Kaletra Tablets
SIDE EFFECTS
The following adverse reactions are discussed in greater detail in other sections of the labeling.
- 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 practice.
Adults - Clinical Trials Experience
The safety profile of KALETRA in adults is primarily based on 891 HIV-1 infected patients in clinical trials.
The most common adverse reaction was diarrhea, which was generally of mild to moderate severity. The incidence of diarrhea was greater for KALETRA capsules once-daily compared to KALETRA capsules twice-daily in Study 418 [See Table 4]. Rates of discontinuation of randomized therapy due to adverse reactions were 3.4% in KALETRA-treated and 3.7% in nelfinavir-treated patients in Study 863.
Treatment-emergent clinical adverse reactions of moderate or severe intensity in ≥ 2% of patients treated with combination therapy for up to 48 weeks (Study 863 and 418) and for up to 360 weeks (Study 720) are presented in Table 4 (treatment-naive patients) and 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-Naive Patients
| Study 863 (48 Weeks) |
Study 418 (48 Weeks) |
Study 720 (360 Weeks) |
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| 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) |
|
| 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% |
| DigestiveSystem | |||||
| Diarrhea | 16% | 17% | 16% | 5% | 28% |
| Nausea | 7% | 5% | 9% | 8% | 16% |
| Vomiting | 2% | 2% | 3% | 4% | 6% |
| Dyspepsia | 2% | < 1% | 0% | 1% | 6% |
| Flatulence | 2% | 1% | 2% | 1% | 4% |
| Anorexia | 1% | < 1% | < 1% | 1% | 2% |
| Metabolic and Nutritional | |||||
| Weight loss | 1% | < 1% | 0% | 0% | 2% |
| Musculoskeletal | |||||
| Myalgia | 1% | 1% | 0% | 0% | 2% |
| Nervous System | |||||
| Insomnia | 2% | 1% | 0% | 0% | 3% |
| Paresthesia | 1% | 1% | 0% | 0% | 2% |
| Depression | 1% | 2% | 1% | 0% | 0% |
| Libido decreased | < 1% | < 1% | 0% | 1% | 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% |
| Amenorrhea | 0% | 0% | 4.5% | 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 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. 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) | Study957 2 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) |
|
| Body as a Whole | |||
| Asthenia | 3% | 6% | 9% |
| Abdominal Pain | 2% | 2% | 4% |
| Fever | 2% | 1% | 2% |
| Headache | 2% | 3% | 2% |
| Chills | 2% | 0% | 0% |
| Cardiovascular | |||
| Hypertension | 0% | 0% | 2% |
| Digestive System | |||
| Diarrhea | 7% | 9% | 23% |
| Nausea | 7% | 16% | 5% |
| Vomiting | 4% | 12% | 2% |
| Dyspepsia | 1% | 1% | 2% |
| Flatulence | 1% | 2% | 2% |
| Dysphagia | 2% | 1% | 0% |
| Anorexia | 1% | 3% | 0% |
| Metabolic and Nutritional | |||
| Weight loss | 0% | 1% | 3% |
| Musculoskeletal | |||
| Myalgia | 1% | 1% | 2% |
| Nervous System | |||
| Depression | 1% | 2% | 2% |
| Paresthesia | 1% | 0% | 2% |
| Insomnia | 0% | 2% | 2% |
| Skin and Appendages | |||
| Rash | 2% | 1% | 2% |
| 1 Includes adverse reactions of
possible or probable relationship to study drug. 2 Includes adverse reaction 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 adverse reaction 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. 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 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, breast enlargement, gynecomastia, impotence, kidney calculus, nephritis, and urine abnormality.
Laboratory Abnormalities
The percentages of adult patients treated with combination therapy with Grade 3-4 laboratory abnormalities are presented in Table 6 (treatment-naive patients) and Table 7 (treatment-experienced patients).
