Reyataz

What is REYATAZ and how is it used?

REYATAZ is a prescription HIV-1 (Human Immunodeficiency Virus-type 1) medicine that is used with other antiretroviral medicines to treat HIV-1 infection in adults and children 3 months of age and older and who weigh at least 11 pounds (5 kg). HIV-1 is the virus that causes AIDS (Acquired Immunodeficiency Syndrome).

REYATAZ should not be used in children younger than 3 months of age. When used with other antiretroviral medicines to treat HIV-1 infection, REYATAZ may help:

• reduce the amount of HIV-1 in your blood. This is called “viral load”.
• increase the number of CD4+ (T) cells in your blood that help fight off other infections.

Reducing the amount of HIV-1 and increasing the CD4+ (T) cells in your blood may help improve your immune system. This may reduce your risk of death or getting infections that can happen when your immune system is weak (opportunistic infections).

What are the possible side effects of REYATAZ?

REYATAZ can cause serious side effects, including:

• A change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
• Skin rash. Skin rash is common with REYATAZ but can sometimes be severe. Skin rash usually goes away within 2 weeks without any change in treatment. Severe rash may develop in association with other symptoms which could be serious. If you develop a severe rash or a rash with any of the following symptoms, stop taking REYATAZ and call your healthcare provider right away:
  • general feeling of discomfort or “flu- like” symptoms
  • blisters
  • fever
  • mouth sores
  • muscle or joint aches
  • swelling of your face
  • red or inflamed eyes, like “pink eye” (conjunctivitis)
  • painful, warm, or red lump under your skin
• Yellowing of your skin or the white part of your eyes is common with REYATAZ, and is usually not harmful in adults and infants older than 3 months of age; but it could also be a symptom of a serious problem. These effects may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Although these effects may not be damaging to your liver, skin, or eyes, tell your healthcare provider right away if your skin or the white part of your eyes turns yellow.
• Liver problems. If you have liver problems, including hepatitis B or C infection, your liver problems may get worse when you take REYATAZ. Your healthcare provider will do blood tests to check your liver before you start REYATAZ and during treatment. Tell your healthcare provider right away if you get any of the following symptoms:
  • dark “tea-colored” urine
  • itching
  • your skin or the white part of your eyes turns yellow
  • stomach-area pain
  • light colored stools
  • nausea
• Chronic kidney disease. REYATAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start REYATAZ and during treatment.
• Kidney stones have happened in some people who take REYATAZ. Tell your healthcare provider right away if you get symptoms of kidney stones which may include, pain in your low back or low stomach-area, blood in your urine, or pain when you urinate.
• Gallbladder problems have happened in some people who take REYATAZ. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include:
  • pain in the right or middle upper stomach area
  • nausea and vomiting
  • fever
  • your skin or the white part of your eyes turns yellow
• Diabetes and high blood sugar (hyperglycemia) have happened or have worsened in some people who take protease inhibitor medicines like REYATAZ. Some people have had to start taking medicine to treat diabetes or have had to change their diabetes medicine.
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new symptoms after starting REYATAZ.
• Changes in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
• Increased bleeding problems in people with hemophilia have happened when taking protease inhibitors like REYATAZ.

The most common side effects of REYATAZ include:

• nausea
• dizziness
• headache
• muscle pain
• stomach-area pain
• diarrhea
• vomiting
• depression
• trouble sleeping
• fever
• numbness, tingling, or burning of hands or feet

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of REYATAZ. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

The active ingredient in REYATAZ capsules and oral powder is atazanavir sulfate, which is an HIV-1 protease inhibitor.

The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C₃₈H₅₂N₆O₇•H₂SO₄, which corresponds to a molecular weight of 802.9 (sulfuric acid salt). The free base molecular weight is 704.9. Atazanavir sulfate has the following structural formula:

Atazanavir sulfate is a white to pale-yellow crystalline powder. It is slightly soluble in water (4-5 mg/mL, free base equivalent) with the pH of a saturated solution in water being about 1.9 at 24 ± 3°C.

REYATAZ Capsules are available for oral administration in strengths of 150 mg, 200 mg, or 300 mg of atazanavir, which are equivalent to 170.8 mg, 227.8 mg, or 341.69 mg of atazanavir sulfate, respectively. The capsules also contain the following inactive ingredients: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain the following inactive ingredients: gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C

Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.

REYATAZ oral powder comes in a packet containing 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. The powder is off-white to pale yellow and contains the following inactive ingredients: aspartame, sucrose, and orange-vanilla flavor.

INDICATIONS

REYATAZ® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and in pediatric 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 [see Use In Specific Populations].
• Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions [see Microbiology].

DOSAGE AND ADMINISTRATION

Overview

• REYATAZ capsules and oral powder must be taken with food.
• Do not open the capsules.
• The recommended oral dosage of REYATAZ depends on the treatment history of the patient and the use of other coadministered drugs. When coadministered with H2-receptor antagonists or proton-pump inhibitors, dose separation may be required [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
• REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure [see Clinical Studies].
• REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg [see DOSAGE AND ADMINISTRATION].
• Efficacy and safety of REYATAZ with ritonavir when ritonavir is administered in doses greater than 100 mg once daily have not been established. The use of higher ritonavir doses may alter the safety profile of atazanavir (cardiac effects, hyperbilirubinemia) and, therefore, is not recommended. Prescribers should consult the complete prescribing information for ritonavir when using ritonavir.

Testing Prior To Initiation And During Treatment With REYATAZ

Renal laboratory testing should be performed in all patients prior to initiation of REYATAZ and continued during treatment with REYATAZ. Renal laboratory testing should include serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination [see WARNINGS AND PRECAUTIONS].

Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ [see WARNINGS AND PRECAUTIONS].

Dosage Of REYATAZ In Adult Patients

Table 1 displays the recommended dosage of REYATAZ capsules in treatment-naive and treatment-experienced adults. Table 1 also displays recommended dosage of REYATAZ and ritonavir when given concomitantly with other antiretroviral drugs and H2-receptor antagonists (H2RA). Ritonavir is required with several REYATAZ dosage regimens (see the ritonavir complete prescribing information about the safe and effective use of ritonavir). The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.

Table 1: Recommended REYATAZ and Ritonavir Dosage in Adults^a,b

Dosage Of REYATAZ Capsules In Pediatric Patients

The recommended daily dosage of REYATAZ capsules and ritonavir in pediatric patients (6 years of age to less than 18 years of age) is based on body weight (see Table 2).

Table 2: Recommended Dosage of REYATAZ Capsules and Ritonavir in Pediatric Patients (6 to less than 18 years of age)^a,b

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation.

Dosage And Administration Of REYATAZ Oral Powder In Pediatric Patients

REYATAZ oral powder is for use in treatment-naive or treatment-experienced pediatric patients who are at least 3 months of age and weighing at least 5 kg. REYATAZ oral powder must be mixed with food or a beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir.

Table 3: Recommended Dosage of REYATAZ Oral Powder and Ritonavir in Pediatric Patients (at least 3 months of age and weighing at least 5 kg)^a,b

When transitioning between formulations, a change in dose may be needed. Consult the dosing table for the specific formulation.

