Tofranil injection

Tofranil®

imipramine hydrochloride USP

Ampuls

For intramuscular administration

Prescribing Information

Tofranil, imipramine hydrochloride USP, the original tricyclic antidepressant, is available in ampuls for intramuscular administration. Each 2 mL ampul contains imipramine hydrochloride USP, 25 mg; ascorbic acid, 2 mg; sodium bisulfite, 1 mg; sodium sulfite, anhydrous, 1 mg. Tofranil is a member of the dibenzazepine group of compounds. It is designated 5-[3- (dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride. Its structural formula is

Imipramine hydrochloride USP is a white to off-white, odorless, or practically odorless crystalline powder. It is freely soluble in water and in alcohol, soluble in acetone, and insoluble in ether and in benzene. Its molecular weight is 316.87.

Depression: For the relief of symptoms of depression. Endogenous depression is more likely to be alleviated than other depressive states. One to three weeks of treatment may be needed before optimal therapeutic effects are evident.

The concomitant use of monoamine oxidase inhibiting compounds is contraindicated. Hyperpyretic crises or severe convulsive seizures may occur in patients receiving such combinations. The potentiation of adverse effects can be serious, or even fatal. When it is desired to substitute Tofranil in patients receiving a monoamine oxidase inhibitor, as long an interval should elapse as the clinical situation will allow, with a minimum of 14 days. Initial dosage should be low and increases should be gradual and cautiously prescribed.

The drug is contraindicated during the acute recovery period after a myocardial infarction. Patients with a known hypersensitivity to this compound should not be given the drug. The possibility of cross-sensitivity to other dibenzazepine compounds should be kept in mind.

Children have been reported to be more sensitive than adults to an acute overdosage of imipramine hydrochloride. An acute overdose of any amount in infants or young children, especially, must be considered serious and potentially fatal.

Signs and Symptoms

These may vary in severity depending upon factors such as the amount of drug absorbed, the age of the patient, and the interval between drug ingestion and the start of treatment. Blood and urine levels of imipramine may not reflect the severity at poisoning; they have chiefly a qualitative rather than quantitative value, and are unreliable indicators in the clinical management of the patient.

CNS abnormalities may include drowsiness, stupor, coma, ataxia, restlessness, agitation, hyperactive reflexes, muscle rigidity, athetoid and choreiform movements, and convulsions.

Cardiac abnormalities may include arrhythmia, tachycardia, ECG evidence of impaired conduction, and signs of congestive failure. Respiratory depression, cyanosis, hypotension, shock, vomiting, hyperpyrexia, mydriasis, and diaphoresis may also be present.

Treatment

The recommended treatment for overdosage with tricyclic antidepressants may change periodically. Therefore, it is recommended that the physician contact a poison control center for current information on treatment. Because CNS involvement, respiratory depression and cardiac arrhythmia can occur suddenly, hospitalization and close observation may be necessary, even when the amount ingested is thought to be small or the initial degree of intoxication appears slight or moderate. All patients with ECG abnormalities should have continuous cardiac monitoring and be closely observed until well after cardiac status has returned to normal; relapses may occur after apparent recovery.

In the alert patient, empty the stomach promptly by lavage. In the obtunded patient, secure the airway with a cuffed endotracheal tube before beginning lavage (do not induce emesis). Instillation of activated charcoal slurry may help reduce absorption of imipramine.

Minimize external stimulation to reduce the tendency to convulsions. If anticonvulsants are necessary, diazepam and phenytoin may be useful.

Maintain adequate respiratory exchange. Do not use respiratory stimulants.

Shock should be treated with supportive measures, such as appropriate position, intravenous fluids, and, if necessary, a vasopressor agent. The use of corticosteroids in shock is controversial and may be contraindicated in cases of overdosage with tricyclic antidepressants. Digitalis may increase conduction abnormalities and further irritate an already sensitized myocardium. If congestive heart failure necessitates rapid digitalization, particular care must be exercised.

Hyperpyrexia should be controlled by whatever external means are available, including ice packs and cooling sponge baths, if necessary.

Hemodialysis, peritoneal dialysis, exchange transfusions and forced diuresis have been generally reported as ineffective because of the rapid fixation of imipramine in tissues. Blood and urine levels of imipramine may not correlate with the degree of intoxication, and are unreliable indicators in the clinical management of the patient.

The slow intravenous administration of physostigmine salicylate has been used as a last resort to reverse severe CNS anticholinergic manifestations of overdosage with tricyclic anti- depressants; however, it should not be used routinely, since it may induce seizures and cholinergic crises.

A. Acute: Oral LD50 ranges are as follows:

Rat 355 to 682 mg/kg

Dog 100 to 215 mg/kg

Depending on the dosage in both species, toxic signs proceeded progressively from depression, irregular respiration and ataxia to convulsions and death.

B. Reproduction/Teratogenic: The overall evaluation may be summed up in the following manner:

Oral: Independent studies in three species (rat, mouse, and rabbit) revealed that when Tofranil is administered orally in doses up to approximately 2 ½ times the maximum human dose in the first 2 species and up to 25 times the maximum human dose in the third species, the drug is essentiality free from teratogenic potential. In the three species studied, only one instance of fetal abnormality occurred (in the rabbit) and in that study there was likewise an abnormality in the control group. However, evidence does exist from the rat studies that some systemic and embryotoxic potential is demonstrable. This is manifested by reduced litter size, a slight increase in the stillborn rate and a reduction in the mean birth weight.

Parenteral: In contradistinction to the oral data, Tofranil does exhibit a slight but definite teratogenic potential when administered by the subcutaneous route. Drug effects on both the mother and fetus in the rabbit are manifested in higher resorption rates and decrease in mean fetal birth weights, while teratogenic findings occurred at a level of 5 times the maximum human dose. In the mouse, teratogenicity occurred at 1 ½ and 6 ½ times the maximum human dose, but no teratogenic effects were seen at levels 3 times the maximum human dose. Thus, in the mouse, the findings are equivocal.

667764 

C94-15 (Rev. 7/94)

Geigy

Dist. by: Geigy Pharmaceuticals

Ciba-Geigy Corporation

Ardsley, New York 10502