The following information was generated from the Hazardous Substances Data Bank (HSDB),a database of the National Library of Medicine's TOXNET system(http://toxnet.nlm.nih.gov) on September 19, 2015.Query: Records containing the term 157810 81 6 1 - HSDBNAME: INDINAVIR SULFATEHSN: 7158RN: 157810-81-6OVERVIEW:HUMAN HEALTH EFFECTS:HUMAN TOXICITY EXCERPTS: /HUMAN EXPOSURE STUDIES/ Studies have not been done with the cytochrome p450 CYP3A4 substrates astemizole, cisapride, midazolam, terfenadine, and triazolam; because competition for CYP3A4 by indinavir could result in inhibition of the metabolism of these medications and elevated plasma concentrations, there is a potential for serious and/or life-threatening side effects; concurrent use of indinavir with any of these medications is not recommended.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** /HUMAN EXPOSURE STUDIES/ 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.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /HUMAN EXPOSURE STUDIES/ Adverse cardiovascular effects, including myocardial infarction and angina pectoris, have been reported in patients receiving indinavir. Cerebrovascular disorder has been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /SIGNS AND SYMPTOMS/ Overdosage of indinavir would be expected to produce manifestations that are principally extensions of the adverse reactions reported with the drug. There have been at least 60 reports of acute or chronic overdosage of indinavir (up to 23 times the recommended daily dosage of 2400 mg), and the most commonly reported symptoms of overdosage were renal effects (e.g., nephrolithiasis, flank pain, hematuria) and GI effects (e.g., nausea, vomiting, diarrhea).[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /EPIDEMIOLOGY STUDIES/ ... Patients from the ANRS-1215 cohort in Senegal, started with either one non-nucleoside reverse transcriptase inhibitor (NNRTI) or indinavir, a first-generation non-boosted protease inhibitor (PI), followed for > 6 months and having > 1 viral load (VL) measurement were included. Virological failure was defined as two consecutive VL measurements > 1000 cp/mL. Of the 366 patients included, 89% achieved a VL < 500 cp/mL. The risk of virological failure at 12, 24, and 60 months was 5, 16 and 25%, being higher in younger patients (p=0.05), those receiving a PI-containing regimen (p=0.05) and those with lower adherence (p=0.03). The risk of resistance to any drug at 12, 24, and 60 months was 3, 11 and 18%. After virological failure, 60% of the patients were switched to second-line treatments. While 81% of them patients achieved virological success, the risk of virological failure was 27% at 24 months, mostly in patients with multiple resistances. In this cohort, virological outcomes for first-line treatments were good compared to those from high-resource settings. However, the rate of virological failure for second-line treatment was high, probably because of accumulation of resistances.[De Beaudrap P et al; J Acquir Immune Defic Syndr 2012 Oct 31. (Epub ahead of print)] **PEER REVIEWED** PubMed Abstract /OTHER TOXICITY INFORMATION/ ...In treatment-naive HIV-infected adults, substantial increases in serum amylase concentrations (increases exceeding 200% of the upper limit of the normal range) occurred in 2.1% of patients receiving indinavir monotherapy and 1.9% of patients receiving indinavir in conjunction with zidovudine. Pancreatitis has been reported during postmarketing surveillance. Pancreatitis resulting in death has been reported in a patient receiving didanosine, stavudine, indinavir, and hydroxyurea.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /OTHER TOXICITY INFORMATION/ Acute hemolytic anemia has occurred in patients receiving indinavir and in some cases resulted in death. If acute hemolytic anemia occurs in a patient receiving indinavir, appropriate measures should be taken to treat the condition including discontinuance of indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /OTHER TOXICITY INFORMATION/ Anaphylactoid reaction has been reported with indinavir. ...In treatment-naive HIV-infected adults, pruritus occurred in 4.2 or 2.4% and rash occurred in 1.2 or 0.6% of patients receiving indinavir or indinavir in conjunction with zidovudine, respectively. Erythema multiforme, Stevens-Johnson syndrome, hyperpigmentation, alopecia, urticaria, ingrown toenails, paronychia, and vasculitis have been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /OTHER TOXICITY INFORMATION/ Acute hepatitis sometimes resulting in hepatic failure and death have been reported in a few patients receiving indinavir in conjunction with other drugs. ...Jaundice was reported in 1.5-2.1% of patients receiving indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** DRUG WARNINGS: Nephrolithiasis/urolithiasis, which may present as flank pain with or without hematuria (including microscopic hematuria), has been reported in about 9% of adults and 29% of pediatric patients receiving indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The most frequent adverse effects associated with indinavir therapy involve the GI tract. ...In treatment-naive HIV-infected adults, abdominal pain, nausea, vomiting, and diarrhea occurred in 16.6, 11.7, 8.4, and 3.3%, respectively, and acid regurgitation, anorexia, dyspepsia, increased appetite, and taste perversion occurred in 1.5-2.7% of patients receiving indinavir monotherapy. In patients in study 028 receiving indinavir in conjunction with zidovudine, abdominal pain, nausea, vomiting, and diarrhea occurred in 16, 31.9, 17.8, and 3%, respectively, and acid regurgitation, anorexia, dyspepsia, increased appetite, and taste perversion occurred in 1.5-8.4% of patients. ...Safety and efficacy of indinavir in pediatric patients have not been established. Indinavir has been used in a limited number of HIV-infected children 3 months of age or older without unusual adverse effects. However, nephrolithiasis/urolithiasis has been reported more frequently in pediatric patients receiving indinavir (29%) than in adults receiving the drug (9.2%).[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Asymptomatic hyperbilirubinemia (i.e., total serum bilirubin concentrations exceeding 2.5 mg/dL) has occurred in about 14% of patients receiving indinavir in clinical studies. Asymptomatic bilirubinemia usually has been reported as elevated indirect bilirubin and has been associated with increased serum AST (SGOT) or ALT (SGPT) concentrations only rarely (i.e., in less than 1% of patients receiving the drug).[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Acute hepatitis sometimes resulting in hepatic failure and death have been reported in a few patients receiving indinavir in conjunction with other drugs. ...Jaundice was reported in 1.5-2.1% of patients receiving indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults, headache occurred in 5.4 or 9.6%, dizziness in 3 or 3.9%, and somnolence in 2.4 or 3.3% of adults receiving indinavir monotherapy or indinavir in conjunction with zidovudine, respectively. Oral paresthesia and depression have been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Anaphylactoid reaction has been reported with indinavir. ...In treatment-naive HIV-infected adults, pruritus occurred in 4.2 or 2.4% and rash occurred in 1.2 or 0.6% of patients receiving indinavir or indinavir in conjunction with zidovudine, respectively. Erythema multiforme, Stevens-Johnson syndrome, hyperpigmentation, alopecia, urticaria, ingrown toenails, paronychia, and vasculitis have been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults, back pain occurred in 8.4% of patients receiving indinavir monotherapy and 4.5% of patients receiving indinavir in conjunction with zidovudine. Arthralgia has been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults receiving indinavir alone or in conjunction with zidovudine, neutropenia (neutrophil count < 750/cu mm) occurred in 2.2-2.4% of patients, anemia (hemoglobin concentrations < 7 g/dL) occurred in 0.6-0.9% of patients, and thrombocytopenia (platelet counts < 50,000/cu mm) occurred in 0.9% of patients.