Instructions For Mixing REYATAZ Oral Powder

[see FDA-approved Instructions for Use]

• Determine the number of packets (3, 4, 5 or 6 packets) that are needed.
• Prior to mixing, tap the packet to settle the powder.
• It is preferable to mix REYATAZ oral powder with food such as applesauce or yogurt. Mixing REYATAZ oral powder with a beverage (milk, infant formula, or water) may be used for infants who can drink from a cup. For young infants (less than 6 months) who cannot eat solid food or drink from a cup, REYATAZ oral powder should be mixed with infant formula and given using an oral dosing syringe. Administration of REYATAZ and infant formula using an infant bottle is not recommended because full dose may not be delivered.
• Use a clean pair of scissors to cut each packet along the dotted line.
• Mixing with food: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of one tablespoon of food (such as applesauce or yogurt). Feed the mixture to the infant or young child. Add an additional one tablespoon of food to the small container, mix, and feed the child the residual mixture.
• Mixing with a beverage such as milk or water in a small drinking cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with a minimum of 30 mL of the beverage. 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 taken at the same time.
• Mixing with liquid infant formula using an oral dosing syringe and a small medicine cup: Using a spoon, mix the recommended number of REYATAZ oral powder packets with 10 mL of prepared liquid infant formula. Draw up the full amount of the mixture into an oral syringe and administer into either right or left inner cheek of infant. Pour another 10 mL of formula into the medicine cup to rinse off remaining REYATAZ oral powder in cup. Draw up residual mixture into the syringe and administer into either right or left inner cheek of infant.
• Administer ritonavir immediately following REYATAZ powder administration.
• Administer the entire dosage of REYATAZ oral powder (mixed in the food or beverage) within one hour of preparation [may leave the mixture at a temperature of 68°F to 86°F (20°C to 30°C) for up to one hour]. Ensure that the patient eats or drinks all the food or beverage that contains the powder. Additional food may be given after consumption of the entire mixture.

Dosage Adjustments In Pregnant Patients

Table 4 includes the recommended dosage of REYATAZ capsules and ritonavir in treatment-naive and treatment-experienced pregnant patients. In these patients, REYATAZ must be administered with ritonavir. There are no dosage adjustments for postpartum patients (see Table 1 for the recommended REYATAZ dosage in adults) [see Use In Specific Populations].

Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patients^a

Dosage In Patients With Renal Impairment

For patients with renal impairment, including those with severe renal impairment who are not managed with hemodialysis, no dose adjustment is required for REYATAZ. Treatment-naive patients with end-stage renal disease managed with hemodialysis should receive REYATAZ 300 mg with ritonavir 100 mg. REYATAZ is not recommended in treatment-experienced patients with HIV-1 infection who have end-stage renal disease managed with hemodialysis [see Use In Specific Populations].

Dosage Adjustments In Patients With Hepatic Impairment

Table 5 displays the recommended REYATAZ dosage in treatment-naive patients with hepatic impairment. The use of REYATAZ in patients with severe hepatic impairment (Child-Pugh Class C) is not recommended. The coadministration of REYATAZ with ritonavir in patients with any degree of hepatic impairment is not recommended.

Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment

HOW SUPPLIED

Dosage Forms And Strengths

REYATAZ Capsules

• 150 mg capsule with blue cap and powder blue body, printed with white ink “BMS 150 mg” on the cap and with blue ink “3624” on the body.
• 200 mg capsule with blue cap and blue body, printed with white ink “BMS 200 mg” on the cap and with white ink “3631” on the body.
• 300 mg capsule with red cap and blue body, printed with white ink “BMS 300 mg” on the cap and with white ink “3622” on the body.

REYATAZ Oral Powder

• 50 mg of atazanavir as an oral powder in a packet.

Storage And Handling

REYATAZ Capsules

REYATAZ® (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.

Keep capsules in a tightly closed container.

Store REYATAZ capsules at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

REYATAZ Oral Powder

REYATAZ oral powder is an orange-vanilla flavored powder, packed in child-resistant packets. Each packet contains 50 mg of atazanavir equivalent to 56.9 mg of atazanavir sulfate in 1.5 g of powder. REYATAZ oral powder is supplied in cartons (NDC 0003-3638-10) of 30 packets each. [See DOSAGE AND ADMINISTRATION].

Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C). Store REYATAZ oral powder in the original packet. Do not open until ready to use. After REYATAZ oral powder is mixed with food or liquid, it may be kept at a temperature 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid.

Distributed by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA. Revised: Sep 2020

SIDE EFFECTS

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]
• chronic kidney disease [see WARNINGS AND PRECAUTIONS]
• nephrolithiasis and cholelithiasis [see WARNINGS AND PRECAUTIONS]

Clinical Trial Experience

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.

Adverse Reactions In Treatment-Naive Adult Subjects

The safety profile of REYATAZ in treatment-naive adults is based on 1625 subjects with HIV-1 infection in clinical trials. 536 subjects received REYATAZ 300 mg with ritonavir 100 mg and 1089 subjects 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 subjects 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 Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,^b Study AI424-138

Table 8: Selected Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection,^b Studies AI424-034, AI424-007, and AI424-008

Adverse Reactions In Treatment-Experienced Adult Subjects

The safety profile of REYATAZ in treatment-experienced adults with HIV-1 infection is based on 119 subjects with HIV-1 infection 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 subjects receiving REYATAZ with ritonavir are presented in Table 9.

Table 9: Selected Adverse Reactions^a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection,^b Study AI424-045

Laboratory Abnormalities In Treatment-Naive Subjects

The percentages of adult treatment-naive subjects with HIV-1 infection treated with combination therapy, including REYATAZ 300 mg with ritonavir 100 mg or 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 Subjects with HIV-1 Infection,^a Study AI424-138

Table 11: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Subjects with HIV-1 Infection, Studies AI424-034, AI424-007, and AI424-008

Change In Lipids From Baseline In Treatment-Naive Subjects With HIV-1 Infection

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

Laboratory Abnormalities In Treatment-Experienced Subjects With HIV-1 Infection

The percentages of adult treatment-experienced subjects with HIV-1 infection treated with combination therapy, including REYATAZ with ritonavir having Grade 3-4 laboratory abnormalities, are presented in Table 14.

Table 14: Grade 3-4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Experienced Subjects with HIV-1 Infection, Study AI424-045^a

Change In Lipids From Baseline In Treatment-Experienced Subjects With HIV-1 Infection

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 with 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

Adverse Reactions In Pediatric Subjects With HIV-1 Infection

REYATAZ Capsules - The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric subjects with HIV-1 infection, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A.

The safety profile of REYATAZ in pediatric subjects with HIV-1 infection (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 subjects 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 subjects. The most common Grade 3-4 laboratory abnormalities occurring in pediatric subjects 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%.

Adverse Reactions In Pediatric Subjects With HIV-1 Infection: REYATAZ Oral Powder

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 subjects exposed for 48 weeks. These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric subjects with HIV-1 infection (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 subjects received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs).

The safety profile of REYATAZ in pediatric subjects taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric subjects taking REYATAZ capsules. The most common Grade 3-4 laboratory abnormalities occurring in pediatric subjects 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%.

Adverse Reactions In Subjects With HIV-1 Infection, Co-Infected With Hepatitis B And/Or Hepatitis C Virus

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

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

In Studies AI424-008 and AI424-034, 74 subjects treated with REYATAZ 400 mg 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 subjects treated with REYATAZ, 14% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. AST levels >5 times ULN developed in 9% of the subjects treated with REYATAZ, 5% of the subjects treated with efavirenz, and 17% of the subjects treated with nelfinavir. Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative subjects [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, granulomatous interstitial nephritis, chronic kidney disease [see WARNINGS AND PRECAUTIONS]

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

DRUG INTERACTIONS

Potential For REYATAZ To Affect Other Drugs

Atazanavir is an inhibitor of CYP3A and UGT1A1. Coadministration of REYATAZ and drugs primarily metabolized by CYP3A or UGT1A1 may result in increased plasma concentrations of the other drug that could increase or prolong its therapeutic and adverse effects.

