Atazanavir
- Content
- 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. The use of REYATAZ in treatment-experienced adult patients without ritonavir is not recommended.
- 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).
- 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 should not be administered to HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis.
- 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.
- 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).
- 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 10 kg and less than 25 kg. REYATAZ oral powder must be mixed with food or beverage for administration and ritonavir must be given immediately afterwards. Table 3 displays the recommended dosage of REYATAZ oral powder and ritonavir.
- Instructions for Mixing REYATAZ Oral 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.
- Determine the number of packets (4 or 5 packets) that are needed.
- Prior to mixing, tap the packet to settle the powder. 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 room temperature during this one hour period). 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.
- 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.
- 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.
- Cardiac Conduction Abnormalities
- REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some patients. In healthy volunteers and in patients, abnormalities in atrioventricular (AV) conduction were asymptomatic and generally limited to first-degree AV block. There have been reports of second-degree AV block and other conduction abnormalities. In clinical trials that included electrocardiograms, asymptomatic first-degree AV block was observed in 5.9% of atazanavir-treated patients (n=920), 5.2% of lopinavir/ritonavir-treated patients (n=252), 10.4% of nelfinavir-treated patients (n=48), and 3.0% of efavirenz-treated patients (n=329). In Study AI424-045, asymptomatic first-degree AV block was observed in 5% (6/118) of atazanavir/ritonavir-treated patients and 5% (6/116) of lopinavir/ritonavir-treated patients who had on-study electrocardiogram measurements. Because of limited clinical experience in patients with preexisting conduction system disease (eg, marked first-degree AV block or second- or third-degree AV block). ECG monitoring should be considered in these patients.
- Rash
- In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of patients treated with REYATAZ. The median time to onset of rash in clinical studies was 7.3 weeks and the median duration of rash was 1.4 weeks. Rashes were generally mild-to-moderate maculopapular skin eruptions. Treatment-emergent adverse reactions of moderate or severe rash (occurring at a rate of 2%) are presented for the individual clinical studies. Dosing with REYATAZ was often continued without interruption in patients who developed rash. The discontinuation rate for rash in clinical trials was <1%. Cases of Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions, including drug rash with eosinophilia and systemic symptoms (DRESS syndrome), have been reported in patients receiving REYATAZ. REYATAZ should be discontinued if severe rash develops.
- Hyperbilirubinemia
- Most patients taking REYATAZ experience asymptomatic elevations in indirect (unconjugated) bilirubin related to inhibition of UDP-glucuronosyl transferase (UGT). This hyperbilirubinemia is reversible upon discontinuation of REYATAZ. Hepatic transaminase elevations that occur with hyperbilirubinemia should be evaluated for alternative etiologies. No long-term safety data are available for patients experiencing persistent elevations in total bilirubin >5 times the upper limit of normal (ULN). Alternative antiretroviral therapy to REYATAZ may be considered if jaundice or scleral icterus associated with bilirubin elevations presents cosmetic concerns for patients. Dose reduction of atazanavir is not recommended since long-term efficacy of reduced doses has not been established.
- Patients with Phenylketonuria
- Phenylalanine can be harmful to patients with phenylketonuria (PKU). REYATAZ oral powder contains phenylalanine (a component of aspartame). Each packet of REYATAZ oral powder contains 35 mg of phenylalanine. REYATAZ capsules do not contain phenylalanine.
- Hepatotoxicity
- Patients with underlying hepatitis B or C viral infections or marked elevations in transaminases before treatment may be at increased risk for developing further transaminase elevations or hepatic decompensation. In these patients, hepatic laboratory testing should be conducted prior to initiating therapy with REYATAZ and during treatment.
- Nephrolithiasis and Cholelithiasis
- Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in HIV-infected patients receiving REYATAZ therapy. Some patients required hospitalization for additional management and some had complications. Because these events were reported voluntarily during clinical practice, estimates of frequency cannot be made. If signs or symptoms of nephrolithiasis and/or cholelithiasis occur, temporary interruption or discontinuation of therapy may be considered.
