This document was produced in a Reglan (Metoclopramide) lawsuit. It found that 1 in 500 people who use Reglan or Metoclopramide may develop movement disorders. The FDA now believes that figure is closer to one in five.
Mary Ross Southworth, PharmD
Safety Evaluator, Division of Drug Risk Evaluation
Office of Drug Safety
Center for Drug Evaluation and Research, FDA
Purpose of Review
• MT-100: metoclopramide 16 mg/naproxen 500mg
• Acute migraine treatment
• Proposed dosing chronic, but intermittent manner
- Episodic
- No more than 6 tablets/month
• Risks associated with this type of
Background
• Metoclopramide well known to cause movement disorders
• Product labeling
- Extrapyramidal symptoms occur in 1 of 500 patients receiving 30 to 40 mg daily
- Parkinsonian symptoms occur after prolonged use and are usually reversible
- Tardive dyskinesia most common with prolonged use, but can occur with shorter durations of therapy
- Neuroleptic Malignant Syndrome occurs rarely
• Recommended Daily Dose: 5 to 20 mg QID
• Duration of Therapy should not exceed 12 weeks
Total Number of Prescriptions Dispensed (in thousands) in Retail Pharmacies Nationwide for Metoclopramide Products, IMS Health, NPA PlusTM, 1995-2004
TABLEPoints to consider
• Reversibility of reaction
• Association with dose/duration of therapy
- Relationship to proposed dosing of MT-100
- Potential for chronic continuous/intermittent use
• Associated Risk factors
- Concomitant Drugs
- Other patient specific factors
Purpose of Review
• Characterize cases of specific adverse events reported in the Adverse Event Reporting System (AERS) database associated with metoclopramide
AERS database
• Computerized database containing reports of adverse events
• >3 million reports
• “Spontaneous” reporting
- Not required of health care providers
- Sponsors required to report any adverse event of which they become aware
• Source of reports
- Drug manufacturers/sponsors
- Health care providers
- Lay people (consumers, patients, patients' families, lawyers)
Adverse Events
• Neuroleptic Malignant ... • Number of case reports
Syndrome (NMS) ... • Daily dose
• Acute dystonia ... • Duration of
• Akathisia ... treatment
• Parkinsonism ... • Risk Factors
• Tardive dyskinesia ... • Reversibility
Search Strategy/Results
• Search run using each movement disorder as a search term * “metoclopramide”
• Cases classified according to diagnosis made in the case
• Points
- Case misclassification (tardive vs. acute)
- Chronic/intermittent vs. Chronic/continuous
- Underreporting due to drug label
- Drug has been on the market for a long time
- Quality of reports
• Status of recovery
• Time to recovery
Search Strategy/Results
Search term ... Number of unique reports reviewed
NMS ... 37
Acute Dystonia ... 203
Akathisia ... 57
Parkinson's disease/Parkinsonism ... 35
Tardive Dyskinesia ... 68
Description of case series
• Demographics
• Clinical characteristics
• Recovery
• Review cases with continuing symptoms
• Representative cases
• Focus on short term therapy
Neuroleptic Malignant Syndrome (37 cases)
TABLENeuroleptic Malignant Syndrome (37 cases)
• Concomitant medications associated with development of NMS or NMS-like symptoms reported in 20 cases
- Antidepressants (3)
- Antiemetics (8)
- Antipsychotics (9)
• Drug therapy was used to treat the AE in 18 cases
- Dantrolene (12)
- Diphenhydramine (5)
- Bromocriptine (6)
• Symptoms were reported as improved or resolved in 11 cases (NR in 17 cases)
• Symptoms reported as continuing in 1 case (dystonic jaw clenching)
• Eight patients died
Neuroleptic Malignant Syndrome: Deaths (n=8)
• Daily dose
- 10 mg to 40 mg (NR in 3 cases)
- Mean: 32 mg; Median: 40 mg
- PO dosing in 2 cases; IV dosing in 3 cases (NR in 3 cases)
• Duration of therapy
-2 days (2); 5 days; 7 days; 8 days; 15 days (NR in two cases)
Acute Dystonia (203 cases)
TABLEAcute Dystonia (203 cases)
• Concomitant medications associated with development of movement disorders reported in 64 cases
- Antidepressants (16)
- Antiemetics (27)
• Drug therapy was used to treat the AE in 115 cases
- Diphenhydramine/anticholinergic (90)
- Benztropine (14)
- Anxiolytic (16)
• Symptoms were reported as improved or resolved in 115 cases
• Symptoms were reported as continuing in 12 cases (6%)
Acute Dystonia: Continuing Symptoms (n-12)
• Daily dose
- 10 mg to 40 mg (NR in 425 cases)
- Mean: 25 mg; Median: 20 mg
- Oral dosing in 10 cases; Combination
IV/PO dosing in 1 case (NR in 1 case)
• Duration of therapy
- 1 day (1 dose) to 2065 days
- Mean: 373 days; Median: 2.5 days
Akathisia 57 cases
