İHALE DÜNYASI
İHALE DÜNYASI
CRIXIVAN Registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. Copyright (c) 1996, 1997, 1998, 1999, 2004 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved (indinavir sulfate) is an inhibitor of the human immunodeficiency virus (HIV) protease. CRIXIVAN Capsules are formulated as a sulfate salt and are available for oral administration in strengths of 100, 200, and 400 mg of indinavir (corresponding to 125, 250, and 500 mg indinavir sulfate, respectively). Each capsule also contains the inactive ingredients anhydrous lactose and magnesium stearate. The capsule shell has the following inactive ingredients and dyes: gelatin, titanium dioxide, silicon dioxide, and sodium lauryl sulfate. The chemical name for indinavir sulfate is [1(1 S ,2 R ),5( S )]-2,3,5-trideoxy- N -(2,3-dihydro-2-hydroxy-1 H -inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D- erythro -pentonamide sulfate (1:1) salt. Indinavir sulfate has the following structural formula: Indinavir sulfate is a white to off-white, hygroscopic, crystalline powder with the molecular formula C 36 H 47 N 5 O 4 * H 2 SO 4 and a molecular weight of 711.88. It is very soluble in water and in methanol. structural formula
CRIXIVAN in combination with antiretroviral agents is indicated for the treatment of HIV infection. This indication is based on two clinical trials of approximately 1 year duration that demonstrated: 1) a reduction in the risk of AIDS-defining illnesses or death; 2) a prolonged suppression of HIV RNA. Description of Studies In all clinical studies, with the exception of ACTG 320, the AMPLICOR HIV MONITOR assay was used to determine the level of circulating HIV RNA in serum. This is an experimental use of the assay. HIV RNA results should not be directly compared to results from other trials using different HIV RNA assays or using other sample sources. Study ACTG 320 was a multicenter, randomized, double-blind clinical endpoint trial to compare the effect of CRIXIVAN in combination with zidovudine and lamivudine with that of zidovudine plus lamivudine on the progression to an AIDS-defining illness (ADI) or death. Patients were protease inhibitor and lamivudine naive and zidovudine experienced, with CD4 cell counts of ?200 cells/mm 3 . The study enrolled 1156 HIV-infected patients (17% female, 28% Black, 18% Hispanic, mean age 39 years). The mean baseline CD4 cell count was 87 cells/mm 3 . The mean baseline HIV RNA was 4.95 log 10 copies/mL (89,035 copies/mL). The study was terminated after a planned interim analysis, resulting in a median follow-up of 38 weeks and a maximum follow-up of 52 weeks. Results are shown in Table 4 and Figures 1 & 2. Table 4: ACTG 320 Number (%) of Patients with AIDS-defining Illness or Death Endpoint IDV+ZDV+L IDV = Indinavir, ZDV = Zidovudine, L = Lamivudine (n=577) ZDV+L (n=579) HIV Progression or Death 35 (6.1) 63 (10.9) Death The number of deaths is inadequate to assess the impact of Indinavir on survival. 10 (1.7) 19 (3.3) Study ACTG 320: Figure 1 - Indinavir Protocol ACTG 320 Zidovudine Experienced Plasma Viral RNA - Proportions Below 400 copies/mL Study ACTG 320: Figure 2 - ACTG 320 Zidovudine Experienced CD4 Cell Counts - Mean Change from Baseline Study 028, a double-blind, multicenter, randomized, clinical endpoint trial conducted in Brazil, compared the effects of CRIXIVAN plus zidovudine with those of CRIXIVAN alone or zidovudine alone on the progression to an ADI or death, and on surrogate marker responses. All patients were antiretroviral naive with CD4 cell counts of 50 to 250 cells/mm 3 . The study enrolled 996 HIV-1 seropositive patients [28% female, 11% Black, 1% Asian/Other, median age 33 years, mean baseline CD4 cell count of 152 cells/mm 3 , mean serum viral RNA of 4.44 log 10 copies/mL (27,824 copies/mL)]. Treatment regimens