CLINICAL PHARMACOLOGY:

The mechanism of mood elevation by tricyclic antidepressants is at present unknown.  It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It inhibits the pressor effect of norepinephrine but blocks the pressor response of phenethylamine.

WARNINGS: Patients with cardiovascular disease should be given nortriptyline HCl only under close supervision. Because of its anticholinergic activity, nortriptyline should be used with great caution in patients who have glaucoma or a history of urinary retention. Great care is required if nortriptyline is given to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage.

PRECAUTIONS:

General: Troublesome patient hostility may be aroused by the use of nortriptyline. Epileptiform seizures may accompany its administration, as is true of other drugs of its class. The possibility of a suicidal attempt by a depressed patient remains after the initiation of treatment.

Pregnancy: Safe use of nortriptyline HCl during pregnancy and lactation has not been established.

DRUG INTERACTIONS:

Administration of reserpine during therapy with a tricyclic antidepressant has been shown to produce a "stimulating" effect in some depressed patients.

Close supervision and careful adjustment of the dosage are required when nortriptyline is used with other anticholinergic drugs and sympathomimetic drugs.

Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressant. The patient should be informed that the response to alcohol may be exaggerated.

A case of significant hypoglycemia has been reported in a type II diabetic patient maintained on chlorpropamide (250 mg/day), after the addition of nortriptyline (125 mg/day).

Drugs Metabolized by P4502D6 

The biochemical activity of the drug metabolizing isozyme cytochrome P4502D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7 to 10% of caucasians are so called "poor metabolizers"); reliable estimates of the prevalence of reduced P4502D6 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 P4502D6, 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 p.o. 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 P4502D6 include some that are not metabolized by the enzyme (quinidine; cimetidine) and many that are substrates for P4502D6 (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 P4502D6, 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 T.A. 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 P4502D6 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 co-administered with another drug known to be an inhibitor of P4502D6.

SIDE EFFECTS:

Cardiovascular: Hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke. Psychiatric: Confusional states (especially in the elderly) with hallucinations. Neurologic: ataxia, tremors; extrapyramidal symptoms. Anticholinergic: Dry mouth and rarely, blurred vision, mydriasis; constipation, paralytic ileus; urinary retention. Allergic: Skin rash, petechiae, urticaria, itching, and photosensitization. Hematalogic: Bone marrow depression. Gastrointestinal: Nausea and vomiting, anorexia, epigastric distress, diarrhea. Endocrine: Gynecomastia in the male, breast enlargement and galactorrhea in the female.

OVERDOSE: Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, shock, congestive heart failure, pulmonary edema, 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, restlessness, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia, or any of the acute symptoms listed under . There have been reports of patients recovering from nortriptyline overdoses of up to 525 mg.

Management

General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's 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. Monitoring of plasma drug levels should not guide management of the patient.

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. Serum alkalinization, to a pH of 7.45 to 7.55, using intravenous sodium bicarbonate and hyperventilatlon (as needed) should be instituted for patients with dysrhythmias and/or QRS widening. A pH >7.60 or a pCO <20 mm Hg 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).

 However, hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis generally have been reported as ineffective in tricyclic antidepressant poisoning.

CNS: 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.

Psychiatric Follow-up: Since overdosage is often deliberate, patients may attempt suicide by other means during the recovery phase.

DOSAGE AND ADMINISTRATION: Nortriptyline HCl is not recommended for children. Lower than usual dosages are recommended for elderly patients and adolescents 30 to 50 mg/day, in divided doses, or the total daily dosage may be given once a day..

Usual Adult Dose: 25 mg three or four times daily. As an alternate regimen, the total daily dosage may be given once a day.  Doses above 150 mg/day are not recommended.

How Supplied: Each pack of Ruz-Nortriptyline 10 mg or 25 mg tablets contain 100 film coated tablets in a bottle.

storage: Store at controlled room temperature 15º- 30º C, Dispense contents in a tight container.

Reference: USPDI for Professional Health Care, 2004, Page 283-94

                  Martindale 2005, Page 310-1