- Diabetes Mellitus/Hyperglycemia
- New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in HIV-infected patients receiving protease inhibitor therapy. Some patients required either initiation or dose adjustments of insulin or oral hypoglycemic agents for treatment of these events. In some cases, diabetic ketoacidosis has occurred. In those patients who discontinued protease inhibitor therapy, hyperglycemia persisted in some cases. Because these events have been reported voluntarily during clinical practice, estimates of frequency cannot be made and a causal relationship between protease inhibitor therapy and these events has not been established.
- Immune Reconstitution Syndrome
- Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including REYATAZ. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, or tuberculosis), which may necessitate further evaluation and treatment.
- Autoimmune disorders (such as Graves disease, polymyositis, and Guillain-Barre syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment.
- Fat Redistribution
- Redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and cushingoid appearance have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.
- Hemophilia
- There have been reports of increased bleeding, including spontaneous skin hematomas and hemarthrosis, in patients with hemophilia type A and B treated with protease inhibitors. In some patients additional factor VIII was given. In more than half of the reported cases, treatment with protease inhibitors was continued or reintroduced. A causal relationship between protease inhibitor therapy and these events has not been established.
- Resistance/Cross-Resistance
- Various degrees of cross-resistance among protease inhibitors have been observed. Resistance to atazanavir may not preclude the subsequent use of other protease inhibitors.
- 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.
- 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.
- Laboratory Abnormalities in Treatment-Naive Patients
- 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 34 laboratory abnormalities are presented in Tables 10 and 11, respectively.
- Laboratory Abnormalities in Treatment-Experienced Patients
- The percentages of adult treatment-experienced patients treated with combination therapy including REYATAZ/ritonavir with Grade 34 laboratory abnormalities are presented in Table 12.
- Lipids, Change from Baseline in Treatment-Naive Patients
- For Study AI424-138 and Study AI424-034, changes from baseline in LDL-cholesterol, HDL-cholesterol, total cholesterol, and triglycerides are shown in Tables 13 and 14, respectively.
- Lipids, Change from Baseline in Treatment-Experienced Patients
- 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.
- 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 24 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 34 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 34 laboratory abnormalities occurred with a frequency of less than 3%.
- The data described below reflect exposure to REYATAZ oral powder in 89 subjects weighing from 10 kg to less than 25 kg, including 65 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  and AI424-451 ). Age ranged from 15 months to less than 7.5 years of age. In these studies 53% were female and 47% 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 34 laboratory abnormalities occurring in pediatric patients weighing 10 kg to less than 25 kg taking REYATAZ oral powder were increased amylase (19%), neutropenia (12%), increased SGPT/ALT (5%), elevation of total bilirubin (2.6 times ULN, 12%), increased lipase (5%), and decreased hemoglobin (3%). All other Grade 34 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 efavirenz-treated 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.
- Body as a Whole: edema
- Cardiovascular System: second-degree AV block, third-degree AV block, left bundle branch block, QTc prolongation
- Gastrointestinal System: pancreatitis
- Hepatic System: hepatic function abnormalities
- Hepatobiliary Disorders: cholelithiasis, cholecystitis, cholestasis
- Metabolic System and Nutrition Disorders: diabetes mellitus, hyperglycemia
- Musculoskeletal System: arthralgia
- Renal System: nephrolithiasis, interstitial nephritis
- Skin and Appendages: alopecia, maculopapular rash, pruritus, angioedema
- 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.
- The magnitude of CYP3A-mediated drug interactions on coadministered drug may change when REYATAZ is coadministered 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 REYATAZs 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.
- Established and Other Potentially Significant Drug Interactions
- Table 16 provides dosing recommendations 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.
- Drugs with No Observed or Predicted Interactions with REYATAZ
- 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.
- 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). Additionally, no clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, or atenolol.
