CRIXIVAN (indinavir sulfate) is a specific protease inhibitor active against the Human Immunodeficiency
Virus (HIV-1).

CRIXIVAN is indicated for the treatment of adult and pediatric patients with HIV-1 infection. Clinicalstudies in adults demonstrated:

      reduced risk of progression to an AIDS-defining illness or death
      increased overall survival
      durable reduction in serum viral RNA
      durable increase in CD4 cell counts

CRIXIVAN is contraindicated in patients with clinically significant hypersensitivity to any of its components.

CRIXIVAN should not be administered concurrently with terfenadine, cisapride, astemizole, triazolam,midazolam, pimozide, or ergot derivatives. Inhibition of CYP3A4 by CRIXIVAN could result in elevated plasma concentration of these drugs, potentially causing serious or life-threatening reactions.

Nephrolithiasis
Nephrolithiasis has occurred with CRIXIVAN therapy in adult and pediatric patients. The frequency of nephrolithiasis is higher in pediatric patients than in adult patients. In some cases, nephrolithiasis has been associated with renal insufficiency or acute renal failure; in the majority of these cases, renal insufficiency and acute renal failure were reversible. 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 or discontinuation of therapy may be
considered. Adequate hydration is recommended in all patients treated with CRIXIVAN. (See SIDE EFFECTS and DOSAGE AND ADMINISTRATION.)

Acute Hemolytic Anemia
Acute hemolytic anemia has been reported which in some cases 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 CRIXIVAN.

Hepatitis
Hepatitis including rare cases of hepatic failure have 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
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.

Drug Interactions
Concomitant use of CRIXIVAN with lovastatin or simvastatin is not recommended. Caution should be exercised if protease inhibitors, including CRIXIVAN, are also used concurrently with other HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including CRIXIVAN, are used in combination with these drugs.

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 and may lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors.

Patients with Coexisting Conditions
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 SIDE EFFECTS, Post-Marketed Experience.)

Patients with hepatic insufficiency due to cirrhosis: In these patients, the dosage of CRIXIVAN should be lowered because of decreased metabolism of CRIXIVAN.

There are no adequate and well controlled studies in pregnant women. CRIXIVAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nonteratogenic effects
In Rhesus monkeys, administration of indinavir to neonates caused a mild exacerbation of the transient physiologic hyperbilirubinemia seen in this species after birth. Administration of indinavir to pregnant Rhesus monkeys during the third trimester did not cause a similar exacerbation in neonates; however, only limited placental transfer of indinavir occurred.

Hyperbilirubinemia has occurred in both healthy subjects and HIV-1 infected patients treated with various dosage levels of CRIXIVAN and has rarely been associated with increases in serum transaminases. 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 CRIXIVAN in pregnant women at the time of delivery.

It is not known whether CRIXIVAN is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for adverse reactions from CRIXIVAN in nursing infants, mothers should be instructed to discontinue nursing if they are receiving CRIXIVAN.

CRIXIVAN is recommended for use in pediatric patients 3 years of age and older who can swallow capsules (see DOSAGE AND ADMINISTRATION, Pediatric Patients). CRIXIVAN has not been evaluated in children below 3 years of age.

Specific drug interaction studies were performed with indinavir and the following drugs including:zidovudine, zidovudine/lamivudine, trimethoprim/sulfamethoxazole, fluconazole, isoniazid, clarithromycin, methadone or an oral contraceptive (norethindrone/ethinyl estradiol 1/35). No clinically significant interactions were observed with these drugs. However, clinically significant interactions with other drugs
are described below.

Pimozide
Pimozide should not be used together with indinavir. Inhibition of CYP3A4 by indinavir could result in elevated plasma concentrations of pimozide which could potentially result in QT prolongation and associated ventricular arrhythmias (see CONTRAINDICATIONS).

Rifampin
Rifampin is a potent inducer of P450 3A4 which markedly diminishes plasma concentrations of indinavir. Therefore, CRIXIVAN and rifampin should not be coadministered.

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 CRIXIVAN are necessary when rifabutin is coadministered with CRIXIVAN (see DOSAGE AND ADMINISTRATION).

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.
Itraconazole
Itraconazole is an inhibitor of P-450 3A4 that increases plasma concentrations of indinavir. Therefore, a
dosage reduction of indinavir is recommended when CRIXIVAN and itraconazole are coadministered.
(See DOSAGE AND ADMINISTRATION.)
Delavirdine
Due to an increase in indinavir plasma concentration (preliminary results), a dosage reduction of indinavir
should be considered when CRIXIVAN and delavirdine are coadministered. (See DOSAGE AND
ADMINISTRATION.)

Efavirenz
Due to a decrease in plasma concentrations of indinavir, a dosage increase of CRIXIVAN is
recommended when CRIXIVAN and efavirenz are coadministered. No dosage adjustment of efavirenz is necessary when given with indinavir. (See DOSAGE AND ADMINISTRATION.)

Ritonavir
Ritonavir increases indinavir plasma concentrations; indinavir may affect ritonavir plasma concentrations. Currently, there are no safety or efficacy data available on the use of this combination in patients.

