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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Protease Inhibitors (PIs)

Atazanavir

(Last updated: June 29, 2015; last reviewed: June 29, 2015)

Atazanavir (ATV, Reyataz)

Atazanavir (ATV, Reyataz)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
Formulations

Powder Packet: 50 mg/packet
Capsules: 150 mg, 200 mg, and 300 mg
Fixed-Dose Combination Tablets:
With cobicistat:
  • 300 mg atazanavir plus 150 mg cobicistat (Evotaz)
Capsules and powder packets are not interchangeable.
Dosing Recommendations

Neonate Dose:
  • Not approved for use in neonates and infants <3 months. Atazanavir should not be administered to neonates because of risks associated with hyperbilirubinemia (kernicterus).
Pediatric Dose:
Powder Formulation:a
  • Powder formulation must be administered with ritonavir.
  • Not approved for use in infants <3 months or weight <10 kg or children weighing ≥25 kg.

Infants and Children (Aged ≥3 Months; Weight >10 kg and <25 kg):

Atazanavir Powdera
Weight (kg) Once-Daily Dose
10 to <15 kg Atazanavir 200 mg (4 packets) plus ritonavir 80 mg (5 ml oral solution), both once daily with food
15 to <25 kg Atazanavir 250 mg (5 packets) plus ritonavir 80 mg (5 ml oral solution), both once daily with food
≥25 kgb Powder not recommended

a mg/kg dosing is higher for the powder packets than for the capsules. Bioavailability is higher for the capsules than for the powder when studied in adults.
b For a child who cannot swallow atazanavir capsules, the Panel advises increasing to an experimental dose of 300 mg atazanavir powder plus ritonavir oral solution 80 mg, both once daily with food. This dose is being studied in children who weigh 25 to <35 kg (see text).

Capsule Formulation:c

  • Not approved for use in children <6 years or <15 kg

Children (≥6 to <18 Years; Weight ≥15 kg)

Atazanavir Capsulesc
Weight (kg) Once-Daily Dose
<15 kg Capsules not recommended
15 to <20 kg Atazanavir 150 mg plus ritonavird 100 mg, both once daily with food
20 to <40 kg Atazanavir 200 mg plus ritonavird 100 mg, both once daily with foode
≥40 kg Atazanavir 300 mg plus ritonavird 100 mg, both once daily with food

c mg/kg dosing is higher for the powder packets than for the capsules. Bioavailability is higher for the capsules than for the powder when studied in adults. While not studied in age <6 years, Panel advises that capsules can be used when transitioning from powder in children who can swallow capsules (see text).

d Either ritonavir capsules or ritonavir oral solution can be used.

e Some experts would increase atazanavir to 300 mg at ≥35 kg to avoid underdosing, especially when administered with tenofovir (see text for discussion).

For Treatment-Naive Pediatric Patients who do not Tolerate Ritonavir:
  • Atazanavir powder must be administered with ritonavir.
  • For capsule formulation, atazanavir/ritonavir is preferred for children and adolescents. Current Food and Drug Administration (FDA)-approved prescribing information does not recommend unboosted atazanavir in children aged <13 years. If unboosted atazanavir is used in adolescents, higher doses than those used in adults may be required to achieve target drug concentrations (see Pediatric Use).
  • Only atazanavir/ritonavir should be used in combination with tenofovir disoproxil fumarate (tenofovir) because tenofovir decreases atazanavir exposure.
Adolescent (Aged ≥18 to 21 Years)/Adult Dose
Antiretroviral-Naive Patients:
  • Atazanavir 300 mg plus ritonavir 100 mg once daily with food
  • Atazanavir 300 mg plus cobicistatf 150 mg, both once daily with food or as co-formulated Evotaz once daily with food.
  • Atazanavir 400 mg once daily with food (if unboosted atazanavir is used in adolescents, higher doses than those used in adults may be required to achieve target drug concentrations [see Pediatric Use]).
Antiretroviral-Experienced Patients:
  • Atazanavir 300 mg plus ritonavir 100 mg, both once daily with food
  • Atazanavir 300 mg plus cobicistatf 150 mg, both once daily with food or as co-formulated Evotaz once daily with food

