Indinavir
- Indinavir must be taken at intervals of 8 hours. 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 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. 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
- Delavirdine: Dose reduction of Indinavir 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 Indinavir to 600 mg every 8 hours is recommended when administering itraconazole 200 mg twice daily concurrently.
- Ketoconazole: Dose reduction of Indinavir 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 Indinavir to 1000 mg every 8 hours are recommended when rifabutin and Indinavir are coadministered.

# Hepatic Insufficiency
- The dosage of Indinavir 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.
- Dosage:
Monotherapy: 800 mg every 8 hours
Combined therapy: If combining with ritonavir, 800 mg indinavir and 100 mg ritonavir every 12 hours or 800 mg indinavir and 200 mg ritonavir every 12 hours
- Monotherapy: 800 mg every 8 hours
- Combined therapy: If combining with ritonavir, 800 mg indinavir and 100 mg ritonavir every 12 hours or 800 mg indinavir and 200 mg ritonavir every 12 hours
- Dosage:
Children (3 years to 12 years of age): 450 to 500 mg/m(2) PO q8h
Adolescents (13 years of age or greater): 800 mg PO 3 q8h
- Children (3 years to 12 years of age): 450 to 500 mg/m(2) PO q8h
- Adolescents (13 years of age or greater): 800 mg PO 3 q8h
- Inhibition of CYP3A4 by Indinavir can result in elevated plasma concentrations of the following drugs, potentially causing serious or life-threatening reactions:

# Nephrolithiasis/Urolithiasis
- Nephrolithiasis/urolithiasis has occurred with Indinavir 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 Indinavir; 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 Indinavir.

# Hemolytic Anemia
- Acute hemolytic anemia, including cases resulting in death, has been reported in patients treated with Indinavir  Once a diagnosis is apparent, appropriate measures for the treatment of hemolytic anemia should be instituted, including discontinuation of Indinavir.

