ATAZANAVIR SULFATE (Generic for REYATAZ)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer with food to enhance absorption.
Oral Solid Formulations
Oral capsules
-Capsules must be swallowed whole. Do not open the capsules.

Oral powder
-Preferably, mix atazanavir powder with food such as applesauce or yogurt. The powder may also be mixed with a beverage (milk, infant formula, or water) for infants old enough to drink from a cup. For young infants (younger than 6 months) who cannot eat solid food or drink from a cup, atazanavir powder should be mixed with infant formula and given using an oral dosing syringe.
-Mixing with food: Using a spoon, mix the appropriate number of oral powder packets into a minimum of 1 tablespoon of food. Feed the mixture to the child, and then add an additional tablespoon of food to the container, mix, and feed the child the residual mixture.
-Mixing with a beverage: Using a spoon, mix the appropriate number of oral powder packets with a minimum of 30 mL of the beverage in a small drinking cup. Have the child drink the mixture. Add an additional 15 mL more of beverage to the drinking cup, mix, and have the child drink the residual mixture. If water is used, food should also be given at the same time.
-Mixing with liquid infant formula using an oral dosing syringe: Using a spoon, mix the appropriate number of oral powder packets with 10 ml of prepared liquid infant formula in a small medicine cup. Draw up the full amount of the mixture into an oral syringe and administer into either the right or left inner cheek of the infant. Pour an additional 10 ml of formula into the cup and rinse off the remaining oral powder in a cup. Draw up the residual mixture and administer it to the infant.
-Administer ritonavir immediately after atazanavir powder administration.
-Storage: Administer the entire mixture (mixed in food or beverage) within 1 hour of preparation; mixture may be left at a temperature of 20 to 30 degrees C (68 to 86 degrees F) during the 1 hour. Ensure that the patient consumes all of the food or beverage that contains the powder.

In clinical trials of pediatric patients receiving atazanavir capsules, the safety profile was generally similar to that observed in adult patients. The safety profile of the oral powder in pediatric patients was similar to that observed in pediatric patients receiving the capsules.

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, breast enlargement, gynecomastia, and other Cushingoid features have been reported in patients receiving long-term highly active antiretroviral therapy (HAART) that includes protease inhibitors, such as atazanavir. Any effects of atazanavir on lipoprotein concentrations do not appear to be associated with a decreased incidence of lipodystrophy. The mechanism and long-term consequences of the lipodystrophy syndrome are not known. A causal relationship has not been established, and whether or not atazanavir is associated with a lower incidence of lipodystrophy than other drugs in the class is unknown. 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.

Compared to other protease inhibitors, atazanavir has minor effects on lipoprotein concentrations; however, hypercholesterolemia and hypertriglyceridemia have occurred during adult clinical trials in 6-25% and 4-8%, respectively, of patients treated with atazanavir. Monitor serum cholesterol and triglyceride levels at baseline and periodically throughout treatment. It is unknown if a change to atazanavir from another protease inhibitor that has caused lipoprotein concentration elevations will result in an improved lipoprotein profile. 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. According to the HIV guidelines, patients with hypertriglyceridemia or hypercholesterolemia should be evaluated for risks for cardiovascular events. 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..

Atazanavir, like indinavir, competitively inhibits the enzyme uridinediphosphate-glucuronosyl transferase (UGT) 1A1. Due to the lower concentration of available UGT, unconjugated bilirubin concentrations may rise. In clinical trials, grade 3 or 4 hyperbilirubinemia (>= 3.2 mg/dL) was noted in 58% of pediatric patients. Elevation of bilirubin >= 2.6 x ULN was noted in 16% of pediatric patients. In most patients that develop hyperbilirubinemia, the rise in bilirubin concentration is mild, occurs within the first few days of atazanavir consumption, and resolves promptly with drug discontinuation. The effect of persistent elevations in total bilirubin concentrations greater than 5 times the upper limit of normal is unknown. Elevated hepatic enzymes (grade 3 or 4 elevations in ALT) were noted in 9% of pediatric patients receiving atazanavir in clinical trials. In adult patients, elevated transaminases occurred especially in patients with concurrent hepatitis B and/or hepatitis C. Overall, grade 3 or 4 AST and ALT elevations occurred in 2-9% of adult patients overall and in 9-15% of adult hepatitis patients. Jaundice/scleral icterus occurred in 15% of pediatric patients. Alternative antiretroviral agents may be considered if jaundice or scleral icterus presents cosmetic concerns; however, dose reduction is not recommended as long-term efficacy of reduced doses has not been established. Cholelithiasis, cholecystitis, and cholestasis have all been reported in post-marketing experience.

