RHOTRIMINE CAPSULE

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Active ingredient:
TRIMIPRAMINE (TRIMIPRAMINE MALEATE)
Available from:
SANOFI-AVENTIS CANADA INC
ATC code:
N06AA06
INN (International Name):
TRIMIPRAMINE
Dosage:
75MG
Pharmaceutical form:
CAPSULE
Composition:
TRIMIPRAMINE (TRIMIPRAMINE MALEATE) 75MG
Administration route:
ORAL
Units in package:
100
Prescription type:
Prescription
Therapeutic area:
TRICYCLICS AND OTHER NOREPINEPHRINE-REUPTAKE INHIBITORS
Product summary:
Active ingredient group (AIG) number: 0102479005; AHFS: 28:16.04.28
Authorization status:
APPROVED
Authorization number:
00761656
Authorization date:
2006-05-29

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PRODUCT MONOGRAPH

RHOTRIMINE

(Trimipramine)

12.5, 25, 50 and 100 mg Tablets

75 mg Capsules

Tricyclic Antidepressant

sanofi-aventis Canada Inc.

Date of Preparation:

2150 St. Elzear Blvd. West

May 19, 2006

Laval, Quebec H7L 4A8

Control No. 105835

s-a Version 1.0 dated

ACTION

RHOTRIMINE (trimipramine) is a tricyclic antidepressant with sedative properties. It has also

anticholinergic properties and potentiates the sympathetic responses, presumably by blocking the

re-uptake of norepinephrine which has been released by the presynaptic neurones. Trimipramine has

a quinidine-like effect on the heart and produces E.K.G and E.E.G. changes similar to those of other

tricyclic antidepressants.

INDICATIONS

RHOTRIMINE (trimipramine) is indicated in the drug treatment of depressive illness. It is

particularly effective in endogenous depression. It may also be useful in some patients with neurotic

depression.

CONTRAINDICATIONS

RHOTRIMINE (trimipramine) is contraindicated in cases of known hypersensitivity to the drug. The

possibility of cross-sensitivity with other dibenzazepine compounds should also be kept in mind.

Monoamine oxidase inhibitors should not be administered concomitantly with RHOTRIMINE and

a two-week delay is recommended before using the drug in patients who have received an MAO

inhibitor. Treatment with RHOTRIMINE should be started with small doses and increased

progressively, depending on tolerance and response.

Because of its anticholinergic properties, RHOTRIMINE is contraindicated in patients with narrow

angle glaucoma and prostatic hypertrophy.

It is also contraindicated during the acute recovery phase following myocardial infarction and in the

presence of acute congestive heart failure.

WARNINGS

Tricyclic antidepressants, particularly in high doses, have been reported to produce arrhythmias,

sinus tachycardia, and prolongation of conduction time. A few instances of unexpected death have

been reported in patients with cardiovascular disorders. Myocardial infarction and stroke have also

been reported with drugs of this class. Therefore, RHOTRIMINE (trimipramine) should be

administered with caution to patients with a history of cardiovascular disease, those with circulatory

lability and elderly patients. In such cases, treatment should be initiated with low doses, with

progressive increases only if required and well tolerated.

Close supervision is required for hyperthyroid patients or those receiving thyroid medication.

Patients receiving RHOTRIMINE should be advised against driving or engaging in activities

requiring mental alertness and physical co-ordination until their response to the drug has been well

established. They should also be cautioned that the response to alcohol might be potentiated.

Use in pregnancy

The safety of trimipramine during pregnancy and lactation has not been established and, therefore,

it should not be used in women of childbearing potential or nursing mothers, unless, in the opinion

of the physician, the potential benefits to the patient outweigh the possible hazards to the fetus.

Use in children

RHOTRIMINE is not recommended for use in children since safety and effectiveness in this age

group have not been established.

PRECAUTIONS

RHOTRIMINE

(trimipramine)

precipitate

aggravate

psychotic

manifestations

schizophrenic patients and hypomanic or manic episodes in manic-depressive patients. This may

require reduction of dosage, discontinuation of the drug, and/or administration of an antipsychotic

agent.

The possibility of suicide in seriously depressed patients may remain until significant remission

occurs. Such patients should be closely supervised throughout therapy and consideration should be

given to the possible need for hospitalization and/or concomitant ECT. This type of patient should

not have easy access to large quantities of trimipramine.

