Crixivan (Indinavir Sulfate)

CRIXIVAN®

MSD

Indinavir Sulfate

HIV Protease Inhibitor

Action And Clinical Pharmacology: Indinavir is a selective protease inhibitor active against the Human Immunodeficiency Virus (HIV-1).

Mechanism of Action: HIV protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV. Indinavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature noninfectious viral particles.

Antiretroviral Potency: The relationship between in vitro susceptibility of HIV to indinavir and inhibition of HIV replication in humans has not been established. The in vitro activity of indinavir was assessed in cell lines of lymphoblastic and monocytic origin and in peripheral blood lymphocytes. HIV variants used to infect the different cell types include laboratory-adapted variants, primary clinical isolates and clinical isolates resistant to nucleoside analogue and nonnucleoside inhibitors of the HIV reverse transcriptase. The IC95 (95% inhibitory concentration) of indinavir in these test systems was in the range of 25 to 100 nM. In drug combination studies with the nucleoside analogues zidovudine and didanosine, as well as with an investigational nonnucleoside (L-697,661), indinavir showed synergistic activity in cell culture.

Virus Mutations: Isolates of HIV 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, at which substitutions are associated with resistance, have been identified. Resistance was mediated by the coexpression of multiple and variable substitutions at these positions. In general, higher levels of resistance were associated with the coexpression of greater numbers of substitutions.

Cross-resistance between indinavir and HIV reverse transcriptase inhibitors is unlikely because the enzyme targets involved are different. Cross-resistance was noted between indinavir and the protease inhibitor ritonavir. Varying degrees of cross-resistance have been observed between indinavir and other HIV-protease inhibitors.

Pharmacokinetics: Absorption of orally administered indinavir is rapid. Peak plasma concentration occurs within 1 hour and is not dose dependent. The oral absorption of a 400 mg dose of indinavir is reduced by 78% when administered with a standard meal high in calories, fat and protein contents. Indinavir has a relatively short half-life of 1.8 hours. There is very little drug accumulation following either an 8- or 6-hour dosing regimen over the clinical dose range.

Indinavir is widely distributed in the body and is approximately 60% bound to human plasma proteins. Less than 20% of indinavir is excreted unchanged in the urine. Following a single 400 mg dose of indinavir, patients with mild to moderate hepatic insufficiency and clinical evidence of cirrhosis had a mean AUC which was found to be higher by approximately 60% compared to that in healthy subjects and the half-life increased to approximately 2.8 hours, a reflection of reduced metabolism.

Therapy with indinavir should be initiated at the full recommended dose to increase suppression of viral replication and therefore inhibit the emergence of resistant virus (see Dosage). No titration is necessary upon initiating therapy.

Nephrolithiasis may occur (see Warnings and Adverse Effects). Adequate hydration (at least 1.5 L/day) is recommended in all patients treated with indinavir.

Indirect hyperbilirubinemia has occurred frequently in both healthy subjects and HIV-1 infected patients at various dosage levels of indinavir (see Precautions and Adverse Effects).

Hyperbilirubinemia and nephrolithiasis occurred more frequently at doses exceeding 2.4 g/day.

Indinavir should not be administered concurrently with terfenadine, astemizole, cisapride, triazolam, and midazolam because competition for P450 (CYP3A4) by indinavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening events (i.e., cardiac arrhythmias, prolonged sedation). The potential exists for interaction between indinavir and other P450 (CYP3A4) substrates which have not been studied (see Warnings).

The combination of indinavir and rifabutin results in an increase in the plasma concentrations of rifabutin and a decrease in the plasma concentrations of indinavir. When indinavir is coadministered with rifabutin, dose reduction of rifabutin to half the standard dose and a dose increase of indinavir are recommended (see Precautions and Dosage, Concomitant Therapy).

Due to an increase in the plasma concentrations of indinavir, a dosage reduction of indinavir should be considered when indinavir and ketoconazole are coadministered (see Dosage, Concomitant Therapy).

Rifampin is a potent inducer of P450 (CYP3A4) which markedly diminishes plasma concentrations of indinavir. Therefore, indinavir and rifampin should not be coadministered.

