Atazanavir

704.87

704.86

1308068-626-2

QZU4H47A3S

DTXSID9048691

C66872

J05AE08|J - Antiinfectives for systemic use

171

4.5

crystalline solid

1.178±0.06 g/cm3(Predicted)

198-200 °C @ Solvent: Ethanol, Water

1.562

Free base slightly soluble (4-5 mg/mL)

-20°C Freezer

1.0X10-26 mm Hg at 25 deg C (est)

D -47° (c = 1 in ethanol)

Henry's Law constant = 3.6X10-32 atm-cu m/mole at 25 °C (est)

White to pale yellow crystalline powder. Slightly soluble in water 4-5 mg/mL. pH of saturated solution 1.9 at 24 °C. /Sulfate salt/|Hydroxy radical reaction rate constant = 9.8X10-11 cu cm/molec-sec at 25 °C (est)

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl atazanavir sulfate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Atazanavir Sulfate/

|Danger|H318 (100%): Causes serious eye damage [Danger Serious eye damage/eye irritation]|P260, P264, P270, P273, P280, P305+P351+P338, P310, P314, P391, and P501|Aggregated GHS information provided by 2 companies from 1 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Atazanavir can cause several forms of liver injury including transient serum enzyme elevations, indirect hyperbilirubinemia, idiosyncratic acute liver injury and exacerbation of underlying chronic viral hepatitis.

Pharmacologic interaction with bepridil (potential for serious and/or life-threatening adverse effects). Concomitant use of bepridil and atazanavir not recommended.|Pharmacokinetic interaction with antiarrhythmic agents (i.e., amiodarone, systemic lidocaine, quinidine). Potential for serious and/or life-threatening adverse effects. Monitor plasma concentrations of these antiarrhythmic agents if used concomitantly with atazanavir.|Potential pharmacokinetic interaction (increased plasma concentration of the tricyclic antidepressant). Potential for serious and/or life-threatening adverse effects. Monitor plasma concentrations of these tricyclic antidepressants agents if used concomitantly with atazanavir.|Pharmacokinetic interaction with rifampin (substantial decrease (90%) in the peak plasma concentration and area under the concentration-time curve (AUC) of HIV protease inhibitors). Concomitant use of atazanavir and rifampin not recommended.|For more Interactions (Complete) data for ATAZANAVIR (34 total), please visit the HSDB record page.

Spontaneous bleeding noted with HIV protease inhibitors; caution in patients with a history of hemophilia type A or B. Increased hemostatic (e.g., antihemophilic factor) therapy may be needed.|Experience in those 65 years of age or older insufficient to determine whether they respond differently than younger adults; dosage adjustment based on age alone not recommended. Exercise caution in administration and monitoring; the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease or drug therapy observed in geriatric individuals should be considered.

86% bound to human serum proteins (alpha-1-acid glycoprotein and albumin). Protein binding is independent of concentration.

Atazanavir's production and use as the free base of the HIV drug atazanavir sulfate(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3.8X10+7(SRC), determined from a structure estimation method(2), indicates that atazanavir is expected to be immobile in soil(SRC). Volatilization of atazanavir from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 3.6X10-32 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Atazanavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-26 mm Hg(SRC), determined from a fragment constant method(4). Biodegradation data were not available(SRC, 2005).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3.8X10+7(SRC), determined from a structure estimation method(2), indicates that atazanavir is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 3.6X10-32 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 7.4(SRC), from an estimated log Kow of 2.9(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrolysis may occur however the predicted rate indicates that the reaction would be very slow with half lives corresponding to 10,000 and 100,000 years for pH 8 and 7, respectively(8). These estimated rates suggest that hydrolysis is not expected to be an important fate process. Biodegradation data were not available(SRC,2005).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), atazanavir, which has an estimated vapor pressure of 1.0X10-26 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the atmosphere. Particulate-phase atazanavir may be removed from the air by wet and dry deposition(SRC). Based on other biphenyl compounds(3), atazanavir is not expected to absorb at >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

A base-catalyzed second-order hydrolysis rate constant of 2.1X10-6 L/mole-sec(SRC) was estimated using a structure estimation method(1); this corresponds to half-lives of 100,000 and 10,000 years at pH values of 7 and 8, respectively(1). The estimated data suggest that hydrolysis is not an important fate process. Based on other biphenyl compounds(2), atazanavir is not expected to absorb at >290 nm and therefore is not expected to be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 7.4 was calculated for atazanavir(SRC), using an estimated log Kow of 2.9(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc for atazanavir can be estimated to be 3.8X10+7(SRC). According to a classification scheme(2), this estimated Koc value suggests that atazanavir is expected to be immobile in soil.

