INDINAVIR EN VADEMECUM IQB

	INDINAVIR

	DESCRIPCIONon: El indinavir es un inhibidor de la proteasa antiretroviral oral indicado para el tratamiento de pacientes con infección por el VIH . Indinavir se ha demostrado para reducir la carga viral por 90-99%, con un aumento significativo en el conteo de CD4 . La combinación de indinavir con dos inhibidores nucleósidos de la transcriptasa reversa puede reducir RNA de VIH a niveles indetectables . Ensayos clínicos han demostrado que la terapia de combinación antirretroviral incluyendo indinavir (y zidovudina con o sin lamivudina) reduce el riesgo del SIDA definición de enfermedad o muerte y prolonga la supresión de RNA de VIH . Las recomendaciones actuales de la CDC apoyan un régimen de tres fármacos , incluyendo un inhibidor de la proteasa para el tratamiento inicial de pacientes VIH-infectados . Indinavir is an oral antiretroviral protease inhibitor indicated for the treatment of patients with HIV infection. Indinavir has been shown to reduce the viral load by 90ï¿½99%, with a significant increase in the CD4 count. Combining indinavir with two nucleoside reverse transcriptase inhibitors can reduce HIV RNA to undetectable levels. Clinical trials have shown that combination antiretroviral therapy including indinavir (and zidovudine with or without lamivudine) reduces the risk of AIDS defining illness or death and prolongs suppression of HIV RNA. Current CDC recommendations support a three-drug regimen including one protease inhibitor for the initial treatment of HIV-infected patients.[ Mechanism of Action: Indinavir is a competitive inhibitor of HIV protease, an enzyme involved in the replication of HIV. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature virus budding particles. HIV protease is responsible for cleaving these precursor molecules to produce the final structural proteins of a mature virion core, and to activate reverse transcriptase for a new round of infection. Thus, protease is necessary for the production of mature virions. Viral protease inhibition renders the virus noninfectious. Indinavir inhibits both HIV-1 and HIV-2 proteases. In test systems, the IC95 (95% inhibitory concentration) of indinavir was 25ï¿½100 nM. Indinavir has been shown to be synergistic with zidovudine and didanosine in vitro. The development of resistance to HIV-protease inhibitors occurs as a result of mutations. Mutations produce amino acid substitutions in the viral protease, thereby altering the targets for protease inhibitors. There have been 11 amino acid residue positions identified so far that are associated with resistance to protease inhibitors. Greater levels of resistance were associated with the expression of multiple amino acid substitutions. Varying degrees of cross-resistance have been observed between indinavir and other protease inhibitors. Cross-resistance to ritonavir has been noted. Because different enzyme targets are involved, there is no cross-resistance between ritonavir and reverse transcriptase inhibitors. Pharmacokinetics: Indinavir is administered orally. Following administration, the drug is rapidly absorbed in the fasting state. Peak concentrations occur in 0.8 ï¿½ 0.3 hours. Administration with food high in calories, fat, and protein resulted in a decrease in the AUC of indinavir by 77% and the Cmax by 84%. Lighter meals, such as dry toast with jelly, apple juice, and coffee with skim milk, may cause little or no change in the AUC, Cmax, or trough concentrations. Once absorbed, approximately 60% of indinavir is bound to plasma proteins. Indinavir is metabolized to seven metabolites, one glucuronide conjugate and six oxidative metabolites. In vitro studies show that the oxidative metabolites are generated as a result of metabolism by the cytochrome P450 3A4 enzyme. About 83% of a 400 mg dose is excreted in the feces and urine, with less than 20% of indinavir excreted unchanged in the urine. The elimination half-life is about 2 hours. ï¿½Special Populations: Patients with mild to moderate hepatic impairment with clinical evidence of cirrhosis have an approximately 60% higher mean AUC than do patients without hepatic impairment. The half-life was also increased to about 3 hours. The pharmacokinetics of indinavir have not been studied in patients with renal insufficiency. It is not known if indinavir is dialyzable by peritoneal or hemodialysis. The pharmacokinetic profiles of indinavir in pediatric patients were not comparable to HIV-infected adults receiving 800 mg PO every 8 hours. The AUC and Cmax values were slightly higher and the trough concentrations considerably lower in pediatric patients receiving 500 mg/m2 every 8 hours. Approximately 50% of pediatric patients had trough levels below 100 nM; whereas only about 10% of adults had trough levels below 100 nM. The relationship between trough levels and inhibition of HIV has not been established.