Atazanavir is a weak inhibitor of CYP2C8. Use of REYATAZ without ritonavir is not recommended when coadministered with drugs highly dependent on CYP2C8 with narrow therapeutic indices (eg, paclitaxel, repaglinide). When REYATAZ with ritonavir is coadministered with substrates of CYP2C8, clinically significant interactions are not expected [see CLINICAL PHARMACOLOGY, Table 22].

The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered with ritonavir. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir.

Potential For Other Drugs To Affect REYATAZ

Atazanavir is a CYP3A4 substrate; therefore, drugs that induce CYP3A4 may decrease atazanavir plasma concentrations and reduce REYATAZ's therapeutic effect.

Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H2-receptor antagonists are administered with REYATAZ [see DOSAGE AND ADMINISTRATION].

Established And Other Potentially Significant Drug Interactions

Table 16 provides dosing recommendations in adults as a result of drug interactions with REYATAZ. These recommendations are based on either drug interaction studies or predicted interactions due to the expected magnitude of interaction and potential for serious events or loss of efficacy.

Table 16: Established and Other Potentially Significant Drug Interactions: Alteration in Dose or Regimen May Be Recommended Based on Drug Interaction Studies^a or Predicted Interactions (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

Drugs With No Observed Interactions With REYATAZ

No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see CLINICAL PHARMACOLOGY, Tables 21 and 22].

OVERDOSE

Human experience of acute overdose with REYATAZ is limited. Single doses up to 1200 mg (three times the 400 mg maximum recommended dose) have been taken by healthy subjects without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in a patient with HIV-1 infection (73 times the 400-mg recommended dose) was associated with asymptomatic bifascicular block and PR interval prolongation. These events resolved spontaneously. At REYATAZ doses resulting in high atazanavir exposures, jaundice due to indirect (unconjugated) hyperbilirubinemia (without associated liver function test changes) or PR interval prolongation may be observed [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY].

Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patient’s clinical status. If indicated, elimination of unabsorbed atazanavir should be achieved by emesis or gastric lavage. Administration of activated charcoal may also be used to aid removal of unabsorbed drug. There is no specific antidote for overdose with REYATAZ. 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.

CONTRAINDICATIONS

REYATAZ is contraindicated:

• in patients with previously demonstrated clinically significant hypersensitivity (eg, Stevens-Johnson syndrome, erythema multiforme, or toxic skin eruptions) to any of the components of REYATAZ capsules or REYATAZ oral powder [see WARNINGS AND PRECAUTIONS].
• when coadministered with drugs that are highly dependent on CYP3A or UGT1A1 for clearance, and for which elevated plasma concentrations of the interacting drugs are associated with serious and/or life-threatening events (see Table 6).
• when coadministered with drugs that strongly induce CYP3A and may lead to lower exposure and loss of efficacy of REYATAZ (see Table 6).

Table 6 displays drugs that are contraindicated with REYATAZ.

Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated)

CLINICAL PHARMACOLOGY

Mechanism Of Action

Atazanavir is an HIV-1 antiretroviral drug [see Microbiology].

Pharmacodynamics

Cardiac Electrophysiology

Concentration-and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy subjects receiving atazanavir. In placebo-controlled Study AI424-076, the mean (±SD) maximum change in PR interval from the predose value was 24 (±15) msec following oral dosing with 400 mg of atazanavir (n=65) compared to 13 (±11) msec following dosing with placebo (n=67). The PR interval prolongations in this study were asymptomatic. There is limited information on the potential for a pharmacodynamic interaction in humans between atazanavir and other drugs that prolong the PR interval of the electrocardiogram [see WARNINGS AND PRECAUTIONS].

Electrocardiographic effects of atazanavir were determined in a clinical pharmacology study of 72 healthy subjects. Oral doses of 400 mg (maximum recommended dosage) and 800 mg (twice the maximum recommended dosage) were compared with placebo; there was no concentration-dependent effect of atazanavir on the QTc interval (using Fridericia’s correction). In 1793 subjects with HIV-1 infection, receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or subject with HIV-1 infection in clinical trials had a QTc interval >500 msec [see WARNINGS AND PRECAUTIONS].

Pharmacokinetics

The pharmacokinetics of atazanavir were evaluated in adult subjects who either were healthy, or with HIV infection, after administration of REYATAZ 400 mg once daily and after administration of REYATAZ 300 mg with ritonavir 100 mg once daily (see Table 17).

Table 17: Steady-State Pharmacokinetics of Atazanavir in Healthy Subjects or Subjects with HIV-1 Infection in the Fed State

Figure 1 displays the mean plasma concentrations of atazanavir at steady state after REYATAZ 400 mg once daily (as two 200-mg capsules) with a light meal and after REYATAZ 300 mg (as two 150-mg capsules) with ritonavir 100 mg once daily with a light meal in adult subjects with HIV-1 infection.

Figure 1: Mean (SD) Steady-State Plasma Concentrations of Atazanavir 400 mg (n=13) and 300 mg with Ritonavir (n=10) for HIV-Infected Adult Subjects with HIV-1 Infection

Absorption

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 to 800 mg once daily. Steady state is achieved between Days 4 and 8, with an accumulation of approximately 2.3 fold.

Food Effect

Administration of REYATAZ with food enhances bioavailability and reduces pharmacokinetic variability. Administration of a single 400-mg dose of REYATAZ 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 400-mg dose of REYATAZ 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 REYATAZ 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.

Coadministration of a single 300-mg dose of REYATAZ and a 100-mg dose of 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 both the Cmax and the 24-hour concentration of atazanavir relative to the fasting state. Coadministration with a high-fat meal (951 kcal, 54.7 g fat, 35.9 g protein) did not affect the AUC of atazanavir relative to fasting conditions and the Cmax was within 11% of fasting values. The 24-hour concentration following a high-fat meal was increased by approximately 33% due to delayed absorption; the median Tmax increased from 2.0 to 5.0 hours. Coadministration of REYATAZ with ritonavir with either a light or a high-fat meal decreased the coefficient of variation of AUC and Cmax by approximately 25% compared to the fasting state.

Distribution

Atazanavir is 86% bound to human serum proteins and protein binding is independent of concentration. Atazanavir binds to both alpha-1-acid glycoprotein (AAG) and albumin to a similar extent (89% and 86%, respectively). In a multiple-dose study in subjects with HIV-1 infection dosed with REYATAZ 400 mg once daily with a light meal for 12 weeks, atazanavir was detected in the cerebrospinal fluid and semen. The cerebrospinal fluid/plasma ratio for atazanavir (n=4) ranged between 0.0021 and 0.0226 and seminal fluid/plasma ratio (n=5) ranged between 0.11 and 4.42.

Metabolism

Atazanavir is extensively metabolized in humans. 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. 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

Following a single 400-mg dose of ¹⁴C-atazanavir, 79% and 13% of the total radioactivity was recovered in the feces and urine, respectively. Unchanged drug accounted for approximately 20% and 7% of the administered dose in the feces and urine, respectively. The mean elimination half-life of atazanavir in healthy subjects (n=214) and adult subjects with HIV-1 infection (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.

Specific Populations

Renal Impairment

In healthy subjects, the renal elimination of unchanged atazanavir was approximately 7% of the administered dose. REYATAZ has been studied in adult subjects with severe renal impairment (n=20), including those on hemodialysis, at multiple doses of 400 mg once daily. The mean atazanavir Cmax was 9% lower, AUC was 19% higher, and Cmin was 96% higher in subjects with severe renal impairment not undergoing hemodialysis (n=10), than in age-, weight-, and gender-matched subjects with normal renal function. In a 4-hour dialysis session, 2.1% of the administered dose was removed. When atazanavir was administered either prior to, or following hemodialysis (n=10), the geometric means for Cmax, AUC, and Cmin were approximately 25% to 43% lower compared to subjects with normal renal function. The mechanism of this decrease is unknown. REYATAZ is not recommended for use in treatment-experienced patients with HIV-1 who have end-stage renal disease managed with hemodialysis [see DOSAGE AND ADMINISTRATION].