containing zidovudine were modified in a blinded manner with the optional addition of lamivudine (median time: week 40). The median length of follow-up was 56 weeks with a maximum of 97 weeks. The study was terminated after a planned interim analysis, resulting in a median follow-up of 56 weeks and a maximum follow-up of 97 weeks. Results are shown in Table 5 and Figures 3 and 4. Table 5: Protocol 028 Number (%) of Patients with AIDS-defining Illness or Death Endpoint IDV+ZDV (n=332) IDV (n=332) ZDV (n=332) HIV Progression or Death 21 (6.3) 27 (8.1) 62 (18.7) Death The number of deaths is inadequate to assess the impact of Indinavir on survival. 8 (2.4) 5 (1.5) 11 (3.3) Study 028: Figure 3 - Indinavir Protocol 028 Zidovudine Naive Viral RNA - Proportions Below 500 copies/mL in Serum Study 028: Figure 4 - Indinavir Protocol 028 Zidovudine Naive CD4 Cell Counts - Mean Change from Baseline Study 035 was a multicenter, randomized trial in 97 HIV-1 seropositive patients who were zidovudine-experienced (median exposure 30 months), protease-inhibitor- and lamivudine-naive, with mean baseline CD4 count 175 cells/mm 3 and mean baseline serum viral RNA 4.62 log 10 copies/mL (41,230 copies/mL). Comparisons included CRIXIVAN plus zidovudine plus lamivudine vs. CRIXIVAN alone vs. zidovudine plus lamivudine. After at least 24 weeks of randomized, double-blind therapy, patients were switched to open-label CRIXIVAN plus lamivudine plus zidovudine. Mean changes in log 10 viral RNA in serum, the proportions of patients with viral RNA below 500 copies/mL in serum, and mean changes in CD4 cell counts, during 24 weeks of randomized, double-blinded therapy are summarized in Figures 5, 6, and 7, respectively. A limited number of patients remained on randomized, double-blind treatment for longer periods; based on this extended treatment experience, it appears that a greater number of subjects randomized to CRIXIVAN plus zidovudine plus lamivudine demonstrated HIV RNA levels below 500 copies/mL during one year of therapy as compared to those in other treatment groups. Study 035: Figure 5 - Indinavir Protocol 035 Zidovudine Experienced Viral RNA - Mean Log10 Change from Baseline in Serum Study 035: Figure 6 - Indinavir Protocol 035 Zidovudine Experienced Viral RNA - Proportions Below 500 Copies/mL in Serum Study 035: Figure 7 - Indinavir Protocol 035 Zidovudine Experienced CD4 Cell Counts - Mean Change from Baseline Genotypic Resistance in Clinical Studies Study 006 (10/15/93-10/12/94) was a dose-ranging study in which patients were initially treated with CRIXIVAN at a dose of <2.4 g/day followed by 2.4 g/day. Study 019 (6/23/94-4/10/95) was a randomized comparison of CRIXIVAN 600 mg every 6 hours, CRIXIVAN plus zidovudine, and zidovudine alone. Table 6 shows the incidence of genotypic resistance at 24 weeks in these studies. Table 6: Genotypic Resistance at 24 Weeks Treatment Group Resistance to IDV n/N N - includes patients with non-amplifiable virus at 24 weeks who had amplifiable virus at week 0. Resistance to ZDV n/N IDV - - <2.4 g/day 31/37 (84%) - 2.4 g/day 9/21 (43%) 1/17 (6%) IDV/ZDV 4/22 (18%) 1/22 (5%) ZDV 1/18 (6%) 11/17 (65%) indinavir protocol figure 1 CD4 cell counts Figure 2 - Study ACTG 320 indinavir protocol 028 figure 3 indinavir protocol 028 figure 4 indinavir protocol 035 figure 5 indinavir protocol 035 figure 6 indinavir protocol 035 figure 7