	INDICACIONES Y POSOLOGIA For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents: ï¿½in symptomatic adults or adolescents; asymptomatic adults or adolescents with a CD4 count < 350/mm3 (although controversial with CD4 counts > 200/mm3 and < 350/mm3); or asymptomatic patients with CD4 counts > 350/mm3 and HIV RNA plasma levels > 30,000 bDNA or > 55,000 RT-PCR copies: NOTE: The following abbreviation is used: nucleoside reverse transcriptase inhibitors (NRTIs). Oral dosage: Adults and adolescents: In combination with two NRTIs, either zidovudine in combination with didanosine, zalcitabine, or lamivudine; or stavudine in combination with didanosine or lamivudine, clinical practice guidelines recommend indinavir 800 mg PO every 8 hours. Adolescents in early puberty (Tanner Iï¿½II) should be dosed using pediatric schedules. Monotherapy with indinavir is not recommended.[1800] In patients receiving indinavir concurrently with either delavirdine, itraconazole, or ketoconazole, reduce the indinavir dose to 600 mg PO every 8 hours. Increase indinavir to 1200 mg PO every 8 hours when given in combination with rifabutin. Patients receiving indinavir with efavirenz should increase the indinavir dose to 1000 mg PO every 8 hours. ï¿½in children with clinical symptoms or evidence of immunosuppressionï¿½; or any infant < 12 monthsï¿½; or in asymptomatic children >= 1 year with normal immune status unless other factors favor postponing treatmentï¿½: Oral dosage: Childrenï¿½: The optimal dosage has not been established. A dosage of 500 mg/m2 PO every 8 hours is being evaluated in clinical trials. Monotherapy with indinavir is not recommended. Indinavir should be used in combination with two NRTIs, either zidovudine in combination with didanosine, lamivudine, or zalcitabine; or stavudine in combination with didanosine or lamivudine.[1684] In children unable to swallow capsules, use of other protease inhibitors (e.g., nelfinavir or ritonavir) is preferred. Neonatesï¿½: Safety and efficacy have not been established. Due to the potential for hyperbilirubinemia, indinavir should not be given to neonates until further information is available. For human immunodeficiency virus (HIV) prophylaxisï¿½ after occupational exposure to HIV: Oral dosage: Adults: The CDC recommends that indinavir 800 mg PO every 8 hours or nelfinavir be added to the basic regimen (i.e., zidovudine plus lamivudine) when the exposure is associated with an increased risk of HIV transmission (e.g., severe percutaneous exposure involving blood or other potentially infectious material from a known HIV-positive patient; or any percutaneous exposure or large volume exposure to integrity compromised mucous membrane or skin AND exposure to blood or other potentially infectious material from a patient with advanced AIDS, primary HIV infection, or a high or increasing viral load or low CD4 count) or if the source person's virus is known or suspected to be resistant to one or more antiretrovirals. In all cases, therapy should be initiated as soon as possible (preferably within 1ï¿½2 hours postexposure) and continued for 4 weeks.[487] Patients with hepatic impairment: In patients with mild to moderate hepatic impairment due to cirrhosis, reduce the recommended dose to 600 mg PO every 8 hours. Dosing in patients with severe hepatic impairment has not been studied. Patients with renal impairment: No dosage adjustments are recommended. Less than 20% of indinavir is excreted unchanged in the urine.