Atazanavir In Combination With Efavirenz (Adults) In Treatment-Naive Patients Only:

  • Atazanavir 400 mg plus ritonavir 100 mg plus efavirenz 600 mg, all once daily at separate times.
  • Although atazanavir/ritonavir should be taken with food, efavirenz should be taken on an empty stomach, preferably at bedtime. Efavirenz should not be co-administered with atazanavir (with or without ritonavir) in treatment-experienced patients because efavirenz decreases atazanavir exposure.
Atazanavir In Combination With Tenofovir (Adults):
  • Atazanavir 300 mg plus ritonavir 100 mg plus tenofovir 300 mg, all once daily with food.
  • Atazanavir 300 mg plus cobicistatf 150 mg plus tenofovir 300 mg, all once daily with food.
  • Only boosted atazanavir should be used in combination with tenofovir because tenofovir decreases atazanavir exposure.
f See Cobicistat section for important information about toxicity, drug interactions, and monitoring of patients who receive cobicistat and the combination of cobicistat and tenofovir.
Selected Adverse Events
  • Indirect hyperbilirubinemia
  • Prolonged electrocardiogram (ECG) PR interval, first-degree symptomatic atrioventricular (AV) block in some patients
  • Hyperglycemia
  • Fat maldistribution
  • Possible increased bleeding episodes in patients with hemophilia
  • Nephrolithiasis
  • Skin rash
  • Increased serum transaminases
  • Hyperlipidemia (primarily with ritonavir boosting)
Special Instructions
  • Administer atazanavir with food to enhance absorption.
  • Capsules and powder packets are not interchangeable.
  • Do not open capsules.
  • Powder Administration:
    • Mix atazanavir oral powder with at least 1 tablespoon of food such as applesauce or yogurt. Oral powder mixed with a beverage (at least 30 mL of milk or water) may be used for older infants who can drink from a cup. For young infants (<6 months) who cannot eat solid food or drink from a cup, oral powder should be mixed with at least 10 mL of infant formula and given using an oral dosing syringe.
    • Administer ritonavir immediately following powder administration.
    • Administer the entire dosage of oral powder within 1 hour of preparation.
  • Because atazanavir can prolong the ECG PR interval, use atazanavir with caution in patients with pre-existing cardiac conduction system disease or with other drugs known to prolong the PR interval (e.g., calcium channel blockers, beta-blockers, digoxin, verapamil).
  • Atazanavir absorption is dependent on low gastric pH; therefore, when atazanavir is administered with medications that alter gastric pH, special dosing information is indicated (see Drug Interactions for recommendations on dosing atazanavir when the drug is co-administered with H2 receptor antagonists). When administered with buffered didanosine formulations or antacids, give atazanavir at least 2 hours before or 1 hour after antacid or didanosine administration.
  • The plasma concentration, and therefore therapeutic effect, of atazanavir can be expected to decrease substantially when atazanavir is co-administered with proton-pump inhibitors (PPIs). Antiretroviral therapy (ART)-naive patients receiving PPIs should receive no more than a 20-mg dose equivalent of omeprazole, which should be taken approximately 12 hours before boosted atazanavir. Co-administration of atazanavir with PPIs is not recommended in treatment-experienced patients.
  • Patients with hepatitis B virus or hepatitis C virus infections and patients with marked elevations in transaminases before treatment may be at increased risk of further elevations in transaminases or hepatic decompensation.
