Indinavir Sulfate

Pronunciation: in-DIN-a-vir SUL-fate
Class: Protease inhibitor

Trade Names

Crixivan
- Capsules 100 mg
- Capsules 200 mg
- Capsules 400 mg

Pharmacology

Inhibits HIV protease, the enzyme that cleaves viral polyprotein precursors into functional proteins in HIV-infected cells. Inhibition of this enzyme by indinavir results in formation of immature noninfectious viral particles.

Slideshow: Flashback: FDA Drug Approvals 2013

Pharmacokinetics

Absorption

T max is approximately 0.8 h (fasting). C max is approximately 12,617 nM. The AUC at steady state is approximately 30,691 nM•h. Administration with a high calorie, fat, and protein meal reduced AUC approximately 77% and C max approximately 84%.

Distribution

60% is protein bound.

Metabolism

There are 7 metabolites: 1 glucuronide conjugate and 6 oxidative metabolites. CYP3A4 is major enzyme responsible for formation of oxidative metabolites.

Elimination

The half-life is approximately 1.8 h. Less than 20% is excreted unchanged in the urine.

Special Populations

Renal Function Impairment

The pharmacokinetics have not been studied in patients with renal insufficiency.

Hepatic Function Impairment

Mild to moderate hepatic insufficiency and clinical evidence of cirrhosis decreased metabolism, resulting in an approximate increase in AUC of 60% and increased half-life to approximately 2.8 h.

Children

AUC and C max slightly increased and trough concentrations were considerably lower.

Gender

Women have decreased AUC (13%) and C max (13%).

Race

The pharmacokinetics appear to be comparable between white and black patients.

Pregnancy

Mean AUC at weeks 30 to 32 of gestation was 74% lower than that observed 6 wk postpartum.

Indications and Usage

Treatment of HIV infection in combination with other antiretroviral agents.

Contraindications

Concomitant therapy with alfuzosin, amiodarone, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), alprazolam, oral midazolam, pimozide, triazolam, sildenafil (when used for the treatment of pulmonary arterial hypertension [PAH]); hypersensitivity to any component of the product.

Dosage and Administration

Adults

PO 800 mg (usually two 400 mg capsules) every 8 h.

Concomitant therapy
Delavirdine

Reduce indinavir to 600 mg every 8 h when administering delavirdine 400 mg 3 times a day.

Didanosine

Coadministration should be at least 1 h apart on an empty stomach.

Itraconazole

Reduce indinavir to 600 mg every 8 h when coadministered with itraconazole 200 mg twice daily.

Ketoconazole

Dosage reduction of indinavir to 600 mg every 8 h is recommended when coadministering ketoconazole.

Rifabutin

Reduce rifabutin to half the standard dose and increase dosage of indinavir to 1,000 mg every 8 h when rifabutin and indinavir are coadministered.

Dosage Adjustment in Hepatic Insufficiency
Adults Mild to moderate hepatic insufficiency caused by cirrhosis

PO 600 mg every 8 h.

General Advice

  • Administer with water on an empty stomach, 1 h before or 2 h after a meal.
  • If necessary, may be administered with skim milk, juice, coffee, tea, or with a light meal. Ensure adequate hydration (48 oz of liquid in 24 h).
  • Do not administer with meals high in calories, fat, or protein.
  • Use in combination with other antiretroviral agents.

Storage/Stability

Store in original container with desiccant at 59° to 86°F. Keep tightly closed. Protect from moisture.

Drug Interactions

Alfuzosin, alprazolam, amiodarone, cisapride, ergot derivatives (eg, dihydroergotamine, ergonovine, ergotamine, methylergonovine), midazolam (oral), pimozide, ranolazine, triazolam, vasopressin receptor antagonists (eg, conivaptan, tolvaptan)

Because of potential life-threatening reactions, concomitant use with indinavir is contraindicated.

Antiarrhythmic agents (eg, bepridil, quinidine, systemic lidocaine)

Concentrations of these agents may be elevated; monitoring of antiarrhythmic agent concentration is recommended.

