http://www.forces.gc.ca/health/hs_staff_sites/drug_review_fed/E ngraph/modulon_e.asp

[Guest guest]

Regards the new medication. It was a painful spasm

filled night and morning, but by noon I was actually starting to empty

out. Also now, 2 pm, my hands and feet as well as eyes are losing

the edema I've had for over a month. Just have to stay near the

bathroom. Of course it is only the first day and it will take much

longer to see if this works for me long time. No one can say how

similarly MSA and IBS are really, but well worth the shot. I'll

keep you posted. Surprised no-one has mentioned this med before -

is it avaialbe in the US?

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Agenda Item 11c

Federal Pharmacy and Therapeutics Committee

Health Services

Trimebutine Maleate (Modulon Tablets)

[image]

[information for

Staff]

October 1999

Standards of

1. REQUEST, INDICATIONS, PURPOSE

Practice

Drug Review Federal Request

Medical Info Sheets Purpose

Interim Policy Docs Approved indications

Contraindications

Operations

Recommended dosage

Information

Precautions

Adverse reactions

Management/Technology

Health Information 2. MECHANISM OF ACTION

Links

on the Internet 3.

PHARMACOKINETICS

Physiotherapy

Information

Drug interactions

1HSOTU

4. SEARCH STRATEGY AND FINDINGS

A. Search strategy

B. Inclusion criteria

C. Assessment principles

D. Therapeutic goals

E. Primary outcome measures used in available clinical

trials

F. Search findings

Download Acrobat ReaderG. Trials suitable for critical appraisal

5. CONCLUSIONS BASED ON CLINICAL TRIALS

6. SUPPLEMENTARY INFORMATION

A. Cost and availability

B. Does the drug show incremental benefit in proportion

to incremental cost?

C. Is the drug more acceptable for use in remote areas?

D. Is the drug listed in provincial formularies?

E. Place in therapy

F. Table comparing departmental utilization of select

agents

G. Departmental Coverage Status

7. REFERENCES

---------------------------------------------------------

Federal Pharmacy and Therapeutics Committee

SUMMARY TRIMEBUTINE MALEATE

Brand Name Modulon

Therapeutic 12:08.08 Antimuscarinics and

Classification antispasmodics

ATC A03AX Antispasmodic and

anticholinergic agents and

propulsives: Other synthetic

anticholinergic agents

Dosage form and Trimebutine 100mg tablets

strength

1. REQUEST, INDICATIONS, PURPOSE

Request

A submission was made to NIHB for approval of

trimebutine maleate tablets and injectable. This product

was reviewed in 1997 (previous report included) and was

removed as a benefit December 31, 1997.

Purpose:

To determine if sufficient evidence exists to support

the role of trimebutine maleate in the treatment of

irritable bowel syndrome and postoperative paralytic

ileus.

Approved indications (HPB)

* Treatment and relief of symptoms associated with

irritable bowel syndrom (spastic colon)

* Postoperative paralytic ileus in order to

accelerate the resumption of the intestinal transit

following abdominal surgery.

Contraindications: Patients with known hypersensitivity

to trimebutine maleate or any excipient.

The injectable is contraindicated in neonates.

Recommended dosage

Tablets: up to 600mg daily in divided doses, either as

2-100mg tablets t.i.d. before meals or as 1-200mg tablet

t.i.d. before meals.

[Top of Page]

Precautions:

* Use in pregnant women is not recommended, although

studies have not shown any drug related adverse

effects on the course or outcome of pregnancy in

lab animals by either the oral or parenteral

routes.

* Not recommended for use in children under 12 years

of age.

Adverse reactions

Tablets: gastrointestinal effects (dry mouth, foul

taste, diarrhea, dyspepsia, epigastric pain, nausea and

constipation) occurred in 3.1% of patients

CNS effects (drowsiness, fatigue, dizziness, hot/cold

sensations and headaches) were reported in 3.3%

Allergic reactions (e.g., rash) occurred in 0.4% of

patients.