  • Atazanavir oral powder contains phenylalanine, which can be harmful to patients with phenylketonuria. Each packet contains 35 mg of phenylalanine.
Metabolism
  • Atazanavir is a substrate and inhibitor of cytochrome P (CYP) 3A4 and an inhibitor of CYP1A2, CYP2C9, and uridine diphosphate glucoronosyltransferase (UGT1A1).
  • Dosing of atazanavir in patients with hepatic impairment: Atazanavir should be used with caution in patients with mild-to-moderate hepatic impairment; consult manufacturer’s prescribing information for dosage adjustment in patients with moderate impairment. Atazanavir should not be used in patients with severe hepatic impairment.
  • Dosing of atazanavir in patients with renal impairment: No dose adjustment is required for patients with renal impairment. However, atazanavir should not be given to treatment-experienced patients with end-stage renal disease on hemodialysis.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Metabolism: Atazanavir is both a substrate and an inhibitor of the cytochrome P (CYP) 3A4 enzyme system and has significant interactions with drugs highly dependent on CYP3A4 for metabolism. Atazanavir also competitively inhibits CYP1A2 and CYP2C9. Atazanavir is a weak inhibitor of CYP2C8. There is potential for multiple drug interactions with atazanavir. Atazanavir inhibits the glucuronidation enzyme uridine diphosphate glucoronosyltransferase (UGT1A1). A patient’s medication profile should be carefully reviewed for potential drug interactions with atazanavir before the drug is administered.
  • Nucleoside reverse transcriptase inhibitors (NRTIs): Tenofovir disoproxil fumarate (tenofovir) decreases atazanavir plasma concentrations. Only ritonavir-boosted atazanavir should be used in combination with tenofovir.
  • Non-nucleoside reverse transcriptase inhibitors: Efavirenz, etravirine, and nevirapine decrease atazanavir plasma concentrations significantly. Nevirapine and etravirine should not be co-administered to patients receiving atazanavir (with or without ritonavir). Efavirenz should not be co-administered with atazanavir in treatment-experienced patients, but may be used in combination with atazanavir 400 mg plus ritonavir boosting in treatment-naive adults.
  • Integrase Inhibitors: Atazanavir is an inhibitor of UGT1A1 and may increase plasma concentrations of raltegravir. This interaction may not be clinically significant.
  • Absorption: Atazanavir absorption is dependent on low gastric pH. When atazanavir is administered with medications that alter gastric pH, dosage adjustment is indicated. No information is available on dosing atazanavir in children when the drug is co-administered with medications that alter gastric pH.
  • Initiation of cobicistat, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A, or initiation of medications metabolized by CYP3A in patients already receiving cobicistat, may increase plasma concentration of these medications, which may increase the risk of clinically significant adverse reactions (including life-threatening or fatal reactions) associated with the concomitant medications. Co-administration of cobicistat with atazanavir in combination with CYP3A inducers may lead to lower exposure of cobicistat and atazanavir and loss of efficacy of atazanavir and possible resistance.1 Co-administration of cobicistat and atazanavir with some antiretroviral (ARV) agents (e.g., with etravarine, with efavirenz in treatment-experienced patients, with another ARV that requires pharmacokinetic (PK) enhancement, such as another protease inhibitor [PI] or elvitegravir) may result in decreased plasma concentrations of that agent, leading to loss of therapeutic effect and development of resistance.

