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Norpramin (Desipramine Hydrochloride) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

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 IC antiarrhythmics propafenone and flecainide). While all the SSRIs, e.g., fluoxetine, sertraline, 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 Of particular importance, sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).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 Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required.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.

Close supervision and careful adjustment of dosage are required when this drug is given concomitantly with anticholinergic or sympathomimetic drugs.

Patients should be warned that while taking this drug their response to alcoholic beverages may be exaggerated.

If NORPRAMIN is to be combined with other psychotropic agents such as tranquilizers or sedative/hypnotics, careful consideration should be given to the pharmacology of the agents employed since the sedative effects of NORPRAMIN and benzodiazepines (e.g., chlordiazepoxide or diazepam) are additive. Both the sedative and anticholinergic effects of the major tranquilizers are also additive to those of NORPRAMIN.

Concomitant use of Monoamine Oxidase Inhibitors (MAOIs) and serotonergic drugs may potentially cause life threatening adverse events (See CONTRAINDICATIONS, WARNINGS, and DOSAGE AND ADMINISTRATION).

OVERDOSAGE

Deaths may occur from overdosage with this class of drugs. Overdose of desipramine has resulted in a higher death rate compared to overdoses of other tricyclic antidepressants. 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. There is no specific antidote for desipramine overdosage.

Oral LD

The oral LD50 of desipramine is 290 mg/kg in male mice and 320 mg/kg in female rats.

Manifestations of Overdosage

Critical manifestations of overdose 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. Early changes in the QRS complex include a widening of the terminal 40 msec with a rightward axis in the frontal plane, recognized by the presence of a terminal S wave in Lead 1 and AVL and an R wave in AVR.

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

Aggressive supportive care and serum alkalinization are the mainstays of therapy.

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. Follow ECG, renal function, CPK, and arterial blood gasses as clinically indicated. 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

Emesis is contraindicated. Activated charcoal should be administered to patients who present early after an overdose.

Cardiovascular

A maximal limb-lead QRS duration widening to greater than 100 msec is a significant indicator of toxicity, specifically for the risk of seizures and, eventually, cardiac dysrhythmias. Serum alkalinization with intravenous sodium bicarbonate and hyperventilation (as needed) should be instituted in patients manifesting significant toxicity such as QRS widening. Dysrhythmias despite adequate alkalemia may respond to overdrive pacing, beta-agonist infusions, and magnesium therapy. Type 1A and 1C antiarrhythmics are generally contraindicated (eg, quinidine, disopyramide, and procainamide).

CNS

In patients with CNS depression, early intubation is advised because of the potential for abrupt deterioration. Seizures should be controlled with benzodiazepines. If these are ineffective or seizures recur, other anticonvulsants (eg, phenobarbital, propofol) may be used.

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.

CONTRAINDICATIONS

The use of MAOIs intended to treat psychiatric disorders with NORPRAMIN or within 14 days of stopping treatment with NORPRAMIN is contraindicated because of an increased risk of serotonin syndrome. The use of NORPRAMIN within 14 days of stopping an MAOI intended to treat psychiatric disorders is also contraindicated (see WARNINGS and DOSAGE AND ADMINISTRATION).

Starting NORPRAMIN in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue is also contraindicated because of an increased risk of serotonin syndrome (see WARNINGS and DOSAGE AND ADMINISTRATION).

NORPRAMIN is contraindicated in the acute recovery period following myocardial infarction. It should not be used in those who have shown prior hypersensitivity to the drug. Cross-sensitivity between this and other dibenzazepines is a possibility.

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