- Antiretroviral Pregnancy Registry: To monitor maternal-fetal outcomes of pregnant women exposed to REYATAZ, an Antiretroviral Pregnancy Registry has been established. Physicians are encouraged to register patients by calling 1-800-258-4263.
- Risk Summary
- Atazanavir has been evaluated in a limited number of women during pregnancy and postpartum. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. However, because the studies in humans cannot rule out the possibility of harm, REYATAZ should be used during pregnancy only if clearly needed.
- Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues. Nucleoside analogues are associated with an increased risk of lactic acidosis syndrome.
- Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including pregnant women. All infants, including neonates exposed to REYATAZ in utero, should be monitored for the development of severe hyperbilirubinemia during the first few days of life.
- Clinical Considerations
- Dosing During Pregnancy and the Postpartum Period:
- REYATAZ should not be administered without ritonavir.
- REYATAZ should only be administered to pregnant women with HIV-1 strains susceptible to atazanavir.
- For pregnant patients, no dose adjustment is required for REYATAZ with the following exceptions:
For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
- For treatment-experienced pregnant women during the second or third trimester, when REYATAZ is coadministered with either an H2-receptor antagonist or tenofovir, REYATAZ 400 mg with ritonavir 100 mg once daily is recommended. There are insufficient data to recommend a REYATAZ dose for use with both an H2-receptor antagonist and tenofovir in treatment-experienced pregnant women.
- No dose adjustment is required for postpartum patients. However, patients should be closely monitored for adverse events because atazanavir exposures could be higher during the first 2 months after delivery.
- Human Data
- Clinical Trials: In clinical trial AI424-182, REYATAZ/ritonavir (300/100 mg or 400/100 mg) in combination with zidovudine/lamivudine was administered to 41 HIV-infected pregnant women during the second or third trimester. Among the 39 women who completed the study, 38 women achieved an HIV RNA <50 copies/mL at time of delivery. Six of 20 (30%) women on REYATAZ/ritonavir 300/100 mg and 13 of 21 (62%) women on REYATAZ/ritonavir 400/100 mg experienced hyperbilirubinemia (total bilirubin greater than or equal to 2.6 times ULN). There were no cases of lactic acidosis observed in clinical trial AI424-182.
- Atazanavir drug concentrations in fetal umbilical cord blood were approximately 12% to 19% of maternal concentrations. Among the 40 infants born to 40 HIV-infected pregnant women, all had test results that were negative for HIV-1 DNA at the time of delivery and/or during the first 6 months postpartum. All 40 infants received antiretroviral prophylactic treatment containing zidovudine. No evidence of severe hyperbilirubinemia (total bilirubin levels greater than 20 mg/dL) or acute or chronic bilirubin encephalopathy was observed among neonates in this study. However, 10/36 (28%) infants (6 greater than or equal to 38 weeks gestation and 4 less than 38 weeks gestation) had bilirubin levels of 4 mg/dL or greater within the first day of life.
- Lack of ethnic diversity was a study limitation. In the study population, 33/40 (83%) infants were Black/African American, who have a lower incidence of neonatal hyperbilirubinemia than Caucasians and Asians. In addition, women with Rh incompatibility were excluded, as well as women who had a previous infant who developed hemolytic disease and/or had neonatal pathologic jaundice (requiring phototherapy).
- Additionally, of the 38 infants who had glucose samples collected in the first day of life, 3 had adequately collected serum glucose samples with values of <40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis.
- Antiretroviral Pregnancy Registry Data: As of January 2010, the Antiretroviral Pregnancy Registry (APR) has received prospective reports of 635 exposures to atazanavir-containing regimens (425 exposed in the first trimester and 160 and 50 exposed in second and third trimester, respectively). Birth defects occurred in 9 of 393 (2.3%) live births (first trimester exposure) and 5 of 212 (2.4%) live births (second/third trimester exposure). Among pregnant women in the U.S. reference population, the background rate of birth defects is 2.7%. There was no association between atazanavir and overall birth defects observed in the APR.
