Pediatric Focused Safety Review: Zmax (Azithromycin) Pediatric Advisory Committee Meeting March 22, 2010 Virginia Elgin, M.D., FAAP; Medical Officer Pediatric and Maternal Health Staff Office of New Drugs Center for Drug Evaluation and Research Food and Drug Administration 1 Outline • Background Information • Pediatric PREA Studies • Pediatric PREA Labeling Changes • Additional Relevant Safety Labeling • Drug Use Trends • Adverse Events • Summary 2 Background Drug Information • Drug: Zmax (azithromycin) • Formulation: extended release powder for oral suspension • Therapeutic Category: macrolide antimicrobial • Sponsor: Pfizer • Original Market Approval: June 10th, 2005 – Original oral suspension (zithromax) approved 1994 • Indication: treatment of: – Community-acquired pneumonia (CAP) in adults and children 6 months and older – Acute bacterial sinusitis in adults (ABS) 3 Background Drug Information, cont. • Dosage: – Treatment of CAP and ABS in adults: single dose of 2 grams (oral suspension) – Treatment of CAP in pediatrics: single dose of 60 mg/kg up to a maximum 2 grams • Indication: changed to include children 6 months and older with CAP • PREA Labeling Changes Approved: October 7th, 2008 4 Pediatric PREA Clinical Studies Dosing: • Pharmacokinetic (PK) studies were done in pediatric patients 3 months to 16 years of age. • Pediatric patients received azithromycin 60 mg/kg up to a maximum dose of 2 g under fasting conditions. • Mean PK profiles were comparable between pediatric patients and adults who received 2 grams under fasting conditions. 5 Pediatric PREA Clinical Studies • Safety established for CAP • 907 pediatric patients evaluated in 3 studies – Ages 3 months to 12 years – Patients received a single dose of 60 mg/kg. • Efficacy extrapolated based on trials in adults and known similar pathophysiologic response to treatment for mild to moderate CAP in adults and children down to 6 months of age. • Studies under 6 months of age waived. 6 Zmax: PREA Labeling Changes 1 Indication and usage – Now includes pediatric patients down to 6 months of age for Community Acquired Pneumonia (CAP) 2.2 Pediatric patients – 6 New dosing information: 60 mg/kg as a single dose up to a maximum of 2 grams Adverse reactions – Most common pediatric adverse events: diarrhea, loose stools, vomiting and abdominal pain 7 Zmax: PREA Related Labeling Changes Age Range Number of Pediatric Patients Adverse Events 3-48 months 450 Vomiting (11%); diarrhea (10%); loose stools (9%); abdominal pain (2%) 2-12 years Vomiting (14%); diarrhea (7%), loose stools (2%); nausea (4%); abdominal pain (4%) 337 3-48 months 120 Vomiting 3% 8 Zmax: PREA Labeling Changes 8.4 Pediatric Use – Pediatric studies conducted for the treatment of CAP (6 months and older) due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae - Safety and effectiveness not established • in patients less than 6 months of age • in acute bacterial sinusitis 9 Zmax: Additional Relevant Safety Labeling WARNINGS AND PRECAUTIONS: • 5.1 Severe (including fatal) allergic and skin reactions • 5.2 Clostridium difficile-associated diarrhea • 5.3 Exacerbation of symptoms of myasthenia gravis (October 2008) • 5.4 Gastrointestinal disturbances • 5.5 Prolongation of the QT Interval • 5.6 Development of drug resistant bacteria 10 Total Dispensed Prescriptions for Zmax® and Azithromycin by Patient Age in U.S. Outpatient Retail Pharmacies • Zmax®1 – For pediatric patients, 0 to 16 years old, ~72,000 prescriptions (~5%) were dispensed from June 2005 to September 2009. • ~700 (~0.1%) for 0 to 1 year olds • ~71,000 (~5%) for 2 to 16 year olds • ~1.3 million (~95%) for 17+ year olds • Azithromycin2 – For pediatric patients, 0 to 16 years old, ~58.4 million prescriptions (~26%) were dispensed from October 2005 to September 2009. • ~6.8 million (~12%) for 0 to 1 year olds • ~51.5 million (~88%) for 2 to 16 year olds • ~167.8 million (~74%) for 17+ year olds 1SDI 2SDI Vector One®: National. Extracted 1-7-2010. Source File: VONA 2009-1980 Azithromycin by Age BPCA 1-7-10.xls Vector One®: National. Extracted 1-11-2010. Source File: VONA 2009-1980 