Rash (unspecified) was reported in 14% of pediatric patients during atazanavir trials. Median time to rash onset was 7.3 weeks after initiation of atazanavir and lasted a median of 1.4 weeks. The reported rashes were generally described as mild to moderate maculopapular skin eruptions, although cases of Stevens-Johnson syndrome and erythema multiforme have been reported. Atazanavir was typically not discontinued in patients who developed a mild to moderate rash; the discontinuation rate due to rash in clinical trials was < 1%. Atazanavir should be discontinued if a severe rash develops. Events reported with post-marketing use include: alopecia, maculopapular rash, and pruritus.

Gastrointestinal symptoms were among the most commonly reported adverse events in patients receiving atazanavir. Vomiting was reported in 12% of pediatric patients, while diarrhea was noted in 9% of pediatric patients. Nausea was reported in 3-14% of adult patients and abdominal pain was reported in 4% of adult patients.

Atazanavir may cause PR prolongation; the overall risk is unknown. Prolongation of the PR interval appears to be dose-related and can lead to first- or second-degree AV block; there have been post-marketing reports of second-degree and third-degree AV block. During clinical trials, asymptomatic second-degree AV block was reported in < 2% of pediatric patients. In a placebo-controlled study, the mean maximum change in the PR interval with atazanavir 400 mg daily was 24 msec as compared to 13 msec with placebo. Atazanavir needs to be used with caution, especially in conjunction with other drugs that prolong the PR interval. There have also been post-marketing reports of left bundle-branch block and QT prolongation.

Neutropenia was reported in 9% of pediatric patients during atazanavir clinical trials. Anemia (hemoglobin less than 8 g/dL) was reported in less than 3% of pediatric patients. Thrombocytopenia (2%) has been reported in adult patients.

Peripheral edema was noted in 7% of pediatric patients during clinical trials. Generalized edema and angioedema have been reported during post-marketing use of atazanavir.

There have been postmarketing reports of nephrolithiasis, granulomatous interstitial nephritis, interstitial nephritis, and chronic kidney disease in patients receiving atazanavir. Consider temporary interruption or discontinuation of therapy if nephrolithiasis or progressive kidney disease occurs.

Hypoglycemia was reported in 4% of pediatric patients during atazanavir trials. Hyperglycemia (glucose >= 251 mg/dL) was reported in 5% of atazanavir/ritonavir treated adult patients. Additionally, the development of hyperglycemia and new-onset diabetes mellitus and exacerbation of diabetes mellitus has been reported during post-marketing use of atazanavir. In some cases diabetic ketoacidosis occurred. In some patients who discontinue protease-inhibitor therapy, hyperglycemia persists.

Patients with hemophilia type A or B treated with protease inhibitors, such as atazanavir, have experienced spontaneous bleeding episodes, including hematoma and hemarthrosis. A definitive incidence and causal relationship between protease inhibitors and these adverse events have not been established.

Fever was reported in 18% of pediatric patients receiving atazanavir in clinical trials.

Central nervous system disorders have been noted in patients receiving atazanavir in clinical trials. Headache was reported in 8% of pediatric patients. Insomnia (< 1% to 3%), dizziness (< 1% to 2%), and peripheral neurologic symptoms (< 1% to 4%) occurred in treatment-naive adults in clinical trials. Depression was reported in 2% of treatment-experienced adults.

Extremity pain was reported in 6% of pediatric patients during atazanavir trials. Myalgia was reported in 4% of adults. Arthralgia has been reported in post-marketing surveillance. Elevated creatinine kinase (>= 5.1 x ULN) was noted in 6-11% of adults during clinical trials.

Pediatric patients have experienced respiratory symptoms, including cough (21%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%), during atazanavir clinical trials.

In clinical trials with atazanavir, patients experienced increased lipase concentrations and hyperamylasemia. Elevated lipase (>= 2.1 x ULN) was reported in 8% of pediatric patients and elevated amylase (>= 2.1 x ULN) was reported in 33% of pediatric patients. Pancreatitis has been reported with post-marketing use of atazanavir.