Miscellaneous effects (menstrual problems, painful

enlargement of the breast, anxiety, urine retention, and

slight deafness) were reported infrequently.

2. MECHANISM OF ACTION

Trimebutine is a noncompetitive spasmolytic agent. It

has moderate opiate receptor affinity and has marked

antiserotonin activity especially on 'mu' receptors. The

mechanism of action appears to be poorly understood

since reports in the literature and product monograph

are scant.

3. PHARMACOKINETICS

As with the mechanism of action, the pharmacokinetics of

trimebutine appear to be poorly defined. Descriptions of

pharmacokinetics do not appear to exist, and are not

included in the product monograph.

[Top of Page]

Drug interactions

Trimebutine increases the duration of

d-tubocurarine-induced cuarization. No other interaction

has been noted.

4. SEARCH STRATEGY AND FINDINGS

A. Search strategy

MedLine was searched (1966 to present) using the search

strategy:

" trimebutine " AND " irritable bowel syndrome OR

paralytic

ileus " AND " human "

B. Inclusion criteria

Double-blind, randomized, placebo-controlled or

comparative studies in patients with irritable bowel

syndrome or post-surgical paralytic ileus published

since the previous review by NIHB (February 1997).

C. Assessment principles

* Does trimebutine provide a significant therapeutic

advantage over other agents used in the treatment

of irritable bowel syndrome or post-surgical

paralytic ileus?

* Appropriate comparators identified are dicyclomine

and pinaverium.

D. Therapeutic goals

Improvement in symptoms of IBS.

E. Primary outcome measures used in available clinical

trials

N/A

[Top of Page]

F. Search findings

No clinical studies were located that met with the

inclusion criteria.

Clinical practice guidelines were recently published in

the Canadian Medical Association Journal.

G. Trials suitable for critical appraisal

No clinical trial will be reviewed, since no new trials

have been published since the previous review. Please

refer to review by Dr. W.G. , dated 2/20/97.

The clinical practice guidelines, from CMAJ, appear to

be based on evidence, where available, and clearly

acknowledge the limitations of the published evidence in

the area of IBS. (See appendix)

With regards to medication use, the guidelines' authors

state:

" Most patients require no drug treatment. Moreover, the

prescription pad should not substitute for more

important aspects of treatment such as listening,

validating, educating, and identifying and reinforcing

coping strategies in a long-term therapeutic alliance.

There is no level I evidence that any drug is effective

in alleviating IBS, although individual symptoms may

respond to specific agents. Treatment trials are

confounded by a placebo effect as high as 71%.

Conversely, there is insufficient evidence to recommend

a total ban on drug use. Regrettably, there are no

reports of drug trials in primary care, nor of trials

that test the benefits of medication given as needed for

individual symptoms such as acute pain or bloating. "

More specifically, with regards to antispasmodics,

including trimebutine:

" Antispasmodic agents such as trimebutine, pinaverium

bromide, hyoscine butyl bromide and dicyclomine can

modify colonic motility and therefore may decrease

severe, acute abdominal pain associated with IBS,

especially if it is postprandial. Randomized controlled

trials of these agents in patients with IBS had serious

methodological flaws, and perhaps this explains in part

why none convincingly demonstrated a benefit of any of

these agents over a placebo. Nevertheless, some

physicians believe that a short-term trial of one of

these drugs is justified in patients with attacks of

severe pain. Tricyclic antidepressants in small doses

can alleviate pain in IBS, but they have anticholinergic

side effects that may worsen constipation. Narcotic

analgesics should be avoided. "

[Top of Page]

5. CONCLUSIONS BASED ON CLINICAL TRIALS

As outlined by the authors of the clinical practice

guidelines, high quality evidence to support the use of

trimebutine, or other antispasmodics, in the treatment

of IBS is lacking. They do state that there is also a

lack of evidence to support NOT using medications in the

treatment of IBS. Their recommendation is that the

patient be educated regarding dietary approaches, and

medications be used to target specific symptoms such as

diarrhea or constipation.

The statement regarding short-term trials of

antispasmodic drugs appears to be an opinion, rather

than a solidly grounded recommendation based on

published evidence.

