Atazanavir Sulfate

REYATAZ® (atazanavir) is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection for patients 3 months and older weighing at least 5 kg.

Limitations Of Use

• REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus.
• Use of REYATAZ/ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology].

Antiretroviral; HIV protease inhibitor (PI).1

Administration

Oral Administration

Administer orally in conjunction with low-dose ritonavir (ritonavir-boosted atazanavir) once daily with food.1

Alternatively, administer orally in conjunction with oral cobicistat (cobicistat-boosted atazanavir) once daily with food.238 239

Has been administered orally unboosted (i.e., without low-dose ritonavir or cobicistat) once daily with food.1

If used concomitantly with certain drugs (e.g., antacids, buffered medications, didanosine, histamine H2-receptor antagonists, proton-pump inhibitors), dosage adjustments may be needed and/or doses of atazanavir and the other drug may need to be given at separate times.1 238 239 (See Specific Drugs under Interactions.)

Swallow capsules whole; do not open.1

Used in adults, adolescents, and pediatric patients ≥6 years of age.1

Usually administered with low-dose ritonavir (ritonavir-boosted atazanavir);1 200 201 may be used without low-dose ritonavir in adults and adolescents ≥13 years of age weighing ≥40 kg who are unable to tolerate ritonavir.1

Provided in single-use packets containing 50 mg of atazanavir as an oral powder;1 must be mixed with food or beverage prior to administration.1

Used in pediatric patients ≥3 months of age weighing ≥5 kg.1

Must be administered with low-dose ritonavir (ritonavir-boosted atazanavir).1

Store atazanavir powder in original packet; do not open until ready to use.1 Mixing the powder with food (e.g., applesauce, yogurt) is preferred; may mix with beverage (e.g., milk, infant formula, water) for infants able to drink from a cup.1 For infants <6 months of age not able to eat solid food or drink from a cup, mix with infant formula and administer using oral dosing syringe.1 Administration with infant bottle not recommended since full dose may not be delivered.1

Administer entire dose within 1 hour after mixing with food or beverage; may be left at room temperature (20–30°C) for up to 1 hour after mixing.1

Mixing with food: Tap packet to settle powder; cut packet along dotted line with clean scissors.1 Using a spoon, mix contents of recommended number of packets with ≥1 tablespoon of food (e.g., applesauce, yogurt) in a small container (e.g., cup, bowl); feed mixture to patient.1 Add and mix additional 1 tablespoon of food to the small container; feed residual mixture to patient.1

Mixing with a beverage: Tap packet to settle powder; cut packet along dotted line with clean scissors.1 Using a spoon, mix contents of recommended number of packets in a small drinking cup with ≥30 mL of beverage; give mixture to patient to drink.1 Add and mix additional 15 mL of beverage to drinking cup; give residual mixture to patient to drink.1 If water is used as the beverage, patient also should eat food at time of administration.1

Mixing with liquid infant formula: Tap packet to settle powder; cut packet along dotted line with clean scissors.1 Using a spoon, mix contents of recommended number of packets in a small medicine cup with 10 mL of prepared liquid infant formula.1 Draw entire mixture into oral dosing syringe and administer into infant's right or left inner cheek.1 Pour and mix additional 10 mL of infant formula into medicine cup to rinse off any remaining powder.1 Draw residual mixture into oral dosing syringe and administer into infant's right or left inner cheek.1

When atazanavir capsules used, give at same time as single-entity ritonavir capsules, tablets, or oral solution.1 200

When atazanavir oral powder used, administer single-entity ritonavir immediately following atazanavir dose.1

Administer fixed-combination tablets containing both drugs (atazanavir/cobicistat).238 Alternatively, administer single-entity atazanavir as capsules at same time as single-entity cobicistat tablets.239

Dosage

Single-entity atazanavir available as capsules or oral powder containing atazanavir sulfate;1 dosage expressed in terms of atazanavir.1

Atazanavir/cobicistat available as fixed-combination tablets containing atazanavir sulfate (300 mg of atazanavir) and cobicistat (150 mg).238

Pediatric Patients

Pediatric patients ≥3 months of age weighing ≥5 kg (oral powder): Dosage is based on weight.1 (See Table 1.) Oral powder must be used with low-dose ritonavir (ritonavir-boosted atazanavir).1

In patients weighing 5 to <10 kg who do not tolerate 200 mg (4 packets) of atazanavir oral powder and have not previously received an HIV PI, atazanavir oral powder in a dosage of 150 mg (3 packets) once daily may be used with close HIV viral load monitoring.