	CONTRAINDICACIONES Nephrolithiasis has occurred during indinavir therapy. If signs and symptoms of nephrolithiasis, including flank pain with or without microscopic or gross hematuria, occur, temporary interruption of therapy (e.g., 1ï¿½3 days) during the acute episode of nephrolithiasis or discontinuation of therapy may be considered. Adequate hydration (at least 1.5 liters/day or 48 ounces/day) is required during indinavir therapy to prevent dehydration, which increases the risk of nephrolithiasis. In states of dehydration, indinavir urine concentrations can exceed its solubility. Indinavir should be used with caution in patients with hepatic disease, including cirrhosis. Indinavir is metabolized by the liver, so patients with mild to moderate hepatic dysfunction tend to have increased serum levels of indinavir and require a dosage adjustment (see Dosage). Hepatitis including cases of hepatic failure have been reported in patients treated with indinavir, however, a causal relationship between these events has not been established because the majority of cases had confounding medical conditions and/or were receiving concomitant therapies. Indinavir is an inhibitor of the cytochrome P450 3A4 enzyme. Indinavir is contraindicated in and should not be administered to patients receiving the following drugs: astemizole, cisapride, ergot derivatives, lovastatin, midazolam, simvastatin, St. John's wort, terfenadine, and triazolam (see Drug Interactions). Inhibition of metabolism of these drugs results in increased plasma concentrations, potentially causing serious or life-threatening adverse reactions. Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during indinavir treatment. Some patients may require either initiation or dose adjustments of insulin or oral hyperglycemic agents. Patients should be monitored closely for new onset diabetes mellitus, diabetic ketoacidosis, or hyperglycemia. The issues regarding the use of antiretroviral agents in pregnancy are complex.Protease inhibitors may exacerbate the risk for hyperglycemia during pregnancy; monitoring of glucose levels is recommended. Data are limited concerning potential toxicities in infants whose mothers have received combination antiretroviral therapy. More intensive monitoring of hematologic and electrolyte parameters during the first few weeks of life is advised in these infants. It is strongly recommended that health care providers who are treating HIV-infected pregnant women and their newborns report cases of prenatal exposure to antiretroviral drugs to the Antiretroviral Pregnancy Registry; telephone (800) 258ï¿½4263; fax (800) 800ï¿½1052.[54] Certain adverse reactions of indinavir seen in adults (e.g., hyperbilirubinemia or nephrolithiasis) could be problematic for neonates if placental passage of indinavir occurs. It is unknown is administration of indinavir to the mother during the perinatal period will exacerbate physiologic hyperbilirubinemia in neonates. Because of the short half-life in adults, these concerns may only be relevant if indinavir is administered during labor or near the time of delivery. Safety and efficacy of indinavir have not been established in neonates; use is not recommended. The U.S. Public Health Service Centers for Disease Control recommend that HIV-infected mothers avoid breast-feeding their infants to prevent postnatal transmission of HIV infection. Thus, in the U.S., HIV-infected mothers should be instructed not to breastfeed, even if they are receiving indinavir. It is not known if indinavir is excreted in breast milk. The optimal dosing regimen of indinavir in children has not been established. A dose of 500 mg/m2 has been studied in uncontrolled trials of children 3ï¿½18 years. The pharmacokinetic profiles of indinavir at this dose were not comparable to profiles previously observed in adults receiving the recommended dosage. Although viral suppression was noted in 32 of 70 children receiving this dosage through 24 weeks, a substantially higher incidence of nephrolithiasis was reported as compared to adults. Physicians considering the use of indinavir in pediatric patients with or without other protease inhibitors should be aware of the limited data available and increased risk of nephrolithiasis in this population. Indinavir should be used cautiously in patients with hemophilia type A and B. There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. Some patients required additional factor VIII. However, the manufacturer states that in more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A cause and effect relationship has not been determined. Patients with advanced acquired immunodeficiency syndrome (AIDS) may be at increased risk for developing hypertriglyceridemia and pancreatitis. Patients who exhibit signs or symptoms of pancreatitis should discontinue treatment with indinavir. Fat redistribution and hyperlipidemia have become increasingly recognized side effects with the use of protease inhibitors. According to CDC guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events and pancreatitis. If a patient develops hyperlipidemia during treatment with a protease inhibitor, possible interventions include dietary modification, use of lipid lowering agents, or discontinuation of the protease inhibitor. As with all other antiretroviral agents, antimicrobial resistance can develop when indinavir is used either alone or in combination. Monotherapy with indinavir is not recommended. Varying degrees of cross-resistance have been observed between indinavir and other protease inhibitors. Cross-resistance to ritonavir has been noted. Cross-resistance between reverse transcriptase inhibitors and protease inhibitors is unlikely because different enzyme targets are involved.