- Animal Data
- In animal reproduction studies, there was no evidence of teratogenicity in offspring born to animals at systemic drug exposure levels (AUC) 0.7 (in rabbits) to 1.2 (in rats) times those observed at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). In pre- and postnatal development studies in the rat, atazanavir caused body weight loss or weight gain suppression in the animal offspring with maternal drug exposure (AUC) 1.3 times the human exposure at this clinical dose. However, maternal toxicity also occurred at this exposure level.
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Atazanavir in women who are pregnant.
- The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 10 kg were established in three open-label, multicenter clinical trials: PACTG 1020A, AI424-451, and AI424-397. The safety profile in pediatric patients was generally similar to that observed in adults.

## Signs and Symptoms
- 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 volunteers without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in an HIV-infected patient (73 times the 400mg 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.

## Management
- Treatment of overdosage with REYATAZ should consist of general supportive measures, including monitoring of vital signs and ECG, and observations of the patients 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.

# Chronic Overdose
There is limited information regarding Chronic Overdose of Atazanavir in the drug label.
- The chemical name for atazanavir sulfate is (3S,8S,9S,12S)-3,12-Bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentaazatetradecanedioic acid dimethyl ester, sulfate (1:1). Its molecular formula is C38H52N6O7H2SO4, 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  3C.
- 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.
- Concentration- and dose-dependent prolongation of the PR interval in the electrocardiogram has been observed in healthy volunteers receiving atazanavir. In a 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.
- 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 Fridericias correction). In 1793 HIV-infected patients receiving antiretroviral regimens, QTc prolongation was comparable in the atazanavir and comparator regimens. No atazanavir-treated healthy subject or HIV-infected patient in clinical trials had a QTc interval >500 msec.
- 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 HIV-infected adult patients.
- 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 Patients
- 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 HIV-infected patients 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 volunteers (n=214) and HIV-infected adult patients (n=13) was approximately 7 hours at steady state following a dose of 400 mg daily with a light meal.
- 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 gendermatched 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 HIV-treatment-experienced patients with end stage renal disease managed with hemodialysis.
- 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 volunteers. The mean half-life of atazanavir in hepatically impaired subjects was 12.1 hours compared to 6.4 hours in healthy volunteers. 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.
- Pediatrics
- The pharmacokinetic parameters for atazanavir at steady state in pediatric patients taking the powder formulation are summarized in Table 18 by weight ranges that correspond to the recommended doses.
- The pharmacokinetic parameters for atazanavir at steady state in pediatric patients 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.
- Pregnancy
- The pharmacokinetic data from HIV-infected pregnant women receiving REYATAZ Capsules with ritonavir are presented in Table 20.
- 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 M. Atazanavir is also a direct inhibitor for UGT1A1 (Ki=1.9 M) and CYP2C8 (Ki=2.1 M).
- 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 6-OH cortisol to cortisol versus baseline, indicating that CYP3A production was not induced.
- 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.
- 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. ATV has activity against HIV-1 Group M subtype viruses A, B, C, D, AE, AG, F, G, and J isolates in cell culture. ATV 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 ATV showed no antagonism in cell culture with NNRTIs (delavirdine, efavirenz, and nevirapine), PIs (amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, and saquinavir), NRTIs (abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, zalcitabine, 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 ATV have been selected in cell culture and obtained from patients treated with ATV or atazanavir/ritonavir (ATV/RTV). HIV-1 isolates with 93- to 183-fold reduced susceptibility to ATV from three different viral strains were selected in cell culture by 5 months. The substitutions in these HIV-1 viruses that contributed to ATV 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 ATV and amprenavir, respectively, and did not appear to be cross-resistant.
- Clinical Studies of Treatment-Naive Patients: 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 HIV-infected treatment-naive patients. A summary of the number of virologic failures and virologic failure isolates with ATV resistance in each arm is shown in Table 23.
- Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 300 mg with Ritonavir 100 mg: In Phase III study AI424-138, an as-treated genotypic and phenotypic analysis was conducted on samples from patients who experienced virologic failure (HIV-1 RNA 400 copies/mL) or discontinued before achieving suppression on ATV/RTV (n=39; 9%) and LPV/RTV (n=39; 9%) through 96 weeks of treatment. In the ATV/RTV arm, one of the virologic failure isolates had a 56-fold decrease in ATV 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 ATV/RTV-virologic failure isolates had baseline phenotypic ATV 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 ATV susceptibility from baseline and the other failure isolate with baseline ATV resistance and PI substitutions (M46M/I and I84I/V) had additional IAS-defined major PI substitutions (V32I, M46I, and I84V) emerge on ATV treatment associated with a 3-fold decrease in ATV susceptibility from baseline. Five of the treatment failure isolates in the ATV/RTV 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 LPV/RTV arm, one of the virologic failure patient isolates had a 69-fold decrease in LPV 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 LPV/RTV virologic failure isolates developed the M184V substitution and phenotypic emtricitabine resistance and two developed phenotypic tenofovir disoproxil resistance.
- Clinical Studies of Treatment-Naive Patients Receiving REYATAZ 400 mg without Ritonavir: ATV-resistant clinical isolates from treatment-naive patients who experienced virologic failure on REYATAZ 400 mg treatment without ritonavir often developed an I50L substitution (after an average of 50 weeks of ATV 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 patients, viral isolates that developed the I50L substitution, without other major PI substitutions, showed phenotypic resistance to ATV 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 Patients: In studies of treatment-experienced patients treated with ATV or ATV/RTV, most ATV-resistant isolates from patients 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 patients who failed treatment with ATV 300 mg once daily and RTV 100 mg once daily (together with tenofovir 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 ATV/RTV treatment including E34K/A/Q, G48V, I84V, N88S/D/T, and L90M occurred in less than 10% of patient isolates. Generally, if multiple PI resistance substitutions were present in the HIV-1 virus of the patient at baseline, ATV 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 patients experiencing virologic failure after long-term treatment. Protease cleavage site changes also emerged on ATV treatment but their presence did not correlate with the level of ATV resistance.
- Clinical Studies of Pediatric Subjects in AI424-397 (PRINCE I) and AI424-451(PRINCE II): No treatment-emergent ATV-associated substitutions were detected among treatment failures in AI424-397, but four known resistance-associated substitutions to other PIs arose in the viruses from one subject each (L19I/R, M36M/I, H69K/R, and I72I/V). None of these viruses acquired phenotypic resistance to ATV, ATV/RTV, or any NNRTI or NRTI. In AI424-451, ATV-associated resistance substitution (I84V) and other PI substitutions arose in the virus of one subject, including M46M/V, V82V/I, I84I/V, and L90L/M; however, these substitutions did not result in phenotypic resistance to ATV (ATV phenotypic fold change: 1.74, using a commercial investigational assay with an ATV cutoff of 2.2 fold change). Secondary PI substitutions also arose in the viruses of one subject each, including V11V/I, G16G/E, D30D/G, E35E/D, K45K/R, L63P/S, and I72I/T. Q61D and Q61/E/G emerged in the viruses of two subjects who failed treatment with ATV/RTV. Viruses from three subjects developed M184V in the reverse transcriptase, and all three exhibited phenotypic resistance to emtricitabine and lamivudine.
- Cross-Resistance
- Cross-resistance among PIs has been observed. Baseline phenotypic and genotypic analyses of clinical isolates from ATV clinical trials of PI-experienced patients showed that isolates cross-resistant to multiple PIs were cross-resistant to ATV. Greater than 90% of the isolates with substitutions that included I84V or G48V were resistant to ATV. Greater than 60% of isolates containing L90M, G73S/T/C, A71V/T, I54V, M46I/L, or a change at V82 were resistant to ATV, and 38% of isolates containing a D30N substitution in addition to other changes were resistant to ATV. Isolates resistant to ATV 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 patients, 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 ATV susceptibility before initiation of ATV/RTV 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 patients receiving ATV/RTV once daily or lopinavir (LPV)/RTV 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 patients. In the ATV/RTV group, patients 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 patients with 12 PI substitutions, including one of these substitutions.