Pediatric patients 6 years to <18 years of age (capsules): Dosage is based on weight.1 (See Table 2.) Capsules usually used with low-dose ritonavir (ritonavir-boosted atazanavir).1

Unboosted atazanavir (i.e., without low-dose ritonavir or cobicistat) in antiretroviral-naive adolescents ≥13 years of age weighing ≥40 kg unable to tolerate ritonavir: 400 mg once daily.1 Do not use unboosted atazanavir in antiretroviral-experienced adolescents.1

Adults

Ritonavir-boosted atazanavir: Single-entity atazanavir 300 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).1

Cobicistat-boosted atazanavir: 1 tablet of atazanavir/cobicistat (300 mg of atazanavir and 150 mg of cobicistat) once daily.238 Alternatively, single-entity atazanavir 300 mg (one 300-mg atazanavir capsule) once daily in conjunction with single-entity cobicistat (150 mg once daily).239

Unboosted atazanavir (adults unable to tolerate ritonavir): 400 mg once daily.1

Ritonavir-boosted atazanavir: Single-entity atazanavir 300 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).1

Cobicistat-boosted atazanavir: 1 tablet of atazanavir/cobicistat (300 mg of atazanavir and 150 mg of cobicistat) once daily.238 Alternatively, single-entity atazanavir 300 mg (one 300-mg atazanavir capsule) once daily in conjunction with single-entity cobicistat (150 mg once daily).239

Ritonavir-boosted atazanavir: Single-entity atazanavir 300 mg once daily in conjunction with low-dose ritonavir (100 mg once daily).199 Use in conjunction with 2 NRTIs (see Postexposure Prophylaxis following Occupational Exposure to HIV under Uses).199

Initiate PEP as soon as possible following occupational exposure to HIV (preferably within hours); continue for 4 weeks, if tolerated.199

Prescribing Limits

Pediatric Patients

Do not exceed adult dosage.1

Ritonavir-boosted atazanavir (children ≥6 years of age): Maximum 300 mg once daily with low-dose ritonavir (100 mg once daily).1

Unboosted atazanavir (antiretroviral-naive adolescents ≥13 years of age weighing ≥40 kg): Maximum 400 mg once daily (without low-dose ritonavir).1

Special Populations

Hepatic Impairment

Unboosted atazanavir in treatment-naive adults with mild hepatic impairment (Child-Pugh class A): 400 mg once daily.1

Unboosted atazanavir in treatment-naive adults with moderate hepatic impairment (Child-Pugh class B): 300 mg once daily.1 200

Unboosted atazanavir in severe hepatic impairment (Child-Pugh class C): Do not use.1 200

Ritonavir-boosted or cobicistat-boosted atazanavir: Do not use in patients with any degree of hepatic impairment.1 238 239

Renal Impairment

Ritonavir-boosted or unboosted atazanavir in patients with renal impairment not undergoing hemodialysis: Dosage adjustments not needed.1

Ritonavir-boosted atazanavir in antiretroviral-naive adults with end-stage renal disease undergoing hemodialysis: 300 mg once daily with low-dose ritonavir (100 mg once daily).1

Cobicistat-boosted atazanavir: Assess estimated Clcr prior to initiation of fixed-combination atazanavir/cobicistat or, alternatively, single-entity atazanavir with single-entity cobicistat.238 239 Experts state dosage adjustments of cobicistat-boosted atazanavir not necessary in patients with renal impairment who do not require hemodialysis.200 However, these experts and manufacturer state do not use cobicistat-boosted atazanavir in conjunction with tenofovir DF in patients with estimated Clcr <70 mL/minute.200 238 239

Antiretroviral-experienced adults with end-stage renal disease undergoing hemodialysis: Do not use ritonavir-boosted, cobicistat-boosted, or unboosted atazanavir.1 238 239

Geriatric Patients

Dosage adjustments based solely on age not required in patients ≥65 years of age.1

Pregnant and Postpartum Women

Use ritonavir-boosted atazanavir;1 202 do not use unboosted atazanavir.1 202 Monitor closely for adverse effects, especially during first 2 months after delivery.1 (See Pregnancy under Cautions.)