Other drugs that induce CYP3A4 less potently than rifampin, such as phenobarbital, phenytoin, carbamazepine, and dexamethasone should be used cautiously together with indinavir since they could also diminish plasma concentrations of indinavir.

Indications And Clinical Uses: For use in combination with reverse transcriptase inhibitor (RTI) nucleoside analogues for the treatment of adults with HIV-1 infection.

This indication is based on analyses of surrogate endpoints obtained at 24 weeks. There are no results from clinical trials confirming clinical benefit in terms of disease progression or survival.

Data from 2 double-blind randomized trials evaluating patients with CD4 counts of 50 to 500 cells/mmand mean RNA levels of approximately 20 000 copies/mL who took indinavir alone, or indinavir plus zidovudine, or zidovudine alone demonstrate greater immunologic and virologic responses in groups containing indinavir.

Data from a double-blind randomized trial evaluating patients with CD4 counts of 50 to 400 cells/mmand mean RNA levels of approximately 38 000 copies/mL who took indinavir alone, or indinavir plus zidovudine plus lamivudine, or zidovudine plus lamivudine demonstrate greater immunologic and virologic responses in groups containing indinavir.

Data from an open-label randomized trial evaluating patients with CD4 counts of less than 500 cells/mmand mean RNA levels of approximately 100 000 copies/mL who took indinavir alone, or indinavir plus zidovudine plus didanosine, or zidovudine plus didanosine suggest greater virologic response in the group containing indinavir and the 2 nucleosides.

No efficacy results are available for combinations involving indinavir and other nucleoside analogue reverse transcriptase inhibitors or other antiretrovirals. Preliminary data from other trials support the safety profile of indinavir when used concomitantly with zalcitabine or stavudine (see Pharmacology).

Contra-Indications: In patients with clinically significant hypersensitivity to any of its components.

Manufacturers’ Warnings In Clinical States: Nephrolithiasis may occur with indinavir. If signs and symptoms of nephrolithiasis, including flank pain with or without hematuria (including microscopic hematuria), occur, temporary interruption of therapy (e.g., 1 to 3 days) during the acute episode of nephrolithiasis may be considered. Adequate hydration is recommended in all patients treated with indinavir (see Adverse Effects, Nephrolithiasis and Dosage, Nephrolithiasis).

Indinavir should not be administered concurrently with terfenadine, astemizole, cisapride, triazolam, and midazolam because competition for P450 (CYP3A4) by indinavir could result in inhibition of the metabolism of these drugs and create the potential for serious and/or life-threatening events (i.e., cardiac arrhythmias, prolonged sedation). The potential exists for interaction between indinavir and other P450 (CYP3A4) substrates which have not been studied.

Rifampin: Rifampin is a potent inducer of P450 (CYP3A4) which markedly diminishes plasma concentrations of indinavir. Therefore, indinavir and rifampin should not be coadministered.

Other drugs that induce CYP3A4 less potently than rifampin, such as phenobarbital, phenytoin, carbamazepine, and dexamethasone should be used cautiously together with indinavir since they could also diminish plasma concentrations of indinavir.

Hyperglycemia: There have been reports of new onset diabetes mellitus or hyperglycemia, or exacerbation of pre-existing diabetes mellitus occurring in HIV-infected patients receiving protease inhibitor therapy. Many of these reports occurred in patients with confounding medical conditions, some of which required therapy with agents that have been associated with the development of diabetes mellitus or hyperglycemia. 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 the majority of cases, treatment with protease inhibitors was continued while in some cases treatment was either discontinued or interrupted. In some patients, hyperglycemia persisted after the protease inhibitor was withdrawn, whether or not diabetes was reported at baseline. A causal relationship between protease inhibitor therapy and these events has not been established.

Precautions: General: Indirect hyperbilirubinemia has occurred frequently in both healthy subjects and HIV-1 infected patients at various dosage levels of indinavir and has infrequently been associated with increases in serum transaminases (see Adverse Effects). However, because of the theoretical potential for the compound to exacerbate the physiologic hyperbilirubinemia seen in human neonates, careful consideration must be given to the use of indinavir in pregnant women at the time of delivery (see Pregnancy).

Acute Hemolytic Anemia: Acute hemolytic anemia has been reported. In some cases, it was severe and progressed rapidly. Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted which may include discontinuation of indinavir.