Azithromycin Market by Age BPCA 1-7-10.xls 11 Total Number of Projected Patients on Zmax® and Azithromycin by Patient Age in U.S. Outpatient Retail Pharmacies • Zmax®3 – For pediatric patients, 0 to 16 years old, ~69,000 patients (~5%) received a prescription for Zmax® from June 2005 to September 2009. • ~750 (~0.1%) for 0 to 1 year olds • ~68,000 (~5%) for 2 to 16 year olds • ~1.2 million (~94%) for 17+ year olds • Azithromycin4 – For pediatric patients, 0 to 16 years old, ~28.3 million patients (~5%) received a prescription for Azithromycin from October 2005 to September 2009. • ~4.3 million (~15%) for 0 to 1 year olds • ~25.6 million (~90%) for 2 to 16 year olds • ~83.9 million (~75%) for 17+ year olds 3SDI, Total Patient Tracker, 2005-2009. Extracted January 2010. Files: TPT 2009-1980 Azithromycin BPCA Display 1-25-10.xls; TPT 20091980 Azithromycin BPCA Aggregate 1-25-10.xls 4SDI, Total Patient Tracker, 2004-2009. Extracted February 2010. Files: TPT 2009-1980 Azithromycin (molecule) BPCA Display 12 Zmax®: Drug Use Trends • Top Prescribing Specialty: – General Practice/Family Medicine1 • Top Diagnosis Code3 : – Otitis Media (age 0-1 year); – Chronic Sinusitis and Acute Pharyngitis (2-16 years) 1 SDI Vector One®: National, 2004-2009, Extracted: January, 2010 3 SDI Physician Drug and Diagnosis Audit, National, 2004-2009, Extracted: 01/2010 13 Adverse Event Reports Since Market Approval (June 10, 2005 to September 30, 2009) Zmax (azithromycin) Crude counts* All reports (US) Serious** (US) Total All Ages 131(89) 128 (88) 5(1) - Adults (> 17) 66 (42) 64 (41) 5(1) 9 (6) 9 (6) 0 (0) 56 (41) 55 (41) 0 (0) - Pediatrics (0-16 yrs) - Unknown Age Death (US) *may include duplicates **Serious AEs per regulatory definition (CFR 314.80) include death, lifethreatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important medical events 14 Zmax: Postmarketing Pediatric Adverse Event Reports: • No deaths • 9 crude count serious AE reports – 8 unduplicated serious AE cases • Unlabeled SAE cases (n= 4) – Drug ineffective in 16 year old with tonsillitis – Hallucinations and fever in a 5 year old (Zithromac SR®) – Speech disorder and chattering teeth in an 11 year who was taking Adderall XR (resolved when Adderall XR discontinued) – Muscle and joint pain in a 13 year old. 15 Zmax: Postmarketing Pediatric Adverse Event Reports: • Labeled SAE cases (n=4) – Black stools and black nasal discharge in 1 year old exposed to clarithromycin then Zithromac® fine granules – Swelling, rash and welts in an 8 year old – Syncopal episode in an 8 year old (Zithromac® fine granules) – Elevated glucose (472) in a 15 year old with diabetes 16 Adverse Event Reports: Azithromycin (all formulations) (October 1st, 2008 to September 30, 2009) Crude counts* All reports (US) Serious** (US) Death (US) Total All Ages 526 (259) 464 (204) 43 (19) - Adults (> 17) 351 (194) 307 (152) 30 (10) - Pediatrics (0-16 yrs) 49 (26) 43 (20) 2 (1) - Unknown Age 126 (39) 114 (32) 11 (8) *may include duplicates **Serious AEs per regulatory definition (CFR 314.80) include death, lifethreatening, hospitalization (initial or prolonged), disability, congenital anomaly and other serious important medical events 17 Adverse Event Reports Azithromycin (all formulations) October 1, 2008 to September 30, 2009 • Crude count reports (n= 49) • Unduplicated cases (n= 43) – 11 Excluded (non-serious, expected or unrelated to azithromycin) • Cases reviewed (n=32) – – – – – Death (n=1) Serious or life-threatening (n=9) Premature birth and neonatal anemia (n=1) Pyloric stenosis (n=2) Labeled or not serious (n=19) 18 Adverse Event Reports Azithromycin (all formulations) October 1, 2008 to September 30, 2009 • Death (n=1) – Choking in 15 month female • Serious or life-threatening (n=9) – Anaphylaxis (n=1) – Stevens-Johnson syndrome (n=3) • Labeling: Warning and precautions – Cardiac arrest (n=2) in patients receiving IV boluses • Contrary to labeled instructions 19 Adverse Event Reports Azithromycin (all formulations) October 1, 2008 to September 30, 2009 • Serious or life-threatening (n=9) (continued) – Acute severe liver injury (n= 3) • 1 liver transplant • Unclear causality: congestive heart failure, hepatotoxic drugs, and acute viral hepatitis remain alternative etiologies • Labeling: 6.2 Postmarketing Experience: abnormal liver function….rare cases of hepatic necrosis and hepatic failure. 