Ritonavir-boosted atazanavir: Manufacturer states usually recommended adult dosage can be used during pregnancy or postpartum period unless used concomitantly with certain drugs.1 Experts recommend using increased atazanavir dosage of 400 mg once daily with low-dose ritonavir (100 mg once daily) during second and third trimesters.202

Ritonavir-boosted atazanavir: Antiretroviral-experienced pregnant women in second or third trimester also receiving either a histamine H2-receptor antagonist or tenofovir: Increase atazanavir dosage to 400 mg once daily with low-dose ritonavir (100 mg once daily).1 Not recommended in antiretroviral-experienced pregnant women receiving both a histamine H2-receptor antagonist and tenofovir.1

Storage

Oral

Atazanavir: 25°C (may be exposed to 15–30°C).1

Atazanavir: <30°C in original packet.1 After mixing with food or beverage, may store for up to 1 hour at room temperature (20–30°C).1

Atazanavir/cobicistat: 25°C (may be exposed to 15–30°C).238

• Active against HIV-1;1 has some in vitro activity against HIV-2.1 40

• Inhibits replication of HIV-1 by interfering with HIV protease.1

• Atazanavir may be administered with low-dose ritonavir (ritonavir-boosted atazanavir) or with cobicistat (cobicistat-boosted atazanavir) resulting in increased exposures to atazanavir.1 200 201 238 239

• Antiretroviral activity of ritonavir-boosted atazanavir or cobicistat-boosted atazanavir due to atazanavir.1 238

• HIV-1 with reduced susceptibility to atazanavir have been selected in vitro and have emerged during therapy with the drug.1 11

• Varying degrees of cross-resistance occur among HIV PIs.1

Atazanavir is an antiviral medication in a group of HIV medicines called protease (PRO-tee-ayz) inhibitors. Atazanavir prevents human immunodeficiency virus (HIV) cells from multiplying in your body.

Atazanavir is used to treat HIV, which causes acquired immunodeficiency syndrome (AIDS). Atazanavir is not a cure for HIV or AIDS.

Atazanavir may also be used for purposes not listed in this medication guide.

You should not take this medication if you are allergic to atazanavir.

There are many other drugs that should not be used together with atazanavir. Tell your doctor about all other medicines you use. Do not start a new medication without telling your doctor. Keep a list of all your medicines and show it to any healthcare provider who treats you.

Before using atazanavir, tell your doctor if you have liver disease, hepatitis, kidney disease (or if you are on dialysis), diabetes, a bleeding disorder, high cholesterol, heart problems, or if you have ever used a protease inhibitor in the past.

Taking this medication will not prevent you from passing HIV to other people. Avoid having unprotected sex or sharing razors or toothbrushes. Sharing drug or medicine needles is never safe, even for a healthy person.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• cardiac conduction abnormalities [see WARNINGS AND PRECAUTIONS]
• rash [see WARNINGS AND PRECAUTIONS]
• hyperbilirubinemia [see WARNINGS AND PRECAUTIONS]
• nephrolithiasis and cholelithiasis [see WARNINGS AND PRECAUTIONS]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trial Experience

The safety profile of REYATAZ in treatment-naive adults is based on 1625 HIV-1 infected patients in clinical trials. 536 patients received REYATAZ 300 mg with ritonavir 100 mg and 1089 patients received REYATAZ 400 mg or higher (without ritonavir).

The most common adverse reactions were nausea, jaundice/scleral icterus, and rash.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-naive patients receiving combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) are presented in Tables 7 and 8, respectively.

Table 7: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Naive Patients,b Study AI424138

Table 8: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Naive Patients,b Studies AI424-034, AI424-007, and AI424-008

The safety profile of REYATAZ in treatment-experienced adults is based on 119 HIV-1 infected patients in clinical trials.

The most common adverse reactions are jaundice/scleral icterus and myalgia.

Selected clinical adverse reactions of moderate or severe intensity reported in ≥ 2% of treatment-experienced patients receiving REYATAZ/ritonavir are presented in Table 9.

Table 9: Selected Adverse Reactionsa of Moderate or Severe Intensity Reported in ≥ 2% of Adult Treatment-Experienced Patients,b Study AI424-045

The percentages of adult treatment-naive patients treated with combination therapy including REYATAZ 300 mg with ritonavir 100 mg and REYATAZ 400 mg (without ritonavir) with Grade 3-4 laboratory abnormalities are presented in Tables 10 and 11, respectively.

Table 10: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Naive Patients,a Study AI424-138

Table 11: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Naive Patients,a Studies AI424-034, AI424-007, and AI424-008

For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 12 and 13, respectively.

Table 12: Lipid Values, Mean Change from Baseline, Study AI424-138

Table 13: Lipid Values, Mean Change from Baseline, Study AI424-034

The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 3-4 laboratory abnormalities are presented in Table 14.

