Nortriptyline Hydrochloride (Page 3 of 5)
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 hydrochloride oral solution 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% to 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 co-administered with another drug known to be an inhibitor of P450 2D6.
Monoamine Oxidase Inhibitors (MAOIs)
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION).
(See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION).
Safety and effectiveness in the pediatric population have not been established (See BOX WARNING and WARNINGS, Clinical Worsening and Suicide Risk). Anyone considering the use of nortriptyline hydrochloride in a child or adolescent must balance the potential risks with the clinical need.
Clinical studies of nortriptyline hydrochloride 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 tricyclic antidepressant administration in the elderly. Higher plasma concentrations of the active nortriptyline metabolite, 10-hydroxynortriptyline, have also been reported in elderly patients. As with other tricyclic antidepressants, dose selection for an elderly patient should usually be limited to the smallest effective total daily dose (See DOSAGE AND ADMINISTRATION).
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; 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; eosinophilia; purpura; thrombocytopenia.
Gastrointestinal – Nausea and vomiting, anorexia, epigastric distress, diarrhea; peculiar taste, stomatitis, abdominal cramps, black tongue.
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, 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.
The following adverse drug reaction has been reported during post-approval use of nortriptyline hydrochloride. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency.
Cardiac Disorders – Brugada syndrome
Eye Disorders – angle-closure glaucoma
To report SUSPECTED ADVERSE REACTIONS, contact Pharmaceutical Associates, Inc. at 1-800-845-8210 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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