Hepatic Impairment

REYATAZ has been studied in adult subjects with moderate-to-severe hepatic impairment (14 Child-Pugh B and 2 Child-Pugh C subjects) after a single 400-mg dose. The mean AUC(0-∞) was 42% greater in subjects with impaired hepatic function than in healthy subjects. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy subjects. A dose reduction to 300 mg is recommended for patients with moderate hepatic impairment (Child-Pugh Class B) who have not experienced prior virologic failure as increased concentrations of atazanavir are expected. REYATAZ is not recommended for use in patients with severe hepatic impairment. The pharmacokinetics of REYATAZ in combination with ritonavir has not been studied in subjects with hepatic impairment; thus, coadministration of REYATAZ with ritonavir is not recommended for use in patients with any degree of hepatic impairment [see DOSAGE AND ADMINISTRATION].

Pediatrics

The pharmacokinetic parameters for atazanavir at steady state in pediatric subjects taking the powder formulation are summarized in Table 18 by weight ranges [see DOSAGE AND ADMINISTRATION].

Table 18: Steady-State Pharmacokinetics of Atazanavir (powder formulation) with Ritonavir in Pediatric Subjects with HIV-1

The pharmacokinetic parameters for atazanavir at steady state in pediatric subjects taking the capsule formulation were predicted by a population pharmacokinetic model and are summarized in Table 19 by weight ranges that correspond to the recommended doses [see DOSAGE AND ADMINISTRATION].

Table 19: Predicted Steady-State Pharmacokinetics of Atazanavir (capsule formulation) with Ritonavir in Pediatric Subjects with HIV-1 Infection

Pregnancy

The pharmacokinetic data from pregnant women with HIV-1 infection receiving REYATAZ Capsules with ritonavir are presented in Table 20.

Table 20: Steady-State Pharmacokinetics of Atazanavir with Ritonavir in Pregnant Women with HIV-1 Infection in the Fed State

Drug Interaction Data

Atazanavir is a metabolism-dependent CYP3A inhibitor, with a Kinact value of 0.05 to 0.06 min^-1 and Ki value of 0.84 to 1.0 μM. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 μM) and CYP2C8 (Ki=2.1 μM).

Atazanavir has been shown in vivo not to induce its own metabolism nor to increase the biotransformation of some drugs metabolized by CYP3A. In a multiple-dose study, REYATAZ decreased the urinary ratio of endogenous 6β-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.

Clinically significant interactions are not expected between atazanavir and substrates of CYP2C19, CYP2C9, CYP2D6, CYP2B6, CYP2A6, CYP1A2, or CYP2E1. Clinically significant interactions are not expected between atazanavir when administered with ritonavir and substrates of CYP2C8. See the complete prescribing information for ritonavir for information on other potential drug interactions with ritonavir.

Based on known metabolic profiles, clinically significant drug interactions are not expected between REYATAZ and dapsone, trimethoprim/sulfamethoxazole, azithromycin, or erythromycin. REYATAZ does not interact with substrates of CYP2D6 (eg, nortriptyline, desipramine, metoprolol).

Drug interaction studies were performed with REYATAZ and other drugs likely to be coadministered and some drugs commonly used as probes for pharmacokinetic interactions. The effects of coadministration of REYATAZ on the AUC, Cmax, and Cmin are summarized in Tables 21 and 22. Neither didanosine EC nor diltiazem had a significant effect on atazanavir exposures (see Table 22 for effect of atazanavir on didanosine EC or diltiazem exposures). REYATAZ did not have a significant effect on the exposures of didanosine (when administered as the buffered tablet), stavudine, or fluconazole. For information regarding clinical recommendations, see DRUG INTERACTIONS.

Table 21: Drug Interactions: Pharmacokinetic Parameters for Atazanavir in the Presence of Coadministered Drugs^a

Table 22: Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of REYATAZ^a

Microbiology

Mechanism Of Action

Atazanavir (ATV) is an azapeptide HIV-1 protease inhibitor (PI). 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.

Antiviral Activity In Cell Culture

Atazanavir exhibits anti-HIV-1 activity with a mean 50% effective concentration (EC50) in the absence of human serum of 2 to 5 nM against a variety of laboratory and clinical HIV-1 isolates grown in peripheral blood mononuclear cells, macrophages, CEM-SS cells, and MT-2 cells.

Atazanavir has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. Atazanavir has variable activity against HIV-2 isolates (1.9-32 nM), with EC50 values above the EC50 values of failure isolates. Two-drug combination antiviral activity studies with atazanavir showed no antagonism in cell culture with PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NNRTIs (delavirdine, efavirenz, and nevirapine), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir DF, and zidovudine), the HIV-1 fusion inhibitor enfuvirtide, and two compounds used in the treatment of viral hepatitis, adefovir and ribavirin, without enhanced cytotoxicity.

Resistance

In Cell Culture

HIV-1 isolates with a decreased susceptibility to atazanavir have been selected in cell culture and obtained from patients treated with atazanavir or atazanavir with ritonavir. HIV-1 isolates with 93-to 183-fold reduced susceptibility to atazanavir from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to atazanavir resistance include I50L, N88S, I84V, A71V, and M46I. Changes were also observed at the protease cleavage sites following drug selection. Recombinant viruses containing the I50L substitution without other major PI substitutions were growth impaired and displayed increased susceptibility in cell culture to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir). The I50L and I50V substitutions yielded selective resistance to atazanavir and amprenavir, respectively, and did not appear to be cross-resistant.

Clinical Studies Of Treatment-Naive Subjects

Comparison of Ritonavir-Boosted REYATAZ vs Unboosted REYATAZ: Study AI424-089 compared REYATAZ 300 mg once daily with ritonavir 100 mg vs REYATAZ 400 mg once daily when administered with lamivudine and extended-release stavudine in treatment-naive subjects with HIV-1 infection. A summary of the number of virologic failures and virologic failure isolates with atazanavir resistance in each arm is shown in Table 23.

Table 23: Summary of Virologic Failures^a at Week 96 in Study AI424-089: Comparison of Ritonavir Boosted REYATAZ vs Unboosted REYATAZ: Randomized Subjects

Clinical Studies of Treatment-Naive Subjects Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase 3 Study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from subjects who experienced virologic failure (HIV-1 RNA ≥400 copies/mL) or discontinued before achieving suppression on atazanavir with ritonavir (n=39; 9%) and lopinavir/ritonavir (n=39; 9%) through 96 weeks of treatment. In the atazanavir with ritonavir arm, one of the virologic failure isolates had a 56-fold decrease in atazanavir susceptibility emerge on therapy with the development of PI resistance-associated substitutions L10F, V32I, K43T, M46I, A71I, G73S, I85I/V, and L90M. The NRTI resistance-associated substitution M184V also emerged on treatment in this isolate conferring emtricitabine resistance. Two atazanavir with ritonavir-virologic failure isolates had baseline phenotypic atazanavir resistance and IAS-defined major PI resistance-associated substitutions at baseline. The I50L substitution emerged on study in one of these failure isolates and was associated with a 17-fold decrease in atazanavir susceptibility from baseline and the other failure isolate with baseline atazanavir resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on atazanavir treatment associated with a 3-fold decrease in atazanavir susceptibility from baseline. Five of the treatment failure isolates in the atazanavir with ritonavir arm developed phenotypic emtricitabine resistance with the emergence of either the M184I (n=1) or the M184V (n=4) substitution on therapy and none developed phenotypic tenofovir disoproxil resistance. In the lopinavir/ritonavir arm, one of the virologic failure subject isolates had a 69-fold decrease in lopinavir susceptibility emerge on therapy with the development of PI substitutions L10V, V11I, I54V, G73S, and V82A in addition to baseline PI substitutions L10L/I, V32I, I54I/V, A71I, G73G/S, V82V/A, L89V, and L90M. Six lopinavir/ritonavir virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.

