1. ROUTE OF ADMINISTRATION

Oral

DOSAGE AND ADMINISTRATION
The recommended dosage of Indinavir Sulphate is 800 mg(two 400-mg capsules) orally every 8 hours.
For optimal absorption, Indinavir Sulphate should be administered without food but with water 1 hour before or 2 hours after a meal. Alternatively, Indinavir Sulphate 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 the patient drink atleast 1.5 liters (approximately 48 ounces) of liquids during the course of 24 hours.

Hepatic Insufficiency
The dosage of Indinavir Sulphate 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. 1-3 days) or discontinuation of therapy.

Delavirdine
Dose reduction of Indinavir Sulphate 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 beadministered at least one hour apart on an empty stomach.
Efavirenz
Dose increase of Indinavir Sulphate to 1000 mg every 8 hours is recommended when administering efavirenz concurrently.

Itraconazole
Dose reduction of Indinavir Sulphate to 600 mg every 8 hours is recommended when administering itraconazole 200 mg twice daily concurrently.

Ketoconazole
Dose reduction of Indinavir Sulphate to 600 mg every 8 hours is recommended when administering ketoconazole concurrently.

Rifabutin
Dose reduction of rifabutin to half the standard dose and a dose increase of indinavir to 1000mg (three 333-mg capsules) every 8 hours are recommended when rifabutin and indinavir are coadministered

2. THERAPEUTIC / DIAGNOSTIC CLAIMS

Indinavir Sulphate Capsules in combination with antiretroviral agents is indicated for the treatment of HIV infection in adults only.

3. DESCRIPTION OF DOSAGE FORM

Indinavir Sulphate is an inhibitor of the human immunodeficiency virus (HIV) protease.
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 and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins, resulting in the formation of immature noninfectious viral particles.

Warnings And Precautions :

Nephrolithiasis/Urolithiasis
Nephrolithiasis/Urolithiasis has occurred with indinavir therapy. In some cases, nephrolithiasis has been associated with renal insufficiency or acute renal failure. 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 Anaemia
Acute haemolytic anaemia, including cases resulting in death, has been reported in patients treated with indinavir. Once a diagnosis is apparent, appropriate measures for the treatment of haemolytic anaemia 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 casual 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 the treatments of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases.

Precautions:
Drug Interactions
Concomitant use of indinavir with lovastatin or simvastatin is not recommended. Caution should be exercised if HIV protease inhibitors, including indinavir, are used concurrently with other HMG-CoA reductase inhibitors that are also metabolized by the CYP3A4 pathway (e.g. atorvastatin or cerivastatin). The risk of myopathy including rhabdomyolysis may be increased when HIV protease inhibitors, including indinavir are used in combination with these drugs.
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.
Delavirdine
Due to an increase in indinavir plasma concentrations (preliminary results), a dosage reduction of indinavir should be considered when ritonavir and delavirdine are coadministered (see dosage and administration).
Efavirenz
Due to a decrease in the plasma concentrations of indinavir, a dosage increase of indinavir is recommended when indinavir and efavirenz are coadministered. No adjustment of the dose of efavirenz is necessary when given with indinavir (see dosage and administration).
Itraconazole
Itraconazole is an inhibitor of P-450 3A4 that increases plasma concentrations of indinavir. Therefore, a dosage reduction of indinavir is recommended when Indinavir Sulphate and itraconazole are co-administered (see dosage and administration)
Ketoconazole
Ketoconazole is an inhibitor of P-450 3A4 that increases plasma concentration of indinavir. Therefore a dosage reductions of indinavir is recommended when Indinavir Sulphate and Itraconazole are co-administered (see dosage and administration)
Rifabutin
When rifabutin and indinavir are coadministered, there is an increase in the plasma concentrations of rifabutin and a decrease in plasma concentrations of indinavir. A dosage reduction of rifabutin and a dosage increase of Indinavir Sulphate-200 are necessary when rifabutin is coadministered with Indinavir Sulphate-200. The suggested dose adjustments are expected to result in rifabutin concentrations at least 50% higher than typically observed when rifabutin is administered alone at its usual dose (300 mg/day) and indinavir concentrations which may be slightly less than typically observed when indinavir is administered alone at its usual dose (800 mg every 8 hours) (see ‘Dosage and Administration’).
Rifampin
Rifampin is a potent inducer of P-450 3A4 that markedly diminishes plasma concentrations of indinavir. Therefore, Indinavir Sulphate and rifampin should not be coadministered.
Others
If Indinavir Sulphate and didanosine are administered concomitantly, they should be administered at least one hour apart on an empty stomach; a normal (acidic) gastric pH may be necessary for optimum absorption of indinavir; whereas acid rapidly degrades didanosine which is formulated with buffering agents to increase pH.
Interactions between indinavir and less potent CYP3A4 inducers than rifampin, such as phenobarbital, phenytoin, carbamazepine and dexamethasone have not been studied. These agents should be used with caution if administered concomitantly with indinavir because it may result in decreased indinavir plasma concentrations.