Guidelines for dosing atazanavir with antacids, H2 receptor antagonists, and proton-pump inhibitors (PPIs) in adults are as follows:

  • Antacids: Atazanavir concentrations are decreased when the drug is co-administered with antacids and buffered medications (including buffered didanosine formulations); therefore, atazanavir should be administered 2 hours before or 1 hour after these medications.
  • H2-receptor antagonists (unboosted atazanavir in treatment-naive patients): H2 receptor antagonists are expected to decrease atazanavir concentrations by interfering with absorption of the ARV agent. Atazanavir 400 mg should be administered at least 2 hours before or at least 10 hours after a dose of the H2 receptor antagonist (a single dose of an H2 receptor antagonist should not exceed a dose comparable to famotidine 20 mg; a total daily dose should not exceed a dose comparable to famotidine 40 mg).
  • H2-receptor antagonists (boosted atazanavir in treatment-naive or treatment-experienced patients): H2 receptor antagonists are expected to decrease atazanavir concentrations by interfering with absorption of the ARV. Dose recommendations for H2 receptor antagonists are either a ≤40-mg dose equivalent of famotidine twice daily for treatment-naive patients or a ≤20-mg dose equivalent of famotidine twice daily for treatment-experienced patients. Boosted atazanavir (atazanavir 300 mg plus ritonavir 100 mg) should be administered simultaneously with and/or ≥10 hours after the dose of H2 receptor antagonist.
  • H2-receptor antagonists (boosted atazanavir with tenofovir): Treatment-experienced patients using both tenofovir and H2-receptor antagonists should be given an increased dose of atazanavir (atazanavir 400 mg plus ritonavir 100 mg plus tenofovir 300 mg).
  • PPIs: Co-administration of PPIs with atazanavir is expected to substantially decrease atazanavir plasma concentrations and decrease its therapeutic effect. Dose recommendations for therapy-naive patients are ≤20-mg dose equivalent of omeprazole taken approximately 12 hours before boosted atazanavir (atazanavir 300 mg plus ritonavir 100 mg). Co-administration of atazanavir with PPIs is not recommended in treatment-experienced patients.

Major Toxicities

  • More common: Indirect hyperbilirubinemia that can result in jaundice or icterus, but is not a marker of hepatic toxicity. Headache, fever, arthralgia, depression, insomnia, dizziness, nausea, vomiting, diarrhea, and paresthesia.
  • Less common: Prolongation of PR interval of electrocardiogram (ECG). Abnormalities in atrioventricular (AV) conduction generally limited to first-degree AV block, but with rare reports of second-degree AV block. Rash, generally mild to moderate, but in rare cases includes life-threatening Stevens-Johnson syndrome. Fat maldistribution and lipid abnormalities may be less common than with other PIs. However, the addition of ritonavir to atazanavir is associated with lipid abnormalities but to a lesser extent than with other boosted PIs.
  • Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing diabetes mellitus, spontaneous bleeding in hemophiliacs, and elevation in serum transaminases. Nephrolithiasis. Hepatotoxicity (patients with hepatitis B or hepatitis C are at increased risk).

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/DR/).

Pediatric Use

Approval
Atazanavir is Food and Drug Administration (FDA)-approved for use in infants (aged >3 months and weight ≥10 kg), children, and adolescents.

Pharmacokinetics and Dosing
Oral Capsule
The results of the IMPAACT/PACTG 1020A trial in children and adolescents indicate that, in the absence of ritonavir boosting, atazanavir can achieve protocol-defined PK targets, but only when used at higher doses of atazanavir (on a mg/kg body weight or mg/m2 body surface area basis) than doses currently recommended in adults. In IMPAACT/PACTG 1020A, children aged >6 to < 13 years required atazanavir dosing of 520 mg/m2 per day of atazanavir capsule formulation to achieve PK targets.2 Unboosted atazanavir at this dose was well tolerated in those aged <13 years who were able to swallow capsules.3 Doses required for older adolescents were greater than the adult approved dose of 400 mg atazanavir given without ritonavir boosting once daily: adolescents aged >13 years required atazanavir dosing of 620 mg/m2 per day.2 In this study, the areas under the curve (AUCs) for the unboosted arms were similar to the ritonavir-boosted atazanavir groups but the maximum plasma concentration (Cmax) was higher and minimum plasma concentration (Cmin) lower for the unboosted arms. Median doses of atazanavir in mg/m2 both with and without ritonavir boosting from IMPAACT/PACTG 1020A are outlined in the following table. When dosing unboosted atazanavir in pediatric patients, therapeutic drug monitoring (TDM) is recommended to ensure that adequate atazanavir plasma concentrations have been achieved. A minimum target trough concentration for atazanavir is 150 ng/mL.4 Higher target trough concentrations may be required in PI-experienced patients.