Clinical Studies of Treatment-Naive Subjects Receiving REYATAZ 400 mg without Ritonavir: atazanavir -resistant clinical isolates from treatment-naive subjects who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of atazanavir therapy), often in combination with an A71V substitution, but also developed one or more other PI substitutions (eg, V32I, L33F, G73S, V82A, I85V, or N88S) with or without the I50L substitution. In treatment-naive subjects, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to atazanavir but retained in cell culture susceptibility to other PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir); however, there are no clinical data available to demonstrate the effect of the I50L substitution on the efficacy of subsequently administered PIs.

Clinical Studies of Treatment-Experienced Subjects: In studies of treatment-experienced subjects treated with atazanavir or atazanavir with ritonavir, most atazanavir-resistant isolates from subjects who experienced virologic failure developed substitutions that were associated with resistance to multiple PIs and displayed decreased susceptibility to multiple PIs. The most common protease substitutions to develop in the viral isolates of subjects who failed treatment with atazanavir 300 mg once daily and ritonavir 100 mg once daily (together with tenofovir DF and an NRTI) included V32I, L33F/V/I, E35D/G, M46I/L, I50L, F53L/V, I54V, A71V/T/I, G73S/T/C, V82A/T/L, I85V, and L89V/Q/M/T. Other substitutions that developed on atazanavir with ritonavir treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of subject isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the subject at baseline, atazanavir resistance developed through substitutions associated with resistance to other PIs and could include the development of the I50L substitution. The I50L substitution has been detected in treatment-experienced subjects experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on atazanavir treatment but their presence did not correlate with the level of atazanavir resistance.

Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451 (PRINCE II): Treatment-emergent atazanavir with ritonavir resistance-associated amino acid substitution M36I in the protease was detected in the virus of one subject among treatment failures in AI424-397. In addition, three known resistance-associated substitutions for other PIs arose in the viruses from one subject each (L19I/R, H69K/R, and I72I/V). Reduced susceptibility to atazanavir, ritonavir, or atazanavir with ritonavir was not seen with these viruses. In AI424-451, atazanavir with ritonavir resistance-associated substitutions G16E, V82A/I/T, I84V, and/or L90M arose in the viruses of two subjects. The virus population harboring the M46M/V, V82V/I, I84I/V, and L90L/M substitutions acquired phenotypic resistance to ritonavir (ritonavir phenotypic fold-change of 3.5, with a ritonavir cutoff of 2.5-fold change). However, these substitutions did not result in phenotypic resistance to atazanavir (atazanavir phenotypic fold-change of <1.8, with an atazanavir cutoff of 2.2-fold change). Secondary PI resistance-associated amino acid substitutions also arose in the viruses of one subject each, including V11V/I, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61E/G emerged in the viruses of two subjects who failed treatment with atazanavir with ritonavir. Viruses from nine subjects in the two studies developed NRTI resistance-associated substitutions: K65K/R (n=1), M184V (n=7), and T215I (n=1).

Cross-Resistance

Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from atazanavir clinical trials of PI-experienced subjects showed that isolates cross-resistant to multiple PIs were cross-resistant to atazanavir. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to atazanavir. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to atazanavir, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to atazanavir. Isolates resistant to atazanavir were also cross-resistant to other PIs with >90% of the isolates resistant to indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir, and 80% resistant to amprenavir. In treatment-experienced subjects, PI-resistant viral isolates that developed the I50L substitution in addition to other PI resistance-associated substitution were also cross-resistant to other PIs.

Baseline Genotype/Phenotype And Virologic Outcome Analyses

Genotypic and/or phenotypic analysis of baseline virus may aid in determining atazanavir susceptibility before initiation of atazanavir with ritonavir therapy. An association between virologic response at 48 weeks and the number and type of primary PI resistance-associated substitutions detected in baseline HIV-1 isolates from antiretroviral-experienced subjects receiving atazanavir with ritonavir once daily or lopinavir / ritonavir (fixed-dose product) twice daily in Study AI424-045 is shown in Table 24.

Overall, both the number and type of baseline PI substitutions affected response rates in treatment-experienced subjects. In the atazanavir with ritonavir group, subjects had lower response rates when 3 or more baseline PI substitutions, including a substitution at position 36, 71, 77, 82, or 90, were present compared to subjects with 1–2 PI substitutions, including one of these substitutions.

Table 24: HIV-1 RNA Response by Number and Type of Baseline PI Substitution, Antiretroviral-Experienced Subjects in Study AI424­045, As-Treated Analysis

The response rates of antiretroviral-experienced subjects in Study AI424-045 were analyzed by baseline phenotype (shift in susceptibility in cell culture relative to reference, Table 25). The analyses are based on a select population with 62% of subjects receiving an NNRTI-based regimen before study entry compared to 35% receiving a PI-based regimen. Additional data are needed to determine clinically relevant break points for REYATAZ.

Table 25: Baseline Phenotype by Outcome, Antiretroviral-Experienced Subjects in Study AI424-045, As-Treated Analysis

Clinical Studies

Adult Subjects Without Prior Antiretroviral Therapy

Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of either REYATAZ or lopinavir/ritonavir, each in combination with fixed-dose tenofovir DF-emtricitabine in treatment-naive subjects with HIV-1infection. Study AI424-138 (NCT00272779) was a 96-week, open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with the fixed-dose product, tenofovir DF/emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive subjects. Subjects had a mean age of 36 years (range: 19-72), 49% were Caucasian, 18% Black, 9% Asian, 23% Hispanic/Mestizo/mixed race, and 68% were male. The median baseline plasma CD4+ cell count was 204 cells/mm³ (range: 2 to 810 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.94 log₁₀ copies/mL (range: 2.60 to 5.88 log₁₀ copies/mL). Treatment response and outcomes through Week 96 are presented in Table 26.

Table 26: Outcomes of Treatment Through Week 96 in Treatment-Naive Adults (Study AI424-138)

Through 96 weeks of therapy, the proportion of responders among subjects with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the REYATAZ with ritonavir (165 of 223 subjects, 74%) and lopinavir/ritonavir (148 of 222 subjects, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm³ for the REYATAZ with ritonavir arm and 273 cells/mm³ for the lopinavir/ritonavir arm.

Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. Study AI424-034 (NCT00013897) was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with the fixed-dose product of lamivudine /zidovudine (150 mg/300 mg) given twice daily, in 810 antiretroviral treatment-naive subjects. Subjects had a mean age of 34 years (range: 18 to 73), 36% were Hispanic, 33% were Caucasian, and 65% were male. The mean baseline CD4+ cell count was 321 cells/mm³ (range: 64 to 1424 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.8 log₁₀ copies/mL (range: 2.2 to 5.9 log₁₀ copies/mL). Treatment response and outcomes through Week 48 are presented in Table 27.

Table 27: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-034)

Through 48 weeks of therapy, the proportion of responders among subjects with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms. The mean increase from baseline in CD4+ cell count was 176 cells/mm³ for the REYATAZ arm and 160 cells/mm³ for the efavirenz arm.

