Protriptyline HCl is N-  methyl-5 H  -dibenzo[ a,d  ]-cycloheptene-5-propanamine hydrochloride. Its empirical formula is C 19 H 21 N·HCl and its structural formula is:

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Protriptyline HCl, a dibenzocycloheptene derivative, has a molecular weight of 299.84. It is a white to yellowish powder that is freely soluble in water and soluble in dilute HCl.

VIVACTIL* (Protriptyline HCl) is supplied as 10 mg film coated tablets. Inactive ingredients are calcium phosphate, cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, starch, talc, titanium dioxide, FD&C Yellow 6, and D&C Yellow 10.


* Registered trademark of MERCK & CO., INC.

ACTIONS

VIVACTIL is an antidepressant agent. The mechanism of its antidepressant action in man is not known. It is not a monoamine oxidase inhibitor, and it does not act primarily by stimulation of the central nervous system.

VIVACTIL has been found in some studies to have a more rapid onset of action than imipramine or amitriptyline. The initial clinical effect may occur within one week. Sedative and tranquilizing properties are lacking. The rate of excretion is slow.

INDICATIONS

VIVACTIL is indicated for the treatment of symptoms of mental depression in patients who are under close medical supervision. Its activating properties make it particularly suitable for withdrawn and anergic patients.

CONTRAINDICATIONS

VIVACTIL is contraindicated in patients who have shown prior hypersensitivity to it.

It should not be given concomitantly with a monoamine oxidase inhibiting compound. Hyperpyretic crises, severe convulsions, and deaths have occurred in patients receiving tricyclic antidepressant and monoamine oxidase inhibiting drugs simultaneously. When it is desired to substitute VIVACTIL for a monoamine oxidase inhibitor, a minimum of 14 days should be allowed to elapse after the latter is discontinued. VIVACTIL should then be initiated cautiously with gradual increase in dosage until optimum response is achieved.

VIVACTIL is contraindicated in patients taking cisapride because of the possibility of adverse cardiac interactions including prolongation of the QT interval, cardiac arrhythmias and conduction system disturbances.

This drug should not be used during the acute recovery phase following myocardial infarction.

VIVACTIL may block the antihypertensive effect of guanethidine or similarly acting compounds.

VIVACTIL should be used with caution in patients with a history of seizures, and, because of its autonomic activity, in patients with a tendency to urinary retention, or increased intraocular tension.

Tachycardia and postural hypotension may occur more frequently with VIVACTIL than with other antidepressant drugs. VIVACTIL should be used with caution in elderly patients and patients with cardiovascular disorders; such patients should be observed closely because of the tendency of the drug to produce tachycardia, hypotension, arrhythmias, and prolongation of the conduction time. Myocardial infarction and stroke have occurred with drugs of this class.

On rare occasions, hyperthyroid patients or those receiving thyroid medication may develop arrhythmias when this drug is given.

In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage.

Pediatric Usage

The safety and effectiveness of VIVACTIL in pediatric patients have not been established.

Usage in Pregnancy

Safe use in pregnancy and lactation has not been established; therefore, use in pregnant women, nursing mothers or women who may become pregnant requires that possible benefits be weighed against possible hazards to mother and child.

In mice, rats, and rabbits, doses about ten times greater than the recommended human doses had no apparent adverse effects on reproduction.

PRECAUTIONS

General

When protriptyline HCl is used to treat the depressive component of schizophrenia, psychotic symptoms may be aggravated. Likewise, in manic-depressive psychosis, depressed patients may experience a shift toward the manic phase if they are treated with an antidepressant drug. Paranoid delusions, with or without hostility, may be exaggerated. In any of these circumstances, it may be advisable to reduce the dose of VIVACTIL or to use a major tranquilizing drug concurrently.

Symptoms, such as anxiety or agitation, may be aggravated in overactive or agitated patients.

The possibility of suicide in depressed patients remains during treatment and until significant remission occurs. This type of patient should not have access to large quantities of the drug.

Concurrent administration of VIVACTIL and electroshock therapy may increase the hazards of therapy. Such treatment should be limited to patients for whom it is essential. Discontinue the drug several days before elective surgery, if possible.

Both elevation and lowering of blood sugar levels have been reported.

