Reyataz Drug Information
Generic name: ATAZANAVIR
Uses of Reyataz
- 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.
- Use of REYATAZ with ritonavir in treatment-experienced patients should be guided by the number of baseline primary protease inhibitor resistance substitutions. REYATAZ is a protease inhibitor indicated for use 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.
Dosage & Administration of Reyataz
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 H 2 -receptor antagonists or proton-pump inhibitors, dose separation may be required. • REYATAZ capsules without ritonavir are not recommended for treatment-experienced adult or pediatric patients with prior virologic failure. • REYATAZ oral powder must be taken with ritonavir and is not recommended for use in children who weigh less than 5 kg. • 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. Hepatic laboratory testing should be performed in patients with underlying liver disease prior to initiation of REYATAZ and continued during treatment with REYATAZ.
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 H 2 -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).
Table 1: Recommended REYATAZ and Ritonavir Dosage in Adults a,b a See Drug Interactions for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors ), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir.
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 a Administer REYATAZ capsules and ritonavir simultaneously with food. b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir.
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.
See Drug Interactions for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. d Each packet contains 50 mg of REYATAZ. Instructions for Mixing REYATAZ Oral Powder • Determine the number of packets 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. 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).
Table 4: Recommended Dosage of REYATAZ and Ritonavir in Pregnant Patients a a See Drug Interactions for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA.
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 who have 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.
Table 5: Recommended Dosage of REYATAZ Capsules in Treatment-Naive Adults with Hepatic Impairment
| a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or proton pump inhibitors [PPIs]), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For adult patients who cannot swallow the capsules, REYATAZ oral powder is taken once daily with food at the same recommended adult dosage as the capsules along with ritonavir. | ||
| REYATAZ Once Daily Dosage | Ritonavir Once Daily Dosage | |
| Treatment-Naive Adult Patients | ||
| recommended regimen | 300 mg | 100 mg |
| unable to tolerate ritonavir | 400 mg | N/A |
| in combination with efavirenz | 400 mg | 100 mg |
| Treatment-Experienced Adult Patients | ||
| recommended regimen | 300 mg | 100 mg |
| in combination with both H2RA and tenofovir DF | 400 mg | 100 mg |
| a Administer REYATAZ capsules and ritonavir simultaneously with food. b The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). c In treatment-experienced patients, REYATAZ capsules must be administered with ritonavir. | ||
| Body weight | REYATAZ Daily Dosage | Ritonavir Daily Dosage |
| Treatment-Naive and Treatment-Experienced c | ||
| Less than 15 kg | Capsules not recommended | N/A |
| At least 15 kg to less than 35 kg | 200 mg | 100 mg |
| At least 35 kg | 300 mg | 100 mg |
| Treatment-Naive, at least 13 years old and cannot tolerate ritonavir | ||
| At least 40 kg | 400 mg | N/A |
| a The same recommendations regarding the timing and maximum doses of concomitant PPIs and H2RAs in adults also apply to pediatric patients. See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b For pediatric patients at least 25 kg who cannot swallow REYATAZ capsules, 300 mg (6 packets) REYATAZ oral powder is taken once daily with food along with 100 mg ritonavir. c Only patients weighing 5 to less than 10 kg who do not tolerate the 200 mg (4 packets) dose of REYATAZ oral powder and have not previously taken an HIV protease inhibitor, may take 150 mg (3 packets) REYATAZ oral powder with close HIV viral load monitoring. d Each packet contains 50 mg of REYATAZ. | ||
| Body Weight | Daily Dosage of REYATAZ Oral Powder | Daily Dosage of Ritonavir Oral Solution |
| 5 kg to less than 15 kg | 200 mg (4 packets) c,d | 80 mg |
| 15 kg to less than 25 kg | 250 mg (5 packets) d | 80 mg |
| a See Drug Interactions (7) for instructions concerning coadministration of acid-reducing medications (eg, H2RA or PPIs), and other antiretroviral drugs (eg, efavirenz, tenofovir DF, and didanosine). b REYATAZ is not recommended for treatment-experienced pregnant patients during the second and third trimester taking REYATAZ with BOTH tenofovir DF and H2RA. | ||
| REYATAZ Once Daily Dosage | Ritonavir Once Daily Dosage | |
| Treatment-Naive and Treatment-Experienced | ||
| Recommended Regimen | 300 mg | 100 mg |
| Treatment-Experienced During the Second or Third Trimester When Coadministered with either H2RA or Tenofovir DF b | ||
| In combination with EITHER H2RA OR tenofovir DF | 400 mg | 100 mg |
| REYATAZ Once Daily Dosage | |
| Mild hepatic impairment (Child-Pugh Class A) | 400 mg |
| Moderate hepatic impairment (Child-Pugh Class B) | 300 mg |
| Severe hepatic impairment (Child-Pugh Class C) | REYATAZ with or without ritonavir is not recommended |
Side Effects of Reyataz
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. The most common adverse reactions were nausea, jaundice/scleral icterus, and rash. Table 7: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Study AI424- Table 8: Selected Adverse Reactions a of Moderate or Severe Intensity Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, b Studies AI424-034, AI424-007, and AI424-008 Adverse Reactions in Treatment-Experienced Adult Participants The safety profile of REYATAZ in treatment-experienced adults with HIV-1 is based on 119 participants with HIV-1 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 participants receiving REYATAZ with ritonavir are presented in Table 9. Table 10: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Study AI424- Table 11: Grade 3–4 Laboratory Abnormalities Reported in ≥2% of Adult Treatment-Naive Participants with HIV-1, a Studies AI424-034, AI424-007, and AI424-008 in Treatment-Naive Participants with HIV-1 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 Table 13: Lipid Values, Mean Change from Laboratory Abnormalities in Treatment-Experienced Participants with HIV-1 The percentages of adult treatment-experienced participants with HIV-1 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 Participants with HIV-1, Study AI424-045 a in Treatment-Experienced Participants with HIV-1 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 Adverse Reactions in Pediatric Participants with HIV-1: REYATAZ Capsules The safety and tolerability of REYATAZ Capsules with and without ritonavir have been established in pediatric participants with HIV-1, at least 6 years of age from the open-label, multicenter clinical trial PACTG 1020A. The safety profile of REYATAZ in pediatric participants with HIV-1 (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 participants were cough (2 ). Asymptomatic second-degree atrioventricular block was reported in <2% of participants. All other Grade 3–4 laboratory abnormalities occurred with a frequency of less than 3%.
These data are from two pooled, open-label, multi-center clinical trials in treatment-naive and treatment-experienced pediatric participants with HIV-1 (AI424-397 and AI424-451 ). Age ranged from 3 months to 10 years of age. In these studies, 51% were female and 49% were male.
All participants received ritonavir and 2 nucleoside reverse transcriptase inhibitors (NRTIs). The safety profile of REYATAZ in pediatric participants taking REYATAZ oral powder was generally similar to that observed in clinical studies of REYATAZ in pediatric participants taking REYATAZ capsules. Adverse Reactions in Participants with HIV-1 and Hepatitis B and/or Hepatitis C Virus In Study AI424-138, 60 participants administered REYATAZ 300 mg with ritonavir 100 mg once daily, and 51 participants 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.
Within REYATAZ and control regimens, no difference in frequency of bilirubin elevations was noted between seropositive and seronegative participants.
