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Kaletra Capsules

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Kaletra Capsules

Kaletra Capsules

SIDE EFFECTS

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

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.

Adult Clinical Trial 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 418, the incidence of diarrhea was greater for KALETRA Capsules once daily compared to KALETRA Capsules twice-daily (57% vs. 35% - events of all grades and probably or possibly related to drug; 16% vs. 5% - events of at least moderate severity and probably or possibly related to drug). 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.

Selected treatment-emergent clinical adverse reactions of moderate or severe intensity in greater than or equal to 2% of patients treated with combination therapy for up to 48 weeks (Studies 863, 418, and 730) and for up to 360 weeks (Study 720) are presented in Table 2 (treatment-na´ve patients); and for up to 48 weeks (Studies 888 and 802), 84 weeks (Study 957) and 144 weeks (Study 765) in Table 3 (protease inhibitor-experienced patients).

Table 2: Percentage of Adult Patients with Selected Treatment-Emergent1 Adverse Reactions of Moderate or Severe Intensity Reported in greater than or equal to 2% of Adult Antiretroviral-Na´ve Patients

  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 Daily2 + 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 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% 0% 0%
Gastrointestinal Disorders
Diarrhea 16% 17% 28% 16% 5% 17% 15%
Nausea 7% 5% 16% 9% 8% 7% 5%
Vomiting 2% 2% 6% 3% 4% 3% 4%
Abdominal Pain 4% 3% 11% 3% 3% 1% 1%
Dyspepsia 2% < 1% 6% 0% 1% 0% 0%
Flatulence 2% 1% 4% 2% 1% 1% 1%
General Disorders and Administration Site Conditions
Asthenia 4% 3% 9% 0% 0% < 1% < 1%
Infections and Infestations
Bronchitis 0% 0% 2% 0% 0% 0% < 1%
Investigations
Weight Decreased 1% < 1% 2% 0% 0% 0% < 1%
Metabolism and Nutrition Disorders
Anorexia 1% < 1% 2% < 1% 1% < 1% 1%
Musculoskeletal and Connective Tissue Disorders
Myalgia 1% 1% 2% 0% 0% 0% 0%
Nervous System Disorders
Headache 2% 2% 6% 3% 3% 2% 2%
Paresthesia 1% 1% 2% 0% 0% 0% 0%
Psychiatric Disorders
Insomnia 2% 1% 3% 0% 0% 1% 0%
Depression 1% 2% 0% 1% 0% 0% 0%
Libido Decreased < 1% < 1% 2% 0% 1% 0% < 1%
Skin and Subcutaneous Tissue Disorders
Rash 1% 2% 5% 1% 0% < 1% 1%
Vascular Disorders
Vasodilation 0% 0% 3% 0% 0% 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 3: Percentage of Adult Patients with Selected Treatment-Emergent1 Adverse Reactions of Moderate or Severe Intensity Reported in greater than or equal to 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 (includes selected adverse reactions based on investigator causality assessment and Abbott medical review) occurring in less than 2% of adult patients receiving KALETRA during Abbott clinical trials 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 4 (treatment-na´ve patients) and Table 5 (treatmentexperienced patients).

Table 4: Grade 3-4 Laboratory Abnormalities Reported in greater than or equal to 2% of Adult Antiretroviral-Na´ve 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 > 215 U/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%
Triglycerides > 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 5: 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 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)
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 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

The percentages of pediatric patients treated with combination therapy including KALETRA with Grade 3-4 laboratory abnormalities are presented in Table 6.

Table 6: 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 > 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 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 [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].

Skin and Appendages

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

Read the Kaletra Capsules (lopinavir, ritonavir capsules) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

See also CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, CLINICAL PHARMACOLOGY

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 7.

Additionally, KALETRA induces glucuronidation.

Potential for Other Drugs to Affect Lopinavir

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.

Established and Other Potentially Significant Drug Interactions

Table 7 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 CLINICAL PHARMACOLOGY for magnitude of interaction].

