverse events of any severity in pediatric patients treated with combination therapy including Kaletra for up to 48 weeks in Study 940. A total of 8 children experienced moderate or severe adverse events at least possibly related to Kaletra. Rash (reported in 3%) was the only drug-related clinical adverse event of moderate to severe intensity observed in ≥ 2% of children enrolled.

Laboratory Abnormalities

The percentages of pediatric patients treated with combination therapy including Kaletra with Grade 3-4 laboratory abnormalities are presented in Table 16.

Table 16. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% Pediatric Patients

Variable	Limit1	Kaletra BID+ RTIs (N = 100)
1   ULN = upper limit of the normal range. 2   Subjects with Grade 3-4 amylase confirmed by elevations in pancreatic amylase.
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%

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Side Effects by Body System - for Healthcare Professionals

General

Diarrhea, usually of mild to moderate severity, is the most common side effect associated with lopinavir-ritonavir. During 48 weeks of one study, diarrhea (any severity) occurred in 60% of patients receiving lopinavir-ritonavir tablets once a day compared to 57% receiving the tablets twice a day. In the same trial, treatment was discontinued in 4.8% of patients receiving lopinavir-ritonavir tablets once a day as compared to 3% receiving twice daily dosing due to any adverse effects. During 48 weeks of a different study, diarrhea (any severity) occurred in 50% of patients receiving lopinavir-ritonavir tablets once a day compared to 39% receiving the tablets twice a day. Moderate or severe drug-related diarrhea reported in this study occurred in 14% of patients receiving the once daily regimen as compared to 11% receiving the twice daily regimen. In the same trial, treatment was discontinued due to any side effect in 4.3% of patients receiving lopinavir-ritonavir tablets once a day as compared to 7% receiving twice daily dosing. During another clinical trial, discontinuations due to side effects were observed in 3.4% of patients receiving lopinavir-ritonavir versus 3.7% receiving comparator.

Cardiovascular

Cardiovascular side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included hypertension (up to 3%), distended veins (3%), and angina pectoris, atrial fibrillation, atrioventricular (AV) block, myocardial infarction, cerebral infarction, deep vein thrombosis, chest pain, hypertension, palpitation, postural hypotension, tricuspid valve incompetence, thrombophlebitis, varicose vein, and vasculitis in less than 2% of adult patients. Sinus arrest and bradycardia-tachycardia syndrome have also been reported. Bradyarrhythmias, first-degree AV block, second-degree AV block, third-degree AV block, QTc interval prolongation, and torsades de pointes have been reported during postmarketing experience.

Dermatologic

Dermatologic side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included rash (up to 5%) and acne, alopecia, dry skin, eczema, acneiform dermatitis, allergic dermatitis, exfoliative dermatitis, cellulitis, folliculitis, furunculosis, lipomatosis, idiopathic capillaritis, maculopapular rash, generalized rash, nail disorder, seborrhea, pruritus, benign skin neoplasm, skin discoloration, skin hypertrophy, skin ulcer, skin striae, swelling face, and hyperhidrosis in less than 2% of patients. Acute generalized exanthematous pustulosis has also been reported. Toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme have been reported during postmarketing experience.

Endocrine

Episodes of hyperglycemia, new onset diabetes mellitus, and exacerbation of preexisting diabetes mellitus have been reported during postmarketing studies in HIV-infected patients receiving protease inhibitors. In some cases, diabetic ketoacidosis has occurred. No causal relationship has been established. Careful monitoring of blood glucose levels should be done and either initiation or dose adjustments of insulin or oral hypoglycemic agents may be needed.

Endocrine side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included Cushing's syndrome, diabetes mellitus, and hypothyroidism in less than 2% of patients. Ketoacidosis has been reported.

Gastrointestinal

Pancreatitis, including fatalities, has occurred in patients receiving lopinavir-ritonavir therapy, including those who developed hypertriglyceridemia. Although a causal relationship has not been established, marked triglyceride elevation is a risk factor for the development of pancreatitis. Patients who experience signs or symptoms of pancreatitis should be evaluated and lopinavir-ritonavir should be stopped if a diagnosis of pancreatitis is made.

Gastrointestinal side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included diarrhea (7% to 28%), nausea (3% to 16%), vomiting (2% to 6%), abdominal pain (up to 11%), abnormal stools (up to 6%), dyspepsia (up to 6%), dysphagia (up to 2%), flatulence (1% to 4%), upper abdominal pain (up to 2%), and anorexia (up to 2%). Cholangitis, cholecystitis, abdominal discomfort, abdominal distention, lower abdomen pain, constipation, duodenitis, dry mouth, enterocolitis, eructation, esophagitis, fecal incontinence, gastric disorder, gastric ulcer, gastritis, gastroesophageal reflux disease, hemorrhoids, gastroenteritis, hemorrhagic enterocolitis, increased and decreased appetite, pancreatitis, periodontitis, rectal hemorrhage, sialadenitis, stomatitis, stomach discomfort, and ulcerative stomatitis have been reported in less than 2% of patients.