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 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, granulomatous interstitial nephritis, chronic kidney disease Skin and Appendages: alopecia, maculopapular rash, pruritus, angioedema
| None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d Administered as a fixed-dose. e As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. | ||
| 96 weeks c REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine d (n=441) | 96 weeks c lopinavir/ritonavir d 400 mg / 100 mg (twice daily) and tenofovir DF/emtricitabine e (n=437) | |
| Digestive System | ||
| Nausea | 4% | 8% |
| Jaundice/scleral icterus | 5% | |
| Diarrhea | 2% | 12% |
| Skin and Appendages | ||
| Rash | 3% | 2% |
| None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on regimens containing REYATAZ. c Median time on therapy. d Includes long-term follow-up. e As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. | ||||
| Study AI424-034 | Studies AI424-007, -008 | |||
| 64 weeks c REYATAZ 400 mg (once daily) with lamivudine/ zidovudine e (n=404) | 64 weeks c efavirenz 600 mg (once daily) with lamivudine/ zidovudine e (n=401) | 120 weeks c,d REYATAZ 400 mg (once daily) with stavudine and lamivudine or didanosine (n=279) | 73 weeks c,d nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or didanosine (n=191) | |
| Body as a Whole | ||||
| Headache | 6% | 6% | 1% | 2% |
| Digestive System | ||||
| Nausea | 14% | 12% | 6% | 4% |
| Jaundice/scleral icterus | 7% | 7% | ||
| Vomiting | 4% | 7% | 3% | 3% |
| Abdominal pain | 4% | 4% | 4% | 2% |
| Diarrhea | 1% | 2% | 3% | 16% |
| Nervous System | ||||
| Insomnia | 3% | 3% | <1% | |
| Dizziness | 2% | 7% | <1% | |
| Peripheral neurologic symptoms | <1% | 1% | 4% | 3% |
| Skin and Appendages | ||||
| Rash | 7% | 10% | 5% | 1% |
| None reported in this treatment arm. a Includes events of possible, probable, certain, or unknown relationship to treatment regimen. b Based on the regimen containing REYATAZ. c Median time on therapy. d As a fixed-dose product. | ||
| 48 weeks c REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI (n=119) | 48 weeks c lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI (n=118) | |
| Body as a Whole | ||
| Fever | 2% | |
| Digestive System | ||
| Jaundice/scleral icterus | 9% | |
| Diarrhea | 3% | 11% |
| Nausea | 3% | 2% |
| Nervous System | ||
| Depression | 2% | <1% |
| Musculoskeletal System | ||
| Myalgia | 4% | |
| a Based on the regimen containing REYATAZ. b Median time on therapy. c Administered as a fixed-dose product. d As a fixed-dose product: 300 mg tenofovir DF, 200 mg emtricitabine once daily. e ULN=upper limit of normal. | |||
| 96 weeks b REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine c | 96 weeks b lopinavir/ritonavir 400 mg /1 00 mg c (twice daily) and tenofovir DF/emtricitabine d | ||
| Variable | Limit e | (n=441) | (n=437) |
| Chemistry | High | ||
| SGOT/AST | ≥5.1 × ULN | 3% | 1% |
| SGPT/ALT | ≥5.1 × ULN | 3% | 2% |
| Total Bilirubin | ≥2.6 × ULN | 44% | <1% |
| Lipase | ≥2.1 × ULN | 2% | 2% |
| Creatine Kinase | ≥5.1 × ULN | 8% | 7% |
| Total Cholesterol | ≥240 mg/dL | 11% | 25% |
| Hematology | Low | ||
| Neutrophils | <750 cells/mm 3 | 5% | 2% |
| None reported in this treatment arm. a Based on regimen(s) containing REYATAZ. b Median time on therapy. c Includes long-term follow-up. d ULN = upper limit of normal. e As a fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. | |||||
| Study AI424-034 | Studies AI424-007, -008 | ||||
| 64 weeks b REYATAZ 400 mg once daily and lamivudine / zidovudine e | 64 weeks b efavirenz 600 mg once daily and lamivudine / zidovudine e | 120 weeks b,c REYATAZ 400 mg once daily with stavudine and lamivudine or with stavudine and didanosine | 73 weeks b,c nelfinavir 750 mg TID or 1250 mg BID with stavudine and lamivudine or with stavudine and didanosine | ||
| Variable | Limit d | (n=404) | (n=401) | (n=279) | (n=191) |
| Chemistry | High | ||||
| SGOT/AST | ≥5.1 × ULN | 2% | 2% | 7% | 5% |
| SGPT/ALT | ≥5.1 × ULN | 4% | 3% | 9% | 7% |
| Total Bilirubin | ≥2.6 × ULN | 35% | <1% | 47% | 3% |
| Amylase | ≥2.1 × ULN | 14% | 10% | ||
| Lipase | ≥2.1 × ULN | <1% | 1% | 4% | 5% |
| Creatine Kinase | ≥5.1 × ULN | 6% | 6% | 11% | 9% |
| Total Cholesterol | ≥240 mg/dL | 6% | 24% | 19% | 48% |
| Triglycerides | ≥751 mg/dL | <1% | 3% | 4% | 2% |
| Hematology | Low | ||||
| Hemoglobin | <8.0 g/dL | 5% | 3% | <1% | 4% |
| Neutrophils | <750 cells/mm 3 | 7% | 9% | 3% | 7% |
| a REYATAZ 300 mg with ritonavir 100 mg once daily with the fixed-dose product: 300 mg tenofovir DF/ 200 mg emtricitabine once daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 1% in the lopinavir/ritonavir treatment arm and 1% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 8% in the lopinavir/ritonavir treatment arm and 2% in the REYATAZ with ritonavir arm. Through Week 96, serum lipid-reducing agents were used in 10% in the lopinavir/ritonavir treatment arm and 3% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400 mg/100 mg) twice daily with the fixed-dose product 300 mg tenofovir DF/200 mg emtricitabine once daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 or Week 96 values and is not a simple difference of the baseline and Week 48 or Week 96 mean values, respectively. e Number of participants with LDL-cholesterol measured. f Fasting. | ||||||||||
| REYATAZ with ritonavir a,b | lopinavir/ritonavir b,c | |||||||||
| Baseline | Week 48 | Week 96 | Baseline | Week 48 | Week 96 | |||||
| mg/dL | mg/dL | Change d | mg/dL | Change d | mg/dL | mg/dL | Change d | mg/dL | Change d | |
| (n=428 e ) | (n=372 e ) | (n=372 e ) | (n=342 e ) | (n=342 e ) | (n=424 e ) | (n=335 e ) | (n=335 e ) | (n=291 e ) | (n=291 e ) | |
| LDL-Cholesterol f | 92 | 105 | +14% | 105 | +14% | 93 | 111 | +19% | 110 | +17% |
| HDL-Cholesterol f | 37 | 46 | +29% | 44 | +21% | 36 | 48 | +37% | 46 | +29% |
| Total Cholesterol f | 149 | 169 | +13% | 169 | +13% | 150 | 187 | +25% | 186 | +25% |
| Triglycerides f | 126 | 145 | +15% | 140 | +13% | 129 | 194 | +52% | 184 | +50% |
| a REYATAZ 400 mg once daily with the fixed-dose product: 150 mg lamivudine, 300 mg zidovudine twice daily. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 0% in the efavirenz treatment arm and <1% in the REYATAZ arm. Through Week 48, serum lipid-reducing agents were used in 3% in the efavirenz treatment arm and 1% in the REYATAZ arm. c Efavirenz 600 mg once daily with the fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. | ||||||
| REYATAZ a,b | efavirenz b,c | |||||
| Baseline mg/dL (n=383 e ) | Week 48 mg/dL (n=283 e ) | Week 48 Change d (n=272 e ) | Baseline mg/dL (n=378 e ) | Week 48 mg/dL (n=264 e ) | Week 48 Change d (n=253 e ) | |
| LDL-Cholesterol f | 98 | 98 | +1% | 98 | 114 | +18% |
| HDL-Cholesterol | 39 | 43 | +13% | 38 | 46 | +24% |
| Total Cholesterol | 164 | 168 | +2% | 162 | 195 | +21% |
| Triglycerides f | 138 | 124 | −9% | 129 | 168 | +23% |
| a Based on regimen(s) containing REYATAZ. b Median time on therapy. c ULN = upper limit of normal. d As a fixed-dose product. | |||