Study AI424-008: REYATAZ 400 mg once daily compared to REYATAZ 600 mg once daily, and compared to nelfinavir 1250 mg twice daily, each in combination with stavudine and lamivudine twice daily. Study AI424-008 (NCT identifier not available) was a 48-week, randomized, multicenter trial, blinded to dose of REYATAZ, comparing REYATAZ at two dose levels (400 mg and 600 mg once daily) to nelfinavir (1250 mg twice daily), each in combination with stavudine (40 mg) and lamivudine (150 mg) given twice daily, in 467 antiretroviral treatment-naive subjects. Subjects had a mean age of 35 years (range: 18 to 69), 55% were Caucasian, and 63% were male.

The mean baseline CD4+ cell count was 295 cells/mm³ (range: 4 to 1003 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.7 log₁₀ copies/mL (range: 1.8 to 5.9 log₁₀ copies/mL). Treatment response and outcomes through Week 48 are presented in Table 28.

Table 28: Outcomes of Randomized Treatment Through Week 48 in Treatment-Naive Adults (Study AI424-008)

Through 48 weeks of therapy, the mean increase from baseline in CD4+ cell count was 234 cells/mm³ for the REYATAZ 400-mg arm and 211 cells/mm³ for the nelfinavir arm.

Adult Subjects With Prior Antiretroviral Therapy

Study AI424-045: REYATAZ once daily with ritonavir once daily compared to REYATAZ once daily and saquinavir (soft gelatin capsules) once daily, and compared to lopinavir/ritonavir twice daily, each in combination with tenofovir DF and one NRTI. Study AI424-045 (NCT00035932): was a randomized, multicenter trial comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to REYATAZ (400 mg once daily) with saquinavir soft gelatin capsules (1200 mg once daily), and to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with tenofovir DF and one NRTI, in 347 (of 358 randomized) subjects who experienced virologic failure on highly active antiretroviral therapy regimens containing PIs, NNRTIs, and NRTIs. The mean time of prior exposure to antiretrovirals was 139 weeks for PIs, 85 weeks for NNRTIs, and 283 weeks for NRTIs. The mean age was 41 years (range: 24 to 74); 60% were Caucasian, and 78% were male. The mean baseline CD4+ cell count was 338 cells/mm³ (range: 14 to 1543 cells/mm³) and the mean baseline plasma HIV-1 RNA level was 4.4 log₁₀ copies/mL (range: 2.6 to 5.88 log₁₀ copies/mL).

Treatment outcomes through Week 48 for the REYATAZ with ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ with ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV-1 RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ with ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV-1 RNA lower limit of quantification [see Microbiology, Tables 24 and 25].

Table 29: Outcomes of Treatment Through Week 48 in Study AI424-045 (Subjects with Prior Antiretroviral Experience)

No subjects in the REYATAZ with ritonavir treatment arm and three subjects in the lopinavir/ritonavir treatment arm experienced a new-onset CDC Category C event during the study.

In Study AI424-045, the mean change from baseline in plasma HIV-1 RNA for REYATAZ 400 mg with saquinavir (n=115) was -1.55 log₁₀ copies/mL, and the time-averaged difference in change in HIV-1 RNA levels versus lopinavir/ritonavir was 0.33. The corresponding mean increase in CD4+ cell count was 72 cells/mm³. Through 48 weeks of treatment, the proportion of subjects in this treatment arm with plasma HIV-1 RNA <400 (<50) copies/mL was 38% (26%). In this study, coadministration of REYATAZ and saquinavir did not provide adequate efficacy [see DRUG INTERACTIONS].

Study AI424-045 also compared changes from baseline in lipid values. [See ADVERSE REACTIONS]

Study AI424-043 (NCT00028301): Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily as fixed-dose product), each in combination with two NRTIs, in 300 subjects who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of subjects with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for subjects randomized to REYATAZ (n=144) and 69% (53%) for subjects randomized to lopinavir/ritonavir (n=146).

The mean change from baseline was -1.59 log₁₀ copies/mL in the REYATAZ treatment arm and -2.02 log₁₀ copies/mL in the lopinavir/ritonavir arm. Based on the results of this study, REYATAZ without ritonavir was inferior to lopinavir/ritonavir in PI-experienced subjects with prior virologic failure and is not recommended for such patients.

Pediatric Subjects

Pediatric Trials With REYATAZ Capsules

Study AI424-040; PACTG 1020A (NCT00006604)

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from this open-label, multicenter clinical trial which included subjects from 6 years to 21 years of age. In this study, 105 subjects (43 antiretroviral-naive and 62 antiretroviral-experienced) received once daily REYATAZ capsule formulation, with or without ritonavir, in combination with two NRTIs.

One-hundred five (105) subjects (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an intent-to-treat (ITT) analysis, the overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced subjects with HIV-1 RNA <50 copies/mL at Week 96 were 47% (20/43) and 24% (15/62), respectively. The median increase from baseline in absolute CD4 count at 96 weeks of therapy was 335 cells/mm³ in antiretroviral-naive subjects and 220 cells/mm³ in antiretroviral-experienced subjects.

Pediatric Trials With REYATAZ Oral Powder

Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ oral powder was based on data from two open-label, multicenter clinical trials.

• AI424-397 (PRINCE I; NCT01099579): In pediatric subjects from 3 months to less than 6 years of age
• AI424-451 (PRINCE II; NCT01335698): In pediatric subjects from 3 months to less than 11 years of age

In these studies 155 subjects (59 antiretroviral-naive and 96 antiretroviral-experienced) received once daily REYATAZ oral powder with ritonavir, in combination with two NRTIs.

For inclusion in both trials, treatment-naive subjects had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced subjects had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Subjects exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Subjects who received REYATAZ or REYATAZ with ritonavir at any time prior to study enrollment or who had a history of treatment failure on two or more protease inhibitors were excluded from the trials.

One hundred thirty-four (134) subjects from both studies weighing 5 kg to less than 35 kg treated with REYATAZ oral powder with ritonavir were evaluated. Subjects 5 kg to less than 10 kg received either 150 mg or 200 mg REYATAZ and 80 mg ritonavir oral solution; subjects 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution; subjects 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution; and subjects 25 kg to less than 35 kg received 300 mg REYATAZ and 100 mg ritonavir.

Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviralexperienced subjects with HIV-1 RNA <400 copies/mL at Week 48 were 79% (41/52) and 62% (51/82), respectively in subjects who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced subjects with HIV-1 RNA <50 copies/mL at Week 48 were 54% (28/52) and 50% (41/82), respectively, in subjects who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy (last observation carried forward) was 215 cells/mm³ (6%) in antiretroviral-naive subjects and 133 cells/mm³ (4%) in antiretroviral-experienced subjects who received REYATAZ oral powder with ritonavir.

PATIENT INFORMATION

REYATAZ®
(RAY-ah-taz) (atazanavir) capsules

REYATAZ®
(RAY-ah-taz) (atazanavir) oral powder

Important: Ask your healthcare provider or pharmacist about medicines that should not be taken with REYATAZ. For more information, see “Do not take REYATAZ if you” and “Before taking REYATAZ”.

What is REYATAZ?

REYATAZ is a prescription medicine that is used to treat human immunodeficiency virus-1 (HIV-1) infection, in combination with other HIV-1 medicines in adults and children 3 months of age and older and who weigh at least 11 pounds (5 kg).

HIV-1 is the virus that causes AIDS (Acquired Immunodeficiency Syndrome).

REYATAZ should not be used in children younger than 3 months of age.