- The response rates of antiretroviral-experienced patients 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 patient population with 62% of patients 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.
- Long-term carcinogenicity studies in mice and rats were carried out with atazanavir for two years. In the mouse study, drug-related increases in hepatocellular adenomas were found in females at 360 mg/kg/day. The systemic drug exposure (AUC) at the NOAEL (no observable adverse effect level) in females, (120 mg/kg/day) was 2.8 times and in males (80 mg/kg/day) was 2.9 times higher than those in humans at the clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir, non-pregnant patients). In the rat study, no drug-related increases in tumor incidence were observed at doses up to 1200 mg/kg/day, for which AUCs were 1.1 (males) or 3.9 (females) times those measured in humans at the clinical dose.
- Atazanavir tested positive in an in vitro clastogenicity test using primary human lymphocytes, in the absence and presence of metabolic activation. Atazanavir tested negative in the in vitro Ames reverse-mutation assay, in vivo micronucleus and DNA repair tests in rats, and in vivo DNA damage test in rat duodenum (comet assay).
- At the systemic drug exposure levels (AUC) 0.9 (in male rats) or 2.3 (in female rats) times that of the human clinical dose, (300 mg/day atazanavir boosted with 100 mg/day ritonavir) significant effects on mating, fertility, or early embryonic development were not observed.
- Study AI424-138: a 96-week study comparing the antiviral efficacy and safety of REYATAZ/ritonavir with lopinavir/ritonavir, each in combination with fixed-dose tenofovir-emtricitabine in HIV-1 infected treatment-naive subjects. Study AI424-138 was a 96-week, open-label, randomized, multicenter study, comparing REYATAZ (300 mg once daily) with ritonavir (100 mg once daily) to lopinavir with ritonavir (400/100 mg twice daily), each in combination with fixed-dose tenofovir with emtricitabine (300/200 mg once daily), in 878 antiretroviral treatment-naive treated patients. Patients 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.
- Through 96 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV RNA 100,000 copies/mL) was comparable for the REYATAZ/ritonavir (165 of 223 patients, 74%) and lopinavir/ritonavir (148 of 222 patients, 67%) arms. At 96 weeks, the median increase from baseline in CD4+ cell count was 261 cells/mm3 for the REYATAZ/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 was a randomized, double-blind, multicenter trial comparing REYATAZ (400 mg once daily) to efavirenz (600 mg once daily), each in combination with a fixed-dose combination of lamivudine (3TC) (150 mg) and zidovudine (ZDV) (300 mg) given twice daily, in 810 antiretroviral treatment-naive patients. Patients 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.
- Through 48 weeks of therapy, the proportion of responders among patients with high viral loads (ie, baseline HIV 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 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 patients. Patients 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.
- 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 Patients with Prior Antiretroviral Therapy
- Study AI424-045: REYATAZ once daily + ritonavir once daily compared to REYATAZ once daily + saquinavir (soft gelatin capsules) once daily, and compared to lopinavir + ritonavir twice daily, each in combination with tenofovir + one NRTI. Study AI424-045 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), each in combination with tenofovir and one NRTI, in 347 (of 358 randomized) patients who experienced virologic failure on HAART 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/ritonavir and lopinavir/ritonavir treatment arms are presented in Table 29. REYATAZ/ritonavir and lopinavir/ritonavir were similar for the primary efficacy outcome measure of time-averaged difference in change from baseline in HIV RNA level. Study AI424-045 was not large enough to reach a definitive conclusion that REYATAZ/ritonavir and lopinavir/ritonavir are equivalent on the secondary efficacy outcome measure of proportions below the HIV RNA lower limit of quantification.
- No patients in the REYATAZ/ritonavir treatment arm and three patients 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 patients 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.