	Indinavir is classified as FDA pregnancy risk category C. It is recommended that HIV-infected women who are receiving combination therapy for HIV should continue their regimen. However, there are insufficient data to support or refute teratogenic risk of antiretroviral drugs when administered during the first 10ï¿½12 weeks of gestation. If the woman decides to discontinue therapy, all drugs should be stopped and reintroduced simultaneously to avoid the development of resistance. For women not currently receiving antiretroviral therapy when the pregnancy is recognized, determination of antiretroviral therapy should be based on the same parameters used for non-pregnant persons, although the known and potential risks and benefits of such therapy during pregnancy must be considered and discussed. Women who are in the first trimester of pregnancy may consider delaying initiation of therapy until after 10ï¿½12 weeks of gestation. The three-part zidovudine chemoprophylaxis regimen (see Zidovudine Dosage) should be recommended for all HIV-infected pregnant women to reduce the risk for perinatal transmission. In HIV-infected women receiving antiretroviral therapy in whom pregnancy is recognized after the first trimester, treatment should continue. In any HIV-infected pregnant woman, if the current antiretroviral regimen does not contain zidovudine, the addition of zidovudine or substitution of zidovudine for another NRTI is recommended after 14 weeks gestation.
	Interactions Indinavir is metabolized primarily by cytochrome P450 3A4 (CYP3A4). Rifabutin and, to a greater degree, rifampin are potent inducers of this enzyme. Concurrent administration of indinavir and rifampin is not recommended. Administration of indinavir and rifampin for one week resulted in a 89% decrease in the indinavir AUC. Coadministration of indinavir and rifabutin for 10 days resulted in a 32 ï¿½ 19% decrease in indinavir AUC and a 204 ï¿½ 142% increase in rifabutin AUC (data on file with manufacturer). Data from drug interaction studies suggest that the dosage of indinavir should be increased to 1200 mg every 8 hours if used in combination with rifabutin (unpublished data, Merck Research Laboratories). According to CDC guidelines, the dose of rifabutin should be reduced to 150 mg PO daily or 300 mg PO 2ï¿½3 times weekly if used in combination with indinavir. [1299] Indinavir and isoniazid, INH, administered concurrently for 1 week resulted in a 13% increase in isoniazid AUC. No effects on indinavir pharmacokinetics were reported. No dosage adjustments for either agent are recommended. Due to effects on cytochrome P450 3A4, the combination of azole antifungals and indinavir may result in changes in concentrations of one or both of the agents. Ketoconazole administered concurrently with indinavir resulted in a 68% increase in the AUC of indinavir. In a multiple-dose study, administration of itraconazole capsules 200 mg twice daily with indinavir 600 mg every 8 hours resulted in an indinavir AUC similar to that observed during administration of indinavir 800 mg every 8 hours alone for one week. The manufacturer of indinavir recommends that indinavir dosages be reduced in patients receiving indinavir concurrently with ketoconazole or itraconazole. Concurrent use of fluconazole with indinavir resulted in a 19% decrease in indinavir AUC. Due to inhibition of cytochrome P450 3A4 (CYP3A4), indinavir should not be administered concurrently with astemizole, cisapride, dalfopristin; quinupristin, ergot alkaloids, pimozide, and terfenadine. Coadministration could inhibit the metabolism of these drugs and create the potential for serious and/or life-threatening events such as cardiac arrhythmias and/or prolonged sedation. Coadministration of indinavir with certain benzodiazepines may result in prolonged sedation and respiratory depression due to inhibition of hepatic oxidative metabolism of the benzodiazepine by indinavir. Because of the potential for serious events, indinavir should not be coadministered with midazolam or triazolam. Lorazepam or oxazepam may be safer alternatives if a benzodiazepine must be administered in combination with indinavir, as these benzodiazepines are not oxidatively metabolized. Indinavir may interfere with the metabolism of alfentanil, cyclosporine, docetaxel, donepezil, fentanyl, paclitaxel, sibutramine, sirolimus, tacrolimus, vinblastine, vincristine, and vinorelbine. Caution is warranted with concomitant administration. Interactions between indinavir and less potent CYP3A4 enzyme inducers such as dexamethasone, fosphenytoin, phenobarbital, phenytoin, and pioglitazone have not been studied. These agents should be used with caution if administered concomitantly with indinavir because altered plasma concentrations of one or both agents may result. Carbamazepine increases the metabolism of the protease inhibitors and may lead to decreased efficacy of these medications. Treatment failures have been reported with indinavir when