Since tricyclic agents are known to reduce the seizure threshold, trimipramine should be

administered

with

caution

patients

with

history

convulsive

disorders.

Concurrent

administration of ECT and trimipramine may be hazardous and, therefore, such treatment should be

limited to patients for whom it is essential.

Tricyclic antidepressants may give rise to paralytic ileus, particularly in the elderly and in

hospitalized patients. Therefore, appropriate measures should be taken if constipation occurs.

Combined use with other drugs acting on the central nervous system, such as alcohol, barbiturates

and other CNS depressants, should be undertaken with recognition of the possibility of potentiation.

Tricyclic drugs may also block the antihypertensive effects of guanethidine and related compounds.

When trimipramine is given with anticholinergic agents or sympathomimetic drugs, close

supervision and careful adjustment of dosages are required. Caution is also advised if patients

receive large doses of ethchlorvynol and tricyclic antidepressants concurrently.

Trimipramine should be used with caution in patients with impaired liver function or with a history

of hepatic damage or blood dyscrasias. Periodic blood counts and liver function tests should be

performed when patients receive trimipramine in large doses or over prolonged periods.

ADVERSE REACTIONS

The similarities among the tricyclic antidepressant drugs require that each of the reactions be

considered when trimipramine is administered. Some of the adverse reactions included in this listing

have not in fact been reported with trimipramine.

Behavioral

Drowsiness (mainly during initial therapy), fatigue, excitement, agitation, restlessness, insomnia,

shifts

hypomania

mania,

activation

latent

psychosis,

disorientation,

confusion,

hallucinations, delusions, nightmares, jitteriness, anxiety, giddiness.

Neurological

Seizures, dizziness, dysarthria, ataxia, tremor, dystonia, extrapyramidal symptoms, numbness,

tingling, paresthesias of the limbs, peripheral neuropathy, headache, alteration in EEG patterns,

tinnitus, slurred speech.

Autonomic

Dry mouth, urinary retention, constipation, paralytic ileus, disturbance of accomodation, blurred

vision, precipitation of latent and aggravation of existing glaucoma, mydriasis, vertigo, syncope.

Cardiovascular

Palpitations, tachycardia, orthostatic hypotension, hypertension, a quinidine-like effect and other

reversible EKG changes such as flattening or inversion of T-waves, bundle branch block, depressed

S-T segments, prolonged conduction time and asystole, arrhythmias, heart block, fibrillation,

myocardial infarction, stroke, and unexpected death in patients with cardiovascular disorders.

Endocrine

Changes in libido, weight gain and loss, testicular swelling, gynecomastia and impotence in the

male, breast enlargement and galactorrhea in the female, elevation and lowering of blood sugar

levels.

Allergic or Toxic

Skin rash, edema, pruritus, photosensitivity, obstructive jaundice and bone marrow depression,

including agranulocytosis, leukopenia, eosinophilia, purpura and thrombocytopenia.

Gastrointestinal

Nausea, epigastric distress, heartburn, vomiting, anorexia, increased appetite, stomatitis, peculiar

taste, diarrhea.

Miscellaneous

Weakness, urinary frequency, increased perspiration, alopecia, parotid swelling, black tongue.

Withdrawal Symptoms

Abrupt cessation of treatment after prolonged administration may produce nausea, headache and

malaise. These symptoms are not indicative of addiction.

SYMPTOMS AND TREATMENT OF OVERDOSAGE

Symptoms

Drowsiness, mydriasis, dysarthria, general weakness, excitement, agitation, hyperactive reflexes,

muscle spasms and rigidity, hypothermia, hyperpyrexia, vomiting, perspiration, rapid thready pulse,

convulsions, severe hypotension, hypertension, tachycardia, disturbances of cardiac conduction,

arrhythmia, congestive heart failure, circulatory collapse, respiratory depression and coma. In

patients with glaucoma, even average doses may precipitate an attack.

Treatment

There is no specific antidote and treatment is essentially symptomatic and supportive. Cardiac

arrythmias and CNS involvement pose the greatest threat and may occur suddenly even when initial

symptoms appear to be mild. Therefore, patients who may have ingested an overdosage of

trimipramine, particularly children, should be hospitalized and kept under close surveillance.