Bleeding in Hemophiliacs: There have been reports of increased bleeding including spontaneous skin hematomas and hemarthrosis in patients with Hemophilia Type A and Type B treated with protease inhibitors. In some patients, additional Factor VIII was given. In many of the reported cases, treatment with protease inhibitors was continued or reintroduced. There is no proven relationship between protease inhibitors and such bleeding, however, the frequency of bleeding episodes should be closely monitored in patients on indinavir.

Children: Safety and effectiveness in children have not been established.

Geriatrics: Safety and effectiveness in elderly patients have not been established.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Indinavir may be used during pregnancy only if the potential benefit justifies potential risk to the fetus.

Hyperbilirubinemia has occurred in patients during treatment with indinavir. It is unknown whether indinavir will exacerbate physiologic hyperbilirubinemia in neonates. The potential risk of this effect is being investigated in an ongoing study in Rhesus monkeys. At present, careful consideration must be given to the use of indinavir in pregnant women at the time of delivery.

Lactation : It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse reactions from indinavir in nursing infants, mothers should be instructed to discontinue nursing if they are receiving indinavir. In addition, it is advisable for HIV-infected women not to breast-feed to avoid postnatal transmission of HIV to a child who may not be infected.

Patients with Hepatic Insufficiency due to Cirrhosis: In these patients, the dosage of indinavir should be lowered because of decreased metabolism of the drug (see Dosage).

Patients with Renal Insufficiency: Patients with renal insufficiency have not been studied.

CNS Penetration: CNS penetration of indinavir has not been established.

Drug Interactions: See Warnings: Specific drug interaction studies were performed with indinavir and the following drugs: zidovudine, zidovudine/lamivudine, trimethoprim/sulfamethoxazole, fluconazole, isoniazid, clarithromycin, norethindrone/ethinyl estradiol 1/35. No clinically significant interactions were observed with these drugs. However, clinically significant interactions with other drugs are described below.

Rifabutin: Due to an increase in the plasma concentrations of rifabutin and a decrease in the plasma concentrations of indinavir, a dosage reduction of rifabutin and a dosage increase of indinavir are necessary when rifabutin is coadministered with indinavir (see Dosage, Concomitant Therapy).

Ketoconazole: Due to an increase in the plasma concentrations of indinavir, a dosage reduction of indinavir should be considered when indinavir and ketoconazole are coadministered (see Dosage, Concomitant Therapy).

Rifampin: Rifampin is a potent inducer of P450 (CYP3A4) which markedly diminishes plasma concentrations of indinavir. Therefore, indinavir and rifampin should not be coadministered.

Didanosine: When indinavir and didanosine are administered concomitantly, they should be administered at least 1 hour apart on an empty stomach.

Other: See Warnings: Indinavir should not be administered concurrently with terfenadine, astemizole, cisapride, triazolam and midazolam because coadministration with inhibitors of P450 (CYP3A4) may result in inhibition of metabolism of these drugs and create the potential for serious and/or life-threatening events (i.e., cardiac arrhythmias or prolonged sedation).

Other drugs that induce CYP3A4 less potently than rifampin, such as phenobarbital, phenytoin, carbamazepine, and dexamethasone should be used cautiously together with indinavir since they could also diminish plasma concentations of indinavir.

Information for the Patient: Patients should be informed that while indinavir reduces HIV-1 RNA levels, it is not a cure for HIV infection and that they may continue to develop opportunistic infections or other illnesses associated with HIV-1 disease. Indinavir has not been shown to reduce the incidence or frequency of such illnesses.

Patients should be told that the long-term effects of indinavir are unknown at this time. They should be advised that treatment with indinavir has not been shown to reduce the risk of transmission of HIV-1 to others through sexual contact or blood contamination. Studies evaluating the impact of indinavir alone or in combination with approved antiretroviral agents (i.e., nucleoside analogues) on HIV-1 disease progression (such as opportunistic infections and survival) are ongoing.

Capsules of indinavir are sensitive to moisture. Patients should be informed that indinavir should be stored in a tightly closed container at room temperature (15 to 30°C) and protected from moisture.