Do not take REYATAZ if you:

• are allergic to atazanavir or any of the ingredients in REYATAZ. See the end of this leaflet for a complete list of ingredients in REYATAZ.
• are taking any of the following medicines. Taking REYATAZ with these medicines may affect how REYATAZ works. REYATAZ may cause serious or life-threatening side effects, or death when used with these medicines:
  • alfuzosin
  • amiodarone (when REYATAZ is used with ritonavir)
  • cisapride
  • elbasvir and grazoprevir
  • ergot medicines including:
    • dihydroergotamine
    • ergonovine
    • ergonovine ergotamine
    • methylergonovine
  • glecaprevir and pibrentasvir
  • indinavir
  • irinotecan
  • lurasidone (when REYATAZ is used with ritonavir)
  • lomitapide
  • lovastatin
  • midazolam, when taken by mouth for sedation
  • nevirapine
  • pimozide
  • quinidine (when REYATAZ is used with ritonavir)
  • rifampin
  • sildenafil, when used for the treatment of pulmonary arterial hypertension
  • simvastatin
  • St. John’s wort
  • triazolam

Before taking REYATAZ, tell your healthcare provider about all of your medical conditions, including if you:

• have heart problems
• have liver problems, including hepatitis B or C virus infection
• have phenylketonuria (PKU). The artificial sweetener aspartame in REYATAZ oral powder contains phenylalanine, which can be harmful to people with PKU.
• have kidney problems
• are receiving dialysis treatment
• have diabetes
• have hemophilia
• are pregnant or plan to become pregnant.
  • REYATAZ must be taken with ritonavir during pregnancy.
  • Hormonal forms of birth control, such as injections, vaginal rings or implants, contraceptive patch, and some birth control pills may not work during treatment with REYATAZ. Talk to your healthcare provider about forms of birth control that may be used during treatment with REYATAZ.
  • Pregnancy Exposure Registry. There is a pregnancy exposure registry for people who take REYATAZ during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
  • After your baby is born, tell your healthcare provider if your baby’s skin or the white part of their eyes turns yellow.
• are breastfeeding or plan to breastfeed. Do not breastfeed if you are taking REYATAZ.
• You should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. REYATAZ can pass into your breast milk.
• Talk to your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Some medicines interact with REYATAZ. Keep a list of your medicines to show your healthcare provider and pharmacist.

• You can ask your healthcare provider or pharmacist for a list of medicines that interact with REYATAZ.
• Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take REYATAZ with other medicines.

How should I take REYATAZ?

• Take REYATAZ exactly as your healthcare provider tells you to.
• Do not change your dose or stop taking REYATAZ unless your healthcare provider tells you to.
• Stay under the care of your healthcare provider during treatment with REYATAZ.
• REYATAZ must be used with other HIV-1 medicines.
• Take REYATAZ 1 time each day.
• REYATAZ comes as capsules and oral powder.
• Take REYATAZ capsules and oral powder with food.
• Swallow the capsules whole. Do not open the capsules.
• REYATAZ oral powder must be mixed with food or liquid. Your child’s healthcare provider will prescribe the right dose of REYATAZ based on your child’s weight. See the detailed “Instructions for Use” that comes with REYATAZ oral powder for information about the correct way to mix and give a dose of REYATAZ oral powder to your child.
• REYATAZ oral powder must be taken with ritonavir.
• If you miss a dose of REYATAZ, take it as soon as you remember. Then take the next dose at your regular time. Do not take 2 doses at the same time.
• If you take too much REYATAZ, call your healthcare provider or go to the nearest hospital emergency room right away.

When your supply of REYATAZ starts to run low, get more from your healthcare provider or pharmacy. It is important not to run out of REYATAZ. The amount of HIV-1 in your blood may increase if the medicine is stopped for even a short time. The virus may become resistant to REYATAZ and harder to treat.

What are the possible side effects of REYATAZ?

REYATAZ can cause serious side effects, including:

• A change in the way your heart beats (heart rhythm change). Tell your healthcare provider right away if you get dizzy or lightheaded. These could be symptoms of a heart problem.
• Skin rash. Skin rash is common with REYATAZ but can sometimes be severe. Severe rash may develop with other symptoms which could be serious. If you develop a severe rash or a rash with any of the following symptoms, stop taking REYATAZ and call your healthcare provider or go to the nearest hospital emergency room right away:
  • general feeling of discomfort or “flu-like” symptoms
  • blisters
  • fever
  • mouth sores
  • muscle or joint aches
  • swelling of your face
  • red or inflamed eyes, like “pink eye” (conjunctivitis)
  • painful, warm, or red lump under your skin
• Liver problems. If you have liver problems, including hepatitis B or C infection, your liver problems may get worse when you take REYATAZ. Your healthcare provider will do blood tests to check your liver before you start REYATAZ and during treatment. Tell your healthcare provider right away if you get any of the following symptoms:
  • dark “tea-colored” urine
  • your skin or the white part of your eyes turns yellow
  • light colored stools
  • nausea
  • itching
  • stomach-area pain
• Chronic kidney disease. REYATAZ may affect how well your kidneys work. Your healthcare provider will do blood and urine tests to check your kidneys before you start REYATAZ and during treatment. Drink plenty of fluids during treatment with REYATAZ.
• Kidney stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of kidney stones which may include pain in your low back or low stomach area, blood in your urine, or pain when you urinate.
• Gallbladder stones have happened in some people who take REYATAZ, and sometimes may lead to hospitalization. Tell your healthcare provider right away if you get symptoms of a gallbladder problem which may include:
  • pain in the right or middle upper stomach area
  • fever
  • nausea and vomiting
  • your skin or the white part of your eyes turns yellow
• Yellowing of your skin or the white part of your eyes is common with REYATAZ but may be a symptom of a serious problem. These symptoms may be due to increases in bilirubin levels in your blood (bilirubin is made by the liver). Tell your healthcare provider right away if your skin or the white part of your eyes turns yellow.
• New or worsening diabetes and high blood sugar (hyperglycemia) have happened in some people who take protease inhibitor medicines like REYATAZ. Some people have had to start taking medicine to treat diabetes or have changes to their dose of their diabetes medicine. Tell your healthcare provider if you notice an increase in thirst or if you start urinating more often while taking REYATAZ.
• Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider if you start having new symptoms after starting REYATAZ.
• Changes in body fat can happen in people taking HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the main part of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these conditions are not known.
• Increased bleeding problems in people with hemophilia have happened when taking protease inhibitors like REYATAZ.

The most common side effects of REYATAZ include:

• nausea
• dizziness
• headache
• muscle pain
• stomach-area pain
• diarrhea
• vomiting
• depression
• trouble sleeping
• fever
• numbness, tingling, or burning of hands or feet

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of REYATAZ. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REYATAZ?

REYATAZ capsules:

• Store REYATAZ capsules at room temperature, between 68°F to 77°F (20°C to 25°C).
• Keep capsules in a tightly closed container.
• The REYATAZ bottle comes with a child-resistant closure.

REYATAZ oral powder:

• Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C).
• Store REYATAZ oral powder in the original packet. Do not open until ready to use.
• After REYATAZ oral powder is mixed with food or liquid it may be kept at a temperature of 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid.

Keep REYATAZ and all medicines out of the reach of children.

General information about the safe and effective use of REYATAZ

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use REYATAZ for a condition for which it was not prescribed. Do not give REYATAZ to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about REYATAZ that is written for health professionals.

For more information, go to www.reyataz.com or call 1-800-321-1335.

What are the ingredients in REYATAZ?

Active ingredient: atazanavir sulfate

Inactive ingredients:

REYATAZ capsules: crospovidone, lactose monohydrate, and magnesium stearate. The capsule shells contain gelatin, FD&C Blue No. 2, titanium dioxide, black iron oxide, red iron oxide, and yellow iron oxide. The capsules are printed with ink containing shellac, titanium dioxide, FD&C Blue No. 2, isopropyl alcohol, ammonium hydroxide, propylene glycol, n-butyl alcohol, simethicone, and dehydrated alcohol.

REYATAZ oral powder: aspartame, sucrose, and orange-vanilla flavor.