The stomach should be emptied as quickly as possible by gastric lavage or, if the patient is alert, by

induced emesis. It may be helpful to leave the tube in the stomach, with irrigation (with an

electrolyte balanced fluid) and continual aspiration of stomach contents possibly promoting more

rapid elimination of the drug from the body. If the patient is not alert, a cuffed endotracheal tube

should be inserted before lavage is performed and emesis should not be induced. Administration

of activated charcoal may help reduce absorption of RHOTRIMINE. In cases of severe intoxication

dialysis may be undertaken, although the efficacy of such a procedure in tricyclic poisoning is

doubtful due to low plasma concentrations of these drugs.

Treatment should be designed to insure maintenance of the vital functions. An open airway should

be maintained. Failing respiration must be maintained by artificial means, but respiratory stimulants

should not be used. Hyperpyrexia should be controlled by external measures, such as ice packs and

cooling sponge baths. Bladder cathterization should be performed in the unconscious patient.

ECG monitoring in an intensive care unit is recommended in all patients, particularly in the presence

of ECG abnormalities, and should be maintained for several days after the cardiac rhythm has

returned to normal. Because of its effects on cardiac conduction, digitalis should be used only with

caution. If rapid digitalization is required for the treatment of congestive heart failure, special care

should be exercised in using the drug.

External

stimulation

should

minimized

reduce

tendency

convulsions.

anticonvulsant is necessary, administer intravenous diazepam; barbiturates should be avoided since

they intensify respiratory depression, particularly in children, and aggravate hypotension and coma.

Shock should be treated with supportive measures such as intravenous fluids, oxygen and

corticosteroids. Pressor agents, such as noradrenaline (but NOT adrenaline), are rarely indicated and

should be given only after careful consideration and under continuous monitoring.

The slow intravenous administration of physostigmine salicylate has been reported to reverse most

the cardiovascular and

CNS anticholinergic

manifestation of tricyclic overdosage.

recommended dosage in adults has been 1 to 2 mg in very slow intravenous injection. In children,

the initial dosage should not exceed 0.5 mg and should be adjusted to age and response. Since

physostigmine has a short duration of action, administration may have to be repeated at 30 to 60

minute intervals.

Deaths by deliberate or accidental overdosage have occurred with this class of drugs. Since the

propensity for suicide is high in depressed patients, a suicide attempt by other means may occur

during the recovery phase. The possibility of simultaneous ingestion of other drugs should also be

considered.

DOSAGE AND ADMINISTRATION

As with other psychotropic drugs, the dosage of RHOTRIMINE (trimipramine) should be adapted

to the requirements of each individual patient. Treatment should be initiated at the lowest

recommended dose and increased gradually, noting carefully the clinical response and any evidence

of intolerance. It should be kept in mind that a lag in therapeutic response usually occurs at the

onset of therapy, lasting from several days to a few weeks. Increasing the dosage does not normally

shorten this latent period and may increase the incidence of side effects.

Initial Dosage

Adults

The recommended initial dose is 75 mg daily in two or three divided doses. Initial tolerance may be

tested by giving the patient 25 mg in the evening of the first day. The initial dose should be

increased by 25 mg increments, usually up to 150 mg daily, preferably by adding to the late

afternoon and/or bedtime doses. In the case of severely depressed patients, a higher initial dose of

100 mg daily in two or three divided doses may be indicated. The usual optimal dose is 150 to 200

mg daily, but some patients may require up to 300 mg daily, depending on tolerance and response

of each individual patient.

Elderly or debilitated patients

In these patients it is advisable to give a test dose of 12.5 to 25 mg and after 45 minutes examine the

patient sitting and standing to check for orthostatic hypotension. Initial doses should usually be no

more than 50 mg a day in divided doses, with weekly increments of no more than 25 mg a week,

leading to a usual therapeutic dose range of 50 to150 mg a day. Blood pressure and cardiac rhythm

must be checked frequently, particularly in patients who have unstable cardiovascular function.

Maintenance dosage

Once a satisfactory response has been obtained, the dosage should be adjusted to the lowest level

required to maintain symptomatic relief. Medication should be continued for the expected duration

of the depressive episode in order to minimize the possibility of relapse following clinical

improvement.

When a maintenance dosage has been established as described above, RHOTRIMINE may be

administered in a single dose before bedtime, provided such a dosage regimen is well tolerated.

AVAILABILITY

Tablets:

12.5 mg:

Each round, coated, dark pink tablet contains: trimipramine 12.5 mg. One side of the

tablet is plain and the other side contains the logo “RH”. Bottles of 500.