carbamazepine was used concomitantly. The appropriate drug-dose adjustments necessary to ensure optimum levels of both antiretroviral drugs and carbamazepine are unknown. If other protease inhibitors are added to carbamazepine therapy, the patient should be observed for changes in the clinical efficacy of the antiretroviral regimen or carbamazepine treatment. Food interactions are possible with indinavir. Administration with food high in calories, fat, and protein resulted in a decrease in the AUC of indinavir by 77% and the Cmax by 84%. Lighter meals, such as dry toast with jelly, apple juice, and coffee with skim milk, may cause little or no change in the AUC, Cmax, or trough concentrations. For optimal absorption, indinavir requires a normal (acidic) gastric pH. Altered intragastric pH may thus explain some food and drug interations with indinavir. Administration of indinavir and sulfamethoxazole; trimethoprim, SMX-TMP increased the AUC of trimethoprim by 19%. There was no effect on the AUC of indinavir or sulfamethoxazole. Indinavir increases the AUC for ethinyl estradiol and norethindrone by 24% and 26%, respectively. Dosage adjustments of oral contraceptives containing ethinyl estradiol or norethindrone are not required. Coadministration of indinavir and stavudine, d4T for 1 week resulted in a 25% decrease in the AUC of stavudine. When indinavir and zidovudine, ZDV were administered concurrently, the AUC of indinavir and zidovudine was increased by 13% ï¿½ 48% and 17% ï¿½ 23%, respectively. The combination of indinavir, lamivudine, 3TC, and ZDV caused a 36% increase in zidovudine AUC and a 6% decrease in 3TC AUC. Dosage adjustments have not been recommended when either d4T, 3TC, or ZDV is administered with indinavir. Commercial formulations of didanosine, ddI, contain buffers that increase gastric pH. In patients receiving both didanosine and indinavir, indinavir should be administered on an empty stomach at least 1 hour before didanosine. Concurrent administration of ritonavir and indinavir leads to increased indinavir serum concentrations; ritonavir inhibits the clearance of indinavir. In a pharmacokinetic study in healthy volunteers, the AUC of single indinavir dose increased 185ï¿½475% during concurrent ritonavir dosing; the mean indinavir half-life increased form 1.2 to 2.7 hours.[2782] In an observational study of HIV-infected patients, the combination of indinavir 1200 mg and ritonavir 100 mg both twice daily led to high systemic exposure to indinavir and was not well tolerated. The combination of indinavir 800 mg and ritonavir 100 mg twice daily resulted in therapeutic indinavir serum concentrations with improved tolerability and similar maximum serum concentrations as the approved indinavir dosage of 800 mg three times a day.[2783] Patients should be closely monitored for possible indinavir toxicity during concurrent administraion with ritonavir; indinavir dosage reductions may be necessary. Concurrent Kaletraï¿½ (lopinavir; ritonavir) treatment results in increased plasma concentrations of amprenavir, indinavir, or saquinavir. Appropriate doses of the combination with respect to safety and efficacy have not been established in HIV-infected patients. Pharmacokinetics of single-dose indinavir and saquinavir and multi-dose amprenavir in healthy volunteers have been compared to historical data in HIV-infected subjects. Based on these comparisons, amprenavir 700 mg twice daily and indinavir 600 mg twice daily, when coadministered with Kaletraï¿½ 400/100 mg twice daily may produce a similar AUC, lower Cmax, and higher Cmin compared to their established clinical dosing regimens. The clinical significance of the lower Cmax and higher Cmin is unknown. Delavirdine administered concurrently with indinavir resulted in increases in the AUC of indinavir due to delavirdine-induced inhibition of cytochrome P450 3A4. There were no effects on the pharmacokinetics of delavirdine. The manufacturer of indinavir recommends that indinavir dosages be reduced in patients receiving both indinavir and delavirdine. Concurrent administration of indinavir and sildenafil may result in increased sildenafil plasma levels. In a small pharmacokinetic study, the co-administration of sildenafil and indinavir resulted in markedly increased AUC values for silfenafil as compared to historical controls. There was no significant difference in indinavir pharmacokinetics. The proposed mechanism of this interaction is indinavir inhibition of sildenafil hepatic metabolism. The authors of this study recommend lower starting doses of sildenafil in patients receiving concurrent indinavir.