The recommended dosage of CRIXIVAN is 800 mg (usually two 400-mg capsules) orally every 8 hours. CRIXIVAN must be taken at intervals of 8 hours. For optimal absorption, CRIXIVAN should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, CRIXIVAN may be administered with other liquids such as skim milk, juice, coffee, or tea, or with a light meal, e.g., dry toast with jelly, juice, and coffee with skim milk and sugar; or corn flakes, skim milk and sugar. (See CLINICAL PHARMACOLOGY, Effect of Food on Oral Absorption .) To ensure adequate hydration, it is recommended that adults drink at least 1.5 liters (approximately 48 ounces) of liquids during the course of 24 hours. Concomitant Therapy (See CLINICAL PHARMACOLOGY, Drug Interactions , and/or PRECAUTIONS, Drug Interactions .) Delavirdine Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered when administering delavirdine 400 mg three times a day. Didanosine If indinavir and didanosine are administered concomitantly, they should be administered at least one hour apart on an empty stomach (consult the manufacturer's product circular for didanosine). Itraconazole Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended when administering itraconazole 200 mg twice daily concurrently. Ketoconazole Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended when administering ketoconazole concurrently. Rifabutin Dose reduction of rifabutin to half the standard dose (consult the manufacturer's product circular for rifabutin) and a dose increase of CRIXIVAN to 1000 mg every 8 hours are recommended when rifabutin and CRIXIVAN are coadministered. Hepatic Insufficiency The dosage of CRIXIVAN should be reduced to 600 mg every 8 hours in patients with mild-to-moderate hepatic insufficiency due to cirrhosis. Nephrolithiasis/Urolithiasis In addition to adequate hydration, medical management in patients who experience nephrolithiasis/urolithiasis may include temporary interruption (e.g., 1 to 3 days) or discontinuation of therapy.
CRIXIVAN is contraindicated in patients with clinically significant hypersensitivity to any of its components. Inhibition of CYP3A4 by CRIXIVAN can result in elevated plasma concentrations of the following drugs, potentially causing serious or life-threatening reactions: Table 7: Drug Interactions With Crixivan: Contraindicated Drugs Drug Class Drugs Within Class That Are Contraindicated With CRIXIVAN Alpha 1-adrenoreceptor antagonist alfuzosin Antiarrhythmics amiodarone Ergot derivatives dihydroergotamine, ergonovine, ergotamine, methylergonovine GI motility agents cisapride Neuroleptics pimozide PDE5 Inhibitors Revatio Registered trademark of Pfizer, Inc. (sildenafil) [for treatment of pulmonary aterial hypertension] Sedative/hypnotics oral midazolam, triazolam, alprazolam
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.
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.
(also see CONTRAINDICATIONS , WARNINGS , PRECAUTIONS, Drug Interactions ) Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS and WARNINGS ). Based on in vitro data in human liver microsomes, indinavir does not inhibit CYP1A2, CYP2C9, CYP2E1 and CYP2B6. However, indinavir may be a weak inhibitor of CYP2D6. Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir. Drug interaction studies were performed with CRIXIVAN and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of CRIXIVAN on the AUC, C max and C min are summarized in Table 2 (effect of other drugs on indinavir) and Table 3 (effect of indinavir on other drugs). For information regarding clinical recommendations, see Table 9 in PRECAUTIONS. Table 2: Drug Interactions: Pharmacokinetic Parameters for Indinavir in the Presence of the Coadministered Drug (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen) Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without coadministered drug) of Indinavir Pharmacokinetic Parameters (90% CI); No Effect = 1.00 C max AUC C min All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. Cimetidine 600 twice daily, 6 days 400 single dose 12 1.07 (0.77, 1.49) 0.98 (0.81, 1.19) 0.82 (0.69, 0.99) Clarithromycin 500 q12h, 7 days 800 three times daily, 7 days 10 1.08 (0.85, 1.38) 1.19 (1.00, 1.42) 1.57 (1.16, 2.12) Delavirdine 400 three times daily 400 three times daily, 7 days 28 0.64 Relative to indinavir 800 mg three times daily alone. (0.48, 0.86) No significant change 2.18 (1.16, 4.12) Delavirdine 400 three times daily 600 three times daily, 7 days 28 No significant change 1.53 (1.07, 2.20) 3.98 (2.04, 7.78) Efavirenz Study conducted in HIV-positive subjects. 