Questions for discussion:

Is there sufficient evidence to support the use of

trimebutine in the treatment of IBS?

Given the statement regarding use of medications

contained in the CMAJ's clinical practice guidelines for

IBS, what recommendation should be made to the federal

departments regarding the listing of trimebutine?

6. SUPPLEMENTARY INFORMATION

A. Cost and availability

Drug & Recommended Dose Daily cost

Monthly cost

Trimebutine (Modulon)

1.02-1.92 30.60-57.60

100-200mg tid

Dicyclomine (Bentylol,

Formulex) 10-20mg tid-qid

0.33-0.84 9.90-25.20

Pinaverium (Dicetel) 50mg

0.99 29.70

tid

B. Does the drug show incremental benefit in proportion

to incremental cost?

[Top of Page]

The value of trimebutine has not been demonstrated

equivocally, so its cost cannot be clearly justified.

C. Is the drug more acceptable for use in remote areas?

Trimebutine is no more acceptable than use of fibre

products or loperamide. It may be more acceptable than

tricyclic antidepressants due to a lower potential for

overdose.

D. Is the drug listed in provincial formularies?

* Trimebutine is a benefit in British Columbia,

Alberta, Manitoba, New Brunswick, Nova Scotia,

Newfoundland, and Yukon.

* It is not a benefit in Saskatchewan, Ontario,

Quebec, or Prince Island.

E. Place in therapy

Trimebutine is listed as a possible agent for treatment

of pain in IBS in Drugs of Choice.

Irritable bowel syndrome is not included in the most

recent edition of Therapeutic Choices.

7. REFERENCES

Paterson WG, WG, Vanner SJ, et al.

Recommendations for the management of irritable bowel

syndrome in family practice. CMAJ 1999;161:154-60.

(Accessed via Internet address:

http://www.cma.ca/cmaj/vol-161/issue-2/0154.htm)

Levine M, Lexchin J, Pellizzari R. Drugs of Choice: A

formulary for general practice. Canadian Medical

Association, Ottawa. 1997. p. 122.

Last

Modified:

2002-01-04

[Top of Page] Important

Notices

[skip header menu (access key:Z)]

[skip all menus (access key:X)]

Français Contact Help

Search Canada

Us

Site

Health Families

Pay/Benefits Defence

Site

HR HR

Initiatives Support Careers/Training HR Site

Human

Resources

Agenda Item 11c

Federal Pharmacy and Therapeutics Committee

Health Services

Trimebutine Maleate (Modulon Tablets)

[image]

[information for

Staff]

October 1999

Standards of

1. REQUEST, INDICATIONS, PURPOSE

Practice

Drug Review Federal Request

Medical Info Sheets Purpose

Interim Policy Docs Approved indications

Contraindications

Operations

Recommended dosage

Information

Precautions

Adverse reactions

Management/Technology

Health Information 2. MECHANISM OF ACTION

Links

on the Internet 3.

PHARMACOKINETICS

Physiotherapy

Information

Drug interactions

1HSOTU

4. SEARCH STRATEGY AND FINDINGS

A. Search strategy

B. Inclusion criteria

C. Assessment principles

D. Therapeutic goals

E. Primary outcome measures used in available clinical

trials

F. Search findings

Download Acrobat ReaderG. Trials suitable for critical appraisal

5. CONCLUSIONS BASED ON CLINICAL TRIALS

6. SUPPLEMENTARY INFORMATION

A. Cost and availability

B. Does the drug show incremental benefit in proportion

to incremental cost?

C. Is the drug more acceptable for use in remote areas?

D. Is the drug listed in provincial formularies?

E. Place in therapy

F. Table comparing departmental utilization of select

agents

G. Departmental Coverage Status

7. REFERENCES

---------------------------------------------------------

Federal Pharmacy and Therapeutics Committee

SUMMARY TRIMEBUTINE MALEATE

Brand Name Modulon

Therapeutic 12:08.08 Antimuscarinics and

Classification antispasmodics

ATC A03AX Antispasmodic and

anticholinergic agents and

propulsives: Other synthetic

anticholinergic agents

Dosage form and Trimebutine 100mg tablets

strength

1. REQUEST, INDICATIONS, PURPOSE

Request

A submission was made to NIHB for approval of

trimebutine maleate tablets and injectable. This product

was reviewed in 1997 (previous report included) and was

removed as a benefit December 31, 1997.