[2784] Concurrent administration of indinavir and quinidine caused indinavir AUC to increase by about 10%. There were no effects on quinidine pharmacokinetics. Following 7 days of coadministration of indinavir and clarithromycin, the AUC of indinavir increased by 29%. The AUC of clarithromycin increased by 53%. In general, patients with normal renal function require no clarithromycin dosage adjustment when clarithromycin and indinavir are administered concurrently. However, patients with impaired renal function may require a reduced dosage of clarithromycin (see Clarithromycin Dosage). In HIV-positive patients treated with aldesleukin, IL-2, and indinavir, the plasma AUC levels of indinavir increased 88% in 8 of 9 patients. The clearance of indinavir was decreased by 56% by day 5 of concurrent therapy. Treatment with IL-2 increased plasma levels of interleukin (IL)-6, which is an inhibitor of cytochrome P450 3A4 (CYP3A4), by 20-fold in these patients. Increased IL-6 levels may have inhibited CYP3A4, resulting in decreased clearance and increased serum levels of indinavir.[2356] Patients receiving anti-retroviral protease inhibitors, such as indinavir, in combination with cidofovir may have an increased risk of developing iritis or uveitis.[1472] When efavirenz was coadministered with indinavir, the Cmax and AUC of indinavir were decreased by a mean of 16% and 31%, respectively as a result of enzyme induction. Therefore, it is recommended that indinavir doses be increased from 800 mg to 1000 mg every 8 hours when given with efavirenz. Concomitant use of indinavir and either lovastatin or simvastatin is not recommended. Concurrent use of other HMG-CoA reductase inhibitors that are also metabolized by the cytochrome P450 3A4 pathway (e.g., atorvastatin or cerivastatin) and indinavir should be done cautiously. The risk of myopathy, including rhabdomyolysis, may be increased with anti-retroviral protease inhibitors, including indinavir, are used in combination with HMG-CoA reductase inhibitors. Indinavir may inhibit the metabolism of levobupivacaine. Concurrent adminiatration of indinavir and levobupivacaine may result in increased systemic levels of levobupivacaine resulting in toxicity. Indinavir may decrease the clearance of calcium-channel blockers (e.g., diltiazem, felodipine, and verapamil) via inhibition of CYP3A4 metabolism. Indinavir inhibits the metabolism of methadone. There is a potential for excessive side effects to methadone when indinavir is given concurrently. Patients should be monitored closely. However, administration of indinavir with methadone for one week resulted in no change in methadone AUC and little or no change in indinavir AUC. St. John's wort, Hypericum perforatum appears to interact with anti-retroviral protease inhibitors (PIs). In one study of healthy volunteers, the concomitant administration of St. John's wort with indinavir substantially decreased mean indinavir plasma concentrations by 57% and trough concentrations by 81%.[2718] It appears that St. John's wort is an inducer of hepatic cytochrome P450 enzymes, particularly CYP3A4. Such reductions in plasma concentrations of these drugs could lead to HIV treatment failures or the development of viral-resistance. St. John's wort in all forms, including teas, should be avoided in HIV patients treated with indinavir. Coadministration of dofetilide with anti-retroviral protease inhibitors could theoretically inhibit hepatic metabolism of dofetilide (via CYP3A4 isoenzymes) and result in increased plasma dofetilide concentrations. Plasma dofetilide concentrations are correlated with the risk of drug-induced proarrhythmias. Alosetron is partially metabolized by CYP3A4. Anti-retroviral protease inhibitors inhibit this enzyme and may decrease the metabolism of alosetron resulting in increased alosetron plasma concentrations. Coadministration of alosetron with these agents has not been studied. Concurrent administration of zonisamide with anti-retroviral protease inhibitors could theoretically inhibit hepatic metabolism of zonisamide (via CYP3A4 isoenzymes) and result in increased plasma zonisamide concentrations. Coadministration of zonisamide with these agents has not been studied. A patient receiving triple-drug HIV prophylaxis including indinavir, lamivudine, 3TC, and stavudine, d4T, developed a hypertensive crisis within 6 hours of taking a phenylpropanolamine-containing product.[2785] The patient complained of chest tightness, difficulty breathing, weakness in her left arm and pulsing headache. Her blood pressure was 220/120, which returned to normal within 4 hours with no treatment. Although a casual relationship has not been established, the temporal relationship is consistent with an interaction. Caution should be used with this combination of agents due to the severity of the possible reaction. Mifepristone, RU-486 inhibits CYP3A4 in vitro. Coadministration of mifepristone may lead to an increase in serum levels of the anti-retroviral protease inhibitors. Due to the slow elimination of mifepristone from the body, such interactions may be observed for a prolonged period after mifepristone administration. Hepatic CYP3A4 is partially responsible for the metabolism of galantamine. The bioavailability of galantamine may be increased when co-administered with the CYP3A4 inhibitor indinavir.