Anticonvulsant agents (carbamazepine, phenobarbital, phenytoin)

Indinavir concentrations may be decreased, reducing the therapeutic effect. Use with caution.

Aripiprazole, eplerenone, erlotinib, everolimus, maraviroc, tyrosine kinase inhibitors (eg, dasatinib, lapatinib, pazopanib, sorafenib, sunitinib), quetiapine, risperidone, temsirolimus, trazodone

Plasma concentrations of these agents may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the patient and adjust the dose as needed when indinavir is started or stopped.

Atazanavir

Coadministration with indinavir is not recommended because both agents are associated with indirect hyperbilirubinemia.

Benzodiazepines (eg, diazepam)

Serum concentrations of benzodiazepines may be elevated, resulting in prolonged or increased sedation or respiratory depression. Alprazolam, oral midazolam, and triazolam are contraindicated in patients taking indinavir. If parenteral midazolam is coadministered, use with caution. Closely monitor for respiratory depression and/or prolonged sedation. Adjust the midazolam dose as needed.

Bosentan

Start at or adjust bosentan to 62.5 mg daily or every other day based upon individual tolerability.

Buspirone

Plasma concentrations and pharmacologic effects of buspirone may be increased by indinavir. Closely monitor the patient for signs of new-onset parkinsonian symptoms (eg, ataxia, shuffling gait, cogwheel rigidity, resting tremor, sad affect, masked facies) when buspirone and indinavir are coadministered.

Clarithromycin, nelfinavir, ritonavir

Indinavir concentrations may be elevated, increasing the risk of adverse reactions. The appropriate dose of indinavir is not known.

Colchicine

Colchicine and indinavir should not be coadministered to patients with hepatic or renal impairment. For treatment of gout flares, coadminister colchicine 0.6 mg followed by 0.3 mg 1 h later. Do not repeat dose earlier than 3 days. For prophylaxis of gout flares, if the original colchicine regimen was colchicine 0.6 mg twice daily, adjust the dosage to 0.3 mg once a day. If the original colchicine dosage was 0.6 mg once daily, adjust the regimen to colchicine 0.3 mg every other day. For treatment of familial Mediterranean fever, coadminister colchicine at a max daily dosage of 0.3 mg twice a day.

Corticosteroids, inhaled/nasal (eg, fluticasone)

Corticosteroid plasma concentrations may be increased. Monitor for signs of adrenal insufficiency. Consider alternatives to fluticasone for long-term use.

Delavirdine, itraconazole, ketoconazole

Indinavir concentrations may be elevated; consider reducing the indinavir dosage (600 mg every 8 h).

Didanosine

Separate administration of indinavir and didanosine formulations containing buffer by at least 1 h and give on an empty stomach.

Dihydropyridine calcium channel blockers (eg, felodipine, nicardipine, nifedipine)

Concentrations of these agents may be increased by indinavir; clinical monitoring is recommended.

Dronedarone, erythromycin

Plasma concentrations may be elevated, increasing the pharmacologic effects and risk of toxicity. Avoid coadministration.

Efavirenz, nevirapine

Indinavir concentration may be reduced; the optimal dose of indinavir is not known.

Eletriptan

Eletriptan plasma concentrations may be elevated by indinavir, increasing the pharmacologic effects and risk of adverse reactions. Eletriptan should not be used within 72 h of indinavir.

Eszopiclone

Eszopiclone plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Close monitoring is indicated. Consider reducing the eszopiclone dose when coadministered with indinavir.

Fluoxetine

Indinavir may increase plasma concentrations of fluoxetine. Similarly, fluoxetine may increase plasma concentrations of indinavir. Closely monitor the patient for adverse reactions, including serotonin syndrome. Dosage reduction of fluoxetine and/or indinavir may be needed during coadministration of these agents.

Food

Administration of indinavir with a meal high in calories, fat, and protein resulted in a reduction in AUC and C max . Administration with lighter meals resulted in little or no change in AUC, C max , or trough concentration. For optimal absorption, give indinavir without food, but with water, 1 h before or 2 h after a meal.