HMG-CoA Reductase Inhibitors
Concomitant use of CRIXIVAN with lovastatin or simvastatin is not recommended. Caution should be exercised if protease inhibitors, including CRIXIVAN, are also used concurrently with other HMG-CoA reductase inhibitors that are metabolized by the CYP3A4 pathway (e.g., atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when protease inhibitors, including CRIXIVAN, are used in combination with these drugs. St. John’s Wort (Hypericum perforatum) 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 and may lead to loss of virologic response and possible resistance to CRIXIVAN or to the class of protease inhibitors.

Other
If indinavir and didanosine are administered concomitantly, they should be administered at least one hour apart on an empty stomach.

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.

Coadministration of CRIXIVAN with sildenafil is expected to substantially increase sildenafil plasma concentrations and may result in an increase in sildenafil-associated adverse events, including hypotension, visual changes, and priapism (see the manufacturer’s complete prescribing information for sildenafil.)

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

The majority of the adverse experiences reported with CRIXIVAN were of mild intensity and did not result in discontinuation of treatment. Discontinuation of therapy due to any clinical adverse experience occurred in 5.1% of 196 patients treated with CRIXIVAN alone, 5.7% of 53 patients treated with CRIXIVAN in combination with other antiretroviral agents, and in 6.8% of 74 patients treated with other antiretroviral agents alone.

Clinical adverse experiences reported by the investigators as possibly, probably, or definitely drug related in =5% of patients, without regard to severity, treated with CRIXIVAN alone (n=196), were: asthenia/fatigue, abdominal pain, acid regurgitation, diarrhea, dry mouth, dyspepsia, flatulence, nausea, vomiting, lymphadenopathy, dizziness, headache, hypesthesia, insomnia, dry skin, pruritus, rash, and taste perversion. Many of the most common adverse experiences were also identified as a common pre-existing
or frequently occurring medical conditions in this population.

In clinical trials with CRIXIVAN, nephrolithiasis, including flank pain with or without hematuria (including microscopic hematuria), has been reported in approximately 9.8% (252/2577) of patients receiving CRIXIVAN at the recommended dose compared to 2.2% in the control arms. In general, these eventswere not associated with renal dysfunction and resolved with hydration and temporary interruption of therapy (e.g., 1-3 days). (See PRECAUTIONS, Nephrolithiasis, and DOSAGE AND ADMINISTRATION.)

In clinical trials in pediatric patients 3 years of age and older, the adverse experience profile was similar to that for adult patients except for a higher frequency of nephrolithiasis of 24% (13/55) in pediatric patients who were treated with CRIXIVAN at the recommended dose of 500 mg/m2 every 8 hours.

Post-Marketed Experience
The following additional adverse experiences have been reported in post-marketed experience without regard to causality:
Body As A Whole/Site Unspecified: abdominal distention; redistribution/accumulation of body fat in areas such as the back of the neck, breasts, abdomen, and retroperitoneum.
Cardiovascular System: cardiovascular disorders including myocardial infarction and angina pectoris; cerebrovascular disorder.
Digestive System: liver function abnormalities; hepatitis including rare reports of hepatic failure (seePRECAUTIONS); pancreatitis.
Hematologic: increased spontaneous bleeding in patients with hemophilia; acute hemolytic anemia. (See PRECAUTIONS.)
Endocrine/Metabolic: new onset diabetes mellitus or hyperglycemia, or exacerbation of pre-existing diabetes mellitus (see PRECAUTIONS).
Hypersensitivity: anaphylactoid reactions.
Nervous System/Psychiatric: oral paresthesia.
Skin and Skin Appendage: rash including erythema multiforme and Stevens Johnson Syndrome; hyperpigmentation; alopecia; urticaria; ingrown toenails and/or paronychia.
Urogenital System: nephrolithiasis, generally without renal dysfunction; however, there have been reports of nephrolithiasis with renal dysfunction including acute renal failure (see PRECAUTIONS); crystalluria; interstitial nephritis sometimes with indinavir crystal deposits; in some patients, the interstitial nephritis did not resolve following discontinuation of CRIXIVAN.

The most frequently occurring selected laboratory adverse experiences (incidence =5%) considered by the investigator to be possibly, probably, or definitely drug related in the group treated with CRIXIVAN alone were changes in ALT, AST, indirect serum bilirubin, total serum bilirubin, and urine protein. Only 1% of patients discontinued treatment due to these laboratory adverse experiences when treated with CRIXIVAN alone or in combination with other antiretroviral agents.

Isolated asymptomatic hyperbilirubinemia (total bilirubin =2.5 mg/dl), reported predominantly as elevated indirect bilirubin and rarely associated with elevations in ALT, AST, or alkaline phosphatase, has occurred in patients treated with CRIXIVAN alone or in combination with other antiretroviral agents. Most patients continued treatment with CRIXIVAN without dosage reduction and bilirubin values gradually declined toward baseline.

In clinical trials with CRIXIVAN, asymptomatic pyuria of unknown etiology was noted in 10.9% (6/55) of pediatric patients 3 years of age and older who received CRIXIVAN at the recommended dose of 500 mg/m2 every 8 hours. Some of these events were associated with mild elevation of serum creatinine.

Post-Marketed Experience
The following additional laboratory adverse experiences have been reported: Increased serum triglycerides; increased serum cholesterol.

There have been reports of human overdosage with CRIXIVAN. The most commonly reported symptoms were gastrointestinal (e.g., nausea, vomiting, diarrhea) and renal (e.g., nephrolithiasis, flank pain, hematuria).

It is not known whether CRIXIVAN is dialyzable by peritoneal or hemodialysis.

To be filled in locally.