Instructions for Use

REYATAZ®
(RAY-ah-taz)
(atazanavir) oral powder

Read this Instructions for Use before you prepare your child’s first dose of REYATAZ oral powder, each time you get a refill, and as needed. There may be new information. This information does not take the place of talking to your child’s healthcare provider about their medical condition or treatment. Ask your child’s healthcare provider or pharmacist if you have questions about how to mix or give a dose of REYATAZ oral powder.

Important information:

• For more information about REYATAZ oral powder, see the Patient Information leaflet.
• REYATAZ oral powder must be mixed with food or liquid. If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder.
• REYATAZ oral powder must be taken with ritonavir.
• Talk with your child’s healthcare provider to help decide the best schedule for giving your child REYATAZ oral powder.

Instructions for mixing REYATAZ oral powder:

REYATAZ oral powder should be mixed with food such as applesauce or yogurt, instead of a liquid (milk, infant formula, or water) in young children and infants who can take food.

• Infants less than 6 months old and who cannot eat solid food or drink from a cup should be given REYATAZ oral powder mixed with infant formula using an oral dosing syringe.
• REYATAZ oral powder that is mixed in infant formula or liquid should not be given using a baby bottle.

When preparing REYATAZ oral powder with either food or liquid, choose a clean, flat work surface. Place a clean paper towel on the work surface. Place the supplies you will need on the paper towel.

Wash and dry your hands before and after preparing REYATAZ oral powder.

Preparing a dose of REYATAZ oral powder mixed with food:

Before you prepare a dose of REYATAZ oral powder mixed with food, gather the following supplies:

• paper towel
• tablespoon
• small clean container (such as a small cup or bowl)
• a food such as applesauce or yogurt
• the correct number of packets of REYATAZ oral powder needed for the prescribed dose
• a clean pair of scissors

Step 1. Place at least 1 tablespoon of a food such as applesauce or yogurt in the small container (see Figure A).

Figure A

Step 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure B).

Figure B

Step 3. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure C).

Figure C

Step 4. Empty the contents of the packet into the small container onto the food (see Figure D).

Figure D

Repeat Steps 2 through 4 for each packet of REYATAZ oral powder needed for the total prescribed dose.

Step 5. Use a tablespoon to gently mix the powder and the food together (see Figure E).

Figure E

Steps 6 through 8 must be completed within 1 hour of mixing the medicine.

Step 6. Use the tablespoon or a small spoon to feed the REYATAZ oral powder and food mixture to your child. Look in your child’s mouth to make sure that all of the mixture is swallowed.

Step 7. Add 1 tablespoon more of food to the empty container and gently stir to mix with any contents that may still be in the container.

Step 8. Use the tablespoon or a small spoon to feed your child the mixture, making sure your child has swallowed all of the mixture.

Step 9. Give your child ritonavir as prescribed right after taking REYATAZ oral powder.

Step 10. Wash the container and tablespoon. Allow the container and spoon to dry. Throw away the paper towel and clean the work surface.

Preparing a dose of REYATAZ oral powder mixed with liquid in a small drinking cup:

Before you prepare a dose of REYATAZ oral powder mixed with liquid in a small drinking cup, gather the following supplies:

• paper towel
• spoon
• 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure F.
• small drinking cup
• liquid such as milk or water
• the correct number of packets of REYATAZ oral powder needed for the prescribed dose
• a clean pair of scissors

Figure F

Step 1. Using the 30 mL medicine cup, pour at least 30 mL of liquid into the small drinking cup (see Figure G).

Figure G

Step 2. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure H).

Figure H

Step 3. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure I).

Figure I

Step 4. Empty the contents of the packet into the small drinking cup (see Figure J).

Figure J

Repeat Steps 2 through 4 for each packet of REYATAZ oral powder needed for the total prescribed dose.

Step 5. Hold the small drinking cup with one hand. With your other hand, use the spoon to gently mix the powder and the liquid (see Figure K).

Figure K

Steps 6 and 7 must be completed within 1 hour of mixing the medicine.

Step 6. Have your child drink all of the mixture in the small drinking cup.

Step 7. To make sure there is no mixture left in the small drinking cup add 15 mL more liquid to the small drinking cup:

• Stir with the spoon.
• Repeat Step 6 above.

If REYATAZ oral powder is mixed with water, your child must eat food right after taking REYATAZ oral powder.

Step 8. Give your child ritonavir as prescribed right after taking REYATAZ oral powder.

Step 9. Wash the small drinking cup, medicine cup, and spoon. Allow the small drinking cup, medicine cup, and spoon to dry. Throw away the paper towel and clean the work surface.

Preparing a dose of REYATAZ oral powder mixed with liquid infant formula using an oral dosing syringe and a small medicine cup:

Before you prepare a dose of REYATAZ oral powder mixed with infant formula using an oral dosing syringe, gather the following supplies:

• paper towel
• small spoon
• 30 milliliter (mL) medicine cup (ask your pharmacist for this). See Figure L.
• 10 mL oral dosing syringe (ask your pharmacist for this). See Figure L.
• infant formula
• the correct number of packets of REYATAZ oral powder needed for the prescribed dose
• a clean pair of scissors

Figure L

Step 1. Prepare the infant formula according to the directions on the infant formula package.

Step 2. Pour 10 mL of infant formula into the medicine cup (see Figure M).

Figure M

Step 3. Tap the packet of REYATAZ oral powder to settle the contents to the bottom of the packet (see Figure N).

Figure N

Step 4. Using a clean pair of scissors, cut open the packet on the dotted line (see Figure O).

Figure O

Step 5. Empty the contents of the packet into the medicine cup (see Figure P).

Figure P

Repeat Steps 3 through 5 for each packet of REYATAZ oral powder needed for the total prescribed dose.

Step 6. Hold the medicine cup with one hand. With your other hand, use the small spoon to gently mix the powder and the infant formula (see Figure Q).

Figure Q

Steps 7 through 9 must be completed within 1 hour of mixing the medicine.

Step 7. Draw up the powder and infant formula mixture into the oral dosing syringe as follows:

Check that the plunger is completely pushed into barrel of the syringe (see Figure R).

Figure R

Place the tip of the syringe into the powder and infant formula mixture in the medicine cup (see Figure S).

Figure S

Slowly pull back on the plunger and draw up 10 mL of the mixture (see Figure T).

Figure T

Step 8. Place the tip of the oral dosing syringe in your baby’s mouth along the inner cheek on either the right or left side (see Figure U). Slowly push on the plunger to give your baby all of the REYATAZ oral powder and infant formula mixture.

Draw up any remaining mixture with the oral dosing syringe and repeat until all of the mixture has been given to the baby.

Figure U

Step 9. To make sure there is no mixture left in the medicine cup or syringe:

• Repeat Step 1 above to add 10 mL more infant formula to the medicine cup.
• Stir with a small spoon.
• Then repeat Steps 7 through 8 above.

To make sure that your baby gets all of the medicine, do not give REYATAZ oral powder in a baby bottle.

Step 10. Give your baby ritonavir as prescribed right after taking REYATAZ oral powder.

Step 11. Remove the plunger from the oral dosing syringe. Wash the medicine cup, spoon, and oral dosing syringe. Allow the medicine cup, spoon, and oral dosing syringe to dry. Throw away the paper towel and clean the work surface.

How should I store REYATAZ oral powder?

• Store REYATAZ oral powder at a temperature of 68°F to 86°F (20°C to 30°C).
• Store REYATAZ oral powder in the original packet. Do not open until ready to use.
• After REYATAZ oral powder is mixed with food or liquid, it may be kept at a temperature of 68°F to 86°F (20°C to 30°C) for up to 1 hour. Take REYATAZ oral powder within 1 hour after mixing with food or liquid.

Keep REYATAZ oral powder and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.