Garlic

Garlic may reduce indinavir plasma concentrations, decreasing the pharmacologic effects. Avoid garlic ingestion.

Grapefruit juice

Administering indinavir with grapefruit may delay the time to reach indinavir peak plasma concentrations.

HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin)

Coadministration with indinavir is not recommended because of increased risk of myopathy, including rhabdomyolysis. Lovastatin, rosuvastatin, and simvastatin are not recommended for concomitant use with indinavir. Use the lowest possible dose of atorvastatin or rosuvastatin and monitor for adverse reactions. The interaction of indinavir with fluvastatin or pravastatin is not known.

Iloperidone

Iloperidone plasma concentrations and pharmacologic effects may be increased. A modification of the iloperidone dosage is recommended. Reduce the dosage of iloperidone by one-half when coadministered with indinavir. If therapy with indinavir is discontinued, increase the dosage of iloperidone to the original dose.

Immunosuppressants (eg, cyclosporine, sirolimus, tacrolimus)

Plasma concentrations may be elevated by indinavir, increasing the therapeutic and adverse effects. Monitor the clinical response of the patient and immunosuppressant concentrations. Adjust the immunosuppressant dose as needed.

Interleukins (eg, aldesleukin)

Indinavir concentrations may be elevated, increasing the risk of toxicity. Adjust dose of indinavir as needed when interleukins are started or stopped.

Ixabepilone

Ixabepilone plasma concentrations may be elevated, increasing the risk of ixabepilone toxicity. Avoid coadministration or consider a dose reduction of ixabepilone.

Muscarinic receptor antagonists (eg, darifenacin, fesoterodine, solifenacin, tolterodine)

Muscarinic receptor antagonist plasma concentrations may be increased by indinavir. When indinavir is coadministered, the dose of darifenacin should not exceed 7.5 mg daily, the dose of fesoterodine should not exceed 4 mg daily, the dose of solifenacin should not exceed 5 mg daily, and the dose of tolterodine should not exceed 2 mg daily.

Nilotinib

Plasma concentrations and pharmacologic effects of nilotinib may be increased by indinavir. Avoid coadministration. If indinavir must be given, consider interrupting nilotinib therapy. If indinavir must be coadministered with nilotinib, consult official package labeling for specific recommendations.

Opioid analgesics (eg, buprenorphine, fentanyl, oxycodone)

Indinavir may increase plasma concentrations and pharmacologic effects of opioid analgesics. Severe respiratory depression may occur. Closely monitor the clinical status of the patient, including respiratory function. Adjust the opioid analgesic dose as needed.

Phosphodiesterase type 5 inhibitors (eg, sildenafil, tadalafil, vardenafil)

Indinavir may increase concentrations of these agents; dosage reduction is necessary. Coadministration of sildenafil and indinavir is contraindicated for the treatment of PAH. A safe and effective dose has not been established when used with indinavir. For coadministration of indinavir and tadalafil when tadalafil is used for treatment of PAH, start at or adjust the tadalafil dosage to 20 mg once daily. Increase to 40 mg once daily based upon individual tolerability. For the treatment of erectile dysfunction in patients receiving indinavir, the sildenafil dose should not exceed a max of 25 mg in a 48-h period, the tadalafil dose should not exceed a maximum of 10 mg in a 72-h period in patients on concomitant therapy, and the vardenafil dose should not exceed a maximum of 2.5 mg in a 24-h period in patients receiving concomitant therapy.

Proton pump inhibitors (eg, esomeprazole, lansoprazole, omeprazole, pantoprazole)

Coadministration may reduce the antiviral activity of indinavir. Monitor the clinical response of the patient and adjust the indinavir dose as needed.

Rifabutin

When coadministered with indinavir, a dose reduction of rifabutin to 50% the standard dosage and an increase of indinavir to 1,000 mg every 8 h is recommended.

Rifampin, St. John's wort

Coadministration is not recommended because indinavir serum levels may be reduced, decreasing the clinical effect and possibly leading to resistance to indinavir or the class of protease inhibitors.