Purpose:

To determine if sufficient evidence exists to support

the role of trimebutine maleate in the treatment of

irritable bowel syndrome and postoperative paralytic

ileus.

Approved indications (HPB)

* Treatment and relief of symptoms associated with

irritable bowel syndrom (spastic colon)

* Postoperative paralytic ileus in order to

accelerate the resumption of the intestinal transit

following abdominal surgery.

Contraindications: Patients with known hypersensitivity

to trimebutine maleate or any excipient.

The injectable is contraindicated in neonates.

Recommended dosage

Tablets: up to 600mg daily in divided doses, either as

2-100mg tablets t.i.d. before meals or as 1-200mg tablet

t.i.d. before meals.

[Top of Page]

Precautions:

* Use in pregnant women is not recommended, although

studies have not shown any drug related adverse

effects on the course or outcome of pregnancy in

lab animals by either the oral or parenteral

routes.

* Not recommended for use in children under 12 years

of age.

Adverse reactions

Tablets: gastrointestinal effects (dry mouth, foul

taste, diarrhea, dyspepsia, epigastric pain, nausea and

constipation) occurred in 3.1% of patients

CNS effects (drowsiness, fatigue, dizziness, hot/cold

sensations and headaches) were reported in 3.3%

Allergic reactions (e.g., rash) occurred in 0.4% of

patients.

Miscellaneous effects (menstrual problems, painful

enlargement of the breast, anxiety, urine retention, and

slight deafness) were reported infrequently.

2. MECHANISM OF ACTION

Trimebutine is a noncompetitive spasmolytic agent. It

has moderate opiate receptor affinity and has marked

antiserotonin activity especially on 'mu' receptors. The

mechanism of action appears to be poorly understood

since reports in the literature and product monograph

are scant.

3. PHARMACOKINETICS

As with the mechanism of action, the pharmacokinetics of

trimebutine appear to be poorly defined. Descriptions of

pharmacokinetics do not appear to exist, and are not

included in the product monograph.

[Top of Page]

Drug interactions

Trimebutine increases the duration of

d-tubocurarine-induced cuarization. No other interaction

has been noted.

4. SEARCH STRATEGY AND FINDINGS

A. Search strategy

MedLine was searched (1966 to present) using the search

strategy:

" trimebutine " AND " irritable bowel syndrome OR

paralytic

ileus " AND " human "

B. Inclusion criteria

Double-blind, randomized, placebo-controlled or

comparative studies in patients with irritable bowel

syndrome or post-surgical paralytic ileus published

since the previous review by NIHB (February 1997).

C. Assessment principles

* Does trimebutine provide a significant therapeutic

advantage over other agents used in the treatment

of irritable bowel syndrome or post-surgical

paralytic ileus?

* Appropriate comparators identified are dicyclomine

and pinaverium.

D. Therapeutic goals

Improvement in symptoms of IBS.

E. Primary outcome measures used in available clinical

trials

N/A

[Top of Page]

F. Search findings

No clinical studies were located that met with the

inclusion criteria.

Clinical practice guidelines were recently published in

the Canadian Medical Association Journal.

G. Trials suitable for critical appraisal

No clinical trial will be reviewed, since no new trials

have been published since the previous review. Please

refer to review by Dr. W.G. , dated 2/20/97.

The clinical practice guidelines, from CMAJ, appear to

be based on evidence, where available, and clearly

acknowledge the limitations of the published evidence in

the area of IBS. (See appendix)

With regards to medication use, the guidelines' authors

state:

" Most patients require no drug treatment. Moreover, the

prescription pad should not substitute for more

important aspects of treatment such as listening,

validating, educating, and identifying and reinforcing

coping strategies in a long-term therapeutic alliance.

