1 Post-marketing review of Movement Disorders and Neuroleptic Malignant Syndrome associated with metoclopramide Mary Ross Southworth, PharmD Safety Evaluator,

11

Post-marketing review Post-marketing review of Movement Disorders of Movement Disorders and Neuroleptic and Neuroleptic Malignant Syndrome Malignant Syndrome associated with associated with metoclopramidemetoclopramide

Mary Ross Southworth, PharmDMary Ross Southworth, PharmDSafety Evaluator, Division of Drug Risk Safety Evaluator, Division of Drug Risk Evaluation Evaluation Office of Drug SafetyOffice of Drug SafetyCenter for Drug Evaluation and Research, FDACenter for Drug Evaluation and Research, FDA

22

Purpose of ReviewPurpose of Review MT-100: metoclopramide 16 MT-100: metoclopramide 16

mg/naproxen 500mg mg/naproxen 500mg Acute migraine treatmentAcute migraine treatment Proposed dosing chronic, but Proposed dosing chronic, but

intermittent manner intermittent manner – EpisodicEpisodic– No more than 6 tablets/monthNo more than 6 tablets/month

Risks associated with this type of Risks associated with this type of dosing?dosing?

33

BackgroundBackground

Metoclopramide well known to cause Metoclopramide well known to cause movement disordersmovement disorders

Product labelingProduct labeling– Extrapyramidal symptoms occur in 1 of 500 Extrapyramidal symptoms occur in 1 of 500

patients receiving 30 to 40 mg dailypatients receiving 30 to 40 mg daily– Parkinsonian symptoms occur after prolonged use Parkinsonian symptoms occur after prolonged use

and are usually reversibleand are usually reversible– Tardive dyskinesia most common with prolonged Tardive dyskinesia most common with prolonged

use, but can occur with shorter durations of use, but can occur with shorter durations of therapytherapy

– Neuroleptic Malignant Syndrome occurs rarelyNeuroleptic Malignant Syndrome occurs rarely Recommended Daily Dose: 5 to 20 mg QIDRecommended Daily Dose: 5 to 20 mg QID Duration of Therapy should not exceed 12 Duration of Therapy should not exceed 12

weeksweeks

44

Total Number of Prescriptions Dispensed (in thousands) in Retail Total Number of Prescriptions Dispensed (in thousands) in Retail Pharmacies Nationwide for Metoclopramide Products, IMS Health, Pharmacies Nationwide for Metoclopramide Products, IMS Health, NPA PlusNPA Plus™™, 1995-2004, 1995-2004

Source:Source:1995-1996 IMS Health, National Prescription Audit 1995-1996 IMS Health, National Prescription Audit PlusPlus™ book data- Dec 1996, USC 01200-33390™ book data- Dec 1996, USC 01200-333901997-1999 IMS NPA CD-ROM Dataview Analyzer Total Market CD-ROM Years 2000-2004, extracted February 20051997-1999 IMS NPA CD-ROM Dataview Analyzer Total Market CD-ROM Years 2000-2004, extracted February 2005

3448 3152

1682 18352084

5625

64186840 7026

7228

0

1000

2000

3000

4000

5000

6000

7000

8000

1995 1996 1997 1998 1999 2000 2001 2002 2003 2004Year

Pre

scri

pti

on

Dis

pen

sed

(i

n t

ho

usa

nd

s)

55

Points to considerPoints to consider

Reversibility of reactionReversibility of reaction Association with dose/duration of Association with dose/duration of

therapytherapy– Relationship to proposed dosing of MT-100Relationship to proposed dosing of MT-100– Potential for chronic Potential for chronic

continuous/intermittent usecontinuous/intermittent use Associated Risk factorsAssociated Risk factors

– Concomitant DrugsConcomitant Drugs– Other patient specific factorsOther patient specific factors

66

Purpose of ReviewPurpose of Review

Characterize cases of specific Characterize cases of specific adverse events reported in the adverse events reported in the Adverse Event Reporting System Adverse Event Reporting System (AERS) database associated with (AERS) database associated with metoclopramidemetoclopramide

77

AERS databaseAERS database Computerized database containing Computerized database containing

reports of adverse eventsreports of adverse events >3 million reports>3 million reports ““Spontaneous” reportingSpontaneous” reporting

– Not required of health care providersNot required of health care providers– Sponsors required to report any adverse Sponsors required to report any adverse

event of which they become awareevent of which they become aware Source of reportsSource of reports

– Drug manufacturers/sponsorsDrug manufacturers/sponsors– Health care providersHealth care providers– Lay people (consumers, patients, patients’ Lay people (consumers, patients, patients’

families, lawyers)families, lawyers)

88

Adverse Events Adverse Events

Neuroleptic Neuroleptic Malignant Malignant Syndrome (NMS)Syndrome (NMS)

Acute dystoniaAcute dystonia AkathisiaAkathisia ParkinsonismParkinsonism Tardive Tardive

dyskinesiadyskinesia

Number of case Number of case reportsreports

Daily doseDaily dose Duration of Duration of

treatmenttreatment Risk FactorsRisk Factors ReversibilityReversibility

99

Search Search Strategy/ResultsStrategy/Results Search run using each movement Search run using each movement

disorder as a search term + disorder as a search term + “metoclopramide”“metoclopramide”

Cases classified according to diagnosis Cases classified according to diagnosis made in the casemade in the case

PointsPoints– Case misclassification (tardive vs. acute)Case misclassification (tardive vs. acute)– Chronic/intermittent vs. Chronic/continuous Chronic/intermittent vs. Chronic/continuous – Underreporting due to drug labelUnderreporting due to drug label– Drug has been on the market for a long timeDrug has been on the market for a long time– Quality of reports Quality of reports

Status of recoveryStatus of recovery Time to recoveryTime to recovery

1010

Search Search Strategy/ResultsStrategy/Results

Search termSearch term Number of unique Number of unique reports reviewedreports reviewed

NMSNMS 3737

Acute DystoniaAcute Dystonia 203203

AkathisiaAkathisia 5757

Parkinson’s Parkinson’s disease/Parkinsonisdisease/Parkinsonismm

3535

Tardive DyskinesiaTardive Dyskinesia 6868

1111

Description of case Description of case seriesseries DemographicsDemographics Clinical characteristicsClinical characteristics Recovery Recovery Review cases with continuing Review cases with continuing

symptomssymptoms Representative casesRepresentative cases Focus on short term therapy Focus on short term therapy

1212

Neuroleptic Malignant Syndrome (37 Neuroleptic Malignant Syndrome (37 cases)cases)

Age Mean±SD 49.0 ± 17.7 years Daily dose Range

Mean ±SD Unreported PRN dosing

7.5 to 80 mg 33.5 ± 17.0 8 4

Route IV PO PR PO/IV Unreported

14 7 1 1 14

Indication Gastroparesis Nausea/vomiting Other GI disorder Not reported

12 10 3 12

Duration Range Median Mean ± SD Interquartile range Unrptd/Indeterminate

1 to 196 days 3 days 18.9 1, 7 days 16

1313

Neuroleptic Malignant Syndrome (37 cases)Neuroleptic Malignant Syndrome (37 cases)

Concomitant medications associated with Concomitant medications associated with development of NMS or NMS-like symptoms development of NMS or NMS-like symptoms reported in 20 casesreported in 20 cases– Antidepressants (3)Antidepressants (3)– Antiemetics (8)Antiemetics (8)– Antipsychotics (9)Antipsychotics (9)

Drug therapy was used to treat the AE in 18 Drug therapy was used to treat the AE in 18 casescases– Dantrolene (12)Dantrolene (12)– Diphenhydramine (5)Diphenhydramine (5)– Bromocriptine (6)Bromocriptine (6)

Symptoms were reported as improved or Symptoms were reported as improved or resolved in 11 cases (NR in 17 cases)resolved in 11 cases (NR in 17 cases)

Symptoms reported as continuing in 1 case Symptoms reported as continuing in 1 case (dystonic jaw clenching)(dystonic jaw clenching)

Eight patients diedEight patients died

NR= not reported

1414

Neuroleptic Malignant Syndrome: Deaths Neuroleptic Malignant Syndrome: Deaths (n=8)(n=8)

Daily doseDaily dose– 10 mg to 40 mg (NR in 3 cases)10 mg to 40 mg (NR in 3 cases)– Mean: 32 mg; Median: 40 mgMean: 32 mg; Median: 40 mg– PO dosing in 2 cases; IV dosing in 3 PO dosing in 2 cases; IV dosing in 3

cases (NR in 3 cases)cases (NR in 3 cases) Duration of therapyDuration of therapy

– 2 days (2); 5 days; 7 days; 8 days; 2 days (2); 5 days; 7 days; 8 days; 15 days (NR in two cases)15 days (NR in two cases)

NR= not reported

1515

Acute Dystonia (203 cases)Acute Dystonia (203 cases)

Age Mean±SD 32.3 ± 21.5 years Daily dose Range

Mean ±SD Various dosing PRN Unreported

0.6 to 800 mg 71.4 ± 136.2 mg 1 5 42

Route IV: PO: IV/PO: IM: IM/PO PR Unreported

68 113 5 2 1 1 12

Duration Range Median Mean Interquartile range Unreported

1 dose to 2065 days 2 days 49.7 days 1, 3 days 34

Indication Gastroparesis GERD Nausea/Vomiting Hernia Chemotherapy pretx Ulcer Pre-operatvive Other GI disorder Other Not Reported

13 26 57 6 29 4 7 21 4 36

1616

Acute Dystonia (203 cases)Acute Dystonia (203 cases)

Concomitant medications associated with Concomitant medications associated with development of movement disorders reported development of movement disorders reported in 64 casesin 64 cases– Antidepressants (16)Antidepressants (16)– Antiemetics (27)Antiemetics (27)

Drug therapy was used to treat the AE in 115 Drug therapy was used to treat the AE in 115 casescases– Diphenhydramine/anticholinergic (90)Diphenhydramine/anticholinergic (90)– Benztropine (14)Benztropine (14)– Anxiolytic (16)Anxiolytic (16)

Symptoms were reported as improved or Symptoms were reported as improved or resolved in 115 cases resolved in 115 cases

Symptoms were reported as continuing in 12 Symptoms were reported as continuing in 12 cases (6%)cases (6%)

1717

Acute Dystonia: Continuing Symptoms (n-Acute Dystonia: Continuing Symptoms (n-12)12)

Daily doseDaily dose– 10 mg to 40 mg (NR in 425 cases)10 mg to 40 mg (NR in 425 cases)– Mean: 25 mg; Median: 20 mgMean: 25 mg; Median: 20 mg– Oral dosing in 10 cases; Oral dosing in 10 cases;

Combination IV/PO dosing in 1 case Combination IV/PO dosing in 1 case (NR in 1 case)(NR in 1 case)

Duration of therapyDuration of therapy– 1 day (1 dose) to 2065 days1 day (1 dose) to 2065 days– Mean: 373 days; Median: 2.5 daysMean: 373 days; Median: 2.5 days

1818

Akathisia (57 cases)Akathisia (57 cases)Age Mean±SD 45.7 ± 18.7

Daily dose Range Mean ±SD Unreported PRN dosing Weight based

5 to 200 mg 42.3 ± 35.2 mg 10 2 1

Route IV PO SQ IV/PO Unreported

11 42 1 1 2

Duration Range Median Mean ± SD Interquartile range Unreported

1 to 2555 days 17 days 245 days 2, 86.25 days 20

Indication Gastroparesis GERD Nausea/Vomiting Hernia Chemotherapy pretx Ulcer Other GI disorder Other Not Reported

7 13 15 1 3 2 8 3 5

1919

Akathisia (57 cases)Akathisia (57 cases)

Concomitant medications associated with Concomitant medications associated with development of movement disorders development of movement disorders reported in 23 casesreported in 23 cases– Antidepressants (7)Antidepressants (7)– Antiemetics (6)Antiemetics (6)– Antipsychotics (6)Antipsychotics (6)




2020

Akathisia: Continuing symptoms (n=9)Akathisia: Continuing symptoms (n=9)

Daily doseDaily dose– 8.6 mg to 40 mg (NR in 1 case)8.6 mg to 40 mg (NR in 1 case)– Mean: 25 mg; Median: 30 mgMean: 25 mg; Median: 30 mg– Oral dosing in 8 cases (NR in 1 case)Oral dosing in 8 cases (NR in 1 case)

Duration of therapyDuration of therapy– 17 to 2555 days (NR in 1 case)17 to 2555 days (NR in 1 case)– Mean: 525 days; Median: 119 daysMean: 525 days; Median: 119 days

2121

Parkinsonism (35 cases)Parkinsonism (35 cases)

Age Mean±SD 60.5 ± 20.6 years

Daily dose Range Mean ±SD Unreported

10 to 80 mg 36.6 ± 16.9 mg 10

Route IV PO Unreported

2 24 9

Duration Range Median Mean Unreported

1 dose to 1460 days 60 days 115 days 10

Indication Gastroparesis GERD Nausea/Vomiting Hernia Other GI disorder Not Reported

7 9 6 1 3 9

2222

Parkinsonism (35 cases)Parkinsonism (35 cases)

Concomitant medications associated with Concomitant medications associated with development of movement disorders reported development of movement disorders reported in 13 casesin 13 cases– Antidepressants (5)Antidepressants (5)– Antipsychotics (3)Antipsychotics (3)

Drug therapy was used to treat the AE in 18 Drug therapy was used to treat the AE in 18 casescases– Diphenhydramine/anticholinergic (4)Diphenhydramine/anticholinergic (4)– Amantadine (2)Amantadine (2)– Antiparkinson Medication (6)Antiparkinson Medication (6)– Benztropine (3)Benztropine (3)



2323

Parkinsonism: Continuing Parkinsonism: Continuing Symptoms (n=8)Symptoms (n=8)

Daily doseDaily dose– 20 mg to 40 mg (NR in 2 cases)20 mg to 40 mg (NR in 2 cases)– Mean: 32 mg; Median: 30 mgMean: 32 mg; Median: 30 mg– 7 cases PO dosing (NR in 1 case)7 cases PO dosing (NR in 1 case)

Duration of therapyDuration of therapy– 1 day (3 doses) to 203 days (NR in 1 case)1 day (3 doses) to 203 days (NR in 1 case)– Mean: 80 days; Median: 81 daysMean: 80 days; Median: 81 days

2424

Tardive Dyskinesia (67 cases)Tardive Dyskinesia (67 cases)

Age Mean±SD 57.2 ± 18.3 Daily dose Range

Mean ±SD Unreported PRN dosing

5 to 80 mg 35 ± 14.3 mg 27 3

Route IV: PO: Both Unreported

4 52 1 11

Duration Range Median Mean Interquartile Range Unreported

1 to 4715 days 180 days 638 days 29.5, 821.25 days 20

Indication Gastroparesis GERD Nausea/Vomiting Hernia Other GI disorder Not Reported

11 16 7 3 5 26

2525

Tardive Dyskinesia (67 cases)Tardive Dyskinesia (67 cases)

Concomitant medications associated with Concomitant medications associated with development of movement disorders development of movement disorders reported in 25 casesreported in 25 cases– Antidepressants (14)Antidepressants (14)– Antiemetics (3)Antiemetics (3)– Antipsychotics (4)Antipsychotics (4)




2626

Tardive Dyskinesia: Continuing Symptoms Tardive Dyskinesia: Continuing Symptoms (n=20)(n=20)

Daily doseDaily dose– 5 mg to 80 mg (NR in 7 cases)5 mg to 80 mg (NR in 7 cases)– Mean: 53 mg; Median 40 mgMean: 53 mg; Median 40 mg– Oral dosing in 15 cases; IV dosing in Oral dosing in 15 cases; IV dosing in

1 case; Combination IV/PO in one 1 case; Combination IV/PO in one case (NR in 4 cases)case (NR in 4 cases)

Duration of therapyDuration of therapy– 1 day to 4715 days (NR in 5 cases)1 day to 4715 days (NR in 5 cases)– Mean: 769 days; Median 165 daysMean: 769 days; Median 165 days

2727

Further analysisFurther analysis

Characteristics of cases reporting Characteristics of cases reporting continuing symptoms and short continuing symptoms and short term therapyterm therapy

Cases of TD related to short term Cases of TD related to short term therapytherapy

2828

Characteristics of Cases with Characteristics of Cases with Continuing SymptomsContinuing Symptoms

50 cases in review (out of 401) 50 cases in review (out of 401) reported continuing symptomsreported continuing symptoms– 8 Parkinsons8 Parkinsons– 20 TD20 TD– 9 Akathisia9 Akathisia– 12 acute dystonia12 acute dystonia– 1 NMS (likely a dystonic reactions)1 NMS (likely a dystonic reactions)

27/50 cases with continuing symptoms 27/50 cases with continuing symptoms reported a duration of therapy >30 reported a duration of therapy >30 daysdays– 8 cases did not report duration of therapy8 cases did not report duration of therapy

2929

Characteristics of Cases with Characteristics of Cases with Continuing SymptomsContinuing Symptoms

15 cases with continuing symptoms 15 cases with continuing symptoms had a duration of therapy of <31 dayshad a duration of therapy of <31 days– 7 of these cases were 7 of these cases were acute dystoniaacute dystonia

8 cases with continuing symptoms had 8 cases with continuing symptoms had a duration of therapy of ≤ 3 daysa duration of therapy of ≤ 3 days– 1 Parkinsonism, 2 TD, 4 Acute dystonia, 1 1 Parkinsonism, 2 TD, 4 Acute dystonia, 1

NMS (likely a dystonic reaction)NMS (likely a dystonic reaction)– Most (6) occurred after at least 3 dosesMost (6) occurred after at least 3 doses

3030

Representative CaseRepresentative Case

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

3131


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

3232


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

3333

Cases of Cases of Tardive DyskinesiaTardive Dyskinesia associated with Duration of associated with Duration of therapy <30 daystherapy <30 days

Concern about risk to “chronic Concern about risk to “chronic over-users” of migraine therapy over-users” of migraine therapy

Tardive dyskinesia can be a long Tardive dyskinesia can be a long term/permanent adverse eventterm/permanent adverse event

2525thth percentile of duration of percentile of duration of therapy 29.5 daystherapy 29.5 days

3434

Distribution of Distribution of TDTD cases based cases based on duration of therapy (n=67)on duration of therapy (n=67)

0

5

10

15

20

25

30

<16 17 to30

31 to60

61 to90

>91 NR

Number of Cases

Duration of Therapy (days)

3535

Cases of Cases of Tardive DyskinesiaTardive Dyskinesia associated with Duration of associated with Duration of therapy <30 daystherapy <30 days 15 cases of TD reported a duration of 15 cases of TD reported a duration of

therapy <31 daystherapy <31 days Status of recovery not reported in 9 cases Status of recovery not reported in 9 cases Symptoms reported as resolved in 1 caseSymptoms reported as resolved in 1 case Continuing symptoms were reported in 5 Continuing symptoms were reported in 5

cases cases – 2/5 cases reported symptoms as improved2/5 cases reported symptoms as improved– 2/5 cases reported IV dosing2/5 cases reported IV dosing– 4/5 cases reported daily doses of 40 mg4/5 cases reported daily doses of 40 mg

Unable to distinguish Unable to distinguish “chronic/intermittent” vs “chronic/intermittent” vs “chronic/continuous”“chronic/continuous”

3636

Dosing characteristicsDosing characteristics Cases of movement disorders Cases of movement disorders

associated with intermittent associated with intermittent dosing not discriminated in AERSdosing not discriminated in AERS– Intermittent dosing not clearly Intermittent dosing not clearly

described in the reportsdescribed in the reports– Not commonly usedNot commonly used– Not reportedNot reported– Few movement disorder related Few movement disorder related

adverse eventsadverse events

3737

ConclusionsConclusions Most reports with continuing symptoms Most reports with continuing symptoms

of the adverse event involved long term of the adverse event involved long term therapy (>30 days)therapy (>30 days)– Intermittent vs. continuousIntermittent vs. continuous

Eight cases in which very short term Eight cases in which very short term therapy (≤ 3 days) led to continuing therapy (≤ 3 days) led to continuing symptomssymptoms

Five cases of Five cases of TDTD associated with therapy associated with therapy <31 days reported continuing symptoms<31 days reported continuing symptoms

Concomitant medications associated with Concomitant medications associated with movement disorders frequently present movement disorders frequently present in the casesin the cases

2/8 deaths from 2/8 deaths from NMSNMS occurred after <3 occurred after <3 days of therapydays of therapy

3838

AcknowledgementsAcknowledgements

Cindy Kortepeter, PharmD Cindy Kortepeter, PharmD Kate Phelan, RPhKate Phelan, RPh Mark Avigan, MD CMMark Avigan, MD CM Sigal Kaplan, PhD, BS PharmSigal Kaplan, PhD, BS Pharm Judy Staffa, MPH, RPhJudy Staffa, MPH, RPh

Documents

1 Post-marketing review of Movement Disorders and Neuroleptic Malignant Syndrome associated with metoclopramide Mary Ross Southworth, PharmD Safety Evaluator,