Aventyl (Nortriptyline HCl)

AVENTYL®

Lilly

Nortriptyline HCl

Antidepressant

Action And Clinical Pharmacology: The mechanism of mood elevation of tricyclic antidepressants is at present unknown. Nortriptyline is not an MAO inhibitor. It inhibits the activity of such diverse agents as histamine, 5-hydroxytryptamine, and acetylcholine. It increases the pressor effect of norepinephrine but blocks the pressor response of phenethylamine. Studies suggest that nortriptyline interferes with the transport, release, and storage of catecholamines.

Indications And Clinical Uses: The relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states.

Contra-Indications: The concurrent use of nortriptyline or other tricyclic antidepressants with an MAO inhibitor is contraindicated. Hyperpyretic crises, severe convulsions, and fatalities have occurred when similar tricyclic antidepressants were used in such combinations. Discontinue the MAO inhibitor at least 2 weeks before nortriptyline treatment is started. Patients hypersensitive to nortriptyline should not be given the drug.

Cross-sensitivity between nortriptyline and other dibenzazepines is a possibility.

Nortriptyline is contraindicated during the acute recovery period after myocardial infarction.

Manufacturers’ Warnings In Clinical States: Patients with cardiovascular disease should be given nortriptyline only under close supervision because of the tendency of the drug to produce sinus tachycardia and to prolong the conduction time. Myocardial infarction, arrhythmia, and strokes have occurred. The antihypertensive action of guanethidine and similar agents may be blocked. Because of its anticholinergic activity, use nortriptyline with great caution in patients with glaucoma or a history of urinary retention. Patients with a history of seizures should be followed closely when nortriptyline is administered because this drug is known to lower the convulsive threshold. Great care is required if nortriptyline is administered to hyperthyroid patients or those receiving thyroid medication, because cardiac arrhythmias may develop.

Occupational Hazards: Nortriptyline may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore, warn the patient accordingly.

Pregnancy and Lactation: Safe use of nortriptyline during pregnancy and lactation has not been established; therefore, when the drug is administered to pregnant patients, nursing mothers, or women of childbearing age, the potential benefits must be weighed against the possible hazards. Animal reproduction studies have yielded inconclusive results.

Precautions: The use of nortriptyline in schizophrenic patients may result in an exacerbation of the psychosis or may activate latent schizophrenic symptoms. If the drug is given to overactive or agitated patients, increased anxiety and agitation may occur. In manic depressive patients, nortriptyline may cause symptoms of the manic phase to emerge.

Troublesome patient hostility may be aroused by the use of nortriptyline. Epileptiform seizures may accompany its administration, as may happen with other drugs of its class.

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

Inform the patient that the response to alcohol may be exaggerated. 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, especially in patients with histories of emotional disturbances or suicidal ideation.

When it is essential, the drug may be administered concurrently with electroconvulsive therapy, although the hazards may be increased. Discontinue the drug for several days, if possible, prior to elective surgery.

The possibility of a suicidal attempt by depressed patients remains after the initiation of treatment; in this regard, it is important that the least possible quantity of drug be dispensed at any given time.

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

Drug Interactions: Steady-state serum concentrations of the tricyclic antidepressants are reported to fluctuate significantly as cimetidine is either added or deleted from the drug regimen. Serious anticholinergic symptoms (severe dry mouth, urinary retention, blurred vision) have been associated with elevations in the serum levels of the tricyclic antidepressant when cimetidine is added to the drug regimen. In addition, higher than expected steady-state serum concentrations of the tricyclic antidepressant have been observed when therapy is initiated in patients already taking cimetidine.

In well-controlled patients undergoing concurrent therapy with cimetidine, a decrease in the steady-state serum concentrations of the tricyclic antidepressants may occur when cimetidine therapy is discontinued. The therapeutic efficacy of the tricyclic antidepressant may be compromised in these patients as the cimetidine is discontinued. Several of the tricyclic antidepressants have been cited in these reports.

There have been greater than 2-fold increases in previously stable plasma levels of other antidepressants including nortriptyline, when fluoxetine has been administered in combination with these agents. Fluoxetine and its active metabolite, norfluoxetine, have a long half-life (4 to 16 days for norfluoxetine) which might affect strategies during conversion from one drug to another.

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 or sympathomimetic drugs.

The patient should be informed that the response to alcohol may be exaggerated.

Drugs Metabolized by P450IID6: A subset (3 to 10%) of the population has reduced activity of certain drug metabolizing enzymes such as the cytochrome P450 isoenzyme P450IID6. Such individuals are referred to as “poor metabolizers” of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants. These individuals may have higher than expected plasma concentrations of tricyclic antidepressants when given usual doses. In addition, certain drugs that are metabolized by this isoenzyme, including many antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, and others), may inhibit the activity of this isoenzyme, and thus may make normal metabolizers resemble poor metabolizers with regard to concomitant therapy with other drugs metabolized by this enzyme system, leading to drug interactions.

Concomitant use of tricyclic antidepressants with other drugs metabolized by cytochrome P450IID6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Therefore, coadministration of tricyclic antidepressants with other drugs that are metabolized by this isoenzyme, including other antidepressants, phenothiazines, carbamazepine, and Type 1C antiarrhythmics (e.g., propafenone, flecainide, and encainide), or that inhibit this enzyme (e.g., quinidine), should be approached with caution.