600 once daily, 10 days 1000 three times daily, 10 days 20 After morning dose No significant change 0.67 (0.61, 0.74) 0.61 (0.49, 0.76) After afternoon dose No significant change 0.63 (0.54, 0.74) 0.48 (0.43, 0.53) After evening dose 0.71 (0.57, 0.89) 0.54 (0.46, 0.63) 0.43 (0.37, 0.50) Fluconazole 400 once daily, 8 days 1000 three times daily, 7 days 11 0.87 (0.72, 1.05) 0.76 (0.59, 0.98) 0.90 (0.72, 1.12) Grapefruit Juice 8 oz. 400 single dose 10 0.65 (0.53, 0.79) 0.73 (0.60, 0.87) 0.90 (0.71, 1.15) Isoniazid 300 once daily in the morning, 8 days 800 three times daily, 7 days 11 0.95 (0.88, 1.03) 0.99 (0.87, 1.13) 0.89 (0.75, 1.06) Itraconazole 200 twice daily, 7 days 600 three times daily, 7 days 12 0.78 (0.69, 0.88) 0.99 (0.91, 1.06) 1.49 (1.28, 1.74) Ketoconazole 400 once daily, 7 days 600 three times daily, 7 days 12 0.69 (0.61, 0.78) 0.80 (0.74, 0.87) 1.29 (1.11, 1.51) 400 once daily, 7 days 400 three times daily, 7 days 12 0.42 (0.37, 0.47) 0.44 (0.41, 0.48) 0.73 (0.62, 0.85) Methadone 20-60 once daily in the morning, 8 days 800 three times daily, 8 days 10 See text below for discussion of interaction. Quinidine 200 single dose 400 single dose 10 0.96 (0.79, 1.18) 1.07 (0.89, 1.28) 0.93 (0.73, 1.19) Rifabutin 150 once daily in the morning, 10 days 800 three times daily, 10 days 14 0.80 (0.72, 0.89) 0.68 (0.60, 0.76) 0.60 (0.51, 0.72) Rifabutin 300 once daily in the morning, 10 days 800 three times daily, 10 days 10 0.75 (0.61, 0.91) 0.66 (0.56, 0.77) 0.61 (0.50, 0.75) Rifampin 600 once daily in the morning, 8 days 800 three times daily, 7 days 12 0.13 (0.08, 0.22) 0.08 (0.06, 0.11) Not Done Ritonavir 100 twice daily, 14 days 800 twice daily, 14 days 10, 16 Comparison to historical data on 16 subjects receiving indinavir alone. See text below for discussion of interaction. Ritonavir 200 twice daily, 14 days 800 twice daily,14 days 9, 16 See text below for discussion of interaction. Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction. St. John's wort ( Hypericum perforatum , standardized to 0.3 % hypericin) 300 three times daily with meals, 14 days 800 three times daily 8 Not Available 0.46 (0.34, 0.58) 95% CI. 0.19 (0.06, 0.33) Stavudine (d4T) 40 twice daily, 7 days 800 three times daily, 7 days 11 0.95 (0.80, 1.11) 0.95 (0.80, 1.12) 1.13 (0.83, 1.53) Trimethoprim/ Sulfamethoxazole 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days 400 four times daily, 7 days 12 1.12 (0.87, 1.46) 0.98 (0.81, 1.18) 0.83 (0.72, 0.95) Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 1.06 (0.91, 1.25) 1.05 (0.86, 1.28) 1.02 (0.77, 1.35) Zidovudine/ Lamivudine (3TC) 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 9 Parallel group design; n for indinavir + coadministered drug, n for indinavir alone. 1.05 (0.83, 1.33) 1.04 (0.67, 1.61) 0.98 (0.56, 1.73) Table 3: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drug in the Presence of Indinavir (See PRECAUTIONS, Table 9 for Recommended Alterations in Dose or Regimen) Coadministered drug Dose of Coadministered drug (mg) Dose of CRIXIVAN (mg) n Ratio (with/without CRIXIVAN) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 C max AUC C min All interaction studies conducted in healthy, HIV-negative adult subjects, unless otherwise indicated. Clarithromycin 500 twice daily, 7 days 800 three times daily, 7 days 12 1.19 (1.02, 1.39) 1.47 (1.30, 1.65) 1.97 (1.58, 2.46) n=11 Efavirenz 200 once daily, 14 days 800 three times daily, 14 days 20 No significant change No significant change -- Ethinyl Estradiol (ORTHO-NOVUM 1/35) Registered trademark of Ortho Pharmaceutical Corporation 35 mcg, 8 days 800 three times daily, 8 days 18 1.02 (0.96, 1.09) 1.22 (1.15, 1.30) 1.37 (1.24, 1.51) Isoniazid 300 once daily in the morning, 8 days 800 three times daily, 8 days 11 1.34 (1.12, 1.60) 1.12 (1.03, 1.22) 1.00 (0.92, 1.08) Methadone Study conducted in subjects on methadone maintenance. 