# Hepatitis
- Hepatitis including cases resulting in hepatic failure and death has been reported in patients treated with Indinavir  Because the majority of these patients had confounding medical conditions and/or were receiving concomitant therapy(ies), a causal relationship between Indinavir 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 Indinavir with lovastatin or simvastatin is contraindicated due to an increased risk of myopathy including rhabdomyolysis. Caution should be exercised if Indinavir is used concurrently with atorvastatin or rosuvastatin. Titrate the atorvastatin and rosuvastatin doses carefully and use the lowest necessary dose with Indinavir.
- Midazolam is extensively metabolized by CYP3A4. Co-administration with 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 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 Indinavir should not be co-administered with orally administered midazolam, whereas caution should be used with co-administration of 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 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 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.
- Concomitant use of Indinavir and St. John's wort (Hypericum perforatum) or products containing St. John's wort is not recommended. Coadministration of Indinavir 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 Indinavir or to the class of protease inhibitors.
- 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 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 Indinavir  however, the risk over time remains relatively constant. Of the patients treated with 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.
- Asymptomatic hyperbilirubinemia (total bilirubin 2.5 mg/dL), reported predominantly as elevated indirect bilirubin, has occurred in approximately 14% of patients treated with Indinavir. 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 Indinavir alone, 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 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 Indinavir alone, Indinavir in combination with zidovudine or zidovudine plus lamivudine, zidovudine alone, or zidovudine plus lamivudine are presented in Table 11
- Cardiovascular System: cardiovascular disorders including myocardial infarction and angina pectoris; cerebrovascular disorder.
- Digestive System: liver function abnormalities; hepatitis including reports of hepatic failure; pancreatitis; jaundice; abdominal distention; dyspepsia.
- Hematologic: increased spontaneous bleeding in patients with hemophilia; acute hemolytic anemia.
- Endocrine/Metabolic: new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, hyperglycemia.
- Hypersensitivity: anaphylactoid reactions; urticaria; vasculitis.
- Musculoskeletal System: arthralgia, periarthritis.
- 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; interstitial nephritis sometimes with indinavir crystal deposits; in some patients, the interstitial nephritis did not resolve following discontinuation of Indinavir; renal insufficiency; renal failure; leukocyturia, crystalluria; dysuria.
- Laboratory Abnormalities: Increased serum triglycerides; increased serum cholesterol.
- 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 Indinavir and other drugs that inhibit CYP3A4 may decrease the clearance of indinavir and may result in increased plasma concentrations of indinavir.
- In rabbits, at a maternal dose of 240 mg/kg/day, no drug was detected in fetal plasma 1 hour after dosing. Fetal plasma drug levels 2 hours after dosing were approximately 3% of maternal plasma drug levels. In dogs, at a maternal dose of 80 mg/kg/day, fetal plasma drug levels were approximately 50% of maternal plasma drug levels both 1 and 2 hours after dosing. In rats, at maternal doses of 40 and 640 mg/kg/day, fetal plasma drug levels were approximately 10 to 15% and 10 to 20% of maternal plasma drug levels 1 and 2 hours after dosing, respectively.
- Indinavir was administered to Rhesus monkeys during the third trimester of pregnancy (at doses up to 160 mg/kg twice daily) and to neonatal Rhesus monkeys (at doses up to 160 mg/kg twice daily). When administered to neonates, indinavir caused an exacerbation of the transient physiologic hyperbilirubinemia seen in this species after birth; serum bilirubin values were approximately fourfold above controls at 160 mg/kg twice daily. A similar exacerbation did not occur in neonates after in utero exposure to indinavir during the third trimester of pregnancy. In Rhesus monkeys, fetal plasma drug levels were approximately 1 to 2% of maternal plasma drug levels approximately 1 hour after maternal dosing at 40, 80, or 160 mg/kg twice daily.
- Hyperbilirubinemia has occurred during treatment with Indinavir  It is unknown whether Indinavir administered to the mother in the perinatal period will exacerbate physiologic hyperbilirubinemia in neonates.
- There are no adequate and well-controlled studies in pregnant patients. Indinavir should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
- A Indinavir dose of 800 mg every 8 hours (with zidovudine 200 mg every 8 hours and lamivudine 150 mg twice a day) has been studied in 16 HIV-infected pregnant patients at 14 to 28 weeks of gestation at enrollment (study PACTG 358). Given the substantially lower antepartum exposures observed and the limited data in this patient population, indinavir use is not recommended in HIV-infected pregnant patients
- Indinavir was rapidly absorbed in the fasted state with a time to peak plasma concentration (Tmax) of 0.8  0.3 hours (mean  S.D.) (n=11). A greater than dose-proportional increase in indinavir plasma concentrations was observed over the 200-1000 mg dose range. At a dosing regimen of 800 mg every 8 hours, steady-state area under the plasma concentration time curve (AUC) was 30,691  11,407 nMhour (n=16), peak plasma concentration (Cmax) was 12,617  4037 nM (n=16), and plasma concentration eight hours post dose (trough) was 251  178 nM (n=16).
- Effect of Food on Oral Absorption: Administration of indinavir with a meal high in calories, fat, and protein (784 kcal, 48.6 g fat, 31.3 g protein) resulted in a 77%  8% reduction in AUC and an 84%  7% reduction in Cmax (n=10). Administration with lighter meals (e.g., a meal of dry toast with jelly, apple juice, and coffee with skim milk and sugar or a meal of corn flakes, skim milk and sugar) resulted in little or no change in AUC, Cmax or trough concentration.

# Distribution
- Indinavir was approximately 60% bound to human plasma proteins over a concentration range of 81 nM to 16,300 nM.

# Metabolism
- Following a 400-mg dose of 14C-indinavir, 83  1% (n=4) and 19  3% (n=6) of the total radioactivity was recovered in feces and urine, respectively; radioactivity due to parent drug in feces and urine was 19.1% and 9.4%, respectively. Seven metabolites have been identified, one glucuronide conjugate and six oxidative metabolites. In vitro studies indicate that cytochrome P-450 3A4 (CYP3A4) is the major enzyme responsible for formation of the oxidative metabolites.

# Elimination
- Less than 20% of indinavir is excreted unchanged in the urine. Mean urinary excretion of unchanged drug was 10.4  4.9% (n=10) and 12.0  4.9% (n=10) following a single 700-mg and 1000-mg dose, respectively. Indinavir was rapidly eliminated with a half-life of 1.8  0.4 hours (n=10). Significant accumulation was not observed after multiple dosing at 800 mg every 8 hours.
- No. 3756  200 mg capsules: semi-translucent white capsules coded "IndinavurTM 200 mg" in blue. Available as:
NDC 0006-0571-43 unit-of-use bottles of 360 (with desiccant).
- NDC 0006-0571-43 unit-of-use bottles of 360 (with desiccant).
- No. 3758  400 mg capsules: semi-translucent white capsules coded "IndinavurTM 400 mg" in green. Available as:
NDC 0006-0573-62 unit-of-use bottles of 180 (with desiccant)
- NDC 0006-0573-62 unit-of-use bottles of 180 (with desiccant)
- Indinavur Capsules are sensitive to moisture. Indinavur should be dispensed and stored in the original container. The desiccant should remain in the original bottle.
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