The Henry's Law constant for atazanavir is estimated as 3.6X10-32 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that atazanavir is expected to be essentially nonvolatile from moist soil(SRC) and water surfaces(2). Atazanavir is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.0X10-26 mm Hg(SRC), determined from a fragment constant method(3).

It is not known whether atazanavir is distributed into human breast milk. However, atazanavir is distributed into the milk of rats.

Occupational exposure to atazanavir may occur through dermal contact with this compound at workplaces where atazanavir is produced or used. Exposure to the drug among the general population may be limited to those taking Reyataz (an HIV drug) which contains atazanavir sulfate. (SRC)

Used in combination with other antiretroviral agents for the treatment of HIV-1 infection, as well as postexposure prophylaxis of HIV infection in individuals who have had occupational or nonoccupational exposure to potentially infectious body fluids of a person known to be infected with HIV when that exposure represents a substantial risk for HIV transmission.|FDA Label|Atazanavir Mylan, co-administered with low dose ritonavir, is indicated for the treatment of HIV 1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations). There are very limited data available from children aged 6 to less than 18 years.The choice of Atazanavir Mylan in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history.|Reyataz capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products (see section 4.2).Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations).The choice of Reyataz in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history (see sections 4.4 and 5.1).Reyataz oral powder, co-administered with low dose ritonavir, is indicated in combination with other antiretroviral medicinal products for the treatment of HIV-1 infected paediatric patients at least 3 months of age and weighing at least 5 kg (see section 4.2).Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors ( 4 PI mutations). The choice of Reyataz in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history (see sections 4.4 and 5.1).|Atazanavir Krka capsules, co-administered with low dose ritonavir, are indicated for the treatment of HIV-1 infected adults and paediatric patients 6 years of age and older in combination with other antiretroviral medicinal products.Based on available virological and clinical data from adult patients, no benefit is expected in patients with strains resistant to multiple protease inhibitors (≥ 4 PI mutations).The choice of Atazanavir Krka in treatment experienced adult and paediatric patients should be based on individual viral resistance testing and the patient's treatment history.

Atazanavir is an antiretroviral protease inhibitor that is used in the therapy and prevention of human immunodeficiency virus (HIV-1) infection and the acquired immunodeficiency syndrome (AIDS). Atazanavir can cause transient and usually asymptomatic elevations in serum aminotransferase levels, mild elevations in indirect bilirubin concentration and, rarely, clinically apparent, acute liver injury. In HBV or HCV coinfected patients, highly active antiretroviral therapy with atazanavir may result of an exacerbation of the underlying chronic hepatitis B or C.

Atazanavir sulfate is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection. The use of atazanavir sulfate may be considered in antiretroviral-treatment experienced adults with HIV strains that are expected to be susceptible to atazanavir sulfate by genotypic and phenotypic testing. /Included in US product labeling/

Lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have been reported in patients receiving atazanavir in conjunction with nucleoside reverse transcriptase inhibitors (NRTIs). Therapy with NRTIs is known to be associated with an increased risk of lactic acidosis syndrome; female gender and obesity also are known risk factors for this syndrome. Whether atazanavir contributes to the risk of lactic acidosis syndrome remains to be established.|Hyperglycemia (potentially persistent), new-onset diabetes mellitus, or exacerbation of preexisting diabetes mellitus has been reported in patients receiving HIV protease inhibitors. May require initiation of antidiabetic therapy (e.g., insulin, oral antidiabetic agents) or dosage adjustment for existing diabetes; diabetic ketoacidosis can occur.|Abnormalities in AV conduction, including prolongation of the PR interval, have occurred in individuals receiving atazanavir. Cardiac conduction abnormalities generally are limited to first-degree AV block; prolongation of the QTc interval observed in HIV-infected patients receiving atazanavir have not been directly attributed to the drug. Asymptomatic first-degree AV block was observed in 5.9 or 3-10.4% of patients in clinical trials receiving regimens that included atazanavir or comparator antiretrovirals (lopinavir/ritonavir, nelfinavir, efavirenz), respectively; second- or third-degree block was not observed. Atazanavir should be used with caution in patients with cardiac conduction abnormalities (e.g., marked first-degree AV block; second- or third-degree AV block) because of lack of clinical experience.|Because atazanavir is a competitive inhibitor of uridine diphosphate-glucuronosyltransferase (UGT) 1A1 (an enzyme that catalyzes the glucuronidation of bilirubin), reversible asymptomatic elevations in indirect (unconjugated) bilirubin occur in most patients receiving the drug. Total bilirubin concentrations at least 2.6 times the upper limit of normal have been reported in 35-47% of patients receiving the drug in clinical trials; long-term safety data are not available for patients experiencing persistent elevations in total bilirubin exceeding 5 times the upper limit of normal. Increases in serum AST (SGOT) and/or ALT (SGPT) concentrations that occur with hyperbilirubinemia should be evaluated for etiologies other than hyperbilirubinemia. If jaundice or scleral icterus that result from bilirubin elevations cause cosmetic concerns, alternative antiretroviral therapy can be considered; reduction of atazanavir dosage not recommended (efficacy data not available for reduced dosages).|For more Drug Warnings (Complete) data for ATAZANAVIR (17 total), please visit the HSDB record page.