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Acute hemolytic anemia has occurred in patients receiving indinavir and in some cases resulted in death. If acute hemolytic anemia occurs in a patient receiving indinavir, appropriate measures should be taken to treat the condition including discontinuance of indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving HIV protease inhibitors, including indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Cough and dyspnea have occurred in less than 2% of patients receiving indinavir in phase II/III clinical studies. Anterior uveitis has occurred in at least one patient receiving indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...Asthenia/fatigue occurred in 2.1 or 4.2%, fever in 1.5 or 1.5%, and malaise in 2.1 or 2.7% of patients receiving indinavir monotherapy or indinavir in conjunction with zidovudine, respectively. Increased serum cholesterol has been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults, substantial increases in serum amylase concentrations (increases exceeding 200% of the upper limit of the normal range) occurred in 2.1% of patients receiving indinavir monotherapy and 1.9% of patients receiving indinavir in conjunction with zidovudine. Pancreatitis has been reported during postmarketing surveillance. Pancreatitis resulting in death has been reported in a patient receiving didanosine, stavudine, indinavir, and hydroxyurea.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Adverse cardiovascular effects, including myocardial infarction and angina pectoris, have been reported in patients receiving indinavir. Cerebrovascular disorder has been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Nephrolithiasis/urolithiasis has occurred in some patients receiving indinavir and may be associated with substantial renal impairment or acute renal failure. If signs and symptoms of nephrolithiasis/urolithiasis occur, such as flank pain with or without hematuria (including microhematuria), indinavir therapy should be temporarily interrupted during the acute phase (e.g., for 13 days) or the drug should be discontinued. Patients receiving indinavir should be adequately hydrated and should be instructed to drink at least 1.5 L (approximately 48 ounces) of liquids daily (i.e., every 24 hours).[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The possibility that the risk of spontaneous bleeding may be increased in patients with hemophilia receiving an HIV protease inhibitor should be considered.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The possibility that hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus may occur in patients receiving an HIV protease inhibitor should be considered.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** In a limited study in pediatric patients 9-14 years of age receiving indinavir for at least 1 year, about 46% had adverse renal effects that ranged in severity from mild to severe. These adverse effects included flank or abdominal pain without evidence of renal calculi; renal colic with renal calculi and mild transient increase in serum creatinine; renal colic with macrohematuria, recurrent leukocyturia, and eventually acute renal failure.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** We present the case of a 55-year-old heterosexual man who had a generalized alopecia and mood changes associated with the antiretroviral protease inhibitor; indinavir within 6 months of use. This was reversed within 3 months of change of therapy to the protease inhibitor, nelfinavir with demonstrable changes in his Hospital Anxiety and Depression (HAD) scale scores.[Harry TC et al; AIDS. 2000 11 (7): 474-6 (2000)] **PEER REVIEWED** 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 woman during the perinatal period can exacerbate physiologic hyperbilirubinemia in the neonate.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** To define the extent and time course of HIV-proteinase inhibitor (PI) effects on serum lipid levels 148 patients on triple combination therapy including PIs and 91 patients on therapy with two nucleosides as a control group were evaluated. In the PI group there was a significant increase in total cholesterol after 3, 6 and 12 months compared to the baseline level (198, 204 and 203 vs. 176 mg/dl). The increase in triglycerides was 25.5% from the baseline at month 3. Indinavir had a significantly higher impact on cholesterol levels than saquinavir. No changes in lipids were seen in the control group. It was concluded that hyperlipidemia is associated with PI use, becomes evident within 3 months of treatment and seems to be substance specific.[Segerer S et al; Infection 27 (2): 77-81 (1999)] **PEER REVIEWED** PubMed Abstract POPULATIONS AT SPECIAL RISK: The possibility that hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus may occur in patients receiving an HIV protease inhibitor should be considered.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The possibility that the risk of spontaneous bleeding may be increased in patients with hemophilia receiving an HIV protease inhibitor should be considered.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** EMERGENCY MEDICAL TREATMENT:EMERGENCY MEDICAL TREATMENT: EMT COPYRIGHT DISCLAIMER: The information contained in the Truven Health Analytics Inc. products isintended as an educational aid only. All treatments or procedures are intendedto serve as an information resource for physicians or other competent healthcareprofessionals performing the consultation or evaluation of patients and must beinterpreted in view of all attendant circumstances, indications andcontraindications.The use of the Truven Health Analytics Inc. products is atyour sole risk. These products are provided "as is" and "as available" for use,without warranties of any kind, either express or implied. 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Truven Health Analytics Inc. does not assumeany responsibility or risk for your use of the Truven Health Analytics Inc.products.The following Overview, *** AIDS ANTIVIRAL NUCLEOSIDES ***, isrelevant for this HSDB record chemical.LIFE SUPPORT: o This overview assumes that basic life support measures have been instituted.CLINICAL EFFECTS: 0.2.1 SUMMARY OF EXPOSURE 0.2.1.1 ACUTE EXPOSURE A) USES: The nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs) are primarily used in the treatment of HIV-1 and HIV-2 infection. This class includes: emtricitabine, lamivudine, stavudine, abacavir, and tenofovir; zidovudine and didanosine are in this class but are covered in separate managements, and zalcitabine is no longer manufactured. These agents are also used in the treatment of hepatitis B infection and human T-lymphocyte virus (HTLV) 1 and 2. B) PHARMACOLOGY: The NRTIs terminate HIV RNA to DNA transcription by acting as substrates for the HIV reverse transcriptase and terminating DNA elongation. These agents prevent cell infection, but have no effect on already infected cells. C) TOXICOLOGY: Toxicological effects are generally extensions of adverse effects. D) EPIDEMIOLOGY: Overdose is uncommon and severe sequelae from acute overdose are rare. Adverse effects and drug interactions, however, are common. E) WITH THERAPEUTIC USE 1) COMMON: The most common adverse effects from all NRTIs are nausea, vomiting, headache, and malaise. Peripheral neuropathy and elevated transaminases have been reported with most NRTIs. Rash and hypersensitivity reactions are common and are usually self-limited when therapy is continued. 