Unplanned antiretroviral therapy interruption may be necessary in specific situations, such as serious drug toxicity, intercurrent illness or surgery precluding oral intake (e.g., gastroenteritis or pancreatitis), or drug non-availability. If short-term treatment interruption is necessary (i.e., < 1-2 days), in general, it is recommended that all antiretroviral agents be discontinued simultaneously, especially if the interruption is because of serious toxicity. However, if a short-term treatment interruption is anticipated in the case of elective surgery, the pharmacokinetic properties and food requirements of specific drugs should be considered. When the antiretroviral regimen contains drugs with differing half-lives, stopping all drugs simultaneously may result in functional monotherapy of the drug with the longest half-life. For example, after discontinuation, the duration of detectable serum concentrations of efavirenz and nevirapine ranges from < 1 week to > 3 weeks. Simultaneously stopping all drugs in a regimen containing these agents may result in functional monotherapy with the NNRTI and may increase the risk of NNRTI-resistant mutations. Planned long-term treatment interruptions are not recommended due to the potential for HIV disease progression (i.e., declining CD4 counts, viral rebound, acute viral syndrome), development of minor HIV-associated manifestations or serious non-AIDS complications, development of drug resistance, increased risk of HIV transmission, and increased risk for opportunistic infections. If therapy must be discontinued, counsel patient on the potential risks and closely monitor for any clinical or laboratory abnormalities.

Patients with AV block could have worsening of their condition due to PR prolongation from atazanavir. Of 920 treated patients, 5.9% experienced asymptomatic first-degree AV block. Caution is recommended when administering atazanavir to patients with preexisting conduction system disease or patients receiving concomitant medications that may cause PR prolongation. ECG monitoring should be considered in these patients.

Testing for human immunodeficiency virus (HIV) infection resistance is recommended in all antiretroviral treatment-naive patients at the time of HIV diagnosis, regardless of whether treatment will be initiated. Additionally, perform resistance testing prior to initiating or changing any HIV treatment regimen. Transmission of drug-resistant HIV strains has been both well documented and associated with suboptimal virologic response to initial antiretroviral therapy. Therefore, resistance testing at baseline can help optimize treatment and, thus, virologic response. In the absence of therapy, resistant viruses may decline over time to less than the detection limit of standard resistance tests, but may still increase the risk of treatment failure when therapy is eventually initiated. Thus, if therapy is deferred, resistance testing should still be performed during acute HIV infection with the genotypic resistance test results kept in the patient's medical record until they become clinically useful. Additionally, because of the possibility of acquisition of another drug-resistant virus before treatment initiation, repeat resistance testing at the time therapy is initiated would be prudent. As with all other antiretroviral drugs, resistance can develop when atazanavir is used either alone or in combination with other drugs used for HIV infection. Monotherapy with atazanavir is not recommended. Varying degrees of cross-resistance among protease inhibitors have been observed. There is no obvious pattern of cross-resistance between atazanavir and any other commercially available protease inhibitor. Continued administration of atazanavir therapy following loss of viral suppression may increase the likelihood of resistance to other protease inhibitors. A greater number of amino acid changes increases the likelihood of cross-resistance to other protease inhibitors.

Patients with diabetes mellitus or hyperglycemia may experience an exacerbation of their condition during atazanavir 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.

Perform hepatitis B virus (HBV) screening in any patient who presents with HIV-infection to assure appropriate treatment. Patients with hepatitis B and HIV coinfection who require treatment for either infection should be started on a fully suppressive antiretroviral regimen that contains NRTIs with activity against both viruses. Avoid using single-drug therapy to treat HBV (i.e., lamivudine, emtricitabine, or tenofovir as the only active agent) due to the risk of developing resistant strains of HIV. The HIV guidelines recommend that coinfected pediatric patients >= 2 years receive an antiretroviral regimen that contains tenofovir in combination with either lamivudine or emtricitabine as the dual NRTI backbone. If tenofovir cannot be used, another agent with anti-HBV activity should be used in combination with lamivudine or emtricitabine to assure adequate treatment of HBV infection. Management of HIV should be continued with the goal of maximal suppression. Additionally, atazanavir should be used with caution in patients with pre-existing hepatitis. Adults with moderate-to-severe hepatic impairment (Child-Pugh B or C) had a 42% increase in mean AUC compared to that of healthy patients. Patients with underlying hepatitis B or C prior to treatment may be at increased risk for developing further enzyme elevations or hepatic decompensation; monitor liver function tests (LFTs) in these patients.