25 mg:

Each round, coated, dark pink tablet contains: trimipramine 25 mg. The tablet is

plain on one side and identified “25" on the other. Bottles of 100 and 500.

50 mg:

Each round, coated, dark pink tablet contains: trimipramine 50 mg. The tablet is

plain on one side and identified “50" on the other. Bottles of 500.

100 mg:

Each round, coated, dark pink tablet contains: trimipramine 100 mg. The tablet is

plain on one side and identified “100" on the other. Bottles of 100.

Capsules:

Each opaque, gelatin No. 1 capsule with pink cap and chamois body contains:

trimipramine 75 mg. Bottles of 500.

Non-medicinal ingredients:

Tablets: acetic anhyride, cellulose, colloidal silicon dioxide, diethyl phthalate, erythrosine, FD&C

Red No. 3, lactose, magnesium stearate, sodium croscarmellose, talc, titanium dioxide and zein.

Tartrazine-free.

Capsules: calcium phosphate dibasic, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 3,

gelatin, magnesium stearate, polacrillin potassium and titanium oxide. Tartrazine-free.

CHEMISTRY AND PHARMACOLOGY

Trimipramine is 5-3-(2-methyl)dimethylaminopropyl iminodibenzyl and has the following structural

formula:

As with other tricyclic antidepressants trimipramine antagonizes reserpine-induced depression and post-

electroshock depression in the rabbit and in the rat. It also potentiates the narcotic effect of ether and

hexobarbital and depresses spontaneous activity in mice, but has no cataleptic action and does not

significantly block conditioned reflex responses.

RHOTRIMINE has anti-convulsive action against maximal electroshock and a pro-convulsant effect

on metrazol-induced convulsions and displays in vitro antiserotonin and antihistaminic activity. It has

also antiemetic and analgesic properties.

Like other tricyclic drugs, trimipramine potentiates the pressor effect of norepinephrine but reduces or

reverses the pressor effect of epinephrine, and has anticholinergic properties.

It has a transient lowering effect on the blood pressure when injected intravenously and induces

tachycardia of short duration. As other tricyclic agents, in the chloralosed-anesthetized dog, subtoxic

dosage levels depress conduction in the heart muscle and broaden the QRS complex giving the picture

of a quinidine-like effect.

TOXICOLOGY

Acute toxicity

The LD

in the mouse is 58 mg/kg I.V., 200 mg/kg S.C. and 250 mg/kg P.O.

At toxic doses, the animals developed sporadic convulsions and depression; they died from respiratory

arrest during a final convulsive attack. At subtoxic dosages, mice did not present definite spontaneous

psychomotor hyperactivity, but they responded strongly to a variety of stimuli (auditory and

mechanical).

In the rat, the LD

is1140 mg/kg P.O.

In the dog, single doses as high as 2000 mg/kg failed to produce death. This may be due to either the

low toxicity of the drug or a loss of dose by emesis. At all doses levels these animals showed decreased

activity, dyspnea and prostration.

Sub-acute toxicity

Sub-acute studies in rats at oral dosages of 0, 20 and 40 mg/kg and in dogs at 0, 15 and 30 mg/kg did

not influence the weight curve of the treated groups of animals. Hematological tests before, during and

after treatment yielded normal results in the rat, while in the dog signs of anemia became evident at the

end of treatment. A slight increase in urinary bile salts and occasionally in urobilin levels was noted,

but there was no damage to the liver tissue.

Chronic toxicity

A chronic toxicity study using daily oral doses of 6.67, 20 and 60 mg/kg of RHOTRIMINE for 52

weeks in rats and for 26 weeks in dogs, produced at the lowest level no deleterious effect on survival,

weight gain, appearance and behavior. Hematology, organ weights in both species and urinalysis,

SGPT, SGOT, serum alkaline phosphatase, and blood urea nitrogen, in the dogs were within normal

limits.

Dose-related mild liver and kidney changes, were observed in both species; the incidence of kidney

changes being somewhat higher in the rat with a predominance at the 20 mg/kg dose level.

Reproduction studies

There was no difference in the average size of litters produced by female rats given 0, 7 and 50 mg/kg

daily from the sixth to the sixteenth day of pregnancy.