2) Other adverse effects specific to each drug include: ABACAVIR: Hypersensitivity, nausea, vomiting, headache, and a possible increased risk of coronary artery disease. EMTRICITABINE: Rash, diarrhea, hypercholesterolemia, transaminitis, and mild rhabdomyolysis are common. Hepatic failure/steatosis, neutropenia, and lactic acidosis are rare. LAMIVUDINE: Headache and nausea are common. Pancreatitis is rare. STAVUDINE: Peripheral neuropathy in greater than 60% of patients receiving over 4 mg/kg daily. Lactic acidosis and transaminitis are common and do not require therapy or discontinuation unless severe. Dyslipidemia and insulin resistance have been associated with chronic stavudine and zidovudine. TENOFOVIR: Rash, headache, transaminitis, nausea, and vomiting are common. Hepatic failure/steatosis, renal failure, rhabdomyolysis, pancreatitis, and lactic acidosis are rare. ZALCITABINE: Peripheral neuropathy, stomatitis, pancreatitis, transaminitis, and rash. F) WITH POISONING/EXPOSURE 1) MILD TO MODERATE TOXICITY: There are limited data regarding overdose of NRTIs. However, overdose appears to be largely well tolerated with very few reports of severe clinical effects despite over 2 decades of drug availability. Nausea or vomiting, neurologic symptoms (ie, ataxia, lethargy, nystagmus, peripheral neuropathy), signs of bone marrow toxicity (ie, anemia, leukopenia, thrombocytopenia), or an increase in liver enzymes have all been reported in NRTI overdose or chronic toxicity. 2) SEVERE TOXICITY: Severe toxicity has been reported after therapeutic use but not after acute overdose, and may be manifested by pancreatitis, hepatic steatosis, acute renal failure (ie, tenofovir), neuropsychiatric abnormalities, or acidosis. Chronic therapeutic administration may lead to mitochondrial toxicity leading to lactic acidosis, with or without hepatic microsteatosis. Pancreatitis, neuropathy, and myopathy often accompany the syndrome. Severe neuropsychiatric effects (ie, seizures, mania) have been reported. Lactic acidosis has been reported in patients receiving both single and dual nucleoside analogue (NRTI) regimens for HIV infection. This is thought to cause multiorgan failure and most commonly occurs in persons on prolonged (more than 6 months) therapy. 0.2.3 VITAL SIGNS 0.2.14 DERMATOLOGIC 0.2.14.1 ACUTE EXPOSURE A) Dermatologic effects may include the development of skin rashes, eczema, impetigo, pruritus, excoriation, nail pigmentation (zidovudine and emtricitabine), sweating, and erythema. Abacavir has been noted to cause a life-threatening hypersensitivity reaction. Dermatologic effects are common. Stevens-Johnson syndrome is a rarely described complication. 0.2.20 REPRODUCTIVE HAZARDS A) Most AIDS antiviral agents are classified as FDA pregnancy category C or B. Efavirenz/emtricitabine/tenofovir is classified as FDA pregnancy category D. Transient anemia and other blood abnormalities (neutropenia, thrombocytopenia, and lymphopenia), as well as hyperlactatemia, have been reported in zidovudine-exposed, but HIV-uninfected infants. B) An increased risk of severe or fatal lactic acidosis has been seen in pregnant women who take the combination of HIV drugs, stavudine and didanosine, with other antiretroviral agents. Pancreatitis is also a well-documented complication of stavudine and didanosine. 0.2.21 CARCINOGENICITY 0.2.21.2 HUMAN OVERVIEW A) DIDANOSINE 1) At the time of this review, no data were available to assess the carcinogenic potential of this agent. B) ZIDOVUDINE 1) Extremely large doses have been associated with vaginal neoplasms in mice and rats; the significance in humans is not known. 0.2.21.3 ANIMAL OVERVIEW A) No drug-related increases in tumor incidence were determined in long-term carcinogenicity studies of emtricitabine in animals. Increased incidence of liver adenomas were found in female mice at exposures of tenofovir 10 times those observed in humans at the therapeutic dose for HIV infection. 0.2.22 GENOTOXICITY A) DIDANOSINE 1) Tests indicate that didanosine is not mutagenic at pharmacologic doses (Prod Info Videx(R), didanosine, 1996). B) EMTRICITABINE 1) There was no evidence of genotoxicity in the reverse mutation bacterial test (Ames), or the mouse lymphoma or mouse micronucleus assays of emtricitabine(Prod Info STRIBILD(TM) oral tablets, 2012). C) TENOFOVIR 1) There was no evidence of genotoxicity in the in vitro bacterial mutagenicity test (Ames) or the mouse micronucleus assay (for male mice only) of tenofovir. However, in the in vitro mouse lymphoma assay, tenofovir was mutagenic (Prod Info STRIBILD(TM) oral tablets, 2012). D) ZIDOVUDINE 1) In vitro studies with zidovudine have demonstrated weak mutagenicity at high concentrations, and produced dose-related chromosomal abnormalities in human lymphocytes at concentrations of 3 mcg/mL and higher (Prod Info Retrovir(R), zidovudine, 1996). 2) Zidovudine was negative in bacterial mutagenicity assay (Ayers, 1988). 3) In mammalian cells, concentrations of 1000 to 5000 micrograms/mL were weakly mutagenic (Ayers, 1988). 4) Aberrations in cultured human lymphocytes were seen at zidovudine concentrations of 3 micrograms/mL and higher (Ayers, 1988). 5) Torres et al (2007) suggested that the mutagenicity produced by the nucleoside analogs zidovudine, abacavir, and lamivudine are driven by cumulative dose, and raises the concern of whether zidovudine-lamivudine has greater mutagenic effects than zidovudine alone in perinatally-exposed children (Torres et al, 2007).LABORATORY: A) Monitor serum electrolytes and hepatic enzymes. B) Monitor serum lipase in patients with abdominal pain or severe acidosis. C) Lactic acid concentration and serum pH should be monitored in acidotic patients. D) Cardiac failure, likely due to acidosis, has been reported; therefore, cardiac monitoring is recommended in the setting of acidosis or chest pain. E) Sources of infection should be sought in patients with neutropenia or significant acidosis.TREATMENT OVERVIEW: 0.4.2 ORAL EXPOSURE A) MANAGEMENT OF MILD TO MODERATE TOXICITY 1) Supportive therapy remains the mainstay of care. Benzodiazepines or antipsychotics may be used for agitation or manic symptoms. Mild transaminitis can be monitored, discontinuation of therapy is not usually necessary. Therapy should be changed for persistently rising transaminases or evidence of hepatic synthetic dysfunction. Nausea and vomiting should be treated with antiemetics. Peripheral neuropathies are generally reversible with drug withdrawal and can be treated with pain management as needed. Asymptomatic elevation of lactic acid without systemic acidemia does not require discontinuation of the medication. B) MANAGEMENT OF SEVERE TOXICITY 1) Supportive care is the mainstay of care. Aggressive fluid resuscitation should be initiated for severe lactic acidosis. Granulocyte colony stimulating factor may be considered for patients with agranulocytosis complicated by infection. Vasopressors may be necessary in cases with multi-organ failure. Withdrawal of the agent is imperative to improvement in severe adverse reactions. Riboflavin and L-carnitine may be useful in treating nucleoside reverse transcriptase inhibitor (NRTI)-associated lactic acidosis. C) DECONTAMINATION 1) PREHOSPITAL: No prehospital decontamination is indicated. Prehospital care should focus on assessment of vital signs and general supportive care. 2) HOSPITAL: Activated charcoal may be considered for patients that present early after overdose if they are awake, alert, and willing to drink the charcoal. Gastric lavage has no role in the management of NRTI overdose. D) AIRWAY MANAGEMENT 1) Respiratory depression is not expected with overdose of NRTIs. However, coingestants must be considered and airway protection should be employed as needed for airway protection. E) ANTIDOTE 1) There is no specific antidote for NRTI toxicity. F) ACIDOSIS 1) Treat severe metabolic acidosis (pH less than 7.1) with sodium bicarbonate 1 to 2 mEq/kg. Anecdotal evidence suggests that riboflavin and L-carnitine may be useful in reversing NRTI-associated lactic acidosis. Riboflavin has been used at a dose of 50 mg/day orally or intravenously. L-carnitine has been used at a dose of 50 mg/kg/day as a 2-hour infusion divided in 3 doses for patients not receiving dialysis, or a continuous infusion of 100 mg/kg/day in patients receiving dialysis. G) ENHANCED ELIMINATION 1) Hemodialysis and whole bowel irrigation have no role in the management of NRTI overdose. H) PATIENT DISPOSITION 1) HOME CRITERIA: Suicidal patients and those with symptoms should be referred to a healthcare facility. Asymptomatic patients with inadvertent ingestion of NRTIs can be observed at home. 2) OBSERVATION CRITERIA: Asymptomatic or mildly symptomatic patients should be observed for 4 to 6 hours, primarily monitoring signs of coingestant toxicity. 