For optimal absorption, indinavir should be administered without food but with water, 1 hour before or 2 hours after a meal. Alternatively, indinavir may be administered with other liquids such as skim milk, juice, coffee, or tea, or a light meal (e.g., dry toast with jelly, apple juice, and coffee with skim milk and sugar or corn flakes, skim milk and sugar). Ingestion of indinavir with a meal high in calories, fat and protein reduces the absorption of indinavir.

To achieve the best possible antiretroviral activity, indinavir must be taken exactly as prescribed. Patients should be advised to drink at least 1.5 L of liquids during the course of 24 hours. Patients should also be informed that treatment must not be modified or discontinued without first consulting a physician.

Occupational Hazards: Dizziness and blurred vision have been reported with indinavir. Patients should be advised to avoid driving or operating machinery if they experience these reactions.

Adverse Reactions: Nephrolithiasis: Nephrolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 4% (79/2 205) of patients receiving indinavir). In general these events were not associated with renal dysfunction and resolved with hydration and temporary interruption of therapy (e.g., 1 to 3 days). Following the acute episode, 9.2% (7/76) of patients discontinued therapy (see Warnings and Dosage, Nephrolithiasis).

Hyperbilirubinemia: Asymptomatic hyperbilirubinemia (total bilirubin ³42.75 µmol/L (³2.5 mg/dL)), reported predominantly as elevated indirect bilirubin, has occurred in approximately 10% of patients treated with indinavir. Hyperbilirubinemia and nephrolithiasis occurred more frequently at doses exceeding 2.4 g/day.

Clinical Trial Experience: In controlled clinical trials conducted worldwide, indinavir was administered alone or in combination with other antiretroviral agents (zidovudine, didanosine, and/or lamivudine) and was found to be generally well tolerated. Indinavir did not alter the type, frequency, or severity of known major toxicities associated with the use of zidovudine, didanosine or lamivudine.

In Phase I and II controlled trials, the following adverse reactions were reported significantly more frequently by those randomized to indinavir-containing arms than by those randomized to nucleoside analogues: rash, upper respiratory infection, dry skin, pharyngitis, taste perversion.

Adverse reactions occurring in less than 2% of patients receiving indinavir in all Phase II/Phase III studies and considered at least possibly related or of unknown relationship to treatment and of at least moderate intensity are listed below by body system.

Body as a Whole/Site Unspecified: abdominal distention, chest pain, chills, fever, flank pain, flu-like illness, fungal infection, malaise, pain, syncope.

Cardiovascular: cardiovascular disorder, palpitation.

Digestive: acid regurgitation, anorexia, aphthous stomatitis, cheilitis, cholecystitis, cholestasis, constipation, dry mouth, dyspepsia, eructation, flatulence, gastritis, gingivitis, glossodynia, gingival hemorrhage, increased appetite, infectious gastroenteritis, jaundice, liver cirrhosis.

Hemic and Lymphatic: anemia, lymphadenopathy, spleen disorder, bleeding in hemophiliacs (see Precautions).

Metabolic/Nutritional/Immune: food allergy.

Musculoskeletal: arthralgia, back pain, leg pain, myalgia, muscle cramps, muscle weakness, musculoskeletal pain, shoulder pain, stiffness.

Nervous and Psychiatric: agitation, anxiety, anxiety disorder, bruxism, decreased mental acuity, depression, dizziness, dream abnormality, dysesthesia, excitement, fasciculation, hypesthesia, nervousness, neuralgia, neurotic disorder, paresthesia, peripheral neuropathy, sleep disorder, somnolence, tremor, vertigo.

Respiratory: cough, dyspnea, halitosis, pharyngeal hyperemia, pharyngitis, pneumonia, rales/rhonchi, respiratory failure, sinus disorder, sinusitis, upper respiratory infection.

Skin and Skin Appendage: body odor, contact dermatitis, dermatitis, dry skin, flushing, folliculitis, herpes simplex, herpes zoster, night sweats, pruritus, seborrhea, skin disorder, skin infection, sweating, urticaria.

Special Senses: accommodation disorder, blurred vision, eye pain, eye swelling, orbital edema, taste disorder.

Urogenital: dysuria, hematuria, hydronephrosis, nocturia, premenstrual syndrome, proteinuria, renal colic, urinary frequency, urinary tract infection, urine abnormality, urine sediment abnormality, urolithiasis.