Hyperbilirubinemia
Indirect hyperbilirubinemia has occurred frequently during treatment with indinavir and has infrequently been associated with increases in serum transaminases. It is not known whether indinavir will exacerbate the physiologic hyperbilirubinemia seen in neonates.
Coexisting Conditions
Patients with hemophilia: There have been reports of spontaneous bleeding in patients with hemophilia A or 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.
Patients with hepatic insufficiency due to cirrhosis: In these patients, the dosage of Indinavir Sulphate should be lowered because of decreased metabolism of Indinavir Sulphate (see ‘Dosage and Administration’).
Patients with renal insufficiency: Patients with renal insufficiency have not been studied.
Fat Redistribution
Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving protease inhibitors. The mechanism and long-term consequence of these events are currently unknown. A causal relationship has not been established.

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

Lactation:
Although it is not known whether indinavir is excreted in human milk there exists the potential for adverse effects from indinavir in nursing infants. Mothers should be instructed to discontinue nursing if they are receiving Indinavir Sulphate. It is also recommended that HIV-infected mothers not breast-feed their infants to avoid risking postnatal transmission of HIV.

Paediatric Use:
Safety and effectiveness in pediatric patients have not been established.

4. CONTRAINDICATIONS

Indinavir Sulphate is contraindicated in patients with clinically significant hypersensitivity to any of its components.
Indinavir Sulphate should not be administered concurrently with terfenadine, cisapride, astemizole, triazolam, midazolam, pimozide, or ergot derivatives. Inhibition of CYP3A4 by indinavir could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.

5. SIDE EFFECTS

Body As A Whole:
Redistribution/accumulation of body fat.

Cardiovascular System:
Cardiovascular disorders including myocardial infarction and angina pectoris.

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
Muscoskeletal System:
Arthralgia.

Nervous system/Psychiatric;
Oral paraesthesia; depression.

Skin and skin Appendages:
Rash including erythema multi-forme and Stevens-Johnson Syndrome; hyperpigmentation: alopecia; ingrown toenails and/or paronychia; pruritis.

Urinogenital system:
Nephrolithiasis /urolithiasis; in some cases resulting in renal insufficiency or acute renal failure; interstitial nephritis sometimes with indinavir crystal deposits; in some patients, the interstitial nephritis did not resolve following discontinuation of indinavir; crystalluria; dysuria.

Laboratories abnormalities :
Increased serum triglycerides, increased serum cholestrol.

6. TOXIC EFFECT:

Mutagenicity, Carcinogenecity and Teratogenecity
In vitro, Indinavir was not mutagenic or genotoxic in microbial mutagenesis (Ames) tests, alkaline elution assays for DNA breakage , or mammalian cell mutagenesis assays. In addition, there was no evidence of chromosome aberrations in in vitro or in vivo studies.
No evidence of an increased incidence of tumor types was observed in carcinogenicity studies in mice. An increased incidence of thyroid adenomas was observed in male rats given Indinavir 640 mg/kg daily (exposure in rats equivalent to 1.3 times that of daily systemic exposure in humans).
There are no adequate and controlled studies to date using Indinavir in pregnant women, and Indinavir should be used during pregnancy only when the potential benefits justify the possible risk to the fetus. Hyperbilirubinemia, generally reported as an increase in indirect bilirubin, has occurred in patients receiving Indinavir and the manufacturer cautions that it is not known whether administration of the drug to a pregnant women during the perinatal period can exacerbate physiologic hyperbilirubinemia in the neonate.