3) ADMISSION CRITERIA: Patients with severe toxicity should be admitted. Patients with severe lactic acidosis, hepatic failure, or renal failure should be admitted to an intensive care setting. 4) CONSULT CRITERIA: Infectious disease should be consulted if a change to anti-retroviral therapy is indicated. Consult a medical toxicologist for patients with severe toxicity or in whom the diagnosis is not clear. I) PITFALLS 1) Failure to consider toxicity of co-medications due to drug-drug interactions. Failure to remove the offending agent in patients with severe adverse drug reactions. J) PHARMACOKINETICS 1) Intracellular elimination half-lives range from 2 to 24 hours. NRTIs are transported into cells and phosphorylated into an active form for incorporation into the viral reverse transcriptase. The drugs can be dephosphorylated or directly catabolized intracellularly. Formation of intracellular active metabolites has not been fully characterized and therefore pharmacokinetic profiles cannot be accurately predicted. 2) ABACAVIR: Bioavailability 83%, protein binding 50%, volume of distribution 0.86 L/kg, extensive hepatic metabolism with renal elimination of metabolites, half-life 1 to 1.5 hours. 3) EMTRICITABINE: Bioavailability 93%, protein binding less than 4%, little hepatic metabolism (13%), renal excretion 86%, half-life 10 hours. 4) LAMIVUDINE: Bioavailability 82% to 87%, moderate protein binding (less than 36%), volume of distribution 0.9 to 1.7 L/kg, 70% renal elimination of unchanged drug, half-life 2 to 7 hours. 5) STAVUDINE: Bioavailability 86%, negligible protein binding, volume of distribution 46 L, limited hepatic metabolism, renal elimination approximately 40%, half-life 1.6 hours. 6) TENOFOVIR: Bioavailability 25%, protein binding 7%, volume of distribution 1.2 to 1.3 L/kg, 32% excreted unchanged in urine, half-life 17 hours. K) TOXICOKINETICS 1) No data are available regarding toxicokinetics. L) DIFFERENTIAL DIAGNOSIS 1) Other etiologies of hepatic failure (ie, acetaminophen, iron, carbon tetrachloride, etc.) should be considered. Medical etiologies (ie, portal vein thrombosis, viral hepatitis, hepatic abscess, or Budd-Chiari malformation) should be ruled out in cases of hepatitis. Infection must be ruled out in cases predominated by lactic acidosis and organ dysfunction.RANGE OF TOXICITY: A) TOXICITY: A full month supply of many of these agents has been ingested in overdose without clinical effects, though toxicity can occur at therapeutic doses with nucleoside reverse transcriptase inhibitors (NRTIs). LAMIVUDINE: No clinical signs or symptoms developed in an adult ingesting 6 grams of lamivudine. STAVUDINE: No acute toxicity was reported in patients treated with 12 to 24 times the recommended daily dosage. ZALCITABINE: Pediatric: Overdoses of 1.5 mg/kg have been reported; no sequelae developed. B) THERAPEUTIC DOSE: ABACAVIR: ADULT: 300 mg orally twice daily or 600 mg once daily. PEDIATRIC: 8 mg/kg orally twice daily. EMTRICITABINE: ADULT: 200 mg/day capsule, 240 mg/day oral solution. PEDIATRIC: 0 to 3 months of age: 3 mg/kg orally once daily; 3 months to 17 years of age: 6 mg/kg once daily oral solution, up to a maximum of 240 mg; children weighing more than 33 kg and can swallow whole capsule: 200 mg once daily. LAMIVUDINE: ADULT: 150 mg orally twice a day or 300 mg once daily. PEDIATRIC: 0 to 28-days-old: 2 mg/kg orally twice daily; 28 days or older: 4 mg/kg orally twice daily, maximum 150 mg twice daily. STAVUDINE: ADULT: less than 60 kg: 30 mg orally every 12 hours; 60 kg or more: 40 mg orally every 12 hours. PEDIATRIC: 0 to 13-days-old: 0.5 mg/kg/dose orally every 12 hours; 14-days-old and less than 30 kg: 1 mg/kg/dose orally every 12 hours ; 30 kg to less than 60 kg: 30 mg orally every 12 hours; 60 kg or more: 40 mg orally every 12 hours. TENOFOVIR: ADULT: 300 mg orally once daily. PEDIATRIC: at least 12-year-old and 35 kg or more: 300 mg orally once daily.ANTIDOTE AND EMERGENCY TREATMENT: Treatment of overdose: To decrease absorption: Patients may benefit from treatment with activated charcoal. Monitoring: Patient's vital signs should be monitored. Supportive care: Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 2441] **PEER REVIEWED** /SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160] **PEER REVIEWED** /SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160] **PEER REVIEWED** /SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/[Currance, P.L. Clements, B., Bronstein, A.C. (Eds).; Emergency Care For Hazardous Materials Exposure. 3Rd edition, Elsevier Mosby, St. Louis, MO 2005, p. 160-1] **PEER REVIEWED** Emergency and supportive measures: Maintain an open airway and assist ventilation if needed. Treat coma, seizures, hypotension or anaphylaxis if they occur. Replace fluid losses resulting from gastroenteritis with intravenous crystalloids. Maintain steady urine flow with intravenous fluids to alleviate crystalluria and reverse renal dysfunction. Treat lactic acidosis with judicious doses of sodium bicarbonate and by withdrawal of the offending drug. /Antiviral and antiretroviral agents/[OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 126] **PEER REVIEWED** Specific drugs and antidotes: There are no specific antidotes for these agents. Anecdotal cases of patients with severe lactic acidosis suggest that vitamin deficiency may be a contributor to the development of a life-threatening condition. Riboflavin ... and/or thiamine ... may be beneficial if levels are low. /Antiviral and antiretroviral agents/[OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 126] **PEER REVIEWED** Decontamination: Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. /Antiviral and antiretroviral agents/[OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 126] **PEER REVIEWED** ANIMAL TOXICITY STUDIES:NON-HUMAN TOXICITY EXCERPTS: /LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Carcinogenicity studies were conducted in mice and rats. In mice, no increased incidence of any tumor type was observed. The highest dose tested in rats was 640 mg/kg/day; at this dose a statistically significant increased incidence of thyroid adenomas was seen only in male rats.[Medical Economics Co; Physicians Desk Reference 57th ed p.1970 (2003)] **PEER REVIEWED** /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Reproduction studies in rats and rabbits at indinavir exposure levels comparable to or slightly greater than usual human exposure levels have not revealed evidence of teratogenicity or embryotoxicity. There were no treatment-related effects on embryonic/fetal survival or fetal weights in either rats or rabbits. In rabbits, there were no treatment-related changes in external, visceral, or skeletal structures. While there were no treatment-related changes in external or visceral structures in rats, some skeletal changes were observed in these animals. In rats exposed to indinavir levels equivalent to or slightly lower than usual human exposure levels, there was an increased incidence in supernumerary ribs compared with controls; in rats exposed to indinavir levels equivalent to or slightly higher than usual human exposure levels, there was an increased incidence in cervical ribs compared with controls. While in utero exposure to indinavir was substantial in rats and dogs, only limited fetal exposure occurred in rabbits.