| 48 weeks b | 48 weeks b | ||
| REYATAZ with ritonavir 300/100 mg (once daily) and tenofovir DF and NRTI | lopinavir/ritonavir 400/100 mg (twice daily d ) and tenofovir DF and NRTI | ||
| Variable | Limit c | (n=119) | (n=118) |
| Chemistry | High | ||
| SGOT/AST | ≥5.1 × ULN | 3% | 3% |
| SGPT/ALT | ≥5.1 × ULN | 4% | 3% |
| Total Bilirubin | ≥2.6 × ULN | 49% | <1% |
| Lipase | ≥2.1 × ULN | 5% | 6% |
| Creatine Kinase | ≥5.1 × ULN | 8% | 8% |
| Total Cholesterol | ≥240 mg/dL | 25% | 26% |
| Triglycerides | ≥751 mg/dL | 8% | 12% |
| Glucose | ≥251 mg/dL | 5% | <1% |
| Hematology | Low | ||
| Platelets | <50,000 cells/mm 3 | 2% | 3% |
| Neutrophils | <750 cells/mm 3 | 7% | 8% |
| a REYATAZ 300 mg once daily with ritonavir and tenofovir DF, and 1 NRTI. b Values obtained after initiation of serum lipid-reducing agents were not included in these analyses. At baseline, serum lipid-reducing agents were used in 4% in the lopinavir/ritonavir treatment arm and 4% in the REYATAZ with ritonavir arm. Through Week 48, serum lipid-reducing agents were used in 19% in the lopinavir/ritonavir treatment arm and 8% in the REYATAZ with ritonavir arm. c Lopinavir/ritonavir (400/100 mg), as a fixed dose regimen, BID with tenofovir DF and 1 NRTI. d The change from baseline is the mean of within-participant changes from baseline for participants with both baseline and Week 48 values and is not a simple difference of the baseline and Week 48 mean values. e Number of participants with LDL-cholesterol measured. f Fasting. | ||||||
| REYATAZ with ritonavir a,b | Lopinavir/ritonavir b,c | |||||
| Baseline mg/dL (n=111 e ) | Week 48 mg/dL (n=75 e ) | Week 48 Change d (n=74 e ) | Baseline mg/dL (n=108 e ) | Week 48 mg/dL (n=76 e ) | Week 48 Change d (n=73 e ) | |
| LDL-Cholesterol f | 108 | 98 | −10% | 104 | 103 | +1% |
| HDL-Cholesterol | 40 | 39 | −7% | 39 | 41 | +2% |
| Total Cholesterol | 188 | 170 | −8% | 181 | 187 | +6% |
| Triglycerides f | 215 | 161 | −4% | 196 | 224 | +30% |
Warnings & Cautions for Reyataz
Cardiac Conduction Abnormalities REYATAZ has been shown to prolong the PR interval of the electrocardiogram in some study participants. In healthy participants and in participants with HIV-1 treated with atazanavir, 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 participants (n=920), 5.2% of lopinavir/ritonavir-treated participants (n=252), 10.4% of nelfinavir-treated participants (n=48), and 3.0% of efavirenz-treated participants (n=329). Because of limited clinical experience in those 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.
Severe Skin Reactions
In controlled clinical trials, rash (all grades, regardless of causality) occurred in approximately 20% of participants with HIV-1 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, eosinophilia, and systemic symptoms (DRESS) syndrome, have been reported in patients receiving REYATAZ. REYATAZ should be discontinued if severe rash develops.
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 virus 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.
Chronic Kidney Disease
Chronic kidney disease in patients with HIV-1 treated with atazanavir, with or without ritonavir, has been reported during postmarketing surveillance. Reports included biopsy-proven cases of granulomatous interstitial nephritis associated with the deposition of atazanavir drug crystals in the renal parenchyma. Consider alternatives to REYATAZ in patients at high risk for renal disease or with preexisting renal disease.
Renal laboratory testing (including serum creatinine, estimated creatinine clearance, and urinalysis with microscopic examination) should be conducted in all patients prior to initiating therapy with REYATAZ and continued during treatment with REYATAZ. Expert consultation is advised for patients who have confirmed renal laboratory abnormalities while taking REYATAZ. In patients with progressive kidney disease, discontinuation of REYATAZ may be considered.
Nephrolithiasis and Cholelithiasis Cases of nephrolithiasis and/or cholelithiasis have been reported during postmarketing surveillance in patients with HIV-1 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.
Risk of Serious Adverse Reactions Due to Drug Interactions Initiation of REYATAZ with ritonavir, a CYP3A inhibitor, in patients receiving medications metabolized by CYP3A or initiation of medications metabolized by CYP3A in patients already receiving REYATAZ with ritonavir, may increase plasma concentrations of medications metabolized by CYP3A. Initiation of medications that inhibit or induce CYP3A may increase or decrease concentrations of REYATAZ with ritonavir, respectively. These interactions may lead to: • clinically significant adverse reactions potentially leading to severe, life-threatening, or fatal events from greater exposures of concomitant medications. • clinically significant adverse reactions from greater exposures of REYATAZ with ritonavir. • loss of therapeutic effect (virologic response) of REYATAZ with ritonavir and possible development of resistance.
See Table 16 for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy containing REYATAZ with ritonavir; and monitor for the adverse reactions associated with concomitant medications.
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.
Diabetes Mellitus/Hyperglycemia
New-onset diabetes mellitus, exacerbation of preexisting diabetes mellitus, and hyperglycemia have been reported during postmarketing surveillance in patients with HIV-1 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.
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, cytomegalovirus, Pneumocystis jirovecii pneumonia, or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) 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.
Drug Interactions with Reyataz
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. 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 ( see Table 16 ). Atazanavir solubility decreases as pH increases. Reduced plasma concentrations of atazanavir are expected if proton-pump inhibitors, antacids, buffered medications, or H 2 -receptor antagonists are administered with REYATAZ.
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) Concomitant Drug Class: Specific Drugs Effect on Concentration of Atazanavir or Concomitant Drug Clinical Comment a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22. b See Contraindications, Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily.
For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration. is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions. Protease Inhibitors: saquinavir (soft gelatin capsules) ↑ saquinavir Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy. indinavir Coadministration of REYATAZ with indinavir is contraindicated.
Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia. Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations. glecaprevir/pibrentasvir ↑ glecaprevir ↑ pibrentasvir Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations. Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension. and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias.
Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance. phenytoin, phenobarbital ↓ atazanavir ↓ phenytoin ↓ phenobarbital Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities. apalutamide ↓ atazanavir Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression.
This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues. GI Motility Agents: cisapride ↑ cisapride Coadministration of REYATAZ with cisapride is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance.
This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis. atorvastatin, rosuvastatin ↑ atorvastatin ↑ rosuvastatin Titrate atorvastatin dose carefully and use the lowest necessary dose. Other Lipid Modifying Agents: lomitapide ↑ lomitapide Coadministration of REYATAZ with lomitapide is contraindicated. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or With concomitant use of fluticasone propionate and REYATAZ with ritonavir systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate.
Coadministration of fluticasone propionate and REYATAZ with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO ® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated. Proton-pump inhibitors: omeprazole ↓ atazanavir Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance.
In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended.
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.
| Concomitant Drug Class: Specific Drugs | Effect on Concentration of Atazanavir or Concomitant Drug | Clinical Comment |
|---|---|---|
| a For magnitude of interactions see Clinical Pharmacology, Tables 21 and 22 (12.3). b See Contraindications (4), Table 6 for orally administered midazolam. c In combination with atazanavir 300 mg with ritonavir 100 mg once daily. d In combination with atazanavir 400 mg once daily. | ||
| HIV Antiviral Agents | ||
| Nucleoside Reverse Transcriptase Inhibitors (NRTIs): didanosine buffered formulations enteric coated (EC) capsules | ↓ atazanavir ↓ didanosine | It is recommended that REYATAZ be given (with food) 2 h before or 1 h after didanosine buffered formulations. Simultaneous administration of didanosine EC and REYATAZ with food results in a decrease in didanosine exposure. Thus, REYATAZ and didanosine EC should be administered at different times. |
| Nucleotide Reverse Transcriptase Inhibitors: tenofovir disoproxil fumarate (DF) | ↓ atazanavir ↑ tenofovir | When coadministered with tenofovir DF in adults, it is recommended that REYATAZ 300 mg be given with ritonavir 100 mg and tenofovir DF 300 mg (all as a single daily dose with food). The mechanism of this interaction is unknown. Higher tenofovir concentrations could potentiate tenofovir-associated adverse reactions, including renal disorders. Patients receiving REYATAZ and tenofovir DF should be monitored for tenofovir-associated adverse reactions. For pregnant patients taking REYATAZ with ritonavir and tenofovir DF, see Dosage and Administration (2.6). |
| Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs): efavirenz | ↓ atazanavir | In HIV-treatment-naive adult patients: If REYATAZ is combined with efavirenz, REYATAZ 400 mg (two 200-mg capsules) should be administered with ritonavir 100 mg simultaneously once daily with food, and efavirenz 600 mg should be administered once daily on an empty stomach, preferably at bedtime. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with efavirenz is not recommended. |
| nevirapine | ↓ atazanavir ↑ nevirapine | Coadministration of REYATAZ with nevirapine is contraindicated due to the potential loss of virologic response and development of resistance, as well as the potential risk for nevirapine-associated adverse reactions [see Contraindications (4) ]. |
| Protease Inhibitors: saquinavir (soft gelatin capsules) | ↑ saquinavir | Appropriate dosing recommendations for this combination, with or without ritonavir, with respect to efficacy and safety have not been established. In a clinical study, saquinavir 1200 mg coadministered with REYATAZ 400 mg and tenofovir DF 300 mg (all given once daily), and nucleoside analogue reverse transcriptase inhibitors did not provide adequate efficacy [see Clinical Studies (14.2) ]. |
| indinavir | Coadministration of REYATAZ with indinavir is contraindicated. Both REYATAZ and indinavir are associated with indirect (unconjugated) hyperbilirubinemia [see Contraindications (4) ]. | |
| ritonavir | ↑ atazanavir | If REYATAZ is coadministered with ritonavir, it is recommended that REYATAZ 300 mg once daily be given with ritonavir 100 mg once daily with food in adults. See the complete prescribing information for ritonavir for information on drug interactions with ritonavir. |
| Others | ↑ other protease inhibitor | Coadministration with other protease inhibitors is not recommended. |
| Hepatitis C Antiviral Agents | ||
| elbasvir/grazoprevir | ↑ grazoprevir | Coadministration of REYATAZ with grazoprevir is contraindicated due to the potential for increased risk of ALT elevations [see Contraindications (4) ]. |
| glecaprevir/pibrentasvir | ↑ glecaprevir ↑ pibrentasvir | Coadministration of REYATAZ with glecaprevir/pibrentasvir is contraindicated due to the potential for increased the risk of ALT elevations [see Contraindications (4) ]. |
| voxilaprevir/sofosbuvir/velpatasvir | ↑ voxilaprevir | Coadministration with REYATAZ is not recommended. |
| Other Agents | ||
| Alpha 1-Adrenoreceptor Antagonist: alfuzosin | ↑ alfuzosin | Coadministration of REYATAZ with alfuzosin is contraindicated due to risk for hypotension [see Contraindications (4) ]. |
| Antacids and buffered medications: | ↓ atazanavir | REYATAZ should be administered 2 hours before or 1 hour after antacids and buffered medications. |
| Antiarrhythmics: amiodarone, quinidine amiodarone, bepridil, lidocaine (systemic), quinidine | ↑ amiodarone, bepridil, lidocaine (systemic), quinidine | Concomitant use of REYATAZ with ritonavir and either quinidine or amiodarone is contraindicated due to the potential for serious or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. Coadministration with REYATAZ without ritonavir has the potential to produce serious and/or life-threatening adverse events but has not been studied. Caution is warranted and therapeutic concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ without ritonavir. |
| Anticoagulants: warfarin | ↑ warfarin | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening bleeding and has not been studied. It is recommended that International Normalized Ratio (INR) be monitored. |
| Direct-Acting Oral Anticoagulants: betrixaban, dabigatran, edoxaban | ↑ betrixaban ↑ dabigatran ↑ edoxaban | Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to the respective DOAC prescribing information regarding dosing instructions for coadministration with P-gp inhibitors. |
| rivaroxaban | REYATAZ with ritonavir ↑ rivaroxaban | Coadministration of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, and rivaroxaban is not recommended, as it may result in an increased risk of bleeding. |
| REYATAZ ↑ rivaroxaban | Coadministration of REYATAZ, a CYP3A4 inhibitor, and rivaroxaban may result in an increased risk of bleeding. Close monitoring is recommended when REYATAZ is coadministered with rivaroxaban. | |
| apixaban | REYATAZ with ritonavir ↑ apixaban | Concomitant use of REYATAZ with ritonavir, a strong CYP3A4/P-gp inhibitor, may result in an increased risk of bleeding. Refer to apixaban dosing instructions for coadministration with strong CYP3A4 and P-gp inhibitors in the apixaban prescribing information. |
| REYATAZ ↑ apixaban | Concomitant use of REYATAZ, a CYP3A4 inhibitor, and apixaban may result in an increased risk of bleeding. Close monitoring is recommended when apixaban is coadministered with REYATAZ. | |
| Antidepressants: tricyclic antidepressants | ↑ tricyclic antidepressants | Coadministration with REYATAZ has the potential to produce serious and/or life-threatening adverse events and has not been studied. Concentration monitoring of these drugs is recommended if they are used concomitantly with REYATAZ. |