- Study AI424-045 also compared changes from baseline in lipid values.
- Study AI424-043: Study AI424-043 was a randomized, open-label, multicenter trial comparing REYATAZ (400 mg once daily) to lopinavir/ritonavir (400/100 mg twice daily), each in combination with two NRTIs, in 300 patients who experienced virologic failure to only one prior PI-containing regimen. Through 48 weeks, the proportion of patients with plasma HIV-1 RNA <400 (<50) copies/mL was 49% (35%) for patients randomized to REYATAZ (n=144) and 69% (53%) for patients 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 patients with prior virologic failure and is not recommended for such patients.
- Pediatric Patients
- Pediatric Trials with REYATAZ Capsules
- Assessment of the pharmacokinetics, safety, tolerability, and virologic response of REYATAZ capsules was based on data from the open-label, multicenter clinical trial PACTG 1020A which included patients from 6 years to 21 years of age. In this study, 105 patients (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) patients (6 to less than 18 years of age) treated with the REYATAZ capsule formulation, with or without ritonavir, were evaluated. Using an ITT analysis, the overall proportions of antiretroviral-naive and -experienced patients with HIV RNA <400 copies/mL at Week 96 were 51% (22/43) and 34% (21/62), respectively. The overall proportions of antiretroviral-naive and -experienced patients with HIV 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 patients and 220 cells/mm3 in antiretroviral-experienced patients.
- 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): In pediatric patients from 3 months to less than 6 years of age
AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age
- AI424-397 (PRINCE I): In pediatric patients from 3 months to less than 6 years of age
- AI424-451 (PRINCE II): In pediatric patients from 3 months to less than 11 years of age
- In these studies 134 patients (73 antiretroviral-naive and 61 antiretroviral-experienced) received once daily REYATAZ oral powder and ritonavir, in combination with two NRTIs.
- For inclusion in both trials, treatment-naive patients had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced patients had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs. Patients exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Patients who received REYATAZ or REYATAZ/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.
- Sixty-five (65) patients from both studies weighing 10 kg to less than 25 kg treated with REYATAZ oral powder with ritonavir were evaluated. Patients 10 kg to less than 15 kg received 200 mg REYATAZ and 80 mg ritonavir oral solution, and patients 15 kg to less than 25 kg received 250 mg REYATAZ and 80 mg ritonavir oral solution. Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <400 copies/mL at Week 48 were 78% (32/41) and 71% (17/24), respectively in patients who received REYATAZ oral powder with ritonavir. The overall proportions of antiretroviral-naive and antiretroviral-experienced patients with HIV RNA <50 copies/mL at Week 48 were 66% (27/41) and 58% (14/24), respectively in patients who received REYATAZ oral powder with ritonavir. The median increase from baseline in absolute CD4 count (percent) at 48 weeks of therapy was 412 cells/mm3 (10.5%) in antiretroviral-naive patients and 228 cells/mm3 (6%) in antiretroviral-experienced patients who received REYATAZ oral powder with ritonavir.
- REYATAZ (atazanavir) capsules are available in the following strengths and configurations of plastic bottles with child-resistant closures.
- Store REYATAZ capsules at 25C (77F); excursions permitted to 15C-30C (59F-86F).
- 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.
- Store REYATAZ oral powder below 30C (86F). Once the REYATAZ oral powder is mixed with food or beverage, it may be kept at room temperature 20C to 30C (68F-86F) for up to 1 hour prior to administration. Store REYATAZ oral powder in the original packet and do not open until ready to use.
- REYATAZ is not a cure for HIV infection and patients may continue to experience illnesses associated with HIV infection, including opportunistic infections. Patients should remain under the care of a healthcare provider when using REYATAZ.
- Patients should be advised to avoid doing things that can spread HIV infection to others.
- Do not share or re-use needles or other injection equipment.
- Do not share personal items that can have blood or body fluids on them, like toothbrushes and razor blades.