Information for Patients

While on therapy with VIVACTIL, patients should be advised as to the possible impairment of mental and/or physical abilities required for performance of hazardous tasks, such as operating machinery or driving a motor vehicle.

Drug Interactions

When VIVACTIL is given with anticholinergic agents or sympathomimetic drugs, including epinephrine combined with local anesthetics, close supervision and careful adjustment of dosages are required.

Hyperpyrexia has been reported when tricyclic antidepressants are administered with anticholinergic agents or with neuroleptic drugs, particularly during hot weather.

Cimetidine is reported to reduce hepatic metabolism of certain tricyclic antidepressants, thereby delaying elimination and increasing steady-state concentrations of these drugs. Clinically significant effects have been reported with the tricyclic antidepressants when used concomitantly with cimetidine. Increases in plasma levels of tricyclic antidepressants, and in the frequency and severity of side effects, particularly anticholinergic, have been reported when cimetidine was added to the drug regimen. Discontinuation of cimetidine in well-controlled patients receiving tricyclic antidepressants and cimetidine may decrease the plasma levels and efficacy of the antidepressants.

Tricyclic antidepressants may enhance the seizure risk in patients taking ULTRAM** (tramadol hydrochloride).

VIVACTIL may enhance the response to alcohol and the effects of barbiturates and other CNS depressants.


**Trademark of Ortho-McNeil Pharmaceutical

Drugs Metabolized by Cytochrome P450 2D6:   The biochemical activity of the drug-metabolizing isozyme, cytochrome P450 2D6 (debrisoquine hydroxylase), is reduced in a subset of the Caucasian population (about 7-10% of Caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme activity among Asian, African, and other populations are not yet available. Poor metabolizers have higher than expected plasma concentrations of tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small or quite large (8-fold increase in plasma AUC of the TCA).

In addition, certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble poor metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics, propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRIs), e.g., fluoxetine, sertraline, and paroxetine, inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokinetics of the SSRI involved. Nevertheless, caution is indicated in the coadministration of TCAs with any of the SSRIs, and also in switching from one class to the other. Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

Pediatric Use

The safety and effectiveness of VIVACTIL in pediatric patients have not been established.

Geriatric Use

Clinical studies of VIVACTIL did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. (See , DOSAGE AND ADMINISTRATION , and ADVERSE REACTIONS .)

ADVERSE REACTIONS

Within each category the following adverse reactions are listed in order of decreasing severity. Included in the listing are a few adverse reactions which have not been reported with this specific drug. However, the pharmacological similarities among the tricyclic antidepressant drugs require that each of the reactions be considered when protriptyline is administered. VIVACTIL is more likely to aggravate agitation and anxiety and produce cardiovascular reactions such as tachycardia and hypotension.

Cardiovascular:   Myocardial infarction; stroke; heart block; arrhythmias; hypotension, particularly orthostatic hypotension; hypertension; tachycardia; palpitation.

Psychiatric:   Confusional states (especially in the elderly) with hallucinations, disorientation, delusions, anxiety, restlessness, agitation; hypomania; exacerbation of psychosis; insomnia, panic, and nightmares.

Neurological:   Seizures; incoordination; ataxia; tremors; peripheral neuropathy; numbness, tingling, and paresthesias of extremities; extrapyramidal symptoms; drowsiness; dizziness; weakness and fatigue; headache; syndrome of inappropriate ADH (antidiuretic hormone) secretion; tinnitus; alteration in EEG patterns.

Anticholinergic:   Paralytic ileus; hyperpyrexia; urinary retention, delayed micturition, dilatation of the urinary tract; constipation; blurred vision, disturbance of accommodation, increased intraocular pressure, mydriasis; dry mouth and rarely associated sublingual adenitis.

Allergic:   Drug fever; petechiae, skin rash, urticaria, itching, photosensitization (avoid excessive exposure to sunlight); edema (general, or of face and tongue).

Hematologic:   Agranulocytosis; bone marrow depression; leukopenia; thrombocytopenia; purpura; eosinophilia.

Gastrointestinal:   Nausea and vomiting; anorexia; epigastric distress; diarrhea; peculiar taste; stomatitis; abdominal cramps; black tongue.

Endocrine:   Impotence, increased or decreased libido; gynecomastia in the male; breast enlargement and galactorrhea in the female; testicular swelling; elevation or depression of blood sugar levels.