| trazodone | ↑ trazodone | Nausea, dizziness, hypotension, and syncope have been observed following coadministration of trazodone with ritonavir. If trazodone is used with a CYP3A4 inhibitor such as REYATAZ, the combination should be used with caution and a lower dose of trazodone should be considered. |
| Antiepileptics: carbamazepine | ↓ atazanavir ↑ carbamazepine | Coadministration of REYATAZ (with or without ritonavir) with carbamazepine is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. |
| phenytoin, phenobarbital | ↓ atazanavir ↓ phenytoin ↓ phenobarbital | Coadministration of REYATAZ (with or without ritonavir) with phenytoin or phenobarbital is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. |
| lamotrigine | ↓ lamotrigine | Coadministration of lamotrigine and REYATAZ with ritonavir may require dosage adjustment of lamotrigine. No dose adjustment of lamotrigine is required when coadministered with REYATAZ without ritonavir. |
| Antifungals: ketoconazole, itraconazole | REYATAZ with ritonavir: ↑ ketoconazole ↑ itraconazole | Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C max ). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir. |
| voriconazole | REYATAZ with ritonavir in participants with a functional CYP2C19 allele: ↓ voriconazole ↓ atazanavir REYATAZ with ritonavir in participants without a functional CYP2C19 allele: ↑ voriconazole ↓ atazanavir | The use of voriconazole in patients receiving REYATAZ with ritonavir is not recommended unless an assessment of the benefit/risk to the patient justifies the use of voriconazole. Patients should be carefully monitored for voriconazole-associated adverse reactions and loss of either voriconazole or atazanavir efficacy during the coadministration of voriconazole and REYATAZ with ritonavir. Coadministration of voriconazole with REYATAZ (without ritonavir) may affect atazanavir concentrations; however, no data are available. |
| Antigout: colchicine | ↑ colchicine | The coadministration of REYATAZ with colchicine in patients with renal or hepatic impairment is not recommended. Recommended adult dosage of colchicine when administered with REYATAZ: Treatment of gout flares: 0.6 mg (1 tablet) for 1 dose, followed by 0.3 mg (half tablet) 1 hour later. Not to be repeated before 3 days. Prophylaxis of gout flares: If the original regimen was 0.6 mg twice a day, the regimen should be adjusted to 0.3 mg once a day. If the original regimen was 0.6 mg once a day, the regimen should be adjusted to 0.3 mg once every other day. Treatment of familial Mediterranean fever (FMF): Maximum daily dose of 0.6 mg (may be given as 0.3 mg twice a day). |
| Antimycobacterials: rifampin | ↓ atazanavir | Coadministration of REYATAZ with rifampin is contraindicated due to the risk for loss of virologic response and development of resistance [see Contraindications (4) ]. |
| rifabutin | ↑ rifabutin | A rifabutin dose reduction of up to 75% (eg, 150 mg every other day or 3 times per week) is recommended. Increased monitoring for rifabutin-associated adverse reactions including neutropenia is warranted. |
| Antineoplastics: irinotecan | ↑ irinotecan | Coadministration of REYATAZ with irinotecan is contraindicated. Atazanavir inhibits UGT1A1 and may interfere with the metabolism of irinotecan, resulting in increased irinotecan toxicities [see Contraindications (4) ]. |
| apalutamide | ↓ atazanavir | Coadministration of REYATAZ (with or without ritonavir) and apalutamide is contraindicated due to the potential for subsequent loss of virologic response and possible resistance to the class of protease inhibitors [see Contraindications (4) ]. |
| ivosidenib | ↓ atazanavir ↑ ivosidenib | Coadministration of ivosidenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for loss of virologic response and risk of serious adverse events such as QT interval prolongation. |
| encorafenib | ↓ atazanavir ↑ encorafenib | Coadministration of encorafenib with REYATAZ (with or without ritonavir) is contraindicated due to the potential for the loss of virologic response and risk of serious adverse events such as QT interval prolongation. |
| Antiplatelets: | ||
| ticagrelor | ↑ ticagrelor | Coadministration with ticagrelor is not recommended due to potential increase in the risk of dyspnea, bleeding and other adverse events associated with ticagrelor. |
| clopidogrel | ↓ clopidogrel active metabolite | Coadministration of REYATAZ (with or without ritonavir) and clopidogrel is not recommended. This is due to the potential reduction of the antiplatelet activity of clopidogrel. |
| Antipsychotics: pimozide | ↑ pimozide | Coadministration of REYATAZ with pimozide is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. |
| lurasidone | REYATAZ with ritonavir ↑ lurasidone | REYATAZ with ritonavir Coadministration of lurasidone with REYATAZ with ritonavir is contraindicated. This is due to the potential for serious and/or life-threatening reactions [see Contraindications (4) ]. |
| REYATAZ ↑ lurasidone | REYATAZ without ritonavir If coadministration is necessary, reduce the lurasidone dose. Refer to the lurasidone prescribing information for concomitant use with moderate CYP3A4 inhibitors. | |
| quetiapine | ↑ quetiapine | Initiation of REYATAZ with ritonavir in patients taking quetiapine: Consider alternative antiretroviral therapy to avoid increases in quetiapine exposures. If coadministration is necessary, reduce the quetiapine dose to 1/6 of the current dose and monitor for quetiapine-associated adverse reactions. Refer to the quetiapine prescribing information for recommendations on adverse reaction monitoring. Initiation of quetiapine in patients taking REYATAZ with ritonavir: Refer to the quetiapine prescribing information for initial dosing and titration of quetiapine. |
| Benzodiazepines: midazolam (oral) triazolam | ↑ midazolam ↑ triazolam | Coadministration of REYATAZ with either orally administered midazolam or triazolam is contraindicated. Triazolam and orally administered midazolam are extensively metabolized by CYP3A4, and coadministration with REYATAZ can lead to the potential for serious and/or life-threatening events such as prolonged or increased sedation or respiratory depression [see Contraindications (4) ]. |
| parenterally administered midazolam b | ↑ midazolam | Coadministration with parenteral midazolam should be done in a setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Dosage reduction for midazolam should be considered, especially if more than a single dose of midazolam is administered. |
| Calcium channel blockers: diltiazem | ↑ diltiazem and desacetyl-diltiazem | Caution is warranted. A dose reduction of diltiazem by 50% should be considered. ECG monitoring is recommended. Coadministration of diltiazem and REYATAZ with ritonavir has not been studied. |
| felodipine, nifedipine, nicardipine, and verapamil | ↑ calcium channel blocker | Caution is warranted. Dose titration of the calcium channel blocker should be considered. ECG monitoring is recommended. |
| Corticosteroids: dexamethasone and other corticosteroids (all routes of administration) | ↓ atazanavir ↑ corticosteroids | Coadministration with dexamethasone or other corticosteroids that induce CYP3A may result in loss of therapeutic effect of REYATAZ and development of resistance to atazanavir and/or ritonavir. Alternative corticosteroids should be considered. Coadministration with corticosteroids (all routes of administration) that are metabolized by CYP3A, particularly for long-term use, may increase the risk for development of systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression. Consider the potential benefit of treatment versus the risk of systemic corticosteroid effects. For coadministration of cutaneously administered corticosteroids sensitive to CYP3A inhibition, refer to the prescribing information of the corticosteroid for additional information. |