Perform hepatitis C virus (HCV) screening in any child whose mother is known to have HCV infection and all HIV-infected adolescents. Treatment of HCV infection in children < 3 years is not usually recommended; however, treatment should be considered for all children >= 3 years and adolescents with hepatitis C and HIV coinfection who have no contraindications to treatment. For antiretroviral-naive adolescent patients with CD4 counts > 500 cells/mm3, consideration may be given to deferring ARV therapy until the hepatitis C treatment regimen has been completed. Conversely, for adolescent patients with CD4 counts < 200 cells/mm3, consider delaying initiation of the hepatitis C treatment regimen until the patient is stable on a fully suppressive ARV regimen. Administer atazanavir cautiously to patients with pre-existing hepatitis. Adults with moderate-to-severe hepatic impairment (Child-Pugh B or C) had a 42% increase in mean AUC compared to that of healthy patients. Patients with underlying hepatitis C prior to treatment may be at increased risk for developing further enzyme elevations or hepatic decompensation; monitor liver function tests (LFTs) in these patients. All HIV-infected children and adolescents, regardless of HIV and HCV status, should receive standard vaccination with hepatitis A and B vaccines. Additionally, HIV/HCV-coinfected adolescents should be counseled to avoid alcohol.

Use atazanavir with caution in patients with pre-existing hepatic disease, liver enzyme abnormalities (e.g., jaundice), or hepatitis. Patients with underlying hepatitis B or C or marked elevations in liver enzymes prior to treatment may be at increased risk for developing further enzyme elevations or hepatic decompensation; monitor liver function tests (LFTs) in these patients prior to initiation of atazanavir and during treatment. Patients with hepatic disease may require dosage adjustment of atazanavir based upon the severity of the hepatic impairment. Consider a dosage reduction for patients with moderate hepatic insufficiency (Child-Pugh Class B). Use of atazanavir in patients with severe hepatic dysfunction (Child-Pugh Class C) is not recommended. Adults with moderate-to-severe hepatic impairment (Child-Pugh B or C) had a mean AUC to infinity that was 42% greater as compared to the mean value from healthy patients.

Protease inhibitors such as atazanavir should be used cautiously in patients with hemophilia A or B due to reports of spontaneous bleeding episodes requiring treatment with additional factor VIII. In many cases, treatment with protease inhibitors was continued or restarted. A causal relationship has not been established.

Consider patient specific factors, such as preexisting hyperlipidemia, when selecting an antiretroviral treatment regimen. Protease inhibitor-based regimens have been associated with hyperlipidemia; however, compared to other protease inhibitors, atazanavir has minor effects on lipoprotein concentrations. Obtain a random or fasting lipid profile at entry of care, initiation or modification of antiretroviral therapy, every 12 months, and as clinically indicated. Possible interventions for patients who develop hyperlipidemia during treatment with atazanavir include dietary modification, use of lipid lowering agents, or switching to a regimen with a more favorable lipid profile. Clinicians should be aware of the potential for drug interactions with certain cholesterol-lowering drugs.

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy. During the initial phase of HIV treatment, patients whose immune system responds to atazanavir therapy may develop an inflammatory response to indolent or residual opportunistic infections (such as mycobacterium avium complex (MAC), cytomegalovirus (CMV), Pneumocystis pneumonia (PCP), or tuberculosis (TB)), which may necessitate further evaluation and treatment. In addition, autoimmune disease (including Graves' disease, Guillain-Barre syndrome, polymyositis, and autoimmune hepatitis) may also develop; the time to onset is variable and may occur months after treatment initiation.

Cases of nephrolithiasis and cholelithiasis have been reported during post-marketing use of atazanavir. In some cases, treatment required hospitalization. It may be prudent to monitor for signs and symptoms of nephrolithiasis and/or cholelithiasis. Should signs and symptoms occur, temporary interruption or discontinuation of therapy may be considered.

Consider alternatives to atazanavir in patients at high risk for renal disease or with preexisting renal disease or renal impairment. Monitor renal function (including serum creatinine, creatinine clearance, and urinalysis with microscopic examination) in all patients prior to initiation of therapy with atazanavir and during treatment. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking atazanavir. Consider discontinuation of atazanavir in patients who develop progressive kidney disease. Treatment-naive adult patients with end stage renal disease that is managed with hemo-dialysis may receive atazanavir (at a dose of 300 mg, given with ritonavir 100 mg). However, treatment-experienced adult patients with end stage renal disease that is managed with hemo-dialysis should not receive atazanavir. There are no specific pediatric recommendations. Chronic kidney disease has been reported with atazanavir during postmarketing surveillance. Reports include biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma.