	REACCIONES ADVERSAS Nephrolithiasis/urolithiasis, manifested as flank pain with or without hematuria (including microscopic hematuria) has been reported in 9.3% of patients receiving indinavir. Of indinavir-treated patients developing nephrolithiasis, 3.1% developed hydronephrosis and 3.1% underwent stent placement. In some cases nephrolithiasis resulted in renal insufficiency (azotemia), acute renal failure due to renal tubular obstruction, renal colic, or interstitial nephritis with indinavir crystal deposits. In some cases, the interstitial nephritis did not resolve following discontinuation of indinavir. Nephrolithiasis occurred more frequently at indinavir doses > 2.4 g/day. In post-marketing experience crystalluria and dysuria have been reported. Asymptomatic hyperbilirubinemia has been reported in 14% of patients, but elevated hepatic enzymes (AST or ALT) have been reported in < 1% of patients. Jaundice has been reported in about 1% of patients. Hyperbilirubinemia occurred more frequently at indinavir doses of > 2.4 g/day. Abdominal pain (16.6%), nausea/vomiting (11.7%/8.4%), diarrhea (3.3%), gastroesophageal reflux (2.7%), anorexia (2.7%), dysgeusia (2.7%), appetite increase (2.1%), and dyspepsia (1.5%) have been reported in patients treated with indinavir. Hepatitis including cases of hepatic failure and death have been reported in patients treated with indinavir. Because the majority of these patients had confounding medical conditions and/or were receiving concomitant drug therapy, a causal relationship has not been established. Pancreatitis and abdominal distention have been reported during post-marketing surveillance. Adverse reactions affecting the skin and skin structures include pruritus (4.2%) and rash (unspecified) (1.2%), which have included erythema multiforme and Stevens-Johnson syndrome. Alopecia, ingrown toenails and/or paronychia, skin hyperpigmentation, urticaria, and xerosis (dry skin) have been reported as well. Back pain (8.4%) is the most common musculoskeletal adverse reaction reported with indinavir therapy. Arthralgia has also been reported with indinavir. Other adverse reactions affecting the body as a whole include asthenia/fatigue (2.1%), cough (1.5%), malaise (2.1), and fever (1.5%). Anaphylactoid reactions have also been reported. Headache (5.4%), dizziness (3%), and drowsiness/somnolence (2.4%) have been reported in patients receiving indinavir. Depression and oral paresthesias have also been reported in post marketing reports. Cardiovascular disorders including angina pectoris and myocardial infarction have been reported during the post-marketing experience with indinavir. These cardiovascular adverse reactions are considered at least possibly related or of unknown relationship to indinavir treatment. Acute hemolytic anemia, including some cases resulting in death, has been reported in patients treated with indinavir. Once a diagnosis of hemolytic anemia has been made, indinavir therapy should be discontinued. Spontaneous bleeding has been reported in patients with hemophilia and concurrent HIV infection treated with protease inhibitors. The cases of spontaneous bleeding have primarily consisted of hematomas and hemarthroses but more serious bleeding episodes such as intracranial bleeding and GI bleeding have been reported. The bleeding episodes have occurred a median of 22 days after initiating protease inhibitor therapy. The majority of the patients have been able to continue taking their protease inhibitor therapy in spite of the bleeding events. Some patients received additional coagulation factor treatment while continuing protease inhibitor therapy. New onset diabetes mellitus, exacerbation of diabetes mellitus, and hyperglycemia due to insulin resistance have been reported with use of protease inhibitors including indinavir. Onset averaged approximately 63 days after initiating protease inhibitor therapy, but has occurred as early as 4 days after beginning therapy. Diabetic ketoacidosis has occurred in some patients including patients who were not diabetic prior to protease inhibitor treatment; however, the baseline status of these patients was not well characterized. Initiation or adjustment of hypoglycemic therapy was required in some patients after beginning protease inhibitor treatment. On average, 50% of patients discontinued their protease inhibitor therapy as a result of this adverse reaction. In some patients, hyperglycemia persisted following discontinuation of protease inhibitor therapy including those not known to be diabetic at baseline, however, a causal relationship has not been established. It should also be noted that many of these patients have