Possibility of HIV-1 resistant to atazanavir. Resistance profile of atazanavir appears to differ from that of other HIV protease inhibitors; some atazanavir-resistant isolates may retain susceptibility to other HIV protease inhibitors, but isolates cross-resistant to multiple HIV protease inhibitors may be resistant to atazanavir.|... 89% (32 of 36) of atazanavir-resistant isolates from studies of treatment-experienced patients (n=67 evaluable isolates) treated with atazanavir (n=26) or atazanavir plus saquinavir (n=10) showed no evidence of the emergence of the I50L substitution. Instead, these isolates displayed decreased susceptibility to multiple protease inhibitors and contained mutations associated with resistance to multiple protease inhibitors. These mutations included I84V, L90M, A71V/T, N88S/D, and M46I, which conferred atazanavir resistance and reduced the clinical response to atazanavir. Generally, if protease inhibitor mutations were present in the HIV-1 of the patient at baseline, atazanavir resistance developed through mutations associated with resistance to other protease inhibitors instead of the I50L mutation. These mutations conferred high cross-resistance to other protease inhibitors with 100% of the isolates resistant to nelfinavir, >80% of the isolates resistant to indinavir, ritonavir, and saquinavir, and >35% of the isolates resistant to amprenavir and lopinavir. Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir therapy.

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI) with activity against Human Immunodeficiency Virus Type 1 (HIV-1). HIV-1 protease is an enzyme required for the proteolytic cleavage of the viral polyprotein precursors into the individual functional proteins found in infectious HIV-1. Atazanavir binds to the protease active site and inhibits the activity of the enzyme. This inhibition prevents cleavage of the viral polyproteins resulting in the formation of immature non-infectious viral particles. Protease inhibitors are almost always used in combination with at least two other anti-HIV drugs. Atazanivir is pharmacologically related but structurally different from other protease inhibitors and other currently available antiretrovirals.

Inhibitors of HIV PROTEASE, an enzyme required for production of proteins needed for viral assembly. (See all compounds classified as HIV Protease Inhibitors.)

Atazanavir is rapidly absorbed with a T_max of approximately 2.5 hours. Administration of atazanavir with food enhances bioavailability and reduces pharmacokinetic variability. Oral bioavailability is 60-68%.|Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200-800 mg once daily. Steady-state is achieved between Days 4 and 8, with an accumulation of approximately 2.3-fold.|Administration of /atazanavir/ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single dose of /atazanavir/ with a light meal (357 kcal, 8.2 g fat, 10.6 g protein) resulted in a 70% increase in AUC and 57% increase in Cmax relative to the fasting state. Administration of a single dose of /atazanavir/ with a high-fat meal (721 kcal, 37.3 g fat, 29.4 g protein) resulted in a mean increase in AUC of 35% with no change in Cmax relative to the fasting state. Administration of /atazanavir/ with either a light meal or high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately one half compared to the fasting state.|Peak plasma concentration: Healthy subjects: 5199 ng/mL on day 29 following a 400 mg daily dose with a light meal. HIV-infected patients: 2298 ng/mL on day 29 following a 400 mg daily dose with a light meal.|Time to peak concentration: HIV-infected patients: 2 hours.|For more Absorption, Distribution and Excretion (Complete) data for ATAZANAVIR (8 total), please visit the HSDB record page.