Rash is a common adverse reaction associated with atazanavir therapy. In most cases, it is a mild to moderate maculopapular eruption that lasts approximately 1.4 weeks and does not require interruption of therapy. However, serious rashes, including Stevens-Johnson syndrome, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported. Discontinue atazanavir in patients who develop a serious rash.

Use atazanavir oral powder with caution in patients with phenylketonuria because the oral powder is formulated with aspartame, which supplies approximately 35 mg of phenylalanine in each 50 mg packet. Atazanavir oral capsules do not contain phenylalanine.

Atazanavir is not recommended for use in neonates and infants younger than 3 months due to the risk of kernicterus.

Description: Atazanavir is a protease inhibitor for the treatment of human immunodeficiency virus (HIV) infection. Atazanavir is the first drug in its class to be given once daily. Also, it has a unique chemical structure (azapeptide) and resistance profile compared with other available peptidomimetic protease inhibitors. In comparison to other protease inhibitors, it does not appear to have a significant adverse effect on lipoprotein concentrations. Like other protease inhibitors, it should be used in combination with other antiretroviral drugs. Atazanavir is FDA-approved in pediatric patients 3 months of age and older and weighing at least 5 kg.

Initiation of HIV therapy
-Antiretroviral drug resistance testing (preferably genotypic testing) is recommended prior to initiation of therapy in antiretroviral treatment (ART)-naive patients and prior to changing therapy for treatment failure.
-Initiation of treatment immediately or within days after HIV diagnosis is recommended in all pediatric patients, except for patients with cryptococcal meningitis, disseminated Mycobacterium avium complex disease, or Mycobacterium tuberculosis disease. In these patients, initiate treatment for the opportunistic infection first, ahead of ART initiation. The urgency of rapid treatment initiation is especially critical for all patients younger than 1 year, who carry the highest risk of rapid disease progression and mortality. If therapy is deferred for certain circumstances, closely monitor the patient's virologic, immunologic, and clinical status at least every 3 to 4 months. If therapy is deferred, initiate treatment when HIV RNA concentrations increase, CD4 count or percentage values decline (i.e., approaching CDC Stage 2 or 3), the patient develops new HIV-related clinical symptoms, or the ability of the caregiver and patient to adhere to the prescribed regimen has improved.

Place in therapy for HIV
-Atazanavir boosted with ritonavir, in combination with a 2-nucleoside reverse transcriptase inhibitor (NRTI) backbone option, is recommended as an alternative initial regimen for treatment-naive infants and children 3 months and older. Atazanavir boosted with cobicistat, in combination with a 2-NRTI backbone option, is an alternative initial regimen in children weighing 35 kg or more.
-Atazanavir boosted with ritonavir or cobicistat, in combination with a 2-NRTI backbone option, is a preferred initial regimen for treatment-naive adolescents in certain clinical situations.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: human immunodeficiency virus (HIV)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