Summary of Atazanavir Dosing Information Obtained from IMPAACT/PACTG 1020A2
 Age Range (Years)  ATV Given with RTV  ATV Median Dose (mg/m2a)  ATV Median Dose (mga)
6–13 years
No 509 475
6–13 years Yes 208 200
>13 years No
620
900
>13 years
Yes 195 350
a Dose satisfied protocol-defined AUC/PK parameters and met all acceptable safety targets. These doses differ from those recommended by the manufacturer. TDM was used to determine patient-specific dosing in this trial.

In the report of the P1020A data, atazanavir satisfied PK criteria at a dose of 205 mg/m2 in pediatric subjects when dosed with ritonavir.1 However, given the available atazanavir capsule dose strengths, it is not possible to administer the exact mg dose equivalent to the body surface area-based dose. A study of a model-based approach using atazanavir concentration-time data from 3 adult studies and 1 pediatric study (P1020A) supports the use of the following weight-based atazanavir/ritonavir doses that are listed in the current FDA-approved product label for children aged ≥6 to <18 years:

  • 150/100 mg (15 to <20 kg)
  • 200/100 mg (20 to <40 kg)
  • 300/100 mg (≥40 kg)5

The modeling used in the study does not assume 100% treatment adherence and has been shown to perform better than conventional modeling.5 The authors acknowledge that atazanavir/ritonavir at 250/100 mg appeared to be a more appropriate dose than atazanavir/ritonavir at 200/100 mg for the 35 to <40 kg weight group; however, this dose is not achievable with current capsule dose strengths (150, 200, and 300 mg).5 Some experts would increase atazanavir to 300 mg at ≥35 kg to avoid underdosing, especially when administered with tenofovir.

Cobicistat as a Pharmacokinetic Enhancer:
No data on the use of cobicistat are available in pediatric patients.

Oral Powder:
The unboosted atazanavir powder cohorts in IMPAACT/PACTG P1020A were closed based on the inability to achieve target exposures. For the IMPAACT/PACTG P1020A trial, AUC targets were established based on exposures in adults in early studies of unboosted atazanavir. For that study, target AUC range was 30,000 to 90,000 ng*hr/mL. Boosted atazanavir powder cohorts in IMPAACT/PACTG P1020A in children ages 3 months to 2 years, using a dose of 310 mg/m2 daily, achieved average atazanavir exposures that approached but did not meet protocol targets. Variability in exposures was greater, especially among the very young children in this age range.2

Assessment of the PK, safety, tolerability, and virologic response of atazanavir oral powder for FDA approval was based on data from two open-label, multicenter clinical trials:

  • PRINCE I: In pediatric patients aged 3 months to <6 years6
  • PRINCE II: In pediatric patients aged 3 months to <11 years7

Sixty-five treated patients from both studies weighing 10 kg to <25 kg were evaluated. All patients in the PRINCE trials were treated with boosted atazanavir. Patients weighing 10 kg to <15 kg received 200 mg atazanavir and 80 mg ritonavir oral solution, and patients weighing 15 kg to <25 kg received 250 mg atazanavir and 80 mg ritonavir oral solution. Using a modified ITT analysis, overall proportions of ARV-naive and ARV-experienced patients with HIV RNA <50 copies/mL at Week 48 were 66% (27/41) and 58% (14/24), respectively. The median increase from baseline in absolute CD4 T lymphocyte count (percent) at 48 weeks of therapy was 412 cells/mm3 (10.5%) in ARV-naive patients and 228 cells/mm3 (6%) in ARV-experienced patients. No new safety concerns were identified in these trials. The FDA label includes the following PK parameters measured in the PRINCE trials, including mean AUC, for the weight ranges that correspond to the recommended doses:


Pharmacokinetic Parameters for Atazanavir Powder in Children Aged <6 years (PRINCE I and II)a versus Capsules in Young Adultsb and Adultsa
Pharmacokinetic Parameters Prince Triala ATV/r

