IND-400 CAPSULES
(Indinavir Capsules 400mg)
Composition:
Each Capsule contains:
Indinavir Sulphate ... 400 mg.
Presentation:
10x10's
Pharmacology:
Indinavir 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.
Pharmacokinetics:
Absorption:
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 nM"hour (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 A.C. 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
Indications:
Indinavir in combination with antiretroviral agents is indicated
for the treatment of HIV infection in adults only.
Contra-indications:
Indinavir is contraindicated in patients with clinically significant
hypersensitivity to any of its components.
Indinavirshould 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.
Dosage and directions for use:
The recommended dosage of indinavir is 800 mg (two 400-mg capsules)
orally every 8 hours.
For optimal absorption, indinavir 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 the patient
drink at least 1.5 litres (approximately 48 ounces) of liquids
during the course of 24 hours.
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. 1-3 days) or discontinuation of 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.
Efavirenz
Dose increase of indinavir to 1000 mg every 8 hours is recommended
when administering efavirenz concurrently.
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 and a dose
increase of indinavir to 1000 mg (three 333-mg capsules) every
8 hours are recommended when rifabutin and indinavir are coadministered.
Warning:
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 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 case
Side-effects & special precautions:
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
Musculoskeletal System: Arthralgia
Nervous System / Psychiatric: Oral paresthesia;
depression.
Skin and Skin Appendages: 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; interstitial nephritis
sometimes with indinavir crystal deposits; in some patients, the
interstitial nephritis did not resolve following discontinuation
of indinavir; crystalluria; dysuria.
Laboratory abnormalities: Increased serum triglycerides,
increased serum cholesterol.
Special precautions:
Pregnancy
There are no adequate and well-controlled studies in pregnant
women. Indinavir 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 Indivan-400. It is also recommended
that HIV-infected mothers not breast-feed their infants to avoid
risking postnatal transmission of HIV.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
Drug Interaction:
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.
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.
Itraconazole: Itraconazole is an inhibitor of
P-450 3A4 that increases plasma concentrations of indinavir. Therefore,
a dosage induction of indinavir is recommended when indinavir
and itraconazole are co-administered.
Ketoconazole: Ketoconazole is an inhibitor of
P-450 3A4 that increases plasma concentrations of indinavir. Therefore,
a dosage reduction of indinavir is recommended when indinavir
and itraconazole are co-administered.
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
are necessary when rifabutin is coadministered with indinavir.
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).
Rifampin: Rifampin is a potent inducer of P-450
3A4 that markedly diminishes plasma concentrations of indinavir.
Therefore, Indinavirand rifampin should not be coadministered.
Known symptoms of overdosage and particulars of its treatment:
There have been more than 60 reports of acute or chronic human
overdosage (up to 23 times the recommended total daily doses of
2400 mg) with indinavir. The most commonly reported symptoms were
renal (e.g. nephrolithiasis/urolithiasis, flank pain, hematuria)
and gastrointestinal (e.g. nausea, vomiting, diarrhoea).
It is not known whether indinavir is dialyzable by peritoneal
or hemodialysis.
Storage conditions and period.
Store in cool, dry & dark place, preferably below 25°C.
Storage life is 2 years.
Package: 10 capsules packed in blister strip,
10 such blisters packed in a carton.
