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warnings
WARNINGS ALERT: Find out about medicines that should NOT be taken with CRIXIVAN. This statement is included on the product’s bottle label. Nephrolithiasis/Urolithiasis Nephrolithiasis/urolithiasis has occurred with CRIXIVAN therapy. The cumulative frequency of nephrolithiasis is substantially higher in pediatric patients (29%) than in adult patients (12.4%; range across individual trials: 4.7% to 34.4%). The cumulative frequency of nephrolithiasis events increases with increasing exposure to CRIXIVAN; however, the risk over time remains relatively constant. In some cases, nephrolithiasis/urolithiasis has been associated with renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia. If signs or symptoms of nephrolithiasis/urolithiasis occur, (including flank pain, with or without hematuria or microscopic hematuria), temporary interruption (e.g., 1-3 days) or discontinuation of therapy may be considered. Adequate hydration is recommended in all patients treated with CRIXIVAN. (See ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION, Nephrolithiasis/Urolithiasis .) Hemolytic Anemia Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with CRIXIVAN. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of CRIXIVAN. Hepatitis Hepatitis including cases resulting in hepatic failure and death has been reported in patients treated with CRIXIVAN. Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between CRIXIVAN and these events has not been established. Hyperglycemia New onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus and hyperglycemia have been reported during post-marketing surveillance in HIV-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. Drug Interactions Concomitant use of CRIXIVAN with lovastatin, simvastatin, or rosuvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including CRIXIVAN, are used concurrently with atorvastatin. The interaction of CRIXIVAN with pravastatin and fluvastatin is not known. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including CRIXIVAN, are used in combination with these statin drugs (see PRECAUTIONS, Drug Interactions ). Midazolam is extensively metabolized by CYP3A4. Co-administration with CRIXIVAN with or without ritonavir may cause a large increase in the concentration of this benzodiazepine. No drug interaction study has been performed for the co-administration of CRIXIVAN with benzodiazepines. Based on data from other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore CRIXIVAN should not be co-administered with orally administered midazolam (see CONTRAINDICATIONS ), whereas caution should be used with co-administration of CRIXIVAN and parenteral midazolam. Data from concomitant use of parenteral midazolam with other protease inhibitors suggest a possible 3-4 fold increase in midazolam plasma levels. If CRIXIVAN with or without ritonavir is co-administered with parenteral midazolam, it should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. Particular caution should be used when prescribing sildenafil, tadalafil, or vardenafil in patients receiving indinavir. Coadministration of CRIXIVAN with these medications is expected to substantially increase plasma concentrations of sildenafil, tadalafil, and vardenafil and may result in an increase in adverse events, including hypotension, visual changes, and priapism, which have been associated with sildenafil, tadalafil, and vardenafil (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions and Information for Patients , and the manufacturer’s complete prescribing information for sildenafil, tadalafil, or vardenafil). Concomitant use of CRIXIVAN and St. John’s wort ( Hypericum perforatum ) or products containing St. John’s wort is not recommended. Coadministration of CRIXIVAN and St. John’s wort has been shown to substantially decrease indinavir concentrations (see CLINICAL PHARMACOLOGY, Drug Interactions) and may lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors.
ADVERSE REACTIONS Clinical Trials in Adults Nephrolithiasis/urolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 12.4% (301/2429; range across individual trials: 4.7% to 34.4%) of patients receiving CRIXIVAN at the recommended dose in clinical trials with a median follow-up of 47 weeks (range: 1 day to 242 weeks; 2238 patient-years follow-up). The cumulative frequency of nephrolithiasis events increases with duration of exposure to CRIXIVAN; however, the risk over time remains relatively constant. Of the patients treated with CRIXIVAN who developed nephrolithiasis/urolithiasis in clinical trials during the double-blind phase, 2.8% (7/246) were reported to develop hydronephrosis and 4.5% (11/246) underwent stent placement. Following the acute episode, 4.9% (12/246) of patients discontinued therapy. (See WARNINGS and DOSAGE AND