There is no level I evidence that any drug is effective

in alleviating IBS, although individual symptoms may

respond to specific agents. Treatment trials are

confounded by a placebo effect as high as 71%.

Conversely, there is insufficient evidence to recommend

a total ban on drug use. Regrettably, there are no

reports of drug trials in primary care, nor of trials

that test the benefits of medication given as needed for

individual symptoms such as acute pain or bloating. "

More specifically, with regards to antispasmodics,

including trimebutine:

" Antispasmodic agents such as trimebutine, pinaverium

bromide, hyoscine butyl bromide and dicyclomine can

modify colonic motility and therefore may decrease

severe, acute abdominal pain associated with IBS,

especially if it is postprandial. Randomized controlled

trials of these agents in patients with IBS had serious

methodological flaws, and perhaps this explains in part

why none convincingly demonstrated a benefit of any of

these agents over a placebo. Nevertheless, some

physicians believe that a short-term trial of one of

these drugs is justified in patients with attacks of

severe pain. Tricyclic antidepressants in small doses

can alleviate pain in IBS, but they have anticholinergic

side effects that may worsen constipation. Narcotic

analgesics should be avoided. "

[Top of Page]

5. CONCLUSIONS BASED ON CLINICAL TRIALS

As outlined by the authors of the clinical practice

guidelines, high quality evidence to support the use of

trimebutine, or other antispasmodics, in the treatment

of IBS is lacking. They do state that there is also a

lack of evidence to support NOT using medications in the

treatment of IBS. Their recommendation is that the

patient be educated regarding dietary approaches, and

medications be used to target specific symptoms such as

diarrhea or constipation.

The statement regarding short-term trials of

antispasmodic drugs appears to be an opinion, rather

than a solidly grounded recommendation based on

published evidence.

Questions for discussion:

Is there sufficient evidence to support the use of

trimebutine in the treatment of IBS?

Given the statement regarding use of medications

contained in the CMAJ's clinical practice guidelines for

IBS, what recommendation should be made to the federal

departments regarding the listing of trimebutine?

6. SUPPLEMENTARY INFORMATION

A. Cost and availability

Drug & Recommended Dose Daily cost

Monthly cost

Trimebutine (Modulon)

1.02-1.92 30.60-57.60

100-200mg tid

Dicyclomine (Bentylol,

Formulex) 10-20mg tid-qid

0.33-0.84 9.90-25.20

Pinaverium (Dicetel) 50mg

0.99 29.70

tid

B. Does the drug show incremental benefit in proportion

to incremental cost?

[Top of Page]

The value of trimebutine has not been demonstrated

equivocally, so its cost cannot be clearly justified.

C. Is the drug more acceptable for use in remote areas?

Trimebutine is no more acceptable than use of fibre

products or loperamide. It may be more acceptable than

tricyclic antidepressants due to a lower potential for

overdose.

D. Is the drug listed in provincial formularies?

* Trimebutine is a benefit in British Columbia,

Alberta, Manitoba, New Brunswick, Nova Scotia,

Newfoundland, and Yukon.

* It is not a benefit in Saskatchewan, Ontario,

Quebec, or Prince Island.

E. Place in therapy

Trimebutine is listed as a possible agent for treatment

of pain in IBS in Drugs of Choice.

Irritable bowel syndrome is not included in the most

recent edition of Therapeutic Choices.

7. REFERENCES

Paterson WG, WG, Vanner SJ, et al.

Recommendations for the management of irritable bowel

syndrome in family practice. CMAJ 1999;161:154-60.

(Accessed via Internet address:

http://www.cma.ca/cmaj/vol-161/issue-2/0154.htm)

Levine M, Lexchin J, Pellizzari R. Drugs of Choice: A

formulary for general practice. Canadian Medical

Association, Ottawa. 1997. p. 122.

Last

Modified:

2002-01-04

[Top of Page] Important

Notices

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vancouver, bc Canada

web:

http://aletta.0catch.com