Kaletra Tablets
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Kaletra Tablets
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
- QT Interval Prolongation, PR Interval Prolongation [see WARNINGS AND PRECAUTIONS]
- Drug Interactions [see WARNINGS AND PRECAUTIONS]
- Pancreatitis [see WARNINGS AND PRECAUTIONS]
- Hepatotoxicity [see WARNINGS AND PRECAUTIONS]
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 |
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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 |
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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 (treatmentexperienced patients).
Table 6: Grade 3-4 Laboratory Abnormalities Reported
in ≥ 2% of Adult Antiretroviral-Naïve Patients
| Variable | Limit1 | Study 863 (48 Weeks) | Study 720 (360 Weeks) | Study 730 (48 Weeks) | ||
| KALETRA 400/100 mg Twice Daily + d4T +3TC (N = 326) |
Nelfinavir 750 mg Three Times Daily + d4T + 3TC (N = 327) |
KALETRA Twice Daily + d4T + 3TC (N = 100) |
KALETRA Once Daily + TDF +FTC (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
| 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). |
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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 preexisting 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. |
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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].
Skin and Appendages
Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome and erythema multiforme.
Read the Kaletra Tablets (lopinavir, ritonavir tablets) 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 9.
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 9 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 9: Established and Other Potentially Significant
Drug Interactions
| Concomitant Drug Class: Drug Name | Effect on Concentration of Lopinavir or Concomitant Drug | Clinical Comments |
| 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 | KALETRA should not be administered once daily in combination with nelfinavir [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. |
| 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, when coadministered 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 tablets to 500/125 mg (given as two 200/50 mg tablets and one 100/25 mg tablet) 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. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice daily co-administered with efavirenz resulted in significantly higher lopinavir plasma concentrations compared to KALETRA tablets 400/100 mg 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 | KALETRA tablets can be administered simultaneously with didanosine without food. For KALETRA oral solution, it is recommended that didanosine be administered on an empty stomach; therefore, didanosine should be given one hour before or two hours after KALETRA oral solution (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 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:
|
| Antifungals: ketoconazole*, itraconazole, voriconazole | ↑ ketoconazole ↑ itraconazole ↓ voriconazole |
High doses of ketoconazole ( > 200 mg/day) or itraconazole ( > 200 mg/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/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 co- administered antiretroviral agents. A study evaluated combination of rifampin 600 mg once daily, with KALETRA 800/200 mg twice daily or KALETRA 400/100 mg + ritonavir 300 mg twice daily. Pharmacokinetic and safety results from this study do not allow for a dose recommendation. Nine subjects (28%) experienced a ≥ 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 PHARMACOLOGYfor 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. |
| Disulfiram/metronidazole | KALETRA oral solution contains alcohol, which can produce disulfiram-like reactions when co-administered with disulfiram or other drugs that produce this reaction (e.g., metronidazole). | |
| 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/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 ritonavircontaining products have been co-administered with fluticasone propionate or budesonide. |
| Long-acting betaadrenoceptor 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:
|
| * 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.
Last reviewed on RxList: 2/5/2013
This monograph has been modified to include the generic and brand name in many instances.
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