Laboratory Test Abnormalities: The most frequently occurring selected laboratory adverse experiences (incidence ³5%) considered to be possibly, probably, or definitely drug-related by the study investigator in the group treated with indinavir alone, were changes in ALT (15.3%), AST (21.4%), indirect serum bilirubin (30.9%), total serum bilirubin (36.2%), and urine protein (20.9%). Only 1% of patients discontinued treatment due to these laboratory adverse experiences, when treated with indinavir alone or in combination with other antiretroviral agents. With the exception of hyperbilirubinemia, the incidences of these adverse events with indinavir monotherapy were lower than in the groups treated with indinavir in combination with other antiretroviral agents. Similar incidences in drug-related laboratory adverse experiences of changes in ALT, AST, and urine protein were observed in the group treated with zidovudine alone.

Postmarketing Experience: The following additional adverse experiences have been reported in postmarketing experience without regard to causality: Digestive: liver function abnormalities, hepatitis including rare reports of hepatic failure.

Endocrine/Metabolic: new onset diabetes mellitus or hyperglycemia, or exacerbation of pre-existing diabetes mellitus (see Warnings).

Hematologic: increased spontaneous bleeding in patients with hemophilia (see Precautions), acute hemolytic anemia.

Hypersensitivity: angioedema, anaphylaxis.

Skin and Skin Appendage: alopecia, hyperpigmentation, urticaria.

Urogenital: nephrolithiasis, generally without renal dysfunction; however, there have been reports of nephrolithiasis with renal dysfunction including acute renal failure, crystalluria.

The following additional laboratory experiences have been reported: increased serum triglycerides.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: It is not known whether indinavir is dialyzable by peritoneal dialysis or hemodialysis. Although no data are available, administration of activated charcoal may be used to aid in removal of unabsorbed drug.

Dosage And Administration: The recommended dosage is 800 mg orally every 8 hours. Therapy must be initiated at the recommended dose of 2.4 g/day.

For optimal absorption, the drug should be administered without food but with water, 1 hour before or 2 hours after a meal. Alternatively, it may be administered with other liquids such as skim milk, juice, coffee, or tea, or a light meal (e.g., dry toast with jelly, apple juice, and coffee with skim milk and sugar or corn flakes, skim milk and sugar).

To ensure adequate hydration, it is recommended that the patient drink at least 1.5 L of liquids during the course of 24 hours.

Concomitant Therapy: Rifabutin: Dose reduction of rifabutin up to half the standard dose (consult the manufacturers’ Product Monograph), and a dose increase of indinavir to 1 000 mg every 8 hours are recommended when rifabutin and indinavir are coadministered (see Precautions and Pharmacology).

Ketoconazole: Dose reduction of indinavir to 600 mg every 8 hours should be considered when administering ketoconazole concurrently (see Pharmacology).

Hepatic Insufficiency Due to Cirrhosis: Dose reduction of indinavir to 600 mg every 8 hours should be considered in patients with mild to moderate hepatic insufficiency due to cirrhosis (see Pharmacology).

Nephrolithiasis: In addition to adequate hydration, medical management in patients who experience nephrolithiasis may include temporary interruption of therapy (e.g., 1 to 3 days) during the acute episode of nephrolithiasis or discontinuation of therapy.

Availability And Storage: 200 mg: Each white, semi-translucent capsule, coded “CRIXIVAN 200 mg” in blue, contains: indinavir 200 mg (as a sulfate salt ethanolate). Nonmedicinal ingredients: anhydrous lactose and magnesium stearate; empty capsule shell: gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Bottles of 360 (with desiccant).

400 mg: Each white, semi-translucent capsule, coded “CRIXIVAN 400 mg” in green, contains: indinavir 400 mg (as a sulfate salt ethanolate). Nonmedicinal ingredients: anhydrous lactose and magnesium stearate; empty capsule shell: gelatin, silicon dioxide, sodium lauryl sulfate and titanium dioxide. Bottles of 90 and 180 (with desiccant).

Store in a tightly closed container at room temperature (15 to 30°C). Protect from moisture.

CRIXIVAN® MSD Indinavir Sulfate HIV Protease Inhibitor

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