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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 four-fold 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 hours after maternal dosing at 40, 80, or 160 mg/kg twice daily.[Medical Economics Co; Physicians Desk Reference 57th ed p.1970 (2003)] **PEER REVIEWED** /LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ There was no evidence that indinavir affected fertility, mating, or embryo survival in female rats or mating in male rats when given in doses providing exposure levels equivalent to or slightly higher than those provided by the usual human dosage. In addition, there was no evidence that indinavir affected fecundity or fertility in untreated female rats mated to treated male rats.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** /GENOTOXICITY/ No evidence of mutagenicity or genotoxicity was observed in in vitro microbial mutagenesis (Ames) tests, in vitro alkaline elution assays for DNA breakage, in vitro and in vivo chromosomal aberration studies, and in vitro mammalian cell mutagenesis assays.[Medical Economics Co; Physicians Desk Reference 57th ed p.1970 (2003)] **PEER REVIEWED** NON-HUMAN TOXICITY VALUES: LD50 Dog Intraperitoneal > 640 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2081] **PEER REVIEWED** LD50 Dog oral > 640 mg/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2081] **PEER REVIEWED** LD50 Mouse Intraperitoneal > 5 g/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2081] **PEER REVIEWED** LD50 Mouse oral > 5 g/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2081] **PEER REVIEWED** LD50 Rat Intraperitoneal > 5 g/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2081] **PEER REVIEWED** LD50 Rat oral > 5 g/kg[Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2081] **PEER REVIEWED** METABOLISM/ PHARMACOKINETICS:METABOLISM/ METABOLITES: Indinavir is metabolized to at least 7 metabolites including 1 glucuronide conjugate and 6 oxidative metabolites. Major metabolic pathways identified include glucuronidation at the pyridine nitrogen, pyridine N-oxidation, para-hydroxylation of the phenylmethyl group, 3-hydroxylation of the indan, and N-depyridomethylation. In vitro studies indicate that cytochrome P-450 isoenzyme CYP3A4 is the major enzyme involved in the formation of the oxidative metabolites.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ABSORPTION, DISTRIBUTION & EXCRETION: In a study in HIV-infected children 4-17 years of age receiving an antiretroviral regimen that included oral indinavir (initial dosage of 500 mg/sq m every 8 hours; subsequent dosage averaging 2043 mg/sq m daily in 3 or 4 doses); peak and trough plasma concentrations averaging 7.3 and 0.29 ug/ml, respectively.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Indinavir is rapidly absorbed after oral administration, with peak levels achieved in approximately 1 hour. Unlike other drugs in this class, food can adversely affect indinavir bioavailability; a high-calorie, high-fat meal reduces plasma concentrations by 75%.[Brunton, L. Chabner, B, Knollman, B. Goodman and Gillman's The Pharmaceutical Basis of Therapeutics, Twelth Edition, McGraw Hill Medical, New York, NY. 2011, p. 1654] **PEER REVIEWED** Indinavir is excreted principally in the feces, both as unabsorbed drug and metabolites. Following oral administration of 400 mg of radiolabeled indinavir, 83% of the dose is recovered in feces (19.1% as unchanged drug) and 19% is recovered in urine (9.4% as unchanged drug). Following oral administration of a single 700- or 1000-mg dose of indinavir, 10.4 or 12%, respectively, is excreted unchanged in urine.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** To characterize steady-state indinavir pharmacokinetics in cerebrospinal fluid and plasma, 8 adults infected with human immunodeficiency virus underwent intensive cerebrospinal fluid sampling while receiving indinavir (800 mg every 8 hours) plus nucleoside reverse transcriptase inhibitors. Nine and 11 serial cerebrospinal fluid and plasma samples, respectively, were obtained from each subject. Free indinavir accounted for 94.3% of the drug in cerebrospinal fluid and 41.7% in plasma. Mean values of cerebrospinal fluid peak concentration, concentration at 8 hours, and area under the concentration-time profile calculated over the interval 0 to 8 hours (AUC(0-8)) for free indinavir were 294 nmol/L, 122 nmol/L, and 1616 nmol/L x hr, respectively. The cerebrospinal fluid-to-plasma AUC(0-8) ratio for free indinavir was 14.7% +/- 2.6% and did not correlate with indexes of blood-brain barrier integrity or intrathecal immune activation. Indinavir achieves levels in cerebrospinal fluid that should contribute to control of human immunodeficiency virus type 1 replication in this compartment. The cerebrospinal fluid-to-plasma AUC (0-8) ratio suggests clearance mechanisms in addition to passive diffusion across the blood-cerebrospinal fluid barrier, perhaps by P-glycoprotein-mediated efflux.[Haas DW et al; Clin Pharmacol Ther 68 (4): 367-74 (2000)] **PEER REVIEWED** PubMed Abstract It is not known whether indinavir crosses the placenta; the drug crosses the placenta in rats and rabbits. While it is not known whether indinavir is distributed into human milk, it is distributed into milk in rats.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** There is no evidence that indinavir accumulates in plasma in adults with normal renal and hepatic function receiving multiple oral doses of 800 mg every 8 hours. The AUC of indinavir may be increased in patients with hepatic impairment. In adults with cirrhosis and mild to moderate hepatic impairment who received a single 400-mg oral dose of indinavir, the AUC of the drug was 60% higher than that reported in patients with normal hepatic function.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** 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 a maternal dose of 40 and 640 mg/kg/day, fetal plasma drug levels were approximately 10 to 15% and 10 to 20% of maternal drug levels 1 and 2 hours after dosing, respectively.[Medical Economics Co; Physicians Desk Reference 57th ed p.1970 (2003)] **PEER REVIEWED** BIOLOGICAL HALF-LIFE: In a study in adults with cirrhosis and mild to moderate hepatic impairment, the elimination half-life of the drug was prolonged to 2.8 hours.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The plasma half-life of indinavir averages 1.8 hours. In HIV-infected children 4-17 years of age receiving an antiretroviral regimen that included oral indinavir, plasma half-life of the drug averaged 1.1 hours.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** MECHANISM OF ACTION: Combinations of antiretroviral drugs are successfully used for the treatment of acquired immune deficiency syndrome and reduce the incidence of severe human immunodeficiency virus (HIV)-associated dementia. To test whether such drugs affect the GSH metabolism of brain cells, we have exposed astrocyte-rich primary cultures to various antiretroviral compounds. Treatment of the cultures with the protease inhibitors indinavir or nelfinavir in low micromolar concentrations resulted in a time- and concentration-dependent depletion of cellular GSH from viable cells which was accompanied by a matching increase in the extracellular GSH content. In contrast, the reverse transcriptase inhibitors zidovudine, lamivudine, efavirenz or nevirapine did not alter cellular or extracellular GSH levels. Removal of indinavir from the medium by washing the cells terminated the stimulated GSH export immediately, while the nelfinavir-induced accelerated GSH export was maintained even after removal of nelfinavir. The stimulation of the GSH export from viable astrocytes by indinavir or nelfinavir was completely prevented by the application of MK571, an inhibitor of the multidrug resistance protein 1. These data demonstrate that indinavir and nelfinavir stimulate multidrug resistance protein 1-mediated GSH export from viable astrocytes and suggest that treatment of patients with such inhibitors may affect the GSH homeostasis in brain.