Atazanavir is extensively metabolized in humans, primarily by the liver. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.|Atazanavir is extensively metabolized in humans. The major biotransformation pathways of atazanavir in humans consisted of monooxygenation and (atazanavir sulfate) dioxygenation. Other minor biotransformation pathways for atazanavir or its metabolites consisted of glucuronidation, N-dealkylation, hydrolysis, and oxygenation with dehydrogenation. Two minor metabolites of atazanavir in plasma have been characterized. Neither metabolite demonstrated in vitro antiviral activity. In vitro studies using human liver microsomes suggested that atazanavir is metabolized by CYP3A.

Elimination half-life in adults (healthy and HIV infected) is approximately 7 hours (following a 400 mg daily dose with a light meal). Elimination half-life in hepatically impaired is 12.1 hours (following a single 400 mg dose).|The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared with 6.4 hours in healthy volunteers. ...|The mean elimination half-life of atazanavir in healthy volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Atazanavir selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells by binding to the active site of HIV-1 protease, thus preventing the formation of mature virions. Atazanavir is not active against HIV-2.|Atazanavir is an azapeptide HIV-1 protease inhibitor. The compound selectively inhibits the virus-specific processing of viral Gag and Gag-Pol polyproteins in HIV-1 infected cells, thus preventing formation of mature virions.|BMS-232632 is an azapeptide human immunodeficiency virus type 1 (HIV-1) protease (Prt) inhibitor that exhibits potent anti-HIV activity with a 50% effective concentration (EC(50)) of 2.6 to 5.3 nM and an EC(90) of 9 to 15 nM in cell culture. Proof-of-principle studies indicate that BMS-232632 blocks the cleavage of viral precursor proteins in HIV-infected cells, proving that it functions as an HIV Prt inhibitor. Comparative studies showed that BMS-232632 is generally more potent than the five currently approved HIV-1 Prt inhibitors. Furthermore, BMS-232632 is highly selective for HIV-1 Prt and exhibits cytotoxicity only at concentrations 6,500- to 23, 000-fold higher than that required for anti-HIV activity. To assess the potential of this inhibitor when used in combination with other antiretrovirals, BMS-232632 was evaluated for anti-HIV activity in two-drug combination studies. Combinations of BMS-232632 with either stavudine, didanosine, lamivudine, zidovudine, nelfinavir, indinavir, ritonavir, saquinavir, or amprenavir in HIV-infected peripheral blood mononuclear cells yielded additive to moderately synergistic antiviral effects. Importantly, combinations of drug pairs did not result in antagonistic anti-HIV activity or enhanced cytotoxic effects at the highest concentrations used for antiviral evaluation. Our results suggest that BMS-232632 may be an effective HIV-1 inhibitor that may be utilized in a variety of different drug combinations.

Treatment of overdosage with /atazanavir/ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient's clinical status. ... Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with /atazanavir/. Since atazanavir is extensively metabolized by the liver and is highly protein bound, dialysis is unlikely to be beneficial in significant removal of this medicine.|Basic treatment: Establish a patent airway. 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 normal saline 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 ... . /Poison A and B/|Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

/SIGNS AND SYMPTOMS/ At high doses that lead to high drug exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed.|/SIGNS AND SYMPTOMS/ ... Stevens-Johnson syndrome and erythema multiforme have been reported in patients receiving atazanavir.|/CASE REPORTS/ A single self-administered overdose of 29.2 g of /atazanavir/ in an HIV-infected patient (73 times the recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously.

232632, BMS

Oral: Capsules: 100 mg (of atazanavir) Reyataz, (Bristol-Myers Squibb), 150 mg (of atazanavir) Reyataz, (Bristol-Myers Squibb), 200 mg (of atazanavir) Reyataz, (Bristol-Myers Squibb).

While data specific to atazanavir were not available(SRC, 2005), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2). Studies have indicated that several polar pharmaceutically active compounds can leach through subsoils into aquifers(1).

Human drugs -> Atazanavir Mylan -> EMA Drug Category|Antivirals for systemic use -> Human pharmacotherapeutic group|Human drugs -> Reyataz -> EMA Drug Category|Human drugs -> Atazanavir Krka -> EMA Drug Category|Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients