1. 1 Post-marketing review of Movement Disorders and Neuroleptic Malignant Syndrome associated with metoclopramide Mary Ross Southworth, PharmD Safety Evaluator, Division of Drug Risk Evaluation Office of Drug Safety Center for Drug Evaluation and Research, FDA

2. 2 Purpose of Review MT-100: metoclopramide 16 mg/naproxen 500mg MT-100: metoclopramide 16 mg/naproxen 500mg Acute migraine treatment Acute migraine treatment Proposed dosing chronic, but intermittent manner Proposed dosing chronic, but intermittent manner –Episodic –No more than 6 tablets/month Risks associated with this type of dosing? Risks associated with this type of dosing?

3. 3 Background Metoclopramide well known to cause movement disorders Metoclopramide well known to cause movement disorders Product labeling 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 Recommended Daily Dose: 5 to 20 mg QID Duration of Therapy should not exceed 12 weeks Duration of Therapy should not exceed 12 weeks

4. 4 Total Number of Prescriptions Dispensed (in thousands) in Retail Pharmacies Nationwide for Metoclopramide Products, IMS Health, NPA Plus™, 1995-2004 Source: 1995-1996 IMS Health, National Prescription Audit Plus™ book data- Dec 1996, USC 01200-33390 1997-1999 IMS NPA CD-ROM Dataview Analyzer Total Market CD-ROM Years 2000-2004, extracted February 2005

5. 5 Points to consider Reversibility of reaction Reversibility of reaction Association with dose/duration of therapy Association with dose/duration of therapy –Relationship to proposed dosing of MT-100 –Potential for chronic continuous/intermittent use Associated Risk factors Associated Risk factors –Concomitant Drugs –Other patient specific factors

6. 6 Purpose of Review Characterize cases of specific adverse events reported in the Adverse Event Reporting System (AERS) database associated with metoclopramide Characterize cases of specific adverse events reported in the Adverse Event Reporting System (AERS) database associated with metoclopramide

7. 7 AERS database Computerized database containing reports of adverse events Computerized database containing reports of adverse events >3 million reports >3 million reports “Spontaneous” reporting “Spontaneous” reporting –Not required of health care providers –Sponsors required to report any adverse event of which they become aware Source of reports Source of reports –Drug manufacturers/sponsors –Health care providers –Lay people (consumers, patients, patients’ families, lawyers)

8. 8 Adverse Events Neuroleptic Malignant Syndrome (NMS) Neuroleptic Malignant Syndrome (NMS) Acute dystonia Acute dystonia Akathisia Akathisia Parkinsonism Parkinsonism Tardive dyskinesia Tardive dyskinesia Number of case reports Number of case reports Daily dose Daily dose Duration of treatment Duration of treatment Risk Factors Risk Factors Reversibility Reversibility

9. 9 Search Strategy/Results Search run using each movement disorder as a search term + “metoclopramide” Search run using each movement disorder as a search term + “metoclopramide” Cases classified according to diagnosis made in the case Cases classified according to diagnosis made in the case Points 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 Status of recovery Time to recovery Time to recovery

10. 10 Search Strategy/Results Search term Number of unique reports reviewed NMS37 Acute Dystonia 203 Akathisia57 Parkinson’s disease/Parkinsonism 35 Tardive Dyskinesia 68

11. 11 Description of case series Demographics Demographics Clinical characteristics Clinical characteristics Recovery Recovery Review cases with continuing symptoms Review cases with continuing symptoms Representative cases Representative cases Focus on short term therapy Focus on short term therapy

12. 12 Neuroleptic Malignant Syndrome (37 cases)

13. 13 Neuroleptic Malignant Syndrome (37 cases) Concomitant medications associated with development of NMS or NMS-like symptoms reported in 20 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 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 were reported as improved or resolved in 11 cases (NR in 17 cases) Symptoms reported as continuing in 1 case (dystonic jaw clenching) Symptoms reported as continuing in 1 case (dystonic jaw clenching) Eight patients died Eight patients died NR= not reported

14. 14 Neuroleptic Malignant Syndrome: Deaths (n=8) Daily dose 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 Duration of therapy –2 days (2); 5 days; 7 days; 8 days; 15 days (NR in two cases) NR= not reported

15. 15 Acute Dystonia (203 cases)

16. 16 Acute Dystonia (203 cases) Concomitant medications associated with development of movement disorders reported in 64 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 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 improved or resolved in 115 cases Symptoms were reported as continuing in 12 cases (6%) Symptoms were reported as continuing in 12 cases (6%)

17. 17 Acute Dystonia: Continuing Symptoms (n-12) Daily dose 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 Duration of therapy –1 day (1 dose) to 2065 days –Mean: 373 days; Median: 2.5 days

18. 18 Akathisia (57 cases)

19. 19 Akathisia (57 cases) Concomitant medications associated with development of movement disorders reported in 23 cases Concomitant medications associated with development of movement disorders reported in 23 cases –Antidepressants (7) –Antiemetics (6) –Antipsychotics (6) Drug therapy was used to treat the AE in 29 cases Drug therapy was used to treat the AE in 29 cases –Diphenhydramine/anticholinergic (16) –Benztropine (8) –Anxiolytic (14) Symptoms were reported as improved or resolved in 31 cases Symptoms were reported as improved or resolved in 31 cases Symptoms were reported as continuing in 9 cases (16%) Symptoms were reported as continuing in 9 cases (16%)

20. 20 Akathisia: Continuing symptoms (n=9) Daily dose Daily dose –8.6 mg to 40 mg (NR in 1 case) –Mean: 25 mg; Median: 30 mg –Oral dosing in 8 cases (NR in 1 case) Duration of therapy Duration of therapy –17 to 2555 days (NR in 1 case) –Mean: 525 days; Median: 119 days

21. 21 Parkinsonism (35 cases)

22. 22 Parkinsonism (35 cases) Concomitant medications associated with development of movement disorders reported in 13 cases Concomitant medications associated with development of movement disorders reported in 13 cases –Antidepressants (5) –Antipsychotics (3) Drug therapy was used to treat the AE in 18 cases Drug therapy was used to treat the AE in 18 cases –Diphenhydramine/anticholinergic (4) –Amantadine (2) –Antiparkinson Medication (6) –Benztropine (3) Symptoms were reported as improved or resolved in 15 cases Symptoms were reported as improved or resolved in 15 cases Symptoms were reported as continuing in 8 cases (23%) Symptoms were reported as continuing in 8 cases (23%)

23. 23 Parkinsonism: Continuing Symptoms (n=8) Daily dose Daily dose –20 mg to 40 mg (NR in 2 cases) –Mean: 32 mg; Median: 30 mg –7 cases PO dosing (NR in 1 case) Duration of therapy Duration of therapy –1 day (3 doses) to 203 days (NR in 1 case) –Mean: 80 days; Median: 81 days

24. 24 Tardive Dyskinesia (67 cases)

25. 25 Tardive Dyskinesia (67 cases) Concomitant medications associated with development of movement disorders reported in 25 cases Concomitant medications associated with development of movement disorders reported in 25 cases –Antidepressants (14) –Antiemetics (3) –Antipsychotics (4) Drug therapy was used to treat the AE in 19 cases Drug therapy was used to treat the AE in 19 cases –Diphenhydramine/anticholinergic (10) –Benztropine (10) –Anxiolytic (10) Symptoms were reported as improved or resolved in 12 cases Symptoms were reported as improved or resolved in 12 cases Symptoms were reported as continuing in 20 cases (30%) Symptoms were reported as continuing in 20 cases (30%)

26. 26 Tardive Dyskinesia: Continuing Symptoms (n=20) Daily dose Daily dose – 5 mg to 80 mg (NR in 7 cases) –Mean: 53 mg; Median 40 mg –Oral dosing in 15 cases; IV dosing in 1 case; Combination IV/PO in one case (NR in 4 cases) Duration of therapy Duration of therapy –1 day to 4715 days (NR in 5 cases) –Mean: 769 days; Median 165 days

27. 27 Further analysis Characteristics of cases reporting continuing symptoms and short term therapy Characteristics of cases reporting continuing symptoms and short term therapy Cases of TD related to short term therapy Cases of TD related to short term therapy

28. 28 Characteristics of Cases with Continuing Symptoms 50 cases in review (out of 401) reported continuing symptoms 50 cases in review (out of 401) reported continuing symptoms –8 Parkinsons –20 TD –9 Akathisia –12 acute dystonia –1 NMS (likely a dystonic reactions) 27/50 cases with continuing symptoms reported a duration of therapy >30 days 27/50 cases with continuing symptoms reported a duration of therapy >30 days –8 cases did not report duration of therapy

29. 29 Characteristics of Cases with Continuing Symptoms 15 cases with continuing symptoms had a duration of therapy of <31 days 15 cases with continuing symptoms had a duration of therapy of <31 days –7 of these cases were acute dystonia 8 cases with continuing symptoms had a duration of therapy of ≤ 3 days 8 cases with continuing symptoms had a duration of therapy of ≤ 3 days –1 Parkinsonism, 2 TD, 4 Acute dystonia, 1 NMS (likely a dystonic reaction) –Most (6) occurred after at least 3 doses

30. 30 Representative Case A 49 year old female received 2 doses of metoclopramide 20 mg PO over 2 days for treatment of gastric reflux. Concomitant therapy included cimetidine. On day 2 of therapy she developed dystonic reactions consisting of torticollis and trismus. Her dystonic reaction was reversed by diphenhydramine. However she subsequently complained of left sided weakness and temporary loosening of the teeth. A 49 year old female received 2 doses of metoclopramide 20 mg PO over 2 days for treatment of gastric reflux. Concomitant therapy included cimetidine. On day 2 of therapy she developed dystonic reactions consisting of torticollis and trismus. Her dystonic reaction was reversed by diphenhydramine. However she subsequently complained of left sided weakness and temporary loosening of the teeth.

