# Presentation: 023026

## 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**

## 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

## 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

## Drug Use Trends in Outpatient Settings: Alendronate

- Fosamax is the most commonly dispensed bisphosphonate in the US (2001-2004)1
- Total US prescriptions have increased from 18.6 million (May 2001- April 2002) to 22 million (May 2003-April 2004)1
- Pediatric patients (ages 1-16) account for < 1 % (approximately 10,000) prescriptions1,2*
**	****1**IMS Health, National Prescription Audit *Plus*, On-Line, May 2001 - Apr 2004, Data Extracted May 2004
- 	2AdvancePCS Dimension Rx, On-Line, May 2001 - 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

## Drug Use Trends in Outpatient Settings: Alendronate

- Prescribers (May 2001- 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 2001 - Apr 2004, Data Extracted May 2004

## http://www.fda.gov/cder/pediatric/Summaryreview.htm

## 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

## 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 11-16 years and > 40 kg, mean bioavailability is about 0.56 %

## 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)

- 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**

- 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**

## 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**

## 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
**	****	**

## Adverse Event Reports:  Alendronate April 2003 – May 2004 (n=4)

- Hepatocellular injury (2)
- Drug-drug interaction (1)
- Neonatal Hypocalcemia & Prematurity (1)

## 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.

## 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.

## 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

## 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.