For the treatment of human immunodeficiency virus (HIV) infection in combination with other antiretroviral agents:
NOTE: When transitioning between formulations, a change in dose may be necessary. Consult dosing for each specific formulation prior to prescribing.
Oral dosage (oral powder):
Infants and Children 3 months and older weighing 5 to 9 kg: 200 mg PO every 24 hours with ritonavir 80 mg PO every 24 hours. For patients unable to tolerate 200 mg (protease inhibitor-naive patients only), the dose may be reduced to 150 mg PO every 24 hours; however, HIV viral load must be closely monitored. The FDA-approved product labeling does not provide dosing recommendations for pediatric patients who are receiving concomitant efavirenz, tenofovir, H2-receptor blockers, or proton pump inhibitors or in patients not receiving ritonavir for boosting.
Infants and Children 3 months and older weighing 10 to 14 kg: 200 mg PO every 24 hours with ritonavir 80 mg PO every 24 hours. The FDA-approved product labeling does not provide dosing recommendations for pediatric patients who are receiving concomitant efavirenz, tenofovir, H2-receptor blockers, or proton pump inhibitors or in patients not receiving ritonavir for boosting.
Children weighing 15 to 24 kg: 250 mg PO every 24 hours with ritonavir 80 mg PO every 24 hours. The FDA-approved product labeling does not provide dosing recommendations for pediatric patients who are receiving concomitant efavirenz, tenofovir, H2-receptor blockers, or proton pump inhibitors or in patients not receiving ritonavir for boosting.
Children and Adolescents weighing 25 kg or more: 300 mg PO every 24 hours plus ritonavir 100 mg PO every 24 hours. Although specific dosage adjustments for pediatric patients are not specified in the product labeling, the manufacturer makes the general recommendation to increase the dose to 400 mg PO plus ritonavir 100 mg PO once daily when combined with efavirenz (treatment-naive patients only) or BOTH an H2-blocker and tenofovir in adult patients. No dosage adjustment necessary when administered with only an H2-blocker.
Oral dosage (capsules):
Children 6 to 12 years weighing 15 to 34 kg: 200 mg PO every 24 hours with ritonavir 100 mg PO every 24 hours. The FDA-approved product labeling does not provide dosing recommendations for pediatric patients who are receiving concomitant efavirenz, tenofovir, H2-receptor blockers, or proton pump inhibitors or in patients not receiving ritonavir boosting.
Children 6 to 12 years weighing 35 kg or more: 300 mg PO every 24 hours with ritonavir 100 mg PO every 24 hours. Although specific dosage adjustments for pediatric patients are not specified in the product labeling, the manufacturer makes the general recommendation to increase the dose to 400 mg PO plus ritonavir 100 mg PO once daily when combined with efavirenz (treatment-naive patients only) or BOTH an H2-blocker and tenofovir in adult patients. No dosage adjustment necessary when administered with only an H2-blocker.
Adolescents weighing less than 35 kg: 200 mg PO every 24 hours with ritonavir 100 mg PO every 24 hours. The FDA-approved product labeling does not provide dosing recommendations for pediatric patients who are receiving concomitant efavirenz, tenofovir, H2-receptor blockers, or proton pump inhibitors or in patients not receiving ritonavir boosting.
Adolescents weighing 35 to 39 kg: 300 mg PO every 24 hours with ritonavir 100 mg PO every 24 hours. Although specific dosage adjustments for pediatric patients are not specified in the product labeling, the manufacturer makes the general recommendation to increase the dose to 400 mg PO plus ritonavir 100 mg PO once daily when combined with efavirenz (treatment-naive patients only) or BOTH an H2-blocker and tenofovir in adult patients. No dosage adjustment necessary when administered with only an H2-blocker.
Adolescents weighing 40 kg or more: 300 mg PO every 24 hours with ritonavir 100 mg PO every 24 hours. In treatment-naive patients who cannot tolerate ritonavir, the FDA-approved labeling recommends 400 mg PO every 24 hours (without ritonavir); however, guidelines do NOT recommend unboosted atazanavir, as higher doses of atazanavir may be needed in adolescents to achieve target drug concentrations. In a pharmacokinetic study, 620 mg/m2 PO every 24 hours administered without ritonavir achieved protocol-defined pharmacokinetic targets in a cohort of 21 adolescents (median age = 14.6 years, IQR = 2.9). Although specific dosage adjustments for pediatric patients are not specified in the product labeling, the manufacturer makes the general recommendation to increase the dose to 400 mg PO plus ritonavir 100 mg PO once daily when combined with efavirenz (treatment-naive patients only) or BOTH an H2-blocker and tenofovir in adult patients. No dosage adjustment necessary when administered with only an H2-blocker.

Therapeutic Drug Monitoring:
Suggested target trough concentration: 2,000 ng/mL
-Routine monitoring of plasma concentrations of antiretroviral (ARV) drugs is generally not recommended in HIV-infected pediatric patients. However, therapeutic drug monitoring may be considered in the following situations :-use of drugs with limited pharmacokinetic data and/or therapeutic experience in pediatric patients
-use of drugs with significant food and/or drug interactions
-suboptimal treatment response
-suspected suboptimal absorption, distribution, metabolism, or elimination of the drug
-suspected concentration-dependent drug-associated toxicity
-use of alternative dosing regimens and ARV combinations for which safety and efficacy have not been established in clinical trials
-heavily pretreated patients experiencing virologic failure and who may have viral isolates with reduced susceptibility to ARVs


Maximum Dosage Limits:
-Neonates
Not recommended due to the risk of hyperbilirubinemia.
-Infants
1 to 2 months: Not recommended due to the risk of hyperbilirubinemia.
3 to 11 months weighing less than 5 kg: Safety and efficacy have not been established.
3 to 11 months weighing 5 to 14 kg: 200 mg/day PO for oral powder.
-Children
Oral powder
5 to 14 kg: 200 mg/day PO.
15 to 24 kg: 250 mg/day PO.
25 kg or more: 300 mg/day PO.