Table 7: Established and Other Potentially Significant Drug Interactions

Concomitant Drug Class: Drug Name Effect on Concentration of Lopinavir or Concomitant Drug Clinical Comment
HIV-1 Antiviral Agents
HIV-1 Protease Inhibitor: fosamprenavir/ritonavir ↓ amprenavir
↓ lopinavir
An 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 coadministered with KALETRA 400/100 mg twice daily [see CLINICAL PHARMACOLOGY]. KALETRA once daily has not been studied in combination with indinavir.
HIV-1 Protease Inhibitor: nelfinavir* ↑ nelfinavir
↑ M8 metabolite of nelfinavir
↓ lopinavir
Increase KALETRA dose to 533/133 mg and decrease nelfinavir dose to 1000 mg twice daily, when co-administered. KALETRA should not be administered once-daily in combination with nelfinavir [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY - Table 8 and Table 9].
HIV-1 Protease Inhibitor: ritonavir* ↑lopinavir Appropriate 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 (with no additional ritonavir), 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 ↓lopinavir AUC and Cmin KALETRA should not be administered with tipranavir (500 mg twice daily) co-administered with ritonavir (200 mg twice daily).
HIV CCR5 – Antagonist: maraviroc ↑ maraviroc Concurrent administration of maraviroc with KALETRA will increase plasma levels of maraviroc. When co-administered, patients should receive 150 mg twice daily of maraviroc. For further details see complete prescribing information for Selzentry® (maraviroc).
Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* ↓ lopinavir KALETRA dose increase is recommended in all patients [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Increasing the dose of KALETRA Capsules to 533/133 mg (given as four capsules) twice daily co-administered with efavirenz resulted in similar lopinavir concentrations compared to KALETRA Tablets 400/100 mg (given as two 200/50 mg tablets) twice daily without efavirenz. KALETRA should not be administered once-daily in combination with efavirenz or nevirapine [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].
Non-nucleoside Reverse Transcriptase Inhibitor: delavirdine ↑ lopinavir Appropriate doses of the combination with respect to safety and efficacy have not been established.
Nucleoside Reverse Transcriptase Inhibitor: didanosine   It is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA Capsules (given with food).
Nucleoside Reverse Transcriptase Inhibitor: tenofovir ↑ tenofovir KALETRA increases tenofovir concentrations. The mechanism of this interaction is unknown. Patients receiving KALETRA and tenofovir should be monitored for adverse reactions associated with tenofovir.
Nucleoside Reverse Transcriptase Inhibitors: abacavir, zidovudine ↓abacavir
↓ zidovudine
KALETRA induces glucuronidation; therefore, KALETRA has the potential to reduce zidovudine and abacavir plasma concentrations. The clinical significance of this potential interaction is unknown.
Other Agents
Antiarrhythmics: e.g. amiodarone, bepridil, lidocaine (systemic), quinidine ↑ antiarrhythmics Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when coadministered with KALETRA.
Anticancer Agents: vincristine, vinblastine, dasatinib, nilotinib ↑ anticancer agents Concentrations of these drugs may be increased when coadministered with KALETRA resulting in the potential for increased adverse events usually associated with these anticancer agents. For 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.
Anticoagulants: warfarin, rivaroxaban ↑ rivaroxaban Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. Avoid concomitant use of rivaroxaban and KALETRA. Coadministration of KALETRA and rivaroxaban is expected to result in increased exposure of rivaroxaban which may lead to risk of increased bleeding.
Anticonvulsants: carbamazepine, phenobarbital, phenytoin ↓ lopinavir
↓ phenytoin
KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly and should be used with caution. KALETRA should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. 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 ↔ valproate
Co-administration of KALETRA and lamotrigine or valproate may decrease the exposure of lamotrigine or valproate. A dose increase of the lamotrigine or valproate may be needed when coadministered with KALETRA and therapeutic concentration monitoring for lamotrigine may be indicated; particularly during dosage adjustments [see CLINICAL PHARMACOLOGY].
Antidepressant: bupropion ↓ bupropion
↓active metabolite, hydroxybupropion
Concurrent administration of bupropion with KALETRA may decrease plasma levels of both bupropion and its active metabolite (hydroxybupropion). Patients receiving KALETRA and bupropion concurrently should be monitored for an adequate clinical response to bupropion.
Antidepressant: trazodone ↑ trazodone Concomitant use of trazodone and KALETRA may increase concentrations of trazodone. Adverse reactions of nausea, dizziness, hypotension and syncope have been observed following co-administration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as ritonavir, the combination should be used with caution and a lower dose of trazodone should be considered.
Anti-infective: clarithromycin ↑ clarithromycin For patients with renal impairment, the following dosage adjustments should be considered:
  • For patients with CLCR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%.
  • For patients with CLCR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.
No dose adjustment for patients with normal renal function is necessary.
Antifungals: ketoconazole*, itraconazole, voriconazole ↑ ketoconazole
↑itraconazole
↓ voriconazole
High doses of ketoconazole (greater than 200 mg per day) or itraconazole (greater than 200 mg per day) are not recommended.
Co-administration of voriconazole with KALETRA has not been studied.
