CATEGORIES: Depression; Pregnancy Category D; FDA Approved November 1964
Drug Classes: Antidepressants, tricyclic
BRAND NAMES: Aventyl HCl; Pamelor
FOREIGN BRAND AVAILABILITY:
Allegron (New Zealand, Belgium, England);
Ateben (Argentina);
Aventyl (Canada, England, Ireland, Malaysia, South Africa);
Kareon (Argentina);
Martimil (Spain);
Noritren (Denmark, Finland, Italy, Japan, Norway, Sweden);
Norline (Thailand);
Norpress (New Zealand);
Nortrilen (Austria, Belgium, Bulgaria, Germany, Greece, Hong Kong, Netherlands, Switzerland, Thailand);
Nortrix (Portugal);
Nortyline (Thailand);
Norventyl (Canada);
Ortrip (Thailand);
Paxtibi (Spain);
Sensaval (Sweden);
Sensival (India, Japan);
Vividyl (Italy)
COST OF THERAPY:
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Nortriptyline hydrochloride is 1-propanamine, 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-, hydrochloride.
Pamelor Capsules
10, 25, 50, and 75 mg Capsules
10, 25, and 75 mg Capsules
50 mg Capsules
Pamelor Solution
The mechanism of mood elevation by tricyclic antidepressants is at present unknown. Nortriptyline HCl is not a monoamine oxidase 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 HCl interferes with the transport, release, and storage of catecholamines. Operant conditioning techniques in rats and pigeons suggest that nortriptyline HCl has a combination of stimulant and depressant properties.
Nortriptyline HCl is indicated for the relief of symptoms of depression. Endogenous depressions are more likely to be alleviated than are other depressive states.
Non-FDA Approved Indications
Nortriptyline has also been used in the treatment of neuropathic pain, chronic pain, and panic disorder although these uses are not explicitly approved by the FDA. Additionally, some investigators have suggested a role for nortriptyline in the treatment of chronic tinnitus and the depression often associated with chronic tinnitus.
The use of nortriptyline HCl or other tricyclic antidepressants concurrently with a monoamine oxidase (MAO) inhibitor is contraindicated. Hyperpyretic crises, severe convulsions, and fatalities have occurred when similar tricyclic antidepressants were used in such combinations. It is advisable to have discontinued the MAO inhibitor for at least 2 weeks before treatment with nortriptyline HCl is started. Patients hypersensitive to nortriptyline HCl should not be given the drug.
Cross-sensitivity between nortriptyline HCl and other dibenzazepines is a possibility.
Nortriptyline HCl is contraindicated during the acute recovery period after myocardial infarction.
Patients with cardiovascular disease should be given nortriptyline HCl 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, nortriptyline HCl should be used with great caution in patients who have glaucoma or a history of urinary retention. Patients with a history of seizures should be followed closely when nortriptyline HCl is administered, in as much as this drug is known to lower the convulsive threshold. Great care is required if nortriptyline HCl is given to hyperthyroid patients or to those receiving thyroid medication, since cardiac arrhythmias may develop.
Nortriptyline HCl may impair the mental and/or physical abilities required for the performance of hazardous tasks, such as operating machinery or driving a car; therefore, the patient should be warned accordingly.
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.
The concomitant administration of quinidine and nortriptyline may result in a significantly longer plasma half-life, higher AUC, and lower clearance of nortriptyline.
Use in Pregnancy
Safe use of nortriptyline HCl during pregnancy and lactation has not been established; therefore, when the drug is administered to pregnant patients, nursing mothers, or women of childbearing potential, the potential benefits must be weighed against the possible hazards. Animal reproduction studies have yielded inconclusive results.
Pediatric Use
This drug is not recommended for use in children, since safety and effectiveness in the pediatric age group have not been established.
The use of nortriptyline HCl 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 HCl may cause symptoms of the manic phase to emerge.
Troublesome patient hostility may be aroused by the use of nortriptyline HCl. Epileptiform seizures may accompany its administration, as is true of other drugs of its class.
When it is essential, the drug may be administered 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 a depressed patient 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.
Geriatric Use
Glinical studies of nortriptyline HCl did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience indicates that, as with other tricyclic antidepressants, hepatic adverse events (characterized mainly by jaundice and elevated liver enzymes) are observed very rarely in geriatric patients and deaths associated with cholestatic liver damage have been reported in isolated instances. Cardiovascular function, particularly arrhythmias and fluctuations in blood pressure, should be monitored. There have also been reports of confusional states following trycyclic antidepressant administration in the elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10-hydroxynortiptyline, have also been reported in elderly patients. As with other trycyclic antidepressants, dose selection for an elderly patient should usually be limited to the smallest effective total daily dose (see DOSAGE AND ADMINISTRATION).
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 HCl 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 P450 2D6
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin 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 of P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmic 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 co-administration 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 co-administered with another drug known to be an inhibitor of P450 2D6.
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 the reactions be considered when nortriptyline is administered.
Withdrawal Symptoms
Though these are not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise.
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 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 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 overdosage 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 ADVERSE REACTIONS. 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 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 dysrhythmia 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 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 7.45-7.55. 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 PCO2 <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).
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 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 overdosage are similiar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
Nortriptyline HCl is not recommended for children.
Nortriptyline HCl is administered orally in the form of capsules or liquid. Lower than usual dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients than for hospitalized patients who will be under close supervision. The physician should initiate dosage at a low level and increase it gradually, noting carefully the clinical response and any evidence of intolerance. Following remission, maintenance medication may be required for a longer 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.
Pamelor Capsules
Pamelor (nortirptyline HCl) capsules equivalent to 10, 25, 50 or 75 mg of base are available.
Storage: Below 30°C (86°F); tight container.
Pamelor Solution
Pamelor (nortriptyline HCl) solution, equivalent to 10 mg base per 5 ml, is supplied in 16 fluid ounce bottles. Alcohol content 4%.
Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F); tight, light-resistant container.
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