Adverse Reactions: Note: Included in the following list are a few adverse reactions that have not been reported with this specific drug. However, the pharmacologic similarities among the tricyclic antidepressant drugs require that each of these reactions be considered when nortriptyline is administered.

Cardiovascular: hypotension, hypertension, tachycardia, palpitation, myocardial infarction, arrhythmias, heart block, stroke.

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

Neurologic: numbness, tingling, paresthesias of extremities; incoordination, ataxia, tremors; peripheral neuropathy, extrapyramidal symptoms; seizures, alteration of EEG patterns; tinnitus.

Anticholinergic: dry mouth and, rarely, associated sublingual adenitis or gingivitis; blurred vision, disturbance of accommodation, mydriasis; constipation, paralytic ileus; urinary retention, delayed micturition, dilation of the urinary tract.

Allergic: skin rash, petechiae, urticaria, itching, photosensitization (avoid excessive exposure to sunlight); edema (general or of face and tongue), drug fever, cross-sensitivity with other tricyclic drugs.

Hematologic: bone-marrow depression, including agranulocytosis, aplastic anemia; eosinophilia; purpura; thrombocytopenia.

Gastrointestinal: nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue, constipation, paralytic ileus.

Endocrine: gynecomastia in the male; breast enlargement and galactorrhea in the female; increased or decreased libido, impotence; testicular swelling; elevation or depression of blood sugar levels; syndrome of inappropriate ADH (antidiuretic hormone) secretion.

Other: jaundice (simulating obstructive); altered liver function, hepatitis, and liver necrosis; weight gain or loss; perspiration; flushing; urinary frequency, nocturia; drowsiness, dizziness, weakness, fatigue; headache; parotid swelling; alopecia.

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

Symptoms And Treatment Of Overdose: Deaths may occur from overdosage with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate tricyclic antidepressant overdose. As the management is complex and changing, it is recommended that the physician contact a Poison Control Centre 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.Symptoms: Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the ECG, 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 many of the symptoms listed under Adverse Effects.

Treatment: General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient’s airway, establish an i.v. line and initiate gastric decontamination. A minimum of 6 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 later 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 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 ³0.10 seconds may be the best indication of the severity of the overdose. I.V. sodium bicarbonate should be used to maintain the serum pH in the range of 7.35 to 7.45. 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 pCO2
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 consultation with a Poison Control Centre.

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 overdosage are similar. It is strongly recommended that the physician contact the local Poison Control Centre for specific pediatric treatment.

Dosage And Administration: Nortriptyline is not recommended for children. Nortriptyline is administered orally in the form of capsules. Lower than usual dosages are recommended for elderly patients and adolescents. The use of lower dosages for outpatients is more important than for hospitalized patients who will be treated under close supervision. The physician should initiate dosages at a low level and increase it gradually, checking the clinical response carefully and noting any evidence of intolerance. Following remission, maintenance medication may be required for a long period of time at the lowest dose that will maintain remission. If a patient develops minor side effects, the dosage should be reduced. The drug should be discontinued promptly if adverse effects of a serious nature or allergic manifestations occur.

Adults: 25 mg 3 or 4 times daily; dosage should begin at a low level and be increased as required. As an alternate regimen, the total daily dose may be given once a day. When doses above 100 mg daily are administered, plasma levels of nortriptyline should be monitored and maintained in the optimum range of 50 to 150 ng/mL. Doses above 150 mg/day are not recommended.

Geriatric and Adolescent Patients: 30 to 50 mg/day, in divided doses.

Plasma Levels: Optimal responses to nortriptyline have been associated with plasma concentrations of 50 to 150 ng/mL. Higher concentrations may be associated with more adverse experiences. Plasma concentrations are difficult to measure, and physicians should consult with the laboratory professional staff. Larger plasma concentrations of the active nortriptyline metabolite 10-hydroxynortriptyline have been reported in older patients. In one case, such a condition was associated with apparent cardiotoxicity despite the fact that nortriptyline concentrations were within the therapeutic range. Clinical findings should predominate over plasma concentrations as primary determinants of dosage changes.

Availability And Storage: 10 mg: Each No. 3 Pulvule capsule with white, opaque body and yellow, opaque cap with Identi-Code H 17, contains: equivalent of 10 mg nortriptyline base. Nonmedicinal ingredients: butylparaben, benzyl alcohol, D&C Yellow No. 10, dimethicone, edetate calcium disodium, FD&C Yellow No. 6, gelatin, methylparaben, propylparaben, sodium lauryl sulfate, sodium propionate, starch and titanium dioxide. Tartrazine-free. Bottles of 100.

25 mg: Each No. 1 Pulvule capsule with white, opaque body and yellow, opaque cap with Identi-Code H 19, contains: equivalent of 25 mg nortriptyline base. Nonmedicinal ingredients: butylparaben, benzyl alcohol, D&C Yellow No. 10, dimethicone, edetate calcium disodium, FD&C Yellow No. 6, gelatin, methylparaben, propylparaben, sodium lauryl sulfate, sodium propionate, starch and titanium dioxide. Tartrazine-free. Bottles of 100.

Store at controlled room temperature (15 to 30°C).

AVENTYL® Lilly Nortriptyline HCl Antidepressant

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