| Endothelin receptor antagonists: bosentan | REYATAZ ↓ atazanavir REYATAZ with ritonavir ↑ bosentan | Coadministration of bosentan and REYATAZ without ritonavir is not recommended. For adult patients who have been receiving REYATAZ with ritonavir for at least 10 days, start bosentan at 62.5 mg once daily or every other day based on individual tolerability. For adult patients who have been receiving bosentan, discontinue bosentan at least 36 hours before starting REYATAZ with ritonavir. At least 10 days after starting REYATAZ with ritonavir, resume bosentan at 62.5 mg once daily or every other day based on individual tolerability. |
| Ergot derivatives: dihydroergotamine, ergotamine, ergonovine, methylergonovine | ↑ ergot derivatives | Coadministration of REYATAZ with ergot derivatives is contraindicated. This is due to the potential for serious and/or life-threatening events such as acute ergot toxicity characterized by peripheral vasospasm and ischemia of the extremities and other tissues [see Contraindications (4) ]. |
| GI Motility Agents: cisapride | ↑ cisapride | Coadministration of REYATAZ with cisapride is contraindicated. This is due to the potential for serious and/or life-threatening reactions such as cardiac arrhythmias [see Contraindications (4) ]. |
| Gonadotropin-releasing hormone Receptor (GnRH) Antagonists: elagolix | ↓ atazanavir ↑ elagolix | Coadministration of elagolix and REYATAZ with or without ritonavir is not recommended due to the potential of loss of virologic response and the potential risk of adverse events such as bone loss and hepatic transaminase elevations associated with elagolix. In the event coadministration is necessary, limit concomitant use of elagolix 200mg twice daily with REYATAZ with or without ritonavir for up to 1 month or limit concomitant use of elagolix 150 mg once daily with REYATAZ (with or without ritonavir) for up to 6 months and monitor virologic response. |
| Herbal Products: St. John’s wort (Hypericum perforatum) | ↓ atazanavir | Coadministration of products containing St. John’s wort with REYATAZ is contraindicated. This may result in loss of therapeutic effect of REYATAZ and the development of resistance [see Contraindications (4) ]. |
| Kinase inhibitors: fostamatinib | ↑ R406 (active metabolite of fostamatinib) | When coadministering fostamatinib with REYATAZ (with or without ritonavir), monitor for toxicities of R406 exposure resulting in dose-related adverse events such as hepatotoxicity and neutropenia. Fostamatinib dose reduction may be required. |
| Lipid-modifying agents HMG-CoA reductase inhibitors: lovastatin, simvastatin | ↑ lovastatin ↑ simvastatin | Coadministration of REYATAZ with lovastatin or simvastatin is contraindicated. This is due to the potential for serious reactions such as myopathy, including rhabdomyolysis [see Contraindications (4) ]. |
| atorvastatin, rosuvastatin | ↑ atorvastatin ↑ rosuvastatin | Titrate atorvastatin dose carefully and use the lowest necessary dose. Rosuvastatin dose should not exceed 10 mg/day. The risk of myopathy, including rhabdomyolysis, may be increased when HIV protease inhibitors, including REYATAZ, are used in combination with these drugs. |
| Other Lipid Modifying Agents: lomitapide | ↑ lomitapide | Coadministration of REYATAZ with lomitapide is contraindicated. This is due to the potential for risk of markedly increased transaminase levels and hepatotoxicity associated with increased plasma concentrations of lomitapide. The mechanism of interaction is CYP3A4 inhibition by atazanavir and/or ritonavir [see Contraindications (4) ]. |
| H 2 - Receptor antagonists | ↓ atazanavir | Coadministration may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: REYATAZ 300 mg with ritonavir 100 mg once daily with food should be administered simultaneously with, and/or at least 10 hours after, a dose of the H 2 -receptor antagonist (H2RA). An H2RA dose comparable to famotidine 20 mg once daily up to a dose comparable to famotidine 40 mg twice daily can be used with REYATAZ 300 mg with ritonavir 100 mg in treatment-naive patients. OR For patients unable to tolerate ritonavir, REYATAZ 400 mg once daily with food should be administered at least 2 hours before and at least 10 hours after a dose of the H2RA. No single dose of the H2RA should exceed a dose comparable to famotidine 20 mg, and the total daily dose should not exceed a dose comparable to famotidine 40 mg. The use of REYATAZ without ritonavir in pregnant patients is not recommended. In treatment-experienced adult patients: Whenever an H2RA is given to a patient receiving REYATAZ with ritonavir, the H2RA dose should not exceed a dose comparable to famotidine 20 mg twice daily, and the REYATAZ with ritonavir doses should be administered simultaneously with, and/or at least 10 hours after, the dose of the H2RA. • REYATAZ 300 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with both tenofovir DF and an H2RA. • REYATAZ 400 mg with ritonavir 100 mg once daily (all as a single dose with food) if taken with either tenofovir DF or an H2RA for pregnant patients during the second and third trimester. REYATAZ is not recommended for pregnant patients during the second and third trimester taking REYATAZ with both tenofovir DF and an H2RA. |
| Hormonal contraceptives: ethinyl estradiol and norgestimate or norethindrone | ↓ ethinyl estradiol ↑ norgestimate c ↑ ethinyl estradiol ↑ norethindrone d | Use caution if considering coadministration of oral contraceptives with REYATAZ or REYATAZ with ritonavir. If REYATAZ with ritonavir is coadministered with an oral contraceptive, it is recommended that the oral contraceptive contain at least 35 mcg of ethinyl estradiol. If REYATAZ is administered without ritonavir, the oral contraceptive should contain no more than 30 mcg of ethinyl estradiol. Potential safety risks include substantial increases in progesterone exposure. The long-term effects of increases in concentration of the progestational agent are unknown and could increase the risk of insulin resistance, dyslipidemia, and acne. Coadministration of REYATAZ or REYATAZ with ritonavir and other hormonal contraceptives (eg, contraceptive patch, contraceptive vaginal ring, or injectable contraceptives) or oral contraceptives containing progestogens other than norethindrone or norgestimate, or less than 25 mcg of ethinyl estradiol, has not been studied; therefore, alternative methods of contraception are recommended. |
| Immunosuppressants: cyclosporine, sirolimus, tacrolimus | ↑ immunosuppressants | Therapeutic concentration monitoring is recommended for these immunosuppressants when coadministered with REYATAZ. |
| Inhaled beta agonist: salmeterol | ↑ salmeterol | Coadministration of salmeterol with REYATAZ is not recommended. Concomitant use of salmeterol and REYATAZ may result in increased risk of cardiovascular adverse reactions associated with salmeterol, including QT prolongation, palpitations, and sinus tachycardia. |
| Inhaled/nasal steroid: fluticasone | REYATAZ ↑ fluticasone | Concomitant use of fluticasone propionate and REYATAZ without ritonavir should be used with caution. Consider alternatives to fluticasone propionate, particularly for long-term use. |
| REYATAZ with ritonavir ↑ fluticasone | With concomitant use of fluticasone propionate and REYATAZ with ritonavir systemic corticosteroid effects, including Cushing’s syndrome and adrenal suppression, have been reported during postmarketing use in patients receiving ritonavir and inhaled or intranasally administered fluticasone propionate. Coadministration of fluticasone propionate and REYATAZ with ritonavir is not recommended unless the potential benefit to the patient outweighs the risk of systemic corticosteroid side effects [see Warnings and Precautions (5.1) ]. | |
| Macrolide antibiotics: clarithromycin | ↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir | Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with REYATAZ. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of REYATAZ with ritonavir and clarithromycin has not been studied. |
| Opioids: buprenorphine | REYATAZ or REYATAZ with ritonavir ↑ buprenorphine ↑ norbuprenorphine | Coadministration of REYATAZ with ritonavir and buprenorphine warrants clinical monitoring for sedation and cognitive effects. A dose reduction of buprenorphine may be considered. |