Table 14: Grade 3-4 Laboratory Abnormalities Reported in ≥ 2% of Adult Treatment-Experienced Patients, Study AI424-045a

For Study AI424-045, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Table 15. The observed magnitude of dyslipidemia was less with REYATAZ/ritonavir than with lopinavir/ritonavir. However, the clinical impact of such findings has not been demonstrated.

Table 15: Lipid Values, Mean Change from Baseline, Study AI424-045

The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric patients at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.

The safety profile of REYATAZ in pediatric patients (6 to less than 18 years of age) taking the capsule formulation was generally similar to that observed in clinical studies of REYATAZ in adults. The most common Grade 2-4 adverse events ( ≥ 5%, regardless of causality) reported in pediatric patients were cough (21%), fever (18%), jaundice/scleral icterus (15%), rash (14%), vomiting (12%), diarrhea (9%), headache (8%), peripheral edema (7%), extremity pain (6%), nasal congestion (6%), oropharyngeal pain (6%), wheezing (6%), and rhinorrhea (6%). Asymptomatic second-degree atrioventricular block was reported in < 2% of patients. The most common Grade 3-4 laboratory abnormalities occurring in pediatric patients taking the capsule formulation were elevation of total bilirubin ( ≥ 3.2 mg/dL, 58%), neutropenia (9%), and hypoglycemia (4%). All other Grade 3-4 laboratory abnormalities occurred with a frequency of less than 3%.

The data described below reflect exposure to REYATAZ oral powder in 155 subjects weighing at least 5 kg to less than 35 kg, including 134 patients exposed for 48 weeks. These data are from two pooled open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric patients (AI424-397 [PRINCE I] and AI424-451 [PRINCE II]). Age ranged from 3 months to 10 years of age. In these studies 51% were female and 49% were male. All patients received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The safety profile of REYATAZ in pediatric patients taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric patients taking REYATAZ capsules. The most common Grade 3-4 laboratory abnormalities occurring in pediatric patients weighing 5 kg to less than 35 kg taking REYATAZ oral powder were increased amylase (33%), neutropenia (9%), increased SGPT/ALT (9%), elevation of total bilirubin ( ≥ 2.6 times ULN, 16%), and increased lipase (8%). All other Grade 3-4 laboratory abnormalities occurred with a frequency of less than 3%.

In study AI424-138, 60 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 51 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, each with fixed dose tenofovir-emtricitabine, were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times ULN developed in 10% (6/60) of the REYATAZ/ritonavir-treated patients and 8% (4/50) of the lopinavir/ritonavir-treated patients. AST levels > 5 times ULN developed in 10% (6/60) of the REYATAZ/ritonavir-treated patients and none (0/50) of the lopinavir/ritonavir-treated patients.

In study AI424-045, 20 patients treated with REYATAZ/ritonavir 300 mg/100 mg once daily, and 18 patients treated with lopinavir/ritonavir 400 mg/100 mg twice daily, were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times ULN developed in 25% (5/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients. AST levels > 5 times ULN developed in 10% (2/20) of the REYATAZ/ritonavir-treated patients and 6% (1/18) of the lopinavir/ritonavir-treated patients.

In studies AI424-008 and AI424-034, 74 patients treated with 400 mg of REYATAZ once daily, 58 who received efavirenz, and 12 who received nelfinavir were seropositive for hepatitis B and/or C at study entry. ALT levels > 5 times ULN developed in 15% of the REYATAZ-treated patients, 14% of the efavirenz-treated patients, and 17% of the nelfinavir-treated patients. AST levels > 5 times ULN developed in 9% of the REYATAZ-treated patients, 5% of the efavirenztreated patients, and 17% of the nelfinavir-treated patients. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative patients. [See WARNINGS AND PRECAUTIONS]

Postmarketing Experience

The following events have been identified during postmarketing use of REYATAZ. Because these reactions are reported voluntarily from a population of unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: edema

Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation [see WARNINGS AND PRECAUTIONS]

Gastrointestinal System: pancreatitis

Hepatic System: hepatic function abnormalities

Hepatobiliary Disorders: cholelithiasis [see WARNINGS AND PRECAUTIONS], cholecystitis, cholestasis

Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia [see WARNINGS AND PRECAUTIONS]

Musculoskeletal System: arthralgia

Renal System: nephrolithiasis [see WARNINGS AND PRECAUTIONS], interstitial nephritis

Skin and Appendages: alopecia, maculopapular rash [see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS], pruritus, angioedema

Read the entire FDA prescribing information for Reyataz (Atazanavir Sulfate)