Oral capsules
1 to 5 years or weighing less than 15 kg: Safety and efficacy have not been established.
6 to 12 years weighing 15 to 34 kg: 200 mg/day PO.
6 to 12 years weighing 35 kg or more: 300 mg/day PO.
-Adolescents
25 to 34 kg: 200 mg/day PO for oral capsules; 300 mg/day PO for oral powder.
35 to 39 kg: 300 mg/day PO for oral capsules and oral powder.
40 kg or more: 300 mg/day PO with ritonavir and 400 mg/day PO without ritonavir for oral capsules; 300 mg/day PO for oral powder.

Patients with Hepatic Impairment Dosing
Atazanavir plus ritonavir has not been studied in patients with hepatic impairment and is not recommended. For adolescents receiving atazanavir without ritonavir, a reduced dosage may be needed for patients with hepatic impairment. Atazanavir should not be used in patients with severe hepatic dysfunction (Child-Pugh Class C). In adults, the FDA recommends a reduced dosage of 300 mg PO once daily should be considered for patients with moderate hepatic insufficiency (Child-Pugh Class B).

Patients with Renal Impairment Dosing
The FDA-approved labeling suggests that no dosage adjustments are required for patients with any degree of renal impairment who are NOT managed with hemodialysis. Pediatrics are not specifically addressed.

Intermittent hemodialysis
The FDA-approved labeling suggests that treatment-naive adult patients with end stage renal disease that is managed with hemodialysis should receive an atazanavir dose of 300 mg with ritonavir 100 mg and treatment-experienced patients with end stage renal disease that is managed with hemodialysis should not receive atazanavir. Pediatrics are not specifically addressed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Atazanavir inhibits the human immunodeficiency virus (HIV) type 1 aspartic protease, which is an enzyme involved in the replication of HIV. Protease plays a key role in the post-translational processing of the gag and gag-pol gene products into key structural proteins and replication enzymes of HIV-1. During the later stages of the HIV growth cycle, the gag and gag-pol gene products are first translated into polyproteins and become immature budding particles. 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. Protease inhibition renders the virus noninfectious. Because HIV protease inhibitors inhibit the HIV replication cycle after translation and before assembly, they are active in acutely and chronically infected cells, and in cells not normally affected by dideoxynucleoside reverse transcriptase inhibitors (i.e., monocytes and macrophages). The EC-90 (90% effective concentration) of atazanavir is 9-15 nM. In vitro, atazanavir produces additive to moderately synergistic antiviral effects when combined with the reverse transcriptase inhibitors stavudine, zidovudine, tenofovir, zalcitabine, lamivudine, or didanosine, or the protease inhibitors saquinavir, nelfinavir, indinavir, ritonavir, lopinavir, or amprenavir.

Pharmacokinetics: Atazanavir is administered orally. It is 86% bound to albumin and 89% bound to alpha-1-acid glycoprotein. It is extensively metabolized by the liver. The cytochrome P450 (CYP450) system, specifically CYP3A4, is the main metabolic pathway. None of the identified metabolites are active. After chronic receipt of 400 mg daily with a light meal, the mean elimination half-life is 7 hours. About 7% of radiotagged atazanavir is recovered in the feces and approximately 20% of the administered dose is recovered unchanged. Only 13% of radiotagged atazanavir appears in the urine and approximately 7% of the administered dose is recovered unchanged; renal elimination is not a significant elimination pathway. Atazanavir demonstrates nonlinear pharmacokinetics with greater than dose-proportional increases in AUC and Cmax values over the dose range of 200 to 800 mg once daily. Steady state is achieved between 4 to 8 days with an accumulation of approximately 2.3-fold.

Affected cytochrome P450 isoenzymes: CYP3A, CYP2C8, UGT1A1
Atazanavir is an inhibitor of CYP3A, CYP2C8 (weak), and UGT1A1. Additionally, atazanavir is a substrate of CYP3A4. Clinically significant interactions are not expected with substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1.