| REYATAZ ↓ atazanavir | The coadministration of REYATAZ and buprenorphine without ritonavir is not recommended. | |
| PDE5 inhibitors: sildenafil, tadalafil, vardenafil | ↑ sildenafil ↑ tadalafil ↑ vardenafil | Coadministration with REYATAZ has not been studied but may result in an increase in PDE5 inhibitor-associated adverse reactions, including hypotension, syncope, visual disturbances, and priapism. Use of PDE5 inhibitors for pulmonary arterial hypertension (PAH): Coadministration of REYATAZ with REVATIO ® (sildenafil) for the treatment of pulmonary hypertension (PAH) is contraindicated [see Contraindications (4) ]. The following dose adjustments are recommended for the use of ADCIRCA ® (tadalafil) with REYATAZ: Coadministration of ADCIRCA ® in patients on REYATAZ (with or without ritonavir): • For patients receiving REYATAZ (with or without ritonavir) for at least one week, start ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Coadministration of REYATAZ (with or without ritonavir) in patients on ADCIRCA ®: • Avoid the use of ADCIRCA ® when starting REYATAZ (with or without ritonavir). Stop ADCIRCA ® at least 24 hours before starting REYATAZ (with or without ritonavir). At least one week after starting REYATAZ (with or without ritonavir), resume ADCIRCA ® at 20 mg once daily. Increase to 40 mg once daily based on individual tolerability. Use of PDE5 inhibitors for erectile dysfunction: Use VIAGRA ® (sildenafil) with caution at reduced doses of 25 mg every 48 hours with increased monitoring for adverse events. Use CIALIS ® (tadalafil) with caution at reduced doses of 10 mg every 72 hours with increased monitoring for adverse events. REYATAZ with ritonavir: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 72 hours with increased monitoring for adverse reactions. REYATAZ: Use vardenafil with caution at reduced doses of no more than 2.5 mg every 24 hours with increased monitoring for adverse reactions. |
| Proton-pump inhibitors: omeprazole | ↓ atazanavir | Coadministration of REYATAZ with or without ritonavir and omeprazole may result in loss of virologic response and development of resistance. In HIV-treatment-naive adult patients: The proton-pump inhibitor (PPI) dose should not exceed a dose comparable to omeprazole 20 mg and must be taken approximately 12 hours prior to the REYATAZ 300 mg with ritonavir 100 mg dose. In HIV-treatment-experienced adult patients: Coadministration of REYATAZ with PPIs is not recommended. |
Pregnancy Safety for Reyataz
- Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in patients exposed to REYATAZ during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Atazanavir has been evaluated in a limited number of women during pregnancy. Available human and animal data suggest that atazanavir does not increase the risk of major birth defects overall compared to the background rate. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. No treatment-related malformations were observed in rats and rabbits, for which the atazanavir exposures were 0.7-1.2 times of those at the human clinical dose (300 mg/day atazanavir boosted with 100 mg/day ritonavir). When atazanavir was administered to rats during pregnancy and throughout lactation, reversible neonatal growth retardation was observed. Clinical Considerations Dose Adjustments during Pregnancy and the Postpartum Period
- REYATAZ must be administered with ritonavir in pregnant patients.
- For pregnant patients, no dosage 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 H 2 -receptor antagonist or tenofovir DF, 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 H 2 -receptor antagonist and tenofovir DF in treatment-experienced pregnant patients.
- No dosage 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. Maternal Adverse Reactions Cases of lactic acidosis syndrome, sometimes fatal, and symptomatic hyperlactatemia have occurred in pregnant women using REYATAZ in combination with nucleoside analogues, which are associated with an increased risk of lactic acidosis syndrome. Hyperbilirubinemia occurs frequently in patients who take REYATAZ, including those who are pregnant. Advise pregnant women of the potential risks of lactic acidosis syndrome and hyperbilirubinemia. Fetal/Neonatal Adverse Reactions 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. Among the 39 women who completed the study, 38 women achieved an HIV-1 RNA less than 50 copies/mL at time of delivery. 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 pregnant women with HIV-1, 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. 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 less than 40 mg/dL that could not be attributed to maternal glucose intolerance, difficult delivery, or sepsis. Based on prospective reports from the APR of approximately 1600 live births following exposure to atazanavir-containing regimens (including 1037 live births in infants exposed in the first trimester and 569 exposed in second/third trimesters), there was no difference between atazanavir, and overall birth defects compared with the background birth defect rate. In the U.S. general population, the estimated background risk of major birth defects in clinically recognized pregnancies is 2-4%. Animal Data In animal reproduction studies, there was no evidence of mortality or 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 neonatal growth retardation during lactation that reversed after weaning. Maternal drug exposure at this dose was 1.3 times the human exposure at the recommended clinical exposure. Minimal maternal toxicity occurred at this exposure level.
Pediatric Use of Reyataz
Pediatric Use REYATAZ is indicated in combination with other antiretroviral agents for the treatment of pediatric patients with HIV-1, 3 months of age and older weighing at least 5 kg. REYATAZ is not recommended for use in pediatric patients below the age of 3 months due to the risk of kernicterus. All REYATAZ contraindications, warnings, and precautions apply to pediatric patients.
The safety, pharmacokinetic profile, and virologic response of REYATAZ in pediatric patients at least 3 months of age and older weighing at least 5 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. See Dosage and Administration for dosing recommendations for the use of REYATAZ capsules and REYATAZ oral powder in pediatric patients.
Contraindications for Reyataz
- 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.
- 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 are strong inducers of CYP3A due to the potential for loss of therapeutic effect and development of resistance. Coadministration is contraindicated with, but not limited to, the following drugs listed in Table 6: Table 6: Drugs Contraindicated with REYATAZ (Information in the table applies to REYATAZ with or without ritonavir, unless otherwise indicated) a See Drug Interactions, Table 16 for parenterally administered midazolam. b See Drug Interactions, Table 16 for sildenafil when dosed as VIAGRA ® for erectile dysfunction. Drug Class Drugs within class that are contraindicated with REYATAZ Alpha 1-adrenoreceptor antagonist Alfuzosin Anticonvulsants Carbamazepine, phenobarbital, phenytoin Antiarrhythmics Amiodarone (with ritonavir), quinidine (with ritonavir) Antimycobacterials Rifampin Antineoplastics Apalutamide, encorafenib, irinotecan, ivosidenib Antipsychotics Lurasidone (with ritonavir), pimozide Benzodiazepines Orally administered midazolam a, triazolam Ergot Derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine GI Motility Agent Cisapride Hepatitis C Direct-Acting Antivirals Elbasvir/grazoprevir; glecaprevir/pibrentasvir Herbal Products St. John’s wort ( Hypericum perforatum ) Lipid-Modifying Agents: Lomitapide, lovastatin, simvastatin Phosphodiesterase-5 (PDE-5) Inhibitor Sildenafil b when dosed as REVATIO ® for the treatment of pulmonary arterial hypertension Protease Inhibitors Indinavir Non-nucleoside Reverse Transcriptase Inhibitors Nevirapine
- Coadministration with drugs that are strong inducers of CYP3A, due to the potential for loss of therapeutic effect and development of resistance.