[Brandmann M et al; J Neurochem 120 (1): 78-92 (2012)] **PEER REVIEWED** PubMed Abstract Indinavir is a selective, competitive, reversible inhibitor of HIV protease. HIV protease, an aspartic endopeptidase that functions as a homodimer, plays an essential role in the HIV replication cycle and the formation of infectious virus. During HIV replication, HIV protease cleaves viral polypeptide products of the gag and gag-pol genes (i.e., p55 and p160) to form structural proteins of the virion core (i.e., p17, p24, p9, and p7) and essential viral enzymes (i.e., reverse transcriptase, integrase, and protease). Because indinavir is a structural analog of the HIV Phe-Pro protease cleavage site, the drug inhibits the function of the enzyme. By interfering with the formation of these essential proteins and enzymes, indinavir blocks maturation of the virus and causes the formation of nonfunctional, immature, noninfectious virions. Indinavir is active in both acutely and chronically infected cells since it targets the HIV replication cycle after translation and before assembly. Thus, the drug is active in chronically infected cells (e.g., monocytes and macrophages) that generally are not affected by nucleoside reverse transcriptase inhibitors (e.g., didanosine, lamivudine, stavudine, zalcitabine, zidovudine). Indinavir does not affect early stages of the HIV replication cycle; however, the drug interferes with the production of infectious HIV and limits further infectious spread of the virus.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** While the complete mechanisms of antiviral activity of indinavir have not been fully elucidated, indinavir apparently inhibits replication of retroviruses, including human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), by interfering with HIV protease. The drug, therefore, exerts a virustatic effect against retroviruses by acting as an HIV protease inhibitor.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Indinavir is a highly specific inhibitor of HIV protease and does not appear to interfere with the activity of human aspartic endopeptidases at clinically relevant concentrations. In one study, there was no evidence of inhibition of human cathepsin D or renin using indinavir concentrations exceeding 10 uM.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Unlike nucleoside antiretroviral agents, the antiviral activity of indinavir does not depend on intracellular conversion to an active metabolite. Indinavir and other HIV protease inhibitors (e.g., amprenavir, lopinavir, nelfinavir, ritonavir, saquinavir) act at a different stage of the HIV replication cycle than nucleoside and nonnucleoside reverse transcriptase inhibitors, and results of in vitro studies indicate that the antiretroviral effects of HIV protease inhibitors and some nucleoside agents (e.g., didanosine, zidovudine) or nonnucleoside agents (e.g., efavirenz, nevirapine) may be additive or synergistic. In one in vitro study, indinavir used in conjunction with zidovudine resulted in an additive effect against HIV-1; however, addition of lamivudine to these drugs resulted in a synergistic effect.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** INTERACTIONS: Studies have not been done with the cytochrome p450 CYP3A4 substrates astemizole, cisapride, midazolam, terfenadine, and triazolam; because competition for CYP3A4 by indinavir could result in inhibition of the metabolism of these medications and elevated plasma concentrations, there is a potential for serious and/or life-threatening side effects; concurrent use of indinavir with any of these medications is not recommended.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent administration /of cimetidine and indinavir/ does not affect the area under the plasma concentration-time curve (AUC) of indinavir.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Amprenavir interferes with the metabolism of rifabutin and significantly increases rifubutin serum concentrations; it is recommended that the dose of rifabutin be reduced by at least half of the recommended dose; rifabutin decreases the AUC of amprenavir by 15%; patients should be monitored for neutropenia once a week and as clinically indicated if rifabutin is given concurrently with amprenavir.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use /with clarithromycin/ results in a 29% increase in the AUC of indinavir and a 53% increase in the AUC of clarithromycin; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use of indinavir with an estrogen-containing oral contraceptive (Ortho-Novum 1/35) results in a 24% increase in the AUC of ethinyl estradiol and a 26% increase in the AUC of norethindrone; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** If indinavir and didanosine are both part of a treatment regimen, they should be administered at least 1 hour apart on an empty stomach; a normal acidic pH may be necessary for the optimal absorption of indinavir, and didanosine requires a buffer to increase the pH so that acid does not rapidly degrade didanosine.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use /with fluconazole/ results in a 19% decrease in the AUC of indinavir and no change in the AUC of fluconazole; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Administration of a single 400 mg dose of indinavir with grapefruit juice results in a 26% decrease in the AUC of indinavir; dosing modification is not not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent administration /with isoniazid/ results in a 13% increase in the AUC of isoniazid and no change in the AUC of indinavir; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use results in a 68% increase in the AUC of indinavir; a dosage reduction of indinavir to 600 mg every 8 hours is recommended when coadministered with ketoconazole.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent administration of zidovudine and indinavir results in a 13% increase in the AUC of indinavir and a 17% increase in the AUC of zidovudine; administration of indinavir with zidovudine and lamivudine results in no change in the AUC of indinavir, a 36% increase in AUC of zidovudine and a 6% decrease in AUC of lamivudine; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Administration of a single 400 mg dose of indinavir with 200 mg of quinidine sulfate results in a 10% decrease in the AUC of indinavir; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Concurrent use results in a 32% increase in the AUC of indinavir and a 204% increase in the AUC of rifabutin; dosage reduction of rifabutin ... is necessary when it is coadministered with indinavir.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Because rifampin is a potent inducer of CYP3A4, which could significantly decrease the plasma concentration of indinavir, concurrent use with indinavir is not recommended.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Concurrent administration /of sulfamethoxazole and trimethoprim combination/ results in no change in the AUC of indinavir and sulfamethoxazole, and a 19% increase in the AUC of trimethoprim, dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Concurrent administration results in no change in the AUC of indinavir and a 25% increase in the AUC of stavudine; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** St John's wort reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-hr indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure.[Piscitelli SC et al; Lancet 12; 355 (9203): 547-8 (2000)] **PEER REVIEWED** Since indinavir solubility markedly decreases at higher pH, antacids or other buffering agents should not be taken at the same time. Didanosine is coformulated with a buffer and should not be taken within 2 hours before or 1 hour after indinavir.[Brunton, L. Chabner, B, Knollman, B. Goodman and Gillman's The Pharmaceutical Basis of Therapeutics, Twelth Edition, McGraw Hill Medical, New York, NY. 2011, p. 1654] **PEER REVIEWED** PHARMACOLOGY:THERAPEUTIC USES: HIV Protease Inhibitors.[National Library of Medicine's Medical Subject Headings online file (MeSH, 2012)] **PEER REVIEWED** Indinavir with antiretroviral agents is indicated for the treatment of HIV infection. /Included in US product labeling/[Drug Facts and Comparisons 2011. Wolters Kluwer Health St. Louis, MO 2011, p. 2449] **PEER REVIEWED** DRUG WARNINGS: Nephrolithiasis/urolithiasis, which may present as flank pain with or without hematuria (including microscopic hematuria), has been reported in about 9% of adults and 29% of pediatric patients receiving indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The most frequent adverse effects associated with indinavir therapy involve the GI tract. ...In treatment-naive HIV-infected adults, abdominal pain, nausea, vomiting, and diarrhea occurred in 16.6, 11.7, 8.4, and 3.3%, respectively, and acid regurgitation, anorexia, dyspepsia, increased appetite, and taste perversion occurred in 1.5-2.7% of patients receiving indinavir monotherapy. In patients in study 028 receiving indinavir in conjunction with zidovudine, abdominal pain, nausea, vomiting, and diarrhea occurred in 16, 31.9, 17.8, and 3%, respectively, and acid regurgitation, anorexia, dyspepsia, increased appetite, and taste perversion occurred in 1.5-8.4% of patients. ...Safety and efficacy of indinavir in pediatric patients have not been established. Indinavir has been used in a limited number of HIV-infected children 3 months of age or older without unusual adverse effects. However, nephrolithiasis/urolithiasis has been reported more frequently in pediatric patients receiving indinavir (29%) than in adults receiving the drug (9.2%).[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Asymptomatic hyperbilirubinemia (i.e., total serum bilirubin concentrations exceeding 2.5 mg/dL) has occurred in about 14% of patients receiving indinavir in clinical studies. Asymptomatic bilirubinemia usually has been reported as elevated indirect bilirubin and has been associated with increased serum AST (SGOT) or ALT (SGPT) concentrations only rarely (i.e., in less than 1% of patients receiving the drug).[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Acute hepatitis sometimes resulting in hepatic failure and death have been reported in a few patients receiving indinavir in conjunction with other drugs. ...Jaundice was reported in 1.5-2.1% of patients receiving indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults, headache occurred in 5.4 or 9.6%, dizziness in 3 or 3.9%, and somnolence in 2.4 or 3.3% of adults receiving indinavir monotherapy or indinavir in conjunction with zidovudine, respectively. Oral paresthesia and depression have been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Anaphylactoid reaction has been reported with indinavir. ...In treatment-naive HIV-infected adults, pruritus occurred in 4.2 or 2.4% and rash occurred in 1.2 or 0.6% of patients receiving indinavir or indinavir in conjunction with zidovudine, respectively. Erythema multiforme, Stevens-Johnson syndrome, hyperpigmentation, alopecia, urticaria, ingrown toenails, paronychia, and vasculitis have been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults, back pain occurred in 8.4% of patients receiving indinavir monotherapy and 4.5% of patients receiving indinavir in conjunction with zidovudine. Arthralgia has been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults receiving indinavir alone or in conjunction with zidovudine, neutropenia (neutrophil count < 750/cu mm) occurred in 2.2-2.4% of patients, anemia (hemoglobin concentrations < 7 g/dL) occurred in 0.6-0.9% of patients, and thrombocytopenia (platelet counts < 50,000/cu mm) occurred in 0.9% of patients.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Acute hemolytic anemia has occurred in patients receiving indinavir and in some cases resulted in death. If acute hemolytic anemia occurs in a patient receiving indinavir, appropriate measures should be taken to treat the condition including discontinuance of indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Redistribution or accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and general cushingoid appearance, has been reported in patients receiving HIV protease inhibitors, including indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Cough and dyspnea have occurred in less than 2% of patients receiving indinavir in phase II/III clinical studies. Anterior uveitis has occurred in at least one patient receiving indinavir.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...Asthenia/fatigue occurred in 2.1 or 4.2%, fever in 1.5 or 1.5%, and malaise in 2.1 or 2.7% of patients receiving indinavir monotherapy or indinavir in conjunction with zidovudine, respectively. Increased serum cholesterol has been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ...In treatment-naive HIV-infected adults, substantial increases in serum amylase concentrations (increases exceeding 200% of the upper limit of the normal range) occurred in 2.1% of patients receiving indinavir monotherapy and 1.9% of patients receiving indinavir in conjunction with zidovudine. Pancreatitis has been reported during postmarketing surveillance. Pancreatitis resulting in death has been reported in a patient receiving didanosine, stavudine, indinavir, and hydroxyurea.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Adverse cardiovascular effects, including myocardial infarction and angina pectoris, have been reported in patients receiving indinavir. Cerebrovascular disorder has been reported during postmarketing surveillance.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** Nephrolithiasis/urolithiasis has occurred in some patients receiving indinavir and may be associated with substantial renal impairment or acute renal failure. If signs and symptoms of nephrolithiasis/urolithiasis occur, such as flank pain with or without hematuria (including microhematuria), indinavir therapy should be temporarily interrupted during the acute phase (e.g., for 13 days) or the drug should be discontinued. Patients receiving indinavir should be adequately hydrated and should be instructed to drink at least 1.5 L (approximately 48 ounces) of liquids daily (i.e., every 24 hours).[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The possibility that the risk of spontaneous bleeding may be increased in patients with hemophilia receiving an HIV protease inhibitor should be considered.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** The possibility that hyperglycemia, new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus may occur in patients receiving an HIV protease inhibitor should be considered.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** In a limited study in pediatric patients 9-14 years of age receiving indinavir for at least 1 year, about 46% had adverse renal effects that ranged in severity from mild to severe. These adverse effects included flank or abdominal pain without evidence of renal calculi; renal colic with renal calculi and mild transient increase in serum creatinine; renal colic with macrohematuria, recurrent leukocyturia, and eventually acute renal failure.