Other:   Jaundice (simulating obstructive); altered liver function; parotid swelling; alopecia; flushing; weight gain or loss, urinary frequency, nocturia; perspiration.

Withdrawal Symptoms:   Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.

DOSAGE AND ADMINISTRATION

Dosage should be initiated at a low level and increased gradually, noting carefully the clinical response and any evidence of intolerance.

Usual Adult Dosage --Fifteen to 40 mg a day divided into 3 or 4 doses. If necessary, dosage may be increased to 60 mg a day. Dosages above this amount are not recommended. Increases should be made in the morning dose.

Adolescent and Elderly Patients --In general, lower dosages are recommended for these patients. Five mg 3 times a day may be given initially, and increased gradually if necessary. In elderly patients, the cardiovascular system must be monitored closely if the daily dose exceeds 20 mg.

When satisfactory improvement has been reached, dosage should be reduced to the smallest amount that will maintain relief of symptoms.

Minor adverse reactions require reduction in dosage. Major adverse reactions or evidence of hypersensitivity require prompt discontinuation of the drug.

The safety and effectiveness of VIVACTIL in pediatric patients have not been established.

OVERDOSAGE

Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose, therefore, hospital monitoring is required as soon as possible.

MANIFESTATIONS

Critical manifestations of overdosage include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of tricyclic antidepressant toxicity.

Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS.

MANAGEMENT

General

Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient' airway, establish an intravenous line and initiate gastric decontamination. A minimum of six hours of observation with cardiac monitoring and observation for signs of CNS or respiratory depression, hypotension, cardiac dysrhythmias and/or conduction blocks, and seizures is necessary. If signs of toxicity occur at any time during this period, extended monitoring is required. There are case reports of patients succumbing to fatal dysrhythmias late after overdose. These patients had clinical evidence of significant poisoning prior to death and most received inadequate gastrointestinal decontamination. Monitoring of plasma drug levels should not guide management of the patient.

Gastrointestinal Decontamination

All patients suspected of a tricyclic antidepressant overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.

Cardiovascular

A maximal limb-lead QRS duration of >/=0.10 seconds may be the best indication of the severity of the overdose. Intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH response is inadequate, hyperventilation may also be used. Concomitant use of hyperventilation and sodium bicarbonate should be done with extreme caution, with frequent pH monitoring. A pH >7.60 or a pCO 2 <20 mmHg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are generally contraindicated (e.g., quinidine, disopyramide, and procainamide).

In rare instances, hemoperfusion may be beneficial in acute refractory cardiovascular instability in patients with acute toxicity. However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.

CNS

In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines or, if these are ineffective, other anticonvulsants (e.g., phenobarbital, phenytoin). Physostigmine is not recommended except to treat life-threatening symptoms that have been unresponsive to other therapies, and then only in close consultation with a poison control center.

PSYCHIATRIC FOLLOW-UP

Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

PEDIATRIC MANAGEMENT

The principles of management of child and adult overdosages are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

HOW SUPPLIED

No. 3314--Tablets VIVACTIL, 10 mg, are yellow, oval, film coated tablets, coded MSD 47 on one side and VIVACTIL on the other. They are supplied as follows:

NDC 0006-0047-68 bottles of 100

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Keep container tightly closed.

METABOLISM

Metabolic studies indicate that protriptyline is well absorbed from the gastrointestinal tract and is rapidly sequestered in tissues. Relatively low plasma levels are found after administration, and only a small amount of unchanged drug is excreted in the urine of dogs and rabbits. Preliminary studies indicate that demethylation of the secondary amine moiety occurs to a significant extent, and that metabolic transformation probably takes place in the liver. It penetrates the brain rapidly in mice and rats, and moreover that which is present in the brain is almost all unchanged drug.

Studies on the disposition of radioactive protriptyline in human test subjects showed significant plasma levels within 2 hours, peaking at 8 to 12 hours, then declining gradually.

Urinary excretion studies in the same subjects showed significant amounts of radioactivity in 2 hours. The rate of excretion was slow. Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.

7904026   Issued December 1999

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer and reproduced in full color by PDR as a quick-reference identification aid. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug' identity should be verified by chemical analysis.

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