Ritonavir, saquinavir

Concentrations of these medications may be increased.

Romidepsin

Romidepsin plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions, including QT prolongation. If coadministration cannot be avoided, close clinical, laboratory, and ECG monitoring are indicated. Adjust the dosage of romidepsin accordingly.

Salmeterol

The risk of CV adverse events associated with salmeterol, including QT prolongation, palpitation, and sinus tachycardia, may be increased. Coadministration is not recommended.

Thyroid hormones (eg, levothyroxine)

Thyroxine serum concentrations may be increased or decreased, resulting in hyper- or hypothyroidism. Closely monitor thyroid function when indinavir is started or stopped. Adjust the thyroid hormone dose as needed.

Warfarin

The anticoagulant effect of warfarin may be decreased. Monitor coagulation parameters when indinavir is started or stopped. Adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Angina pectoris, cerebrovascular disorder, MI (postmarketing).

CNS

Headache (5%); dizziness (3%); asthenia/fatigue, malaise, somnolence (2%); depression, oral paresthesia (postmarketing).

Dermatologic

Pruritus (4%); rash (1%); alopecia, erythema multiforme, hyperpigmentation, ingrown toenails, paronychia, Stevens-Johnson syndrome (postmarketing).

EENT

Taste perversion (3%).

Endocrine

Exacerbation of preexisting diabetes mellitus, hyperglycemia, new-onset diabetes mellitus (postmarketing).

GI

Abdominal pain (17%); nausea (12%); vomiting (8%); acid regurgitation, anorexia, diarrhea (3%); dyspepsia, increased appetite (2%); abdominal distension, pancreatitis (postmarketing).

Genitourinary

Nephrolithiasis/urolithiasis (9%); dysuria (2%); acute renal failure, crystalluria, dysuria, interstitial nephritis sometimes with indinavir crystal deposits, leukocyturia, pyelonephritis with or without bacteremia, renal insufficiency (postmarketing).

Hematologic-Lymphatic

Anemia (1%); acute hemolytic anemia, increased spontaneous bleeding in patients with hemophilia (postmarketing).

Hepatic

Jaundice (2%); hepatic failure, hepatitis, liver function abnormalities (postmarketing).

Hypersensitivity

Anaphylactoid reactions, urticaria, vasculitis (postmarketing).

Lab Tests

Increased serum bilirubin (12%); increased ALT (5%); increased AST (4%); decreased neutrophils, increased serum amylase (2%); decreased hemoglobin, decreased platelet count, increased glucose (1%); increased serum cholesterol and triglycerides (postmarketing).

Musculoskeletal

Back pain (8%); arthralgia (postmarketing).

Respiratory

Cough (2%).

Miscellaneous

Fever (2%); redistribution/accumulation of body fat (postmarketing).

Precautions

Monitor

Monitor patients for signs or symptoms of nephrolithiasis/urolithiasis (including flank pain with or without hematuria or microscopic hematuria). Monitor blood glucose levels closely; new-onset diabetes or exacerbation of preexisting diabetes has been associated with protease inhibitor therapy. Closely follow patients with asymptomatic severe leukocyturia and frequently monitor with urinalysis.


Pregnancy

Category C .

Lactation

Undetermined. HIV-infected mothers should not breast-feed to avoid risking potential transmission of HIV to infant.

Children

Safety and efficacy not established.

Elderly

Dose selection should be cautious, reflecting greater frequency of decreased hepatic, renal, or cardiac function.

Hepatic Function

Lower the dosage of indinavir in patients with hepatic insufficiency caused by cirrhosis.

Fat redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral and facial wasting, breast enlargement, and cushingoid appearance, have been reported.

Hemolytic anemia

Acute hemolytic anemia, including cases resulting in death, have been reported. Discontinue indinavir and treat appropriately if hemolytic anemia occurs.

Hemophilia

Spontaneous bleeding and increased need for factor VIII has been reported in patients with hemophilia A and B treated with protease inhibitors.

