Crixivan Information
Crixivan (Indinavir) Description
Crixivan (Indinavir) (indinavir sulfate) is an inhibitor of the human immunodeficiency virus (HIV) protease. Crixivan (Indinavir) 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 and titanium dioxide.
The chemical name for indinavir sulfate is [1(1,2),5()]-2,3,5-trideoxy--(2,3-dihydro-2-hydroxy-1-inden-1-yl)-5-[2-[[(1,1-dimethylethyl)amino]carbonyl]-4-(3-pyridinylmethyl)-1-piperazinyl]-2-(phenylmethyl)-D--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 CHNO• HSO and a molecular weight of 711.88. It is very soluble in water and in methanol.
Crixivan (Indinavir) Microbiology
Isolates of HIV-1 with reduced susceptibility to the drug have been recovered from some patients treated with indinavir. Viral resistance was correlated with the accumulation of mutations that resulted in the expression of amino acid substitutions in the viral protease. Eleven amino acid residue positions, (L10l/V/R, K20l/M/R, L24l, M46l/L, l54A/V, L63P, l64V, A71T/V, V82A/F/T, l84V, and L90M), at which substitutions are associated with resistance, have been identified. Resistance was mediated by the co-expression of multiple and variable substitutions at these positions. No single substitution was either necessary or sufficient for measurable resistance (≥4-fold increase in IC). In general, higher levels of resistance were associated with the co-expression of greater numbers of substitutions, although their individual effects varied and were not additive. At least 3 amino acid substitutions must be present for phenotypic resistance to indinavir to reach measurable levels. In addition, mutations in the p7/ p1 and p1/ p6 gag cleavage sites were observed in some indinavir resistant HIV-1 isolates.
In vitro
Crixivan (Indinavir) Clinical Pharmacology
(also see , , )
Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of Crixivan (Indinavir) 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 and ). Based on 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 (Indinavir) 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 (Indinavir) and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of Crixivan (Indinavir) on the AUC, C and C 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 in PRECAUTIONS.
Delavirdine:
Methadone:
Ritonavir:
Table 3
Sildenafil:
Vardenafil:
max
Crixivan (Indinavir) Indications And Usage
Crixivan (Indinavir) 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.
Crixivan (Indinavir) Contraindications
Crixivan (Indinavir) is contraindicated in patients with clinically significant hypersensitivity to any of its components.
Inhibition of CYP3A4 by Crixivan (Indinavir) can result in elevated plasma concentrations of the following drugs, potentially causing serious or life-threatening reactions:
Crixivan (Indinavir) Warnings
Array
Concomitant use of Crixivan (Indinavir) with lovastatin, simvastatin, or rosuvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including Crixivan (Indinavir) , are used concurrently with atorvastatin. The interaction of Crixivan (Indinavir) with pravastatin and fluvastatin is not known. The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including Crixivan (Indinavir) , are used in combination with these statin drugs (see ).
Midazolam is extensively metabolized by CYP3A4. Co-administration with Crixivan (Indinavir) 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 (Indinavir) 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 (Indinavir) should not be co-administered with orally administered midazolam (see ), whereas caution should be used with co-administration of Crixivan (Indinavir) 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 (Indinavir) 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 (Indinavir) 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 and and , and the manufacturer’s complete prescribing information for sildenafil, tadalafil, or vardenafil).
Concomitant use of Crixivan (Indinavir) and St. John’s wort () or products containing St. John’s wort is not recommended. Coadministration of Crixivan (Indinavir) and St. John’s wort has been shown to substantially decrease indinavir concentrations (see and may lead to loss of virologic response and possible resistance to Crixivan (Indinavir) or to the class of protease inhibitors.
Crixivan (Indinavir) Precautions
Reports of tubulointerstitial nephritis with medullary calcification and cortical atrophy have been observed in patients with asymptomatic severe leukocyturia (>100 cells/ high power field). Patients with asymptomatic severe leukocyturia should be followed closely and monitored frequently with urinalyses. Further diagnostic evaluation may be warranted, and discontinuation of Crixivan (Indinavir) should be considered in all patients with severe leukocyturia.
Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy (CART), including Crixivan (Indinavir) . During the initial phase of treatment, patients responding to antiretroviral therapy whose immune system responds to CART may develop an inflammatory response to indolent or residual opportunistic infections (such as MAI, CMV, PCP, or TB), which may necessitate further evaluation and treatment.
Patients with hemophilia: There have been reports of spontaneous bleeding in patients with hemophilia A and B treated with protease inhibitors. In some patients, additional factor VIII was required. In many of the reported cases, treatment with protease inhibitors was continued or restarted. A causal relationship between protease inhibitor therapy and these episodes has not been established. (See .)
Patients with hepatic insufficiency due to cirrhosis: In these patients, the dosage of Crixivan (Indinavir) should be lowered because of decreased metabolism of Crixivan (Indinavir) (see ).
Patients with renal insufficiency: Patients with renal insufficiency have not been studied.
A statement to patients and health care providers is included on the product’s bottle label. A Patient Package Insert (PPI) for Crixivan (Indinavir) is available for patient information.
Crixivan (Indinavir) is not a cure for HIV infection and patients may continue to develop opportunistic infections and other complications associated with HIV disease. The long-term effects of Crixivan (Indinavir) are unknown at this time. Crixivan (Indinavir) has not been shown to reduce the risk of transmission of HIV to others through sexual contact or blood contamination.
Patients should be advised to remain under the care of a physician when using Crixivan (Indinavir) and should not modify or discontinue treatment without first consulting the physician. Therefore, if a dose is missed, patients should take the next dose at the regularly scheduled time and should not double this dose. Therapy with Crixivan (Indinavir) should be initiated and maintained at the recommended dosage.
Crixivan (Indinavir) may interact with some drugs; therefore, patients should be advised to report to their doctor the use of any other prescription, non-prescription medication or herbal products, particularly St. John’s wort.
For optimal absorption, Crixivan (Indinavir) should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, Crixivan (Indinavir) 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 and ). Ingestion of Crixivan (Indinavir) with a meal high in calories, fat, and protein reduces the absorption of indinavir.
Patients receiving a phosphodiesterase type 5 (PDE5) inhibitor (sildenafil, tadalafil, or vardenafil) should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, visual changes, and priapism, and should promptly report any symptoms to their doctors (see and ).
Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy and that the cause and long-term health effects of these conditions are not known at this time.
Crixivan (Indinavir) Capsules are sensitive to moisture. Patients should be informed that Crixivan (Indinavir) should be stored and used in the original container and the desiccant should remain in the bottle.
Indinavir is an inhibitor of the cytochrome P450 isoform CYP3A4. Coadministration of Crixivan (Indinavir) 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 and ).
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 (Indinavir) and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.
Crixivan (Indinavir) Adverse Reactions
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 (Indinavir) 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 (Indinavir) ; however, the risk over time remains relatively constant. Of the patients treated with Crixivan (Indinavir) 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 and .)
Asymptomatic hyperbilirubinemia (total bilirubin ≥2.5 mg/dL), reported predominantly as elevated indirect bilirubin, has occurred in approximately 14% of patients treated with Crixivan (Indinavir) . In
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 (Indinavir) alone, Crixivan (Indinavir) in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 10.
In Phase I and II controlled trials, the following adverse events were reported significantly more frequently by those randomized to the arms containing Crixivan (Indinavir) 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 (Indinavir) alone, Crixivan (Indinavir) in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 11.
Body As A Whole:
PRECAUTIONS, Fat Redistribution
Cardiovascular System:
Digestive System:
WARNINGS
Hematologic:
Endocrine/Metabolic:
WARNINGS
Hypersensitivity:
Musculoskeletal System:
Nervous System/Psychiatric:
Skin and Skin Appendage:
Urogenital System:
Crixivan (Indinavir) Overdosage
There have been more than 60 reports of acute or chronic human overdosage (up to 23 times the recommended total daily dose of 2400 mg) with Crixivan (Indinavir) . The most commonly reported symptoms were renal (e.g., nephrolithiasis/urolithiasis, flank pain, hematuria) and gastrointestinal (e.g., nausea, vomiting, diarrhea).