20-60 once daily in the morning, 8 days 800 three times daily, 8 days 12 0.93 (0.84, 1.03) 0.96 (0.86, 1.06) 1.06 (0.94, 1.19) Norethindrone (ORTHO-NOVUM 1/35) 1 mcg, 8 days 800 three times daily, 8 days 18 1.05 (0.95, 1.16) 1.26 (1.20, 1.31) 1.44 (1.32, 1.57) Rifabutin * 150 mg once daily in the morning, 11 days + indinavir compared to 300 mg once daily in the morning, 11 days alone 150 once daily in the morning, 10 days 300 once daily in the morning, 10 days 800 three times daily, 10 days 800 three times daily, 10 days 14 10 1.29 (1.05, 1.59) 2.34 (1.64, 3.35) 1.54 (1.33, 1.79) 2.73 (1.99, 3.77) 1.99 (1.71, 2.31) n=13 3.44 (2.65, 4.46) n=9 Ritonavir 100 twice daily, 14 days 800 twice daily, 14 days 10, 4 Parallel group design; n for coadministered drug + indinavir, n for coadministered drug alone. 1.61 (1.13, 2.29) 1.72 (1.20, 2.48) 1.62 (0.93, 2.85) 200 twice daily, 14 days 800 twice daily, 14 days 9, 5 1.19 (0.85, 1.66) 1.96 (1.39, 2.76) 4.71 (2.66, 8.33) n=9, 4 Saquinavir Hard gel formulation 600 single dose 800 three times daily, 2 days 6 4.7 (2.7, 8.1) 6.0 (4.0, 9.1) 2.9 (1.7, 4.7) C 6hr Soft gel formulation 800 single dose 800 three times daily, 2 days 6 6.5 (4.7, 9.1) 7.2 (4.3, 11.9) 5.5 (2.2, 14.1) Soft gel formulation 1200 single dose 800 three times daily, 2 days 6 4.0 (2.7, 5.9) 4.6 (3.2, 6.7) 5.5 (3.7, 8.3) Sildenafil 25 single dose 800 three times daily 6 See text below for discussion of interaction. Stavudine Study conducted in HIV-positive subjects. 40 twice daily, 7 days 800 three times daily, 7 days 13 0.86 (0.73, 1.03) 1.21 (1.09, 1.33) Not Done Theophylline 250 single dose (on Days 1 and 7) 800 three times daily, 6 days (Days 2 to 7) 12, 4 0.88 (0.76, 1.03) 1.14 (1.04, 1.24) 1.13 (0.86, 1.49) n=7, 3 Trimethoprim/ Sulfamethoxazole Trimethoprim 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days 400 q6h, 7 days 12 1.18 (1.05, 1.32) 1.18 (1.05, 1.33) 1.18 (1.00, 1.39) Trimethoprim/ Sulfamethoxazole Sulfamethoxazole 800 Trimethoprim/ 160 Sulfamethoxazole q12h, 7 days 400 q6h, 7 days 12 1.01 (0.95, 1.08) 1.05 (1.01, 1.09) 1.05 (0.97, 1.14) Vardenafil 10 single dose 800 three times daily 18 See text below for discussion of interaction. Zidovudine 200 three times daily, 7 days 1000 three times daily, 7 days 12 0.89 (0.73, 1.09) 1.17 (1.07, 1.29) 1.51 (0.71, 3.20) n=4 Zidovudine/ Lamivudine Zidovudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 1.23 (0.74, 2.03) 1.39 (1.02, 1.89) 1.08 (0.77, 1.50) n=5, 5 Zidovudine/ Lamivudine Lamivudine 200/150 three times daily, 7 days 800 three times daily, 7 days 6, 7 0.73 (0.52, 1.02) 0.91 (0.66, 1.26) 0.88 (0.59, 1.33) Delavirdine: Delavirdine inhibits the metabolism of indinavir such that coadministration of 400-mg or 600-mg indinavir three times daily with 400-mg delavirdine three times daily alters indinavir AUC, C max and C min (see Table 2 ). Indinavir had no effect on delavirdine pharmacokinetics (see DOSAGE AND ADMINISTRATION, Concomitant Therapy, Delavirdine ), based on a comparison to historical delavirdine pharmacokinetic data. Methadone: Administration of indinavir (800 mg every 8 hours) with methadone (20 mg to 60 mg daily) for one week in subjects on methadone maintenance resulted in no change in methadone AUC. Based on a comparison to historical data, there was little or no change in indinavir AUC. Ritonavir: Compared to historical data in patients who received indinavir 800 mg every 8 hours alone, twice-daily coadministration to volunteers of indinavir 800 mg and