Table 6. Grade 3-4 Laboratory Abnormalities Reported in ≥ 2%
of Adult Antiretroviral-naive Patients
| Study 863 (48 Weeks) | Study 418 (48 Weeks) | Study 720 (360 Weeks) |
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| 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 BID2 + d4T + 3TC (N = 100) |
|
| Chemistry | High | |||||
| Glucose | > 250mg/dL | 2% | 2% | 3% | 1% | 4% |
| Uric Acid | > 12mg/dL | 2% | 2% | 0% | 3% | 5% |
| SGOT/AST | > 180U/L | 2% | 4% | 5% | 3% | 10% |
| SGPT/ALT | > 215U/L | 4% | 4% | 4% | 3% | 11% |
| GGT | > 300U/L | N/A | N/A | N/A | N/A | 10% |
| Total Cholesterol | > 300mg/dL | 9% | 5% | 3% | 3% | 27% |
| Triglycerides | > 750mg/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% |
| 1 ULN = upper limit of the normal
range; N/A = Not Applicable. 2 Includes adverse event data ID [N = 16] and 400/100 mg BID from dose group I (200/100 mg dose group II (400/100 mg BID [N = 35] and 400/200 mg BID [N severe nausea of probable/possiblerred at a higher rate in the to KALETRA arm compared to the 400/100 mg dose arm in group II. |
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Table 7. Grade 3-4 bnormalities Reported in Laboratory Adult
Protease Inhibitor 2% of experienced Patients
| Study 888 (48 Weeks) | Study 9572 and Study 7653 (84-144 Weeks) |
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| 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) |
| Chemistry | High | |||
| Glucose | > 250mg/dL | 1% | 2% | 5% |
| Total Bilirubin | > 3.48mg/dL | 1% | 3% | 1% |
| SGOT/AST | > 180U/L | 5% | 11% | 8% |
| SGPT/ALT | > 215U/L | 6% | 13% | 10% |
| GGT | > 300U/L | N/A | N/A | 29% |
| Total Cholesterol | > 300mg/dL | 20% | 21% | 39% |
| Triglycerides | > 750mg/dL | 25% | 21% | 36% |
| Amylase | > 2 x ULN | |||
| Chemistry | Low | |||
| Inorganic Phosphorus | < 1.5mg/dL | 4% | 8% | 8% |
| Hematology | Low | 1% | 0% | 2% |
| Neutrophils | < 0.75 x10 9/L | 1% | 2% | 4% |
| 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. |
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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 | Limit 1 | KALETRA BID+ 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 | < 509/L x 10 | 4% |
| Neutrophils | < 0.40 9/L x 10 | 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.
Skin and Appendages
Stevens Johnson Syndrome and erythema multiforme.
DRUG INTERACTIONS
See also CONTRAINDICATIONS, 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 Comment |
|
HIV-1 Antiviral Agents
|
||
| Non-nucleoside Reverse Transcriptase Inhibitors: efavirenz*, nevirapine* |
↓ lopinavir | KALETRA dose increase may be warranted in some patients [See DOSAGE
AND ADMINISTRATION and CLINICAL PHARMACOLOGY]. Increasing the dose of KALETRA tablets to 600/150 mg (given as three 200/50 mg tablets) twice-daily coadministered with efavirenz resulted in significantly higher lopinavir plasma concentrations approximately 35% and ritonavir concentrations approximately 56% to 92% 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 Inhibitor: 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. |
| HIV-1 Protease Inhibitor: amprenavir* |
↑ amprenavir ↓ lopinavir |
KALETRA should not be administered once-daily in combination with amprenavir. [See DOSAGE AND ADMINISTRATION ]. |
| 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 BID, when coadministered with KALETRA 400/100 mg BID [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 BID, when co-administered with KALETRA 400/100 mg BID. 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 twicedaily). |
|
Other Agents
|
||
| Antiarrhythmics: amiodarone, bepridil, lidocaine (systemic), and quinidine |
↑ antiarrhythmics | Caution is warranted and therapeutic concentration monitoring (if available) is recommended for antiarrhythmics when co-administered with KALETRA. |
| Anticoagulant: warfarin |
Concentrations of warfarin may be affected. It is recommended that INR (international normalized ratio) be monitored. | |
| Anticonvulsants: carbamazepine, phenobarbital, phenytoin |
↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. KALETRA should not be administered once-daily in combination with carbamazepine, phenobarbital, or phenytoin. |
| 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 effect is unknown. |
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, administration of voriconazole with ritonavir 400 mg every 12 hours decreased voriconazole steady-state AUC by an average of 82%. The effect of lower ritonavir doses on voriconazole is not known at this time. Until data are available, voriconazole should not be administered to patients receiving KALETRA. |
| 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 QD, with KALETRA 800/200 mg BID or KALETRA 400/100 mg +ritonavir 300 mg BID. 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 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 coadministered with parenteral midazolam, close clinical monitoring for respiratory depression and/or prolonged sedation should be exercised and dosage adjustment should be considered. |
| Calcium Channel Blockers, dihydropyridine: e.g., felodipine, nifedipine, nicardipine |
↑ dihydropyridine calcium channel blockers |
Caution is warranted and clinical monitoring of patients is recommended. |
| Corticosteroid: dexamethasone | ↓ lopinavir | Use with caution. KALETRA may be less effective due to decreased lopinavir plasma concentrations in patients taking these agents concomitantly. |
| 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). | |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil |
↑ sildenafil ↑ tadalafil ↑ vardenafil |
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 associated adverse reactions including hypotension, syncope, visual changes and prolonged erection. It is recommended not to exceed the following doses:
|
| HMG-CoA Reductase Inhibitors: atorvastatin* rosuvastatin |
↑ atorvastatin ↑ rosuvastatin |
Use lowest possible dose of atorvastatin or rosuvastatin with careful monitoring, or consider other HMG-CoA reductase inhibitors such as pravastatin or fluvastatin in combination with KALETRA. |
| Immunosuppressants: cyclosporine, tacrolimus, rapamycin |
↑ immunosuppressants | Therapeutic concentration monitoring is recommended for immunosuppressant agents when co-administered with KALETRA. |
| Inhaled Steroid: fluticasone |
↑ fluticasone | Concomitant use of fluticasone propionate and KALETRA may increase plasma concentrations of fluticasone propionate, resulting in significantly reduced serum cortisol concentrations. Systemic corticosteroid effects including Cushing's syndrome and adrenal suppression have been reported during post-marketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Co-administration of fluticasone propionate and KALETRA is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effect. |
| Narcotic Analgesic: methadone* |
↓ methadone | Dosage of methadone may need to be increased when coadministered with KALETRA. |
| 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. |
| * See CLINICAL PHARMACOLOGY for Magnitude of Interaction. | ||
Drugs with No Observed or Predicted Interactions with KALETRA
Drug interaction studies reveal no clinically significant interaction between KALETRA and desipramine (CYP2D6 probe), pravastatin, stavudine, lamivudine, omeprazole or ranitidine.
Based on known metabolic profiles, clinically significant drug interactions are not expected between KALETRA and fluvastatin, dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.
DRUG INTERACTIONS
See Tables 3 and 9 for listing of drugs that are contraindicated for use with KALETRA due to potentially life-threatening adverse events, significant drug interactions, or loss of virologic activity. [see CONTRAINDICATIONS and DRUG INTERACTIONS].
Pancreatitis
Pancreatitis has been observed in patients receiving KALETRA therapy, including those who developed marked triglyceride elevations. In some cases, fatalities have been observed. Although a causal relationship to KALETRA has not been established, marked triglyceride elevations are a risk factor for development of pancreatitis [See WARNINGS AND PRECAUTIONS]. Patients with advanced HIV-1 disease may be at increased risk of elevated triglycerides and pancreatitis, and patients with a history of pancreatitis may be at increased risk for recurrence during KALETRA therapy.
Pancreatitis should be considered if clinical symptoms (nausea, vomiting, abdominal pain) or abnormalities in laboratory values (such as increased serum lipase or amylase values) suggestive of pancreatitis occur. Patients who exhibit these signs or symptoms should be evaluated and KALETRA and/or other antiretroviral therapy should be suspended as clinically appropriate.
Hepatotoxicity
Patients with underlying hepatitis B or C or marked elevations in transaminase prior to treatment may be at increased risk for developing or worsening of transaminase elevations or hepatic decompensation with use of KALETRA.
There have been postmarketing reports of hepatic dysfunction, including some fatalities. These have generally occurred in patients with advanced HIV-1 disease taking multiple concomitant medications in the setting of underlying chronic hepatitis or cirrhosis. A causal relationship with KALETRA therapy has not been established.
Appropriate laboratory testing should be conducted prior to initiating therapy with KALETRA and patients should be monitored closely during treatment. Increased AST/ALT monitoring should be considered in the patients with underlying chronic hepatitis or cirrhosis, especially during the first several months of KALETRA treatment. [See Use In Specific Populations]
Diabetes Mellitus/Hyperglycemia
New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and hyperglycemia have been reported during post-marketing surveillance in HIV-1 infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
Immune Reconstitution Syndrome
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including KALETRA. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis) which may necessitate further evaluation and treatment.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
Lipid Elevations
Treatment with KALETRA has resulted in large increases in the concentration of total cholesterol and triglycerides [See ADVERSE REACTIONS]. Triglyceride and cholesterol testing should be performed prior to initiating KALETRA therapy and at periodic intervals during therapy. Lipid disorders should be managed as clinically appropriate, taking into account any potential drug-drug interactions with KALETRA and HMG-CoA reductase inhibitors. [See CONTRAINDICATIONS and DRUG INTERACTIONS]
Patients with Hemophilia
There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
Resistance/Cross-resistance
Because the potential for HIV cross-resistance among protease inhibitors has not been fully explored in KALETRA-treated patients, it is unknown what effect therapy with KALETRA will have on the activity of subsequently administered protease inhibitors. [See CLINICAL PHARMACOLOGY]
Generic Name: Lopinavir, Ritonavir Tablets
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