1 One Year Post Exclusivity Adverse Event Review: Alendronate Pediatric Advisory Committee Meeting September 15, 2004 Hari Cheryl Sachs, MD, FAAP Medical.

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Presentation transcript:

1 One Year Post Exclusivity Adverse Event Review: Alendronate Pediatric Advisory Committee Meeting September 15, 2004 Hari Cheryl Sachs, MD, FAAP Medical Officer Division of Pediatric Drug Development Center for Drug Evaluation and Research Food and Drug Administration

2 Background Drug Information Moiety: Fosamax ® (alendronate) Therapeutic Category: Bisphosphonate Sponsor: Merck & Co., Inc Original Market Approval: September 29, 1995 Pediatric Exclusivity Granted: April 28, 2003 Mechanism of action: inhibits osteoclast- mediated bone resorption activity

3 Background Drug Information Adult Indications: –Treatment and prevention of osteoporosis in post- menopausal women –To increase bone mass in men with osteoporosis –Treatment of glucocorticoid-induced osteoporosis –Treatment of Paget’s Disease Adult Dosage: Varies based on indication Pediatric Indications: None

4 Drug Use Trends in Outpatient Settings: Alendronate Fosamax is the most commonly dispensed bisphosphonate in the US ( ) 1 Total US prescriptions have increased from 18.6 million (May April 2002) to 22 million (May 2003-April 2004) 1 Pediatric patients (ages 1-16) account for < 1 % (approximately 10,000) prescriptions 1,2* 1 IMS Health, National Prescription Audit Plus , On-Line, May Apr 2004, Data Extracted May AdvancePCS  Dimension Rx, On-Line, May Apr 2004, Data Extracted May 2004 *Calculation based on application of proportions of pediatric alendronate prescriptions in AdvancePCS  to IMS Health, National Prescription Audit Plus  to estimate number of alendronate prescriptions dispensed nationwide to pediatric population

5 Drug Use Trends in Outpatient Settings: Alendronate Prescribers (May April 2004) 1 –Internists, family practitioners and obstetric/gynecology specialists primary prescribers (70 % of prescriptions written). – Pediatricians only wrote 0.3 % Diagnosis –Adults: osteoporosis and osteopenia –Pediatrics (off-label): Osteoporosis or osteopenia (renal or connective tissue diseases, glucocorticoid tx), fibrous dysplasia, osteogenesis imperfecta 1 IMS Health, National Prescription Audit Plus , On-Line, May Apr 2004, Data Extracted May 2004

6

7 Pediatric Exclusivity Studies: Alendronate Indication: Treatment of severe Osteogenesis Imperfecta (OI) in patients 4-18 years Studies performed: Oral bioavailability (tablets vs injection) 24 month efficacy and safety study

8 Pediatric Exclusivity Studies: Alendronate Pharmacokinetics Oral bioavailability of alendronate similar between OI patients and adults Relative to 125 ug IV dose –35 mg oral dose in pediatric patients 4-14 years and < 40 kg, mean bioavailability is about 0.43 % –70 mg dose in pediatric patients years and > 40 kg, mean bioavailability is about 0.56 %

9 Pediatric Exclusivity Studies: Alendronate Safety and Efficacy Placebo Controlled Trial of 139 patients with OI ages 4-18 years (12 month results) 5 or 10 mg alendronate significantly increased lumbar spine Bone Mineral Density (primary endpoint) No treatment group differences for fractures (key secondary efficacy endpoint) Safety review-AEs appear comparable to adults (12 months)

10 Pregnancy Category C Contraindications: –Delayed esophageal emptying or risk of aspiration –Inability to stand upright –Hypocalcemia –Allergy/hypersensitivity Warning: –GI irritation, esophageal perforation/ulcers/erosions Relevant Safety Labeling

11 Precautions –Monitor calcium, Vitamin D status Adverse Reactions: –Gastrointestinal symptoms (abdominal pain, nausea, dyspepsia, constipation, etc.) –Musculoskeletal pain –Headache, dizziness –Taste perversion Postmarketing –Stevens-Johnsons/Toxic Epidermal Necrolysis Relevant Safety Labeling

12 Adverse Event Reports Since Market Approval: Alendronate September 1995 – May 2004 Total number of reports, all ages: –18,712 reports (14,068 US) serious- 4,265 (2,353 US) deaths- 390 (128 US) Pediatric reports: –17 reports (11 US) 15 serious (9 US) 0 deaths Raw counts (US reports are in parenthesis)- includes duplicates

13 Adverse Event Reports during the One- Year Post-Exclusivity Period: Alendronate April 2003 – May 2004 Total number of reports, all ages: –879 reports (413 US) 850 serious (393 US) 67 deaths (18 US) Pediatric reports: –4 reports (0 US) 4 serious (0 US) 0 deaths

14 Adverse Event Reports: Alendronate April 2003 – May 2004 (n=4) Hepatocellular injury (2) Drug-drug interaction (1) Neonatal Hypocalcemia & Prematurity (1)

15 Hepatotoxicity (n=2) 12 y/o F with JRA (prednisone, ibuprofen, mizoribine, glycyrrhizin, s/p MTX). Liver dysfunction (jaundice and markedly elevated liver enzymes) developed 2 weeks after initiating alendronate for glucocorticoid-induced osteoporosis. Liver biopsy confirmed severe hepatitis, viral studies negative. Resolved after steroid pulse therapy and discontinuation of alendronate 5 y/o M with juvenile idiopathic arthritis and hepatic dysfunction, interstitial pneumonia, and drug-induced agranulocytosis (dexamethasone). Liver dysfunction occurred 1 week after initiation of alendronate for glucocorticoid-induced osteoporosis. Liver enzymes improved after discontinuation of alendronate, treatment with cyclosporine, plasma exchange, G-CSF, and pulse steroids. Biopsy or viral studies not performed.

16 Drug Interaction (n=1) 7 y/o male JRA and steroid-induced cataracts (cyclosporine, prednisolone and ibuprofen). Previously stable cyclosporine levels decreased 1 month after starting alendronate with relapse of arthritis after 5 months. Cyclosporine levels increased once alendronate discontinued.

17 Neonatal Hypocalemia (n=1) 2.7 kg 34 week-premature male with hypocalcemia, hypocortisolism, transient tachypnea and port-wine stain born to 31 y/o with asthma, gestational diabetes, hepatitis C, psychosis endometriosis, and polycystic ovarian disease (dexamethasone, montelukast, albuterol, ipratropium, fluticasone, formoterol, theophylline, terbutaline, *furosemide, torsemide, immune globulin, *interferon, ribavirin, insulin and first trimester alendronate) *drugs known to be associated with hypocalcemia

18 Summary Events confounded, insufficient information to ascribe causality This completes the one-year post- exclusivity adverse event monitoring as mandated by BPCA. FDA will continue its routine monitoring of adverse events for this drug.