confounding medical conditions that require therapy with drugs that have been associated with the development of diabetes mellitus or hyperglycemia. A lipodystrophy syndrome consisting of redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, accumulation of facial fat, lipomas, gynecomastia and other cushingoid features has been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes protease inhibitors such as indinavir. Orginally called "Crix belly" in 1997, the syndrome was reported as abdominal weight gain among patients taking indinavir (Crixivanï¿½). The original link to indinavir is partly due to the fact that up to that time the majority of patients receiving anti-HIV therapy were given indinavir. This syndrome may be associated with metabolic complications such as insulin resistance, hyperglycemia, and dyslipidemia, but not always. Some studies indicate that up to 5ï¿½30% of patients receiving protease inhibitors may develop lipodystrophy. The mechanism and long-term consequences are not known. A casual relationship has not been established. Changes in HAART to reverse lipodystrophy should probably be avoided unless the patient finds the changes in body fat intolerable and more conservative interventions fail. Hyperlipidemia including hypertriglyceridemia and hypercholesterolemia have been reported in patients receiving protease inhibitor-containing regimens. Abnormalities in lipid profiles may develop soon after starting protease inhibitor therapy. Both VLDL and LDL have been reported to increase without a significant rise in HDL. Concern has been raised about the risk of coronary artery disease in patients receiving protease inhibitors; however, other factors such as family history of heart disease, may contribute to the elevated cholesterol and triglyceride levels as well as increased risk for coronary artery disease. In addition, the benefit of highly active antiretroviral therapy (HAART) in the treatment of HIV disease may outweigh the risk of coronary artery disease.
	Indinavir Crixivanï¿½
	REFERENCIAS Centers for Disease Control and Prevention. Public health service guidelines for the management of health-care worker exposures to HIV and recommendations for postexposure prophylaxis. Morbid Mortal Weekly Rep 1998;47:1ï¿½33. Centers for Disease Control and Prevention et al. The Living Document: Guidelines for the use of antiretroviral agents in pediatric HIV infection. Retrieved January 7, 2000. Available on the World Wide Web at http://www.hivatis.org Centers for Disease Control and Prevention et al. The Living Document: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. May 5, 1999. Available on the World Wide Web at http://www.hivatis.org Perinatal HIV Guidelines Working Group Members. Public health service task force recommendations for the use of antiretroviral drugs in pregnant women infected with HIV-1 for maternal health and interventions to reduce perinatal HIV-1 transmission in the United States. Retrieved November 3, 2000. Available on the World Wide Web at: http://hivatis.org/trtgdlns.html. Centers for Disease Prevention and Control. Notice to readers: Updated guidelines for the use of rifabutin or rifampin for the treatment and prevention of tuberculosis among HIV-infected individuals taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. MMWR 2000;49:185ï¿½9. Hsu A, Granneman GR, Cao G, et al. Pharmacokinetic interaction between ritonavir and indinavir in healthy volunteers. Antimicrob Agents Chemother 1998;42:2784ï¿½91. van Heeswijk RP, Veldkamp AI, Hoetelmans RM, et al. The steady-state plasma pharmacokinetics of indinavir alone and in combination with a low dose of ritonavir in twice daily dosing regimens in HIV-1 infected individuals. AIDS 1999; 13:F95ï¿½9. Merry C, Barry MG, Ryan M, et al. Interaction of sildenafil and indinavir when co-administered to HIV-patients. AIDS 1999;13:F101ï¿½7. Piscitelli SC, Vogel S, Figg WD, et al. Alteration in indinavir clearance during interleukin-2 infusions in patients infected with the human immunodeficieny virus. Pharmacotherapy 1998;18:1212ï¿½6. Davis JL et al. Iritis and hypotony after treatment with intravenous cidofovir for cytomegalovirus retinitis. Arch Ophthal 1997;115:733ï¿½7. Piscitelli SC, Burstein AH, Alfaro MS. Indinavir concentrations and St. John's wort. Lancet 2000;355:547ï¿½48. Khuranan V. Hypertensive crisis secondary to phenylpropanolamine interacting with triple-drug therapy for HIV prophylaxis. Am J Med 1999;106:118ï¿½9.
	Monografía creada el 6 de abril de 2015.Equipo de redacciï¿½n de IQB (Centro colaborador de La Administraciï¿½n Nacional de Medicamentos, alimentos y Tecnologï¿½a Mï¿½dica -ANMAT - Argentina). .