31. 31 Representative Case A 34 year old female with nausea received metoclopramide 10 mg PO TID for 3 doses and experienced difficulty breathing, extremity shaking, head and neck “jerking back”. She went to the ED where she was treated with benztropine after which she started to relax, however symptoms still occurred. She was subsequently treated with lorazepam and paroxetine, which did not completely relieve the symptoms. She was seen in the ED and by neurologists several times for reactions milder than the first reaction. Approximately 3 months later she still suffers from head pain, dizziness, tingling, pressure, fatigue, agitation, involuntary shaking, muscle spasms, and neck pain among other symptoms. A 34 year old female with nausea received metoclopramide 10 mg PO TID for 3 doses and experienced difficulty breathing, extremity shaking, head and neck “jerking back”. She went to the ED where she was treated with benztropine after which she started to relax, however symptoms still occurred. She was subsequently treated with lorazepam and paroxetine, which did not completely relieve the symptoms. She was seen in the ED and by neurologists several times for reactions milder than the first reaction. Approximately 3 months later she still suffers from head pain, dizziness, tingling, pressure, fatigue, agitation, involuntary shaking, muscle spasms, and neck pain among other symptoms.

32. 32 Representative Case A 27 year old male received 3 doses of metoclopramide 10 mg PO over 2 days for diabetic gastroparesis. He experienced a dystonic reaction with psychotic tendencies, agitation, and agitation with suicidal tendencies on the second day of therapy. He was treated in the ED with diphenhydramine and lorazepam. Once discharged, he continued to have symptoms of inability to concentrate, slowed mental processing, difficulty focusing, eye strain, vertigo, loss of equilibrium, fatigue, dizziness, and hallucinations A 27 year old male received 3 doses of metoclopramide 10 mg PO over 2 days for diabetic gastroparesis. He experienced a dystonic reaction with psychotic tendencies, agitation, and agitation with suicidal tendencies on the second day of therapy. He was treated in the ED with diphenhydramine and lorazepam. Once discharged, he continued to have symptoms of inability to concentrate, slowed mental processing, difficulty focusing, eye strain, vertigo, loss of equilibrium, fatigue, dizziness, and hallucinations

33. 33 Cases of Tardive Dyskinesia associated with Duration of therapy <30 days Concern about risk to “chronic over- users” of migraine therapy Concern about risk to “chronic over- users” of migraine therapy Tardive dyskinesia can be a long term/permanent adverse event Tardive dyskinesia can be a long term/permanent adverse event 25 th percentile of duration of therapy 29.5 days 25 th percentile of duration of therapy 29.5 days

34. 34 Distribution of TD cases based on duration of therapy (n=67) Duration of Therapy (days)

35. 35 Cases of Tardive Dyskinesia associated with Duration of therapy <30 days 15 cases of TD reported a duration of therapy <31 days 15 cases of TD reported a duration of therapy <31 days Status of recovery not reported in 9 cases Status of recovery not reported in 9 cases Symptoms reported as resolved in 1 case Symptoms reported as resolved in 1 case Continuing symptoms were reported in 5 cases Continuing symptoms were reported in 5 cases –2/5 cases reported symptoms as improved –2/5 cases reported IV dosing –4/5 cases reported daily doses of 40 mg Unable to distinguish “chronic/intermittent” vs “chronic/continuous” Unable to distinguish “chronic/intermittent” vs “chronic/continuous”

36. 36 Dosing characteristics Cases of movement disorders associated with intermittent dosing not discriminated in AERS Cases of movement disorders associated with intermittent dosing not discriminated in AERS –Intermittent dosing not clearly described in the reports –Not commonly used –Not reported –Few movement disorder related adverse events

37. 37 Conclusions Most reports with continuing symptoms of the adverse event involved long term therapy (>30 days) Most reports with continuing symptoms of the adverse event involved long term therapy (>30 days) –Intermittent vs. continuous Eight cases in which very short term therapy (≤ 3 days) led to continuing symptoms Eight cases in which very short term therapy (≤ 3 days) led to continuing symptoms Five cases of TD associated with therapy <31 days reported continuing symptoms Five cases of TD associated with therapy <31 days reported continuing symptoms Concomitant medications associated with movement disorders frequently present in the cases Concomitant medications associated with movement disorders frequently present in the cases 2/8 deaths from NMS occurred after <3 days of therapy 2/8 deaths from NMS occurred after <3 days of therapy

38. 38 Acknowledgements Cindy Kortepeter, PharmD Cindy Kortepeter, PharmD Kate Phelan, RPh Kate Phelan, RPh Mark Avigan, MD CM Mark Avigan, MD CM Sigal Kaplan, PhD, BS Pharm Sigal Kaplan, PhD, BS Pharm Judy Staffa, MPH, RPh Judy Staffa, MPH, RPh