Genitourinary

Genitourinary side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included hypogonadism (2%) and ejaculation disorder, breast enlargement, gynecomastia, hematuria, impotence, menorrhagia, abnormal urine odor, and urine abnormality in less than 2% of patients.

Hematologic

Hematologic side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included decreased neutrophil counts (up to 5%), decreased hemoglobin (up to 2%), and anemia, leukopenia, splenomegaly, and lymphadenopathy in less than 2% of patients. Hemolytic anemia and spontaneous bleeding in hemophiliacs have been reported rarely.

Hepatic

Hepatic side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included elevated AST (1% to 10%), ALT (1% to 11%), and GGT (up to 29%) levels, and jaundice, fatty liver deposit, cytolytic hepatitis, hepatic steatosis, hepatitis, hepatomegaly, and liver tenderness (less than 2% each). Hepatic failure has also been reported.

Lopinavir-ritonavir is primarily metabolized by the liver. Caution should be used when administering this drug to patients with hepatic impairment because lopinavir levels may be increased. Patients with underlying hepatitis B or C or marked elevations in transaminases before initiation of therapy may be at an increased risk for developing further transaminase elevations or liver decompensation. There have been reports of hepatic dysfunction with some cases leading to death. A causal relationship with lopinavir-ritonavir administration has not been proven since these cases have generally occurred in patients with advanced HIV who also had underlying chronic hepatitis or cirrhosis and were taking multiple concomitant medications.

Metabolic

Metabolic side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included elevations in amylase (3% to 8%), bilirubin (1% to 3%), blood glucose (up to 5%), creatine phosphokinase (up to 5%), total cholesterol (3% to 39%), triglycerides (3% to 36%), uric acid (up to 5%), and lipase (up to 5%), decreased phosphorus levels (up to 2%), and weight loss (up to 3%). Avitaminosis, hypovitaminosis, dehydration, decreased glucose tolerance, lactic acidosis, obesity, and weight gain have been reported in less than 2% of patients. Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement, peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. Redistribution/accumulation of body fat has been reported during postmarketing experience.

Musculoskeletal

Musculoskeletal side effects have included myalgia (up to 2%) and arthralgia, arthropathy, back pain, arthrosis, muscular weakness, osteonecrosis, joint disorder, osteoarthritis, extremity pain, and myasthenia in less than 2% of patients receiving lopinavir-ritonavir with other antiretroviral agents.

Nervous system

Nervous system side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included headache (up to 7%), insomnia (up to 3%), decreased libido (up to 2%), and paresthesia (up to 2%). Amnesia, ataxia, balance disorder, convulsion, dizziness, dyskinesia, encephalopathy, facial paralysis, hypertonia, migraine, neuropathy, peripheral neuropathy, peripheral neuritis, somnolence, hyperacusis, tinnitus, tremor, extrapyramidal syndrome, ageusia, dysgeusia, and vertigo have been reported in less than 2%.

Psychiatric

Psychiatric side effects have included depression (up to 3%), and abnormal dreams, affect lability, agitation, anxiety, apathy, confusional state, disorientation, mood swings, nervousness, and abnormal thinking in less than 2% of patients.

Ocular

Ocular side effects have included visual disturbance and eye disorder in less than 2% of patients receiving lopinavir-ritonavir with other antiretroviral agents.

Other

Other side effects associated with lopinavir-ritonavir in combination with other antiretroviral agents have included asthenia (up to 9%), pyrexia (up to 2%), chills (up to 2%), and generalized pain, back pain, back and abdomen enlargement, chest pain, cyst, edema, peripheral edema, fatigue, face edema, flu syndrome, hypertrophy, malaise, lymphadenopathy, drug interaction, and increased drug level in less than 2% of patients. Elevated creatine kinase has also been reported.

Immunologic

Immunologic side effects have included immune reconstitution syndrome, infection (bacterial and viral), influenza, otitis media, and perineal abscess (less than 2%).

Oncologic

Oncologic side effects have included neoplasm and lipoma in less than 2% of patients when lopinavir-ritonavir was administered with other antiretroviral agents.

Renal

Renal side effects have included decreased calculated creatinine clearance (up to 3%) and kidney calculus, nephritis, and renal disorder in less than 2% of patients when lopinavir-ritonavir was administered with other antiretroviral agents.

Respiratory

Respiratory side effects have included bronchitis (up to 2%) and asthma, bronchopneumonia, dyspnea, lung edema, pharyngitis, rhinitis, increased cough, and sinusitis in less than 2% of patients receiving lopinavir-ritonavir with other antiretroviral agents.

Hypersensitivity

Hypersensitivity side effects have included drug hypersensitivity and hypersensitivity in less than 2% of patients receiving lopinavir-ritonavir in combination with other antiretroviral agents. At least one case of a severe skin and mucous hypersensitivity reaction with transient multiorgan failure has been reported.

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