It is not known whether Crixivan (Indinavir) is dialyzable by peritoneal or hemodialysis.
Crixivan (Indinavir) Dosage And Administration
The recommended dosage of Crixivan (Indinavir) is 800 mg (usually 400-mg capsules) orally every 8 hours.
Crixivan (Indinavir) must be taken at intervals of 8 hours. For optimal absorption, Crixivan (Indinavir) should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, Crixivan (Indinavir) 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 .)
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.
Crixivan (Indinavir) How Supplied
Crixivan (Indinavir) Capsules are supplied as follows:
No. 3755 — 100 mg capsules: semi-translucent white capsules coded in green. Available as:
No. 3756 — 200 mg capsules: semi-translucent white capsules coded in blue. Available as:
No. 3758 — 400 mg capsules: semi-translucent white capsules coded in green. Available as:
Crixivan (Indinavir) Patient Package Insert
Please read this information before you start taking Crixivan (Indinavir) . Also, read the leaflet each time you renew your prescription, just in case anything has changed. Remember, this leaflet does not take the place of careful discussions with your doctor. You and your doctor should discuss Crixivan (Indinavir) when you start taking your medication and at regular checkups. You should remain under a doctor’s care when using Crixivan (Indinavir) and should not change or stop treatment without first talking with your doctor.
Crixivan (Indinavir) This Is A Representative Sample Of The Packaging. Please See How Supplied Section For A Complete List Of Available Packaging. Principal Display Panel - Bottle Label - Mg
Crixivan (Indinavir) 100 mg(Indinavir Sulfate) Capsules
NDC 0006-0570-62
Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC.Whitehouse Station, NJ 08889, USA
Each capsule contains indinavir 100 mg (corresponding to indinavir sulfate 125 mg).
Store at room temperature, 15-30°C (59-86ºF). Keep container tightly closed. Protect from moisture.Bottle contains desiccant.
USUAL DOSAGE: See accompanying circular.
ALERTFind out about medicines that should NOT be taken with Crixivan (Indinavir) .
Note to Pharmacist: Do not cover ALERT box with Pharmacy label.
180 Capsules
Rx only
7001145500180 | No. 3755
Crixivan (Indinavir) Principal Display Panel - Bottle Label - Mg
Crixivan (Indinavir) 200 mg(Indinavir Sulfate) Capsules
NDC 0006-0571-43
Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC.Whitehouse Station, NJ 08889, USA
Each capsule contains indinavir 200 mg (corresponding to indinavir sulfate 250 mg).
Store at room temperature, 15-30°C (59-86ºF). Keep container tightly closed. Protect from moisture.Bottle contains desiccant.
USUAL DOSAGE: See accompanying circular.
ALERTFind out about medicines that should NOT be taken with Crixivan (Indinavir) .
Note to Pharmacist: Do not cover ALERT box with Pharmacy label.
360 Capsules
Rx only
9966600360 | No. 3756
Crixivan (Indinavir) Principal Display Panel - Bottle Label - Mg
Crixivan (Indinavir) 400 mg(Indinavir Sulfate) Capsules
NDC 0006-0573-54
Merck Sharp & Dohme Corp., a subsidiary ofMERCK & CO., INC.Whitehouse Station, NJ 08889, USA
Each capsule contains indinavir 400 mg (corresponding to indinavir sulfate 500 mg).
Store at room temperature, 15-30°C (59-86ºF). Keep container tightly closed. Protect from moisture.Bottle contains desiccant.
USUAL DOSAGE: See accompanying circular.
ALERTFind out about medicines that should NOT be taken with Crixivan (Indinavir) .
Note to Pharmacist: Do not cover ALERT box with Pharmacy label.
90 Capsules
Rx only
996680190 | No. 3758