The administration of 0, and 500 mg/kg daily in the diet to rats of both sexes for one month before

mating and then throughout the ensuing gestations and lactations resulted in comparable average litter

sizes; there was no adverse effect on fertility, nor any evidence of embryopathic effects. Oral dosages

of 0, 6 to 7, and 14 to 28 mg/kg administered to pregnant rabbits did not appear to produce significant

teratogenic effects but the results of this study were inconclusive.

BIBLIOGRAPHY

BAN, T.A. Clinical pharmacology of the tricyclic antidepressants. Applied Therapeutics, 8,

(9), 779-785, September 1966.

BURKE, B.V., SAINSBURY, M.J. and MEZO, B.A. A comparative trial of amitriptyline and

trimipramine in the treatment of depression. The Medical Journal of Australia, 1, 1216, June

17, 1967.

DUNLEAVY, D.L.F., BREZINOVA, V., OSWALD, I., MacLEAN, A.W. and TINKER, M.

Changes during weeks in effects of tricyclic drugs on the human sleeping brain. Brit. J.

Psychiat., 120, 1972.

GAMBS, POUGET, CHAMPEAU, MIRIBEL, MARINIER and AUGE. Aspects cliniques et

électro-encéphalographiques du traitement par le 7162 R.P. Ann. Méd.-Psychol., 120, 2 (3),

410-417, October 1962.

GERAUD, J., GAYRAL, L., MOUTON, P., CANDEBAT, L. and ROUX, G. Notes sur

l’emploi de la triméproprimine (Surmontil) pour le traitement de la dépression et de la

mélancolie. Ann. Méd.-Psychol., 120, 2, (2), 258-262, July 1962.

HUSSAIN, M.Z. and CHAUDHRY, Z.A. Single versus Divided Daily Dose of Trimipramine

in the treatment of Depressive Illness. Am. J. Psychiatry, 130, 10, 1142-1144, October 1973.

JUILLET, P., DOREY, R., COREAU, P. and RANCUREL, G. Action de la triméproprimine

(7162 R.P.) dans certains états névrotiques. Ann. Méd.-Psychol., 120, 1, (3), 586-592, March

1962.

JULOU, L., LEAU, O., DUCROT, R., FOURNEL, J. and BARDONE, M.C. Propriétés

pharmacodynamiques générales du (diméthylamino-3'méthyl-2' propyl-1')-5 iminodibenzyle

(7162 R.P.) et de ses isomères optiques, droit (10663 R.P.) et gauche (10645 R.P.). Compt.

Rend. Soc. Biol., 155, (2), 307-312, August 31, 1961.

KRISTOF, F.E., LEHMANN, H.E and BAN, T.A. Systematic studies with trimepramine - a

new antidepressive drug. Cant. Psychiat. Assoc. J., 12, (5), 517-520, October 1967.

LAMBERT,

P.A.

GUYOTAT,

nouvel

antidépresseur

sédatif

dérivé

l’iminodibenzyle, le 7162 R.P. Essais thérapeutiques. Presse Méd., 69, (31), 1425-1428, June

1961.

LAMBERT, P.S., GUYOTAT, J and CHARRIOT, G. La triméproprimine (7162 R.P.) un

nouvel antidépresseur à propriétés sédatives et tranquillisantes. Ann. Méd.-Psychol., 119, 2, (4),

713-718, November 1961.

MARSHALL, B. The treatment of depression in general practice by a single-dose schedule.

The Practitioner, 206, 806-810, June 1971.

RICKELS, K., GORDON, P.E., WEISE, C.C., BAZILIAN, W.E., FELDMAN, H.S., and

WILSON, D.A. Amitriptyline and Trimipramine in Neurotic Depressed Outpatients : A

Collaborative Study. Amer. J. Psychiat. 127(2) : 208-218, Aug. 1970.

ROULEAU, Y. L’emploi du Surmontil dans les états dépressifs. Laval Méd., 35, (10), 1091-

1092, December 1964.

SALZMANN, M.M. A controlled trial with trimipramine, a new antidepressant drug. Brit. J.

Psychiat., 111, (480), 1105-1106, November 1965.

SMITH, R., AMIN, M.M. and BAN, T.A. Trimipramine in the treatment of depression : a

comparison of single vs divided dose administration. Psychopharmacology Bulletin, 14, (1),

42-43, 1978.

VALENTINE, M. A Profile for Trimipramine. J. Int. Med. Res., 4, 125-127, 1976.

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