ritonavir with food for two weeks resulted in a 2.7-fold increase of indinavir AUC 24h , a 1.6-fold increase in indinavir C max, and an 11-fold increase in indinavir C min for a 100-mg ritonavir dose and a 3.6-fold increase of indinavir AUC 24h , a 1.8- fold increase in indinavir C max , and a 24-fold increase in indinavir C min for a 200-mg ritonavir dose. In the same study, twice-daily coadministration of indinavir (800 mg) and ritonavir (100 or 200 mg) resulted in ritonavir AUC 24h increases versus the same doses of ritonavir alone (see Table 3 ). Sildenafil: The results of one published study in HIV-infected men (n=6) indicated that coadministration of indinavir (800 mg every 8 hours chronically) with a single 25-mg dose of sildenafil resulted in an 11% increase in average AUC 0-8hr of indinavir and a 48% increase in average indinavir peak concentration (C max ) compared to 800 mg every 8 hours alone. Average sildenafil AUC was increased by 340% following coadministration of sildenafil and indinavir compared to historical data following administration of sildenafil alone (see CONTRAINDICATIONS , WARNINGS, Drug Interactions and PRECAUTIONS, Drug Interactions ). Vardenafil: Indinavir (800 mg every 8 hours) coadministered with a single 10-mg dose of vardenafil resulted in a 16-fold increase in vardenafil AUC, a 7-fold increase in vardenafil C max , and a 2-fold increase in vardenafil half-life (see WARNINGS, Drug Interactions and PRECAUTIONS, Drug Interactions ). | 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. | Drug Interactions Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of CRIXIVAN and drugs primarily metabolized by CYP3A4 may result in increased plasma concentrations of the other drug, which could increase or prolong its therapeutic and adverse effects (see CONTRAINDICATIONS and WARNINGS ). Indinavir is metabolized by CYP3A4. Drugs that induce CYP3A4 activity would be expected to increase the clearance of indinavir, resulting in lowered plasma concentrations of indinavir. Coadministration of CRIXIVAN and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir. Table 8: Drugs That Should Not Be Coadministered with CRIXIVAN Drug Class: Drug Name Clinical Comment Alpha 1-adrenoreceptor antagonist: alfuzosin Potentially increased alfuzosin concentrations can result in hypotension. Antiarrhythmics: amiodarone CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Antimycobacterial: rifampin May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors or other coadministered antiretroviral agents. Ergot derivatives: dihydroergotamine, ergonovine, ergotamine, methylergonovine CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI motility agents: cisapride CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. Herbal products: St. John's wort ( Hypericum perforatum ) May lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors. HMG-CoA Reductase inhibitors: lovastatin, simvastatin, rosuvastatin Potential for serious reactions such as risk of myopathy including rhabdomyolysis. Neuroleptic: pimozide CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as cardiac arrhythmias. PDE5 inhibitor: Revatio Registered trademark of Pfizer, Inc. (sildenafil) [for treatment of pulmonary arterial hypertension] A safe and effective dose has not been established when used with CRIXIVAN. There is increased potential for sildenafil-associated adverse events (which include visual disturbances, hypotension, prolonged erection, and syncope). Protease inhibitor: atazanavir Both CRIXIVAN and atazanavir are associated with indirect (unconjugated) hyperbilirubinemia. Combinations of these drugs have not been studied and coadministration of CRIXIVAN and atazanavir is not recommended. Sedative/hypnotics: Oral midazolam, triazolam, alprazolam CONTRAINDICATED due to potential for serious and/or life-threatening reactions such as prolonged or increased sedation or respiratory depression. Table 9: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies or Predicted Interaction (See also CLINICAL PHARMACOLOGY for magnitude of interaction, WARNINGS and DOSAGE AND ADMINISTRATION .) Drug Name Effect Clinical Comment HIV Antiviral Agents Note: ?