Overdosage Information for Reyataz
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 participants without symptomatic untoward effects. A single self-administered overdose of 29.2 g of REYATAZ in a patient with HIV-1 (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. 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.
Clinical Studies of Reyataz
Adult
- Participants 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 participants with HIV-1 infection. 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 participants. Treatment response and outcomes through Week 96 are presented in Table 26.
- Study AI424-034: REYATAZ once daily compared to efavirenz once daily, each in combination with fixed-dose lamivudine/zidovudine twice daily. 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 participants with high viral loads (ie, baseline HIV-1 RNA ≥100,000 copies/mL) was comparable for the REYATAZ and efavirenz arms.
- 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.
- 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/mm 3 for the REYATAZ 400-mg arm and 211 cells/mm 3 for the nelfinavir arm.
- Adult Participants 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) participants 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. 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.
- Table 29: Outcomes of Treatment Through Week 48 in Study AI424-045 (Participants with Prior Antiretroviral Experience) No participants in the REYATAZ with ritonavir treatment arm and three participants 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 log 10 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/mm 3. 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 (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 participants who experienced virologic failure to only one prior PI-containing regimen. Based on the results of this study, REYATAZ without ritonavir was inferior to lopinavir/ritonavir in PI-experienced participants with prior virologic failure and is not recommended for such patients.
Pediatric Participants 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 participants from 6 years to 21 years of age. In this study, 105 participants (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 participants (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 participants with HIV-1 RNA <400 copies/mL at Week respectively. 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 participants from 3 months to less than 6 years of age • AI424-451 (PRINCE II; NCT01335698 ): In pediatric participants from 3 months to less than 11 years of age In these studies, 155 participants (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 participants had to have genotypic sensitivity to REYATAZ and two NRTIs, and treatment-experienced participants had to have documented genotypic and phenotypic sensitivity at screening to REYATAZ and at least 2 NRTIs.
Participants exposed only to antiretrovirals in utero or intrapartum were considered treatment-naive. Participants 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 participants from both studies weighing 5 kg to less than 35 kg treated with REYATAZ oral powder with ritonavir were evaluated.
Using a modified ITT analysis, the overall proportions of antiretroviral-naive and antiretroviral-experienced participants with HIV-1 RNA <400 copies/mL at Week respectively in participants who received REYATAZ oral powder with ritonavir.
| a As a fixed-dose product: 300 mg tenofovir DF/200 mg emtricitabine once daily. b As a fixed-dose product: 400 mg lopinavir/100 mg ritonavir (twice daily). c Participants achieved HIV-1 RNA <50 copies/mL at Week 96. Roche Amplicor ®, v1.5 ultra-sensitive assay. d Pre-specified ITT analysis at Week 48 using as-randomized cohort: atazanavir with ritonavir 78% and lopinavir/ritonavir 76% (difference estimate: 1.7% [95% confidence interval: −3.8%, 7.1%]). e Pre-specified ITT analysis at Week 96 using as-randomized cohort: atazanavir with ritonavir 74% and lopinavir/ritonavir 68% (difference estimate: 6.1% [95% confidence interval: 0.3%, 12.0%]). f Includes viral rebound and failure to achieve confirmed HIV-1 RNA <50 copies/mL through Week 96. g Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. | ||
| REYATAZ 300 mg with ritonavir 100 mg (once daily) and tenofovir DF/emtricitabine (once daily) a (n=441) | lopinavir/ritonavir b 400 mg/100 mg (twice daily) with tenofovir DF/emtricitabine (once daily) a (n=437) | |
| Outcome | 96 Weeks | 96 Weeks |
| Responder c,d,e | 75% | 68% |
| Virologic failure f | 17% | 19% |
| Rebound | 8% | 10% |
| Never suppressed through Week 96 | 9% | 9% |
| Death | 1% | 1% |
| Discontinued due to adverse event | 3% | 5% |
| Discontinued for other reasons g | 4% | 7% |
| a Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor ® HIV-1 Monitor™ Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. c Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. d As a fixed-dose product: 150 mg lamivudine/300 mg zidovudine twice daily. | ||
| Outcome | REYATAZ 400 mg once daily and lamivudine / zidovudine d (n=405) | efavirenz 600 mg once daily and lamivudine / zidovudine d (n=405) |
| Responder a | 67% (32%) | 62% (37%) |
| Virologic failure b | 20% | 21% |
| Rebound | 17% | 16% |
| Never suppressed through Week 48 | 3% | 5% |
| Death | – | <1% |
| Discontinued due to adverse event | 5% | 7% |
| Discontinued for other reasons c | 8% | 10% |
| a Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. Roche Amplicor ® HIV-1 Monitor™ Assay, test version 1.0 or 1.5 as geographically appropriate. b Includes viral rebound and failure to achieve confirmed HIV-1 RNA <400 copies/mL through Week 48. c Includes lost to follow-up, participant’s withdrawal, noncompliance, protocol violation, and other reasons. | ||
| Outcome | REYATAZ 400 mg once daily with lamivudine and stavudine (n=181) | nelfinavir 1250 mg twice daily with lamivudine and stavudine (n=91) |
| Responder a | 67% (33%) | 59% (38%) |
| Virologic failure b | 24% | 27% |
| Rebound | 14% | 14% |
| Never suppressed through Week 48 | 10% | 13% |
| Death | <1% | – |
| Discontinued due to adverse event | 1% | 3% |
| Discontinued for other reasons c | 7% | 10% |
| a Time-averaged difference through Week 48 for HIV-1 RNA; Week 48 difference in HIV-1 RNA percentages and CD4+ mean changes, REYATAZ with ritonavir vs lopinavir/ritonavir; CI = 97.5% confidence interval for change in HIV-1 RNA; 95% confidence interval otherwise. b Administered as a fixed-dose product. c Roche Amplicor ® HIV-1 Monitor™ Assay, test version 1.5. d Protocol-defined primary efficacy outcome measure. e Based on participants with baseline and Week 48 CD4+ cell count measurements (REYATAZ with ritonavir, n=85; lopinavir/ritonavir, n=93). f Participants achieved and maintained confirmed HIV-1 RNA <400 copies/mL (<50 copies/mL) through Week 48. | |||
| Outcome | REYATAZ 300 mg with ritonavir 100 mg once daily and tenofovir DF and 1 NRTI (n=119) | lopinavir/ritonavir (400/100 mg) twice daily and tenofovir DF and 1 NRTI (n=118) | Difference a (REYATAZ-lopinavir/ritonavir) b (CI) |
| HIV-1 RNA Change from Baseline (log 10 copies/mL) c | −1.58 | −1.70 | +0.12 c (−0.17, 0.41) |
| CD4+ Change from Baseline (cells/mm 3 ) e | 116 | 123 | −7 (−67, 52) |
| Percent of Participants Responding e | |||
| HIV-1 RNA <400 copies/mL c | 55% | 57% | −2.2% (−14.8%, 10.5%) |
| HIV-1 RNA <50 copies/mL c | 38% | 45% | −7.1% (−19.6%, 5.4%) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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