Dose 200/80 (mg)
Body Weight (kg) 10 to <15
Prince Triala ATV/r

Dose 250/80 (mg)
Body Weight (kg) 15 to <25

Young Adult Studyb  Adult Studya
AUC ng • h/mL

Mean (CV% or (95% CI) [n])

50,305 (67%) [18] 55,525 (46%) [31] 35,971 (30,853–41,898) [22] 46,073 (66%) [10]
C24 ng/mL

Meanc (CV% or (95% CI) [n])
572 (111%) [18]

678 (69%) [31] 578 (474–704) [22] 636 (97%) [10]
aReyataz Product Information7
bThe young adults were also receiving tenofovir; Kiser, Fletcher et al.8
cMeans are geometric means

While the PK targets were met in these PK studies of atazanavir powder, there were large CV%, especially in the youngest patients.

Transitioning from Powder to Capsules:
There is no approved atazanavir powder dose for children who reach a weight ≥25 kg while taking the powder. Atazanavir capsules should be used for the child who swallows pills. Bioavailability is higher for the capsules than for the powder when studied in adults; therefore, a lower mg/kg dose is recommended. Opened capsules have not been studied and so should not be used. For children who reach a weight of 25 kg and who cannot swallow pills, the Panel advises increasing to the experimental dose of 300 mg atazanavir powder plus ritonavir oral solution 80 mg, both once daily with food. The ongoing trial of atazanavir/ritonavir powder, Prince II trial, is evaluating the safety, efficacy, and pharmacokinetics of 300 mg atazanavir powder in children weighing ≥25 kg to <35 kg.  

Toxicity
Nine percent of patients enrolled in the IMPAACT/PACTG 1020A trial had a bilirubin ≥5.1 times the upper limit of normal.3 Asymptomatic EKG abnormalities were observed in a small number of patients: Grade 3 QTC prolongation in 1 patient, Grade 2 PR or HR changes in 9 patients, and Grade 3 PR prolongations in 3 patients. No significant changes in serum cholesterol or triglycerides were observed during 48 weeks of therapy in 63 children receiving unboosted atazanavir in combination with 2 NRTIs.7

References

  1. Cobicistat (Tybost) [package insert].Gilead Sciences. 2014. Available at http://www.gilead.com/~/media/Files/pdfs/medicines/hiv/tybost/tybost_pi.pdf. Accessed February 17, 2015.
  2. Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25(12):1489-1496. Available at http://www.ncbi.nlm.nih.gov/pubmed/21610486.
  3. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children and adolescents: the Pediatric AIDS Clinical Trials Group Protocol 1020A. Pediatr Infect Dis J. 2015;34(2):162-167. Available at http://www.ncbi.nlm.nih.gov/pubmed/25232777.
  4. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. 2014. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf.
  5. Hong Y, Kowalski KG, Zhang J, et al. Model-based approach for optimization of atazanavir dose recommendations for HIV-infected pediatric patients. Antimicrob Agents Chemother. 2011;55(12):5746-5752. Available at http://www.ncbi.nlm.nih.gov/pubmed/21930880.
  6. Strehlau R, Donati AP, Arce PM, et al. PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected antiretroviral-naive and -experienced infants and children aged >/=3 months to <6 years. J Int AIDS Soc. 2015;18:19467. Available at http://www.ncbi.nlm.nih.gov/pubmed/26066346.
  7. Atazanavir sulfate (Reyataz) [package insert]. Bristol-Myers Squibb. 2015. Available at http://packageinserts.bms.com/pi/pi_reyataz.pdf. Accessed June 23, 2015. 
  8. Kiser JJ, Fletcher CV, Flynn PM, et al. Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection-ATN056. Antimicrob Agents Chemother. 2008;52(2):631-637. Available at http://www.ncbi.nlm.nih.gov/pubmed/18025112.

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