= increase; ? = decrease Delavirdine ? indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered when taking delavirdine 400 mg three times a day. Didanosine Indinavir and didanosine formulations containing buffer should be administered at least one hour apart on an empty stomach. Efavirenz ? indinavir concentration The optimal dose of indinavir, when given in combination with efavirenz, is not known. Increasing the indinavir dose to 1000 mg every 8 hours does not compensate for the increased indinavir metabolism due to efavirenz. Nelfinavir ? indinavir concentration The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Nevirapine ? indinavir concentration Indinavir concentrations may be decreased in the presence of nevirapine. The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Ritonavir ? indinavir concentration ? ritonavir concentration The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Preliminary clinical data suggest that the incidence of nephrolithiasis is higher in patients receiving indinavir in combination with ritonavir than those receiving CRIXIVAN 800 mg q8h. Saquinavir ? saquinavir concentration The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Other Agents Antiarrhythmics: bepridil, lidocaine(systemic) and quinidine ? antiarrhythmic agents concentration Caution is warranted and therapeutic concentration monitoring is recommended for antiarrhythmics when coadministered with CRIXIVAN. Anticonvulsants: carbamazepine, phenobarbital, phenytoin ? indinavir concentration Use with caution. CRIXIVAN may not be effective due to decreased indinavir concentrations in patients taking these agents concomitantly. Antidepressant: Trazodone ? trazodone concentration Concomitant use of trazodone and CRIXIVAN may increase plasma concentrations of trazodone. Adverse events of nausea, dizziness, hypotension and syncope have been observed following coadministration of trazodone and ritonavir. If trazodone is used with a CYP3A4 inhibitor such as CRIXIVAN, the combination should be used with caution and a lower dose of trazodone should be considered. Anti-gout: Colchicine ? colchicine concentration Patients with renal or hepatic impairment should not be given colchicine with CRIXIVAN. Treatment of gout flares: Co-administration of colchicine in patients on CRIXIVAN: 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 CRIXIVAN: 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): Co-administration of colchicine in patients on CRIXIVAN: Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). Calcium Channel Blockers, Dihydropyridine: e.g., felodipine, nifedipine, nicardipine ? dihydropyridine calcium channel blockers concentration Caution is warranted and clinical monitoring of patients is recommended. Clarithromycin ? clarithromycin concentration ? indinavir concentration The appropriate doses for this combination, with respect to efficacy and safety, have not been established. Endothelin receptor antagonist: Bosentan ? bosentan concentration Co-administration of bosentan in patients on CRIXIVAN or co-administration of CRIXIVAN in patients on bosentan: Start at or adjust bosentan to 62.5 mg once daily or every other day based upon individual tolerability. HMG-CoA Reductase Inhibitors: atorvastatin, pravastatin, fluvastatin ? atorvastatin concentration pravastatin, fluvastatin-interaction not studied Use the lowest possible dose of atorvastatin with careful monitoring. If no alternative treatment is available, use