- Do not have any kind of sex without protection. Always practice safer sex by using a latex or polyurethane condom to lower the chance of sexual contact with semen, vaginal secretions, or blood.
- Do not breastfeed. It is not known if REYATAZ can be passed to your baby in your breast milk and whether it could harm your baby. Also, mothers with HIV should not breastfeed because HIV can be passed to the baby in breast milk.
- Dosing Instructions
- Patients should be told that sustained decreases in plasma HIV RNA have been associated with a reduced risk of progression to AIDS and death. Patients should remain under the care of a healthcare provider while using REYATAZ. Patients should be advised to take REYATAZ with food every day and take other concomitant antiretroviral therapy as prescribed. REYATAZ must always be used in combination with other antiretroviral drugs. Patients should not alter the dose or discontinue therapy without consulting with their healthcare provider. If a dose of REYATAZ is missed, patients should take the dose as soon as possible and then return to their normal schedule. However, if a dose is skipped the patient should not double the next dose.
- REYATAZ oral powder is available for pediatric patients who are 3 months and older weighing 10 kg to less than 25 kg. Caregivers should be advised on how to mix the REYATAZ oral powder with a food or beverage such as milk or water for infants and young children who can take solid foods or drink liquids from a cup. For infants who cannot take solid food or drink from a cup, the powder formulation mixed in liquid infant formula should be given with an oral dosing syringe. Caregivers should carefully follow the Instructions for Use and storage of the powder.
- Caregivers of patients with phenylketonuria should be advised that REYATAZ oral powder contains phenylalanine.
- Patients or caregivers should call their healthcare provider or pharmacist if they have any questions.
- Drug Interactions
- REYATAZ may interact with some drugs; therefore, patients should be advised to report to their healthcare provider the use of any other prescription, nonprescription medication, or herbal products, particularly St. Johns wort.
- Patients receiving a PDE5 inhibitor and atazanavir should be advised that they may be at an increased risk of PDE5 inhibitor-associated adverse events including hypotension, syncope, visual disturbances, and priapism, and should promptly report any symptoms to their doctor.
- Patients should be informed that REVATIO (used to treat pulmonary arterial hypertension) is contraindicated with REYATAZ and that dose adjustments are necessary when REYATAZ is used with CIALIS, LEVITRA, or VIAGRA (used to treat erectile dysfunction), or ADCIRCA (used to treat pulmonary arterial hypertension).
- Cardiac Conduction Abnormalities
- Patients should be informed that atazanavir may produce changes in the electrocardiogram (eg, PR prolongation). Patients should consult their healthcare provider if they are experiencing symptoms such as dizziness or lightheadedness.
- Rash
- Patients should be informed that mild rashes without other symptoms have been reported with REYATAZ use. These rashes go away within two weeks with no change in treatment. However, there have been reports of severe skin reactions (eg, Stevens-Johnson syndrome, erythema multiforme, and toxic skin eruptions) with REYATAZ use. Patients developing signs or symptoms of severe skin reactions or hypersensitivity reactions (including, but not limited to, severe rash or rash accompanied by one or more of the following: fever, general malaise, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, granulocytopenia, lymphadenopathy, and renal dysfunction) must discontinue REYATAZ and seek medical evaluation immediately.
- Hyperbilirubinemia
- Patients should be informed that asymptomatic elevations in indirect bilirubin have occurred in patients receiving REYATAZ. This may be accompanied by yellowing of the skin or whites of the eyes and alternative antiretroviral therapy may be considered if the patient has cosmetic concerns.
- Nephrolithiasis and Cholelithiasis
- Patients should be informed that kidney stones and/or gallstones have been reported with REYATAZ use. Some patients with kidney stones and/or gallstones required hospitalization for additional management and some had complications. Discontinuation of REYATAZ may be necessary as part of the medical management of these adverse events.
- Fat Redistribution
- Patients should be informed that redistribution or accumulation of body fat may occur in patients receiving antiretroviral therapy including protease inhibitors and that the cause and long-term health effects of these conditions are not known at this time.
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