20 Additional OSE Information: Hepatotoxicity OSE (DPV II) AERS Review notes: • In 2000 a description of hepatotoxic events was added to Section 6.2 under Adverse Events. • Hepatotoxicity and its association with exposure to macrolides continues to be evaluated for all ages. 21 Adverse Event Reports Azithromycin (all formulations - cont.) October 1, 2008 to September 30, 2009 • Pyloric stenosis (n=2): – 4 ½ week female exposed to IV azithromycin for 5 days. 16 days post last dose developed infantile hypertrophic pyloric stenosis. – 7 ½ week female presented with infantile hypertrophic pyloric stenosis. Only known exposure was in utero at 34 weeks when mother took azithromycin (Z-Pak). 22 Additional information: pyloric stenosis • OND Maternal Health Team conclusions: • Available data do not demonstrate an association between increased risk of pyloric stenosis and exposure to azithromycin inutero or through human milk. • OND Maternal Health Team recommendations: • No changes for azithromycin labeling regarding use during pregnancy and risk of pyloric stenosis • Based on current data, do not discourage breastfeeding in women using azithromycin. • The benefits of breastfeeding outweigh the potential risk of infant exposure to a small amount of azithromycin through human milk. 23 Maternal Health Team Conclusions Azithromycin is widely prescribed during pregnancy and lactation. A fetus exposed to azithromycin in-utero during the third trimester of pregnancy would be exposed to relatively higher concentrations and a higher daily dose of azithromycin than a human milk fed infant. With regard to a potential association between pyloric stenosis in the infant and exposure to non-erythromycin macrolides during pregnancy (or specifically during the third trimester), study results are inconsistent and do not specify whether pyloric stenosis cases were associated with azithromycin exposure. Very limited data suggest that concentration of azithromycin in human milk and resulting infant daily dose are relatively low. Despite frequent use of azithromycin in women who are pregnant and lactating, there are no reports of pyloric stenosis in infants with documented exposure to azithromycin through human milk. Based on available data, the benefits of human milk feeding outweigh the risks of infant exposure to small amounts of azithromycin through human milk. 24 Adverse Event Reports Azithromycin (all formulations) October 1, 2008 to September 30, 2009 • Hearing loss (n=1): – 4 year old took a 5 day course of azithromycin (160 mg Day 1 and 80 mg Days 2-5) • Mg/kg unknown; exposure about ½ recommended for child aged 4 years at 50th % for weight (= 15 kg) • No other medications that year • 50% permanent hearing loss – Labeling 6.2 Adverse reactions: • Postmarketing experience; Special senses: hearing loss 25 Summary Zmax (Azithromycin) • • • This completes the focused safety review for Zmax. Safety data from the PREA studies have been incorporated into the drug labeling. No additional safety signals emerged during the safety review. FDA plans to conduct a thorough case review of hepatotoxicity cases for the class of macrolides in all age groups. FDA is considering options about reports of pyloric stenosis which may include adding information to the Postmarketing Experience (Section 6) of the drug labeling. FDA will continue its standard, ongoing safety monitoring for Zmax. • Does the Advisory Committee concur? • • • 26 ACKNOWLEDGEMENTS OND DAIOP Wiley Chambers, M.D. Kimberly Bergman, PhD PMHS Richardae Araojo, PharmD Susan Cummins, MD, MPH Karen B. Feibus, MD Lisa L. Mathis, USPHS, MD Denise Pica-Branco, PhD Hari Cheryl Sachs, MD OPT Debbie Avant, RPh Judith Cope, MD, MPH Suzanne Malli, BA, BSN Dianne Murphy, MD OSE DEPI Laura Governale, PharmD, MBA Stephen Chang, PharmD DPV II Mark Avigan, MD, CM Ronald Wassel, Pharm D, 27