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** We present the case of a 55-year-old heterosexual man who had a generalized alopecia and mood changes associated with the antiretroviral protease inhibitor; indinavir within 6 months of use. This was reversed within 3 months of change of therapy to the protease inhibitor, nelfinavir with demonstrable changes in his Hospital Anxiety and Depression (HAD) scale scores.[Harry TC et al; AIDS. 2000 11 (7): 474-6 (2000)] **PEER REVIEWED** 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 woman during the perinatal period can exacerbate physiologic hyperbilirubinemia in the neonate.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** To define the extent and time course of HIV-proteinase inhibitor (PI) effects on serum lipid levels 148 patients on triple combination therapy including PIs and 91 patients on therapy with two nucleosides as a control group were evaluated. In the PI group there was a significant increase in total cholesterol after 3, 6 and 12 months compared to the baseline level (198, 204 and 203 vs. 176 mg/dl). The increase in triglycerides was 25.5% from the baseline at month 3. Indinavir had a significantly higher impact on cholesterol levels than saquinavir. No changes in lipids were seen in the control group. It was concluded that hyperlipidemia is associated with PI use, becomes evident within 3 months of treatment and seems to be substance specific.[Segerer S et al; Infection 27 (2): 77-81 (1999)] **PEER REVIEWED** PubMed Abstract INTERACTIONS: Studies have not been done with the cytochrome p450 CYP3A4 substrates astemizole, cisapride, midazolam, terfenadine, and triazolam; because competition for CYP3A4 by indinavir could result in inhibition of the metabolism of these medications and elevated plasma concentrations, there is a potential for serious and/or life-threatening side effects; concurrent use of indinavir with any of these medications is not recommended.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent administration /of cimetidine and indinavir/ does not affect the area under the plasma concentration-time curve (AUC) of indinavir.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Amprenavir interferes with the metabolism of rifabutin and significantly increases rifubutin serum concentrations; it is recommended that the dose of rifabutin be reduced by at least half of the recommended dose; rifabutin decreases the AUC of amprenavir by 15%; patients should be monitored for neutropenia once a week and as clinically indicated if rifabutin is given concurrently with amprenavir.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use /with clarithromycin/ results in a 29% increase in the AUC of indinavir and a 53% increase in the AUC of clarithromycin; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use of indinavir with an estrogen-containing oral contraceptive (Ortho-Novum 1/35) results in a 24% increase in the AUC of ethinyl estradiol and a 26% increase in the AUC of norethindrone; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** If indinavir and didanosine are both part of a treatment regimen, they should be administered at least 1 hour apart on an empty stomach; a normal acidic pH may be necessary for the optimal absorption of indinavir, and didanosine requires a buffer to increase the pH so that acid does not rapidly degrade didanosine.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use /with fluconazole/ results in a 19% decrease in the AUC of indinavir and no change in the AUC of fluconazole; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Administration of a single 400 mg dose of indinavir with grapefruit juice results in a 26% decrease in the AUC of indinavir; dosing modification is not not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent administration /with isoniazid/ results in a 13% increase in the AUC of isoniazid and no change in the AUC of indinavir; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent use results in a 68% increase in the AUC of indinavir; a dosage reduction of indinavir to 600 mg every 8 hours is recommended when coadministered with ketoconazole.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Concurrent administration of zidovudine and indinavir results in a 13% increase in the AUC of indinavir and a 17% increase in the AUC of zidovudine; administration of indinavir with zidovudine and lamivudine results in no change in the AUC of indinavir, a 36% increase in AUC of zidovudine and a 6% decrease in AUC of lamivudine; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1535] **PEER REVIEWED** Administration of a single 400 mg dose of indinavir with 200 mg of quinidine sulfate results in a 10% decrease in the AUC of indinavir; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Concurrent use results in a 32% increase in the AUC of indinavir and a 204% increase in the AUC of rifabutin; dosage reduction of rifabutin ... is necessary when it is coadministered with indinavir.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Because rifampin is a potent inducer of CYP3A4, which could significantly decrease the plasma concentration of indinavir, concurrent use with indinavir is not recommended.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Concurrent administration /of sulfamethoxazole and trimethoprim combination/ results in no change in the AUC of indinavir and sulfamethoxazole, and a 19% increase in the AUC of trimethoprim, dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** Concurrent administration results in no change in the AUC of indinavir and a 25% increase in the AUC of stavudine; dosing modification is not required.[MICROMEDEX Thomson Health Care. USPDI - Drug Information for the Health Care Professional. 23rd ed. Volume 1. MICROMEDEX Thomson Health Care, Greenwood Village, CO. 2003. Content Reviewed and Approved by the U.S. Pharmacopeial Convention, Inc., p. 1536] **PEER REVIEWED** St John's wort reduced the area under the curve of the HIV-1 protease inhibitor indinavir by a mean of 57% (SD 19) and decreased the extrapolated 8-hr indinavir trough by 81% (16) in healthy volunteers. A reduction in indinavir exposure of this magnitude could lead to the development of drug resistance and treatment failure.[Piscitelli SC et al; Lancet 12; 355 (9203): 547-8 (2000)] **PEER REVIEWED** Since indinavir solubility markedly decreases at higher pH, antacids or other buffering agents should not be taken at the same time. Didanosine is coformulated with a buffer and should not be taken within 2 hours before or 1 hour after indinavir.[Brunton, L. Chabner, B, Knollman, B. Goodman and Gillman's The Pharmaceutical Basis of Therapeutics, Twelth Edition, McGraw Hill Medical, New York, NY. 2011, p. 1654] **PEER REVIEWED** ENVIRONMENTAL FATE & EXPOSURE:MILK CONCENTRATIONS: While it is not known whether indinavir is distributed into human milk, it is distributed into milk in rats.[American Society of Health-System Pharmacists 2012; Drug Information 2012. Bethesda, MD. 2012] **PEER REVIEWED** ENVIRONMENTAL STANDARDS & REGULATIONS:FDA REQUIREMENTS: The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl indinavir sulfate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.[DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of November 21, 2012: http://www.fda.gov/cder/ob/] **PEER REVIEWED** CHEMICAL/PHYSICAL PROPERTIES:MOLECULAR FORMULA: C36-H47-N5-O4.H2-O4-S **PEER REVIEWED** MOLECULAR WEIGHT: 711.87[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 859] **PEER REVIEWED** COLOR/FORM: Crystals from absolute ethanol[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 859] **PEER REVIEWED** White to off-white hygroscopic crystalline powder[Physicians Desk Reference 66th ed. PDR Network, LLC, Montvale, NJ. p. 1751 (2012)] **PEER REVIEWED** MELTING POINT: 150-153 deg C (decomposes)[O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 859] **PEER REVIEWED** SOLUBILITIES: Very soluble in water and ethanol[Physicians Desk Reference 66th ed. PDR Network, LLC, Montvale, NJ