-Route-Specific Pharmacokinetics
Oral Route
Atazanavir is rapidly absorbed with a Tmax of approximately 2.5 hours. Administration with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400 mg dose with a light meal (357 kcal, 8.2 g of fat, and 10.6 g of protein) resulted in an increase of 70% in the AUC and of 57% in the Cmax relative to the fasted state. Administration of a single 400 mg dose with a high-fat meal (721 kcal, 37.3 g of fat, and 29.4 g of protein) resulted in a 35% increase in AUC and no change in Cmax compared to fasting state. Administration with either type of meal decreased the coefficient of variation of AUC and Cmax by approximately one-half compared to the fasting state. Administration of a single 300 mg dose and ritonavir with a light meal (336 kcal, 5.1 g fat, 9.3 g protein) resulted in a 33% increase in the AUC and a 40% increase in the Cmax relative to the fasting state. Administration of a single 300 mg dose and ritonavir with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC compared to fasting conditions and the Cmax as well as the 24-hour concentration was within 11% of fasting values. The 24-hour concentration after a high-fat meal was increased by approximately 33% due to delayed absorption and the median Tmax increased from 2 to 5 hours. Administration with either type of meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.


-Special Populations
Pediatrics
Infants 3 months and older, Children, and Adolescents
The pharmacokinetics of weight-based atazanavir with ritonavir have been evaluated in HIV-infected pediatric patients 3 months of age and older. The oral powder was evaluated in pediatric patients from 3 months to 11 years, and the capsules were studied in patients ages 6 to 18 years; all doses were administered with food. The pharmacokinetic parameters reported were comparable to those of HIV-infected adults who received a fixed dose of atazanavir 300 mg with ritonavir 100 mg (adult values: Cmax = 4,422 ng/mL; AUC = 46,073 ng x hour/mL; Cmin = 636 ng/mL)). The oral clearance of ritonavir-boosted atazanavir appears to be faster in infants and children less than 12 years of age as compared to adults. The oral clearance of unboosted atazanavir appears to be similar for children ages 6 to 12 years as compared to adults, while in adolescents 13 years and older, oral clearance appears to be faster than adults.

Oral powder
weight 5 to 9 kg (atazanavir 150 mg with ritonavir 80 mg):
Cmax = 4,131 ng/mL
AUC = 32,503 ng x hour/mL
Cmin = 336 ng/mL
weight 5 to 9 kg (atazanavir 200 mg with ritonavir 80 mg):
Cmax = 4,466 ng/mL
AUC = 39,519 ng x hour/mL
Cmin = 550 ng/mL
weight 10 to 14 kg (atazanavir 200 mg with ritonavir 80 mg):
Cmax = 5,197 ng/mL
AUC = 50,305 ng x hour/mL
Cmin = 572 ng/mL
weight 15 to 24 kg (atazanavir 250 mg with ritonavir 80 mg):
Cmax = 5,394 ng/mL
AUC = 55,687 ng x hour/mL
Cmin = 686 ng/mL
weight 25 to 34 kg (atazanavir 300 mg with ritonavir 100 mg):
Cmax = 4,209 ng/mL
AUC = 44,329 ng x hour/mL
Cmin = 468 ng/mL

Oral capsules
weight 15 to 34 kg (atazanavir 200 mg with ritonavir 100 mg):
Cmax = 3,303 ng/mL
AUC = 37,235 ng x hour/mL
Cmin = 538 ng/mL
weight 35 kg or more (atazanavir 300 mg with ritonavir 100 mg):
Cmax = 2,980 ng/mL
AUC = 37,643 ng x hour/mL
Cmin = 653 ng/mL

Hepatic Impairment
Patients with hepatic impairment (Child-Pugh B and C) had a mean atazanavir half-life of 12.1 hours and a mean AUC to infinity that was 42% greater than the mean AUC value of patients with normal hepatic function. Increased serum concentrations of atazanavir are expected in patients with moderate to severe hepatic impairment. Atazanavir is not recommended for use in patients with severe hepatic disease.

Renal Impairment
In patients with severe renal impairment receiving atazanavir not undergoing hemodialysis (n = 10), the mean Cmax is 9% lower, the mean AUC is 19% higher, and the mean Cmin is 96% higher than in patients with normal renal function. In a 4 hour hemodialysis session, 2.1% of the dose is removed. When atazanavir is administered either prior to or after hemodialysis (n = 10), the mean Cmax, AUC, and Cmin are approximately 25% to 43% lower as compared to patients with normal renal function. The mechanism for this decrease is unknown.