However, a study has been shown that administration of voriconazole with ritonavir 100 mg every 12 hours decreased voriconazole steady-state AUC by an average of 39%; therefore, co-administration of KALETRA and voriconazole may result in decreased voriconazole concentrations and the potential for decreased voriconazole effectiveness and should be avoided, unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Otherwise, alternative antifungal therapies should be considered in these patients.
Anti-gout: colchicine ↑ colchicine Patients with renal or hepatic impairment should not be given colchicine with KALETRA.
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)-coadministration of colchicine in patients on KALETRA:
Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day).
Antimycobacterial: rifabutin* ↑ rifabutin and rifabutin metabolite Dosage reduction of rifabutin by at least 75% of the usual dose of 300 mg per 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.
Antimycobacterial: rifampin ↓lopinavir May lead to loss of virologic response and possible resistance to KALETRA or to the class of protease inhibitors or other coadministered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg plus ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a greater than or equal to grade 2 increase in ALT/AST, of which seven (21%) prematurely discontinued study per protocol. Based on the study design, it is not possible to determine whether the frequency or magnitude of the ALT/AST elevations observed is higher than what would be seen with rifampin alone [see CLINICAL PHARMACOLOGY for magnitude of interaction].
Antiparasitic: atovaquone ↓ atovaquone Clinical significance is unknown; however, increase in atovaquone doses may be needed.
Benzodiazepines: parenterally administered midazolam ↑ midazolam Midazolam is extensively metabolized by CYP3A4. Increases in the concentration of midazolam are expected to be significantly higher with oral than parenteral administration. Therefore, KALETRA should not be given with orally administered midazolam [see CONTRAINDICATIONS]. 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 estradiol Because 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.
Corticosteroids (systemic): e.g. budesonide, dexamethasone, prednisone ↓ lopinavir
↑glucocorticoids
Use with caution. KALETRA may be less effective due to
    decreased lopinavir plasma concentrations in patients taking these agents concomitantly.
Concomitant use may result in increased steroid concentrations and reduced serum cortisol concentrations. Concomitant use of glucocorticoids that are metabolized by CYP3A, particularly for long-term use, should consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. Concomitant use may increase the risk for development of systemic corticosteroid effects including Cushing's syndrome and adrenal suppression.
Dihydropyridine Calcium Channel Blockers: e.g. felodipine, nifedipine, nicardipine ↑dihydropyridine calcium channel blockers Caution is warranted and clinical monitoring of patients is recommended.
Endothelin Receptor Antagonists: bosentan ↑bosentan Co-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.
HCV-Protease Inhibitor: boceprevir ↓ lopinavir
↓ boceprevir
↓ ritonavir
It is not recommended to co-administer KALETRA and boceprevir. Concomitant administration of KALETRA and boceprevir reduced boceprevir, lopinavir and ritonavir steady-state exposures [see CLINICAL PHARMACOLOGY].
HCV-Protease Inhibitor: telaprevir ↓telaprevir
↔lopinavir
It is not recommended to co-administer KALETRA and telaprevir.
Concomitant administration of KALETRA and telaprevir reduced steady-state telaprevir exposure, while the steady-state lopinavir exposure was not affected [see CLINICAL PHARMACOLOGY].
HMG-CoA Reductase Inhibitors: atorvastatin, rosuvastatin ↑ atorvastatin
↑rosuvastatin
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 per day. See Drugs with No Observed or Predicted Interactions with KALETRA and CLINICAL PHARMACOLOGY for drug interaction data with other HMG-CoA reductase inhibitors.
Immunosuppressants: e.g. cyclosporine, tacrolimus, sirolimus ↑ immunosuppressants Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA.
Inhaled or Intranasal Steroids: e.g. fluticasone, budesonide ↑ glucocorticoids Concomitant use of KALETRA and fluticasone or other glucocorticoids that are metabolized by CYP3A is not recommended unless the potential benefit of treatment outweighs the risk of systemic corticosteroid effects. Concomitant use may result in increased steroid concentrations and reduce serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during postmarketing use in patients when certain ritonavir-containing products have been co-administered with fluticasone propionate or budesonide.
Long-acting Beta- Adrenoceptor Agonist: salmeterol ↑salmeterol Concurrent 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
↑ fentanyl
Dosage of methadone may need to be increased when coadministered with KALETRA.
Concentrations of fentanyl are expected to increase. 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
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 is expected to substantially increase their concentrations and 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 when used for the treatment of pulmonary arterial hypertension (PAH) because a safe and effective dose has not been established when used with KALETRA [see CONTRAINDICATIONS].
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 hours
Use with increased monitoring for adverse events.
* see CLINICAL PHARMACOLOGY for magnitude of interaction.

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), pitavastatin, pravastatin, stavudine, lamivudine, omeprazole, raltegravir or ranitidine.

Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

Read the Kaletra Capsules Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 2/6/2013
This monograph has been modified to include the generic and brand name in many instances.

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