with careful monitoring. Immunosuppressants: cyclosporine, tacrolimus, sirolimus ? immunosuppressant agents concentration Plasma concentrations may be increased by CRIXIVAN. Inhaled beta agonist: Salmeterol ? salmeterol Concurrent administration of salmeterol with CRIXIVAN is not recommended. The combination may result in increased risk of cardiovascular adverse events associated with salmeterol, including QT prolongation, palpitations and sinus tachycardia. Inhaled/nasal steroid: Fluticasone ? fluticasone concentration Concomitant use of fluticasone propionate and CRIXIVAN may increase plasma concentrations of fluticasone propionate. Use with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. Fluticasone use is not recommended in situations where CRIXIVAN is coadministered with a potent CYP3A4 inhibitor such as ritonavir unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Itraconazole ? indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours is recommended when administering itraconazole concurrently. Ketoconazole ? indinavir concentration Dose reduction of CRIXIVAN to 600 mg every 8 hours should be considered. Midazolam (parenteral administration) ? midazolam concentration Concomitant use of parenteral midazolam with CRIXIVAN may increase plasma concentrations of midazolam. Coadministration 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. Coadministration of oral midazolam with CRIXIVAN is CONTRAINDICATED (see Table 8 ). Rifabutin ? indinavir concentration ? rifabutin concentration Dose reduction of rifabutin to half the standard dose and a dose increase of CRIXIVAN to 1000 mg every 8 hours are recommended when rifabutin and CRIXIVAN are coadministered. Sildenafil ? sildenafil concentration (only the use of sildenafil at doses used for treatment of erectile dysfunction has been studied with CRIXIVAN) May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, syncope, visual disturbances, and priapism. Use of sildenafil for pulmonary arterial hypertension (PAH): Use of Revatio Registered trademark of Pfizer, Inc. (sildenafil) is contraindicated when used for the treatment of pulmonary arterial hypertension (PAH) [see CONTRAINDICATIONS]. Use of sildenafil for erectile dysfunction: Sildenafil dose should not exceed a maximum of 25 mg in a 48-hour period in patients receiving concomitant CRIXIVAN therapy. Use with increased monitoring for adverse events. Tadalafil ? tadalafil concentration May result in an increase in PDE5 inhibitor-associated adverse events, including hypotension, visual disturbances, and priapism. Use of tadalafil for pulmonary arterial hypertension (PAH): The following dose adjustments are recommended for use of Adcirca Registered trademark of Eli Lilly and Company. (tadalafil) with CRIXIVAN: Co-administration of Adcirca in patients on CRIXIVAN or co-administration of CRIXIVAN in patients on Adcirca: Start at or adjust Adcirca to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. Use of tadalafil for erectile dysfunction: Tadalafil dose should not exceed a maximum of 10 mg in a 72-hour period in patients receiving concomitant CRIXIVAN therapy. Use with increased monitoring for adverse events. Vardenafil ? vardenafil concentration Vardenafil dose should not exceed a maximum of 2.5 mg in a 24-hour period in patients receiving concomitant indinavir therapy. Venlafaxine ? indinavir concentration In a study of 9 healthy volunteers, venlafaxine administered under steady-state conditions at 150 mg/day resulted in a 28% decrease in the AUC of a single 800 mg oral dose of indinavir and a 36% decrease in indinavir C max . Indinavir did not affect the pharmacokinetics of venlafaxine and ODV. The clinical significance of this finding is unknown. | Concomitant Therapy (See CLINICAL PHARMACOLOGY, Drug Interactions , and/or PRECAUTIONS, Drug Interactions .)