ADMINISTRATION, Nephrolithiasis/Urolithiasis .) Asymptomatic hyperbilirubinemia (total bilirubin ≥2.5 mg/dL), reported predominantly as elevated indirect bilirubin, has occurred in approximately 14% of patients treated with CRIXIVAN. In <1% this was associated with elevations in ALT or AST. Hyperbilirubinemia and nephrolithiasis/urolithiasis occurred more frequently at doses exceeding 2.4 g/day compared to doses ≤2.4 g/day. Clinical adverse experiences reported in ≥2% of patients treated with CRIXIVAN alone, CRIXIVAN in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 10. Table 10: Clinical Adverse Experiences Reported in ≥2% of Patients Study 028 Considered Drug-Related and of Moderate or Severe Intensity Study ACTG 320 of Unknown Drug Relationship and of Severe or Life-threatening Intensity CRIXIVAN CRIXIVAN plus Zidovudine Zidovudine CRIXIVAN plus Zidovudine plus Lamivudine Zidovudine plus Lamivudine Adverse Experience Percent (n=332) Percent (n=332) Percent (n=332) Percent (n=571) Percent (n=575) Body as a Whole Abdominal pain 16.6 16.0 12.0 1.9 0.7 Asthenia/fatigue 2.1 4.2 3.6 2.4 4.5 Fever 1.5 1.5 2.1 3.8 3.0 Malaise 2.1 2.7 1.8 0 0 Digestive System Nausea 11.7 31.9 19.6 2.8 1.4 Diarrhea 3.3 3.0 2.4 0.9 1.2 Vomiting 8.4 17.8 9.0 1.4 1.4 Acid regurgitation 2.7 5.4 1.8 0.4 0 Anorexia 2.7 5.4 3.0 0.5 0.2 Appetite increase 2.1 1.5 1.2 0 0 Dyspepsia 1.5 2.7 0.9 0 0 Jaundice 1.5 2.1 0.3 0 0 Hemic and Lymphatic System Anemia 0.6 1.2 2.1 2.4 3.5 Musculoskeletal System Back pain 8.4 4.5 1.5 0.9 0.7 Nervous System/Psychiatric Headache 5.4 9.6 6.0 2.4 2.8 Dizziness 3.0 3.9 0.9 0.5 0.7 Somnolence 2.4 3.3 3.3 0 0 Skin and Skin Appendage Pruritus 4.2 2.4 1.8 0.5 0 Rash 1.2 0.6 2.4 1.1 0.5 Respiratory System Cough 1.5 0.3 0.6 1.6 1.0 Difficulty breathing/ dyspnea/ shortness of breath 0 0.6 0.3 1.8 1.0 Urogenital System Nephrolithiasis/urolithiasis Including renal colic, and flank pain with and without hematuria 8.7 7.8 2.1 2.6 0.3 Dysuria 1.5 2.4 0.3 0.4 0.2 Special Senses Taste perversion 2.7 8.4 1.2 0.2 0 In Phase I and II controlled trials, the following adverse events were reported significantly more frequently by those randomized to the arms containing CRIXIVAN than by those randomized to nucleoside analogues: rash, upper respiratory infection, dry skin, pharyngitis, taste perversion. Selected laboratory abnormalities of severe or life-threatening intensity reported in patients treated with CRIXIVAN alone, CRIXIVAN in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 11. Table 11: Selected Laboratory Abnormalities of Severe or Life-threatening Intensity Reported in Studies 028 and ACTG 320 Study 028 Study ACTG 320 CRIXIVAN CRIXIVAN plus Zidovudine Zidovudine CRIXIVAN plus Zidovudine plus Lamivudine Zidovudine plus Lamivudine Percent (n=329) Percent (n=320) Percent (n=330) Percent (n=571) Percent (n=575) Hematology Decreased hemoglobin <7.0 g/dL 0.6 0.9 3.3 2.4 3.5 Decreased platelet count <50 THS/mm 3 0.9 0.9 1.8 0.2 0.9 Decreased neutrophils <0.75 THS/mm 3 2.4 2.2 6.7 5.1 14.6 Blood chemistry Increased ALT >500% ULN Upper limit of the normal range. 4.9 4.1 3.0 2.6 2.6 Increased AST >500% ULN 3.7 2.8 2.7 3.3 2.8 Total serum bilirubin >250% ULN 11.9 9.7 0.6 6.1 1.4 Increased serum amylase >200% ULN 2.1 1.9 1.8 0.9 0.3 Increased glucose >250 mg/dL 0.9 0.9 0.6 1.6 1.9 Increased creatinine >300% ULN 0 0 0.6 0.2 0 Post-Marketing Experience Body As A Whole: redistribution/accumulation of body fat (see PRECAUTIONS, Fat Redistribution ). Cardiovascular System: cardiovascular disorders including myocardial infarction and angina pectoris; cerebrovascular disorder. Digestive System: liver function abnormalities; hepatitis including reports of hepatic failure (see WARNINGS ); pancreatitis; jaundice; abdominal distention; dyspepsia. Hematologic: increased spontaneous bleeding in patients with hemophilia (see PRECAUTIONS ); acute hemolytic anemia (see WARNINGS ). Endocrine/Metabolic: new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia (see WARNINGS ). Hypersensitivity: anaphylactoid reactions; urticaria; vasculitis. Musculoskeletal System: arthralgia. Nervous System/Psychiatric: oral paresthesia; depression. Skin and Skin Appendage: rash including erythema multiforme and Stevens-Johnson syndrome; hyperpigmentation; alopecia; ingrown toenails and/or paronychia; pruritus. Urogenital System: nephrolithiasis/urolithiasis, in some cases resulting in renal insufficiency or acute renal failure, pyelonephritis with or without bacteremia (see WARNINGS ); interstitial nephritis sometimes with indinavir crystal deposits; in some patients, the interstitial nephritis did not resolve following discontinuation of CRIXIVAN; renal insufficiency; renal failure; leukocyturia (see PRECAUTIONS ), crystalluria; dysuria. Laboratory Abnormalities Increased serum triglycerides; increased serum cholesterol.