Hepatic insufficiency/cirrhosis

Lower indinavir doses may be required because indinavir is hepatically metabolized.

Hepatitis

Hepatitis, including cases resulting in death, has been reported during treatment with indinavir.

Hyperbilirubinemia

Indirect hyperbilirubinemia has occurred frequently during treatment with indinavir; increases in serum transaminases have occurred infrequently.

Hyperglycemia

New-onset diabetes mellitus, exacerbation of preexisting diabetes, and hyperglycemia have been reported in patients receiving protease inhibitor therapy.

Immune reconstitution syndrome

Has been reported in patients treated with combination antiretroviral therapy.

Nephrolithiasis/Urolithiasis

Has occurred, more commonly in children than adults. Temporarily interrupt (eg, 1 to 3 days) or discontinue therapy if signs or symptoms of nephrolithiasis/urolithiasis occur (flank pain with or without hematuria or microscopic hematuria).

Tubulointerstitial nephritis

Tubulointerstitial nephritis with medullary calcification and cortical atrophy have been reported in patients with asymptomatic severe leukocyturia (greater than 100 cells/high power field). Follow patients closely, frequently monitor with urinalysis, and consider discontinuing indinavir in patients who develop asymptomatic severe leukocyturia.

Overdosage

Symptoms

Diarrhea, flank pain, hematuria, nausea, nephrolithiasis/urolithiasis, vomiting.

Patient Information

  • Explain name, dose, action, potential side effects of drug, and special storage requirements (store in original container with desiccant and keep tightly closed).
  • Advise patient or caregiver to read the Patient Information leaflet before starting therapy and with each refill.
  • Warn patient that this drug is not to be used by itself but is combined with other antiviral agents and not to change the dose or stop taking any other antiviral agents unless advised by health care provider.
  • Instruct patient to take indinavir exactly as prescribed and not to change the dose or discontinue therapy unless advised by health care provider.
  • Advise patient to take prescribed dose with water on an empty stomach 1 h before or 2 h after meals. Advise patient that if stomach upset occurs, medication may be taken with other liquids (eg, skim milk, juice, coffee or tea) or with a light meal (eg, dry toast with jelly, skim milk, juice, coffee with skim milk and sugar, corn flakes with skim milk and sugar). Caution patient that taking indinavir with a meal high in calories, fat, and protein reduces absorption and effectiveness of indinavir.
  • Advise patient that if a dose is missed to take the dose as soon as possible and then return to the normal schedule. However, if a dose is skipped, caution patient not to double the dose to catch up but to continue with their normal schedule.
  • Advise patient to maintain good hydration and that adults should drink at least 48 oz of liquids every day.
  • Advise patient that indinavir may cause changes in body fat distribution (eg, increased amount of fat in upper back and neck, breasts, and around the back, chest, and stomach area; or loss of fat from arms, legs, and face) and that the cause and long-term health effects of these changes are not know at this time. Advise patient to report changes in body fat distribution to health care provider.
  • Inform patient that indinavir does not completely eliminate HIV virus and therefore does not reduce risk of transmitting HIV to others. Appropriate precautions (eg, practice safer sex using a latex or polyurethane condom to lower chance of sexual contact with semen, vaginal secretions, or blood; not using or sharing dirty needles) must still be followed.
  • Advise patient that indinavir is not a cure for HIV infection and illnesses associated with HIV infection, including opportunistic infections, may continue to be acquired. Patient should remain under a health care provider's care.
  • Instruct patient to not take any prescription or OTC medications, herbal preparations, or dietary supplements, particularly St. John's wort, unless advised by health care provider. Caution patient not to start any new medication or dietary supplement without talking to health care provider first.
  • Instruct diabetic patient to monitor blood glucose more frequently when drug is started or dose is changed and to inform health care provider of significant changes in readings.
  • Advise women to notify health care provider if pregnant, planning to become pregnant, or breast-feeding. Caution HIV-infected mothers that breast-feeding could cause HIV infection in the baby.
  • Remind patient that examinations and laboratory tests will be required to monitor therapy and to keep appointments.

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