Norpramin (Desipramine) Drug Information

Desipramine Description, Indications, Side Effects, Warnings, Pharmacology, and Dosage
Antidepressant Basics

Generic Name: Desipramine
Brand Names: • Norpramin • Treyzafagit • Pertofrane

Class: Antidepressant, Tricyclic

Updated: July 2014

desipramine-tablet-pill-picture

What Is It?

Desipramine hydrochloride, USP is an antidepressant drug of the tricyclic type. Manufactured by Catalent Pharma Solutions. Distributed by Actavis Inc.

What Does It Treat?

Desipramine hydrochloride tablets, USP are indicated for the treatment of depression. Off label uses include the treatment of anxiety, ADHD, cataplexy, chronic itching, bulimia, neuropathic pain, panic attacks, and depression caused by traumatic brain injury.

Some people have thoughts about suicide when first taking an antidepressant. Your doctor will need to check your progress at regular visits while you are using Desipramine. Your family or other caregivers should also be alert to changes in your mood or symptoms.

This medication guide does not take the place of talking to your healthcare provider about your medical condition or treatment. Talk with your healthcare provider if there is something you do not understand or want to learn more about.

Do not start or stop any medicine while taking Desipramine without talking to your healthcare provider first.

Who Should Not Take Desipramine?

Do not take Desipramine if you: 1) are allergic to Desipramine or any of the ingredients in Desipramine. See the end of this section for a complete list of ingredients in Desipramine; 2) are in the acute phase of recovery from a myocardial infarction (heart attack); 3) are allergic to dibenzazepines or tricyclic drugs; 3) take a monoamine oxidase inhibitor (MAOI) or have taken an MAOI in the past 14 days. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid. Do not take an MAOI within 2 weeks of stopping Desipramine unless directed to do so by your physician. Do not start Desipramine if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician. MAOIs include Parnate (Tranylcypromine), Nardil (Phenelzine), Emsam (Selegiline transdermal), and Marplan (Isocarboxazid).

Safety and effectiveness in the pediatric population have not been established. Do not give Desipramine to anyone younger than 18 years old without the advice of a doctor.

Before Starting Desipramine

Tell your healthcare provider about: 1) any medical conditions you have, including seizure, cardiac, liver, kidney, or blood disease; 2) current pregnancy or plans to become pregnant; 3) current breastfeeding or plans to breastfeed; 4) any and all medications and supplements you are taking; 5) any thoughts or feelings of suicide. Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Patients should be told that the concomitant use of Desipramine and alcohol is not advised. Patients should inform their physician if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions. Patients should notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should notify their physician if they are breast feeding an infant. While patients may notice improvement with Desipramine therapy, they should be advised to continue therapy as directed.

Ingredients of DESIPRAMINE:

Active ingredients: Desipramine hydrochloride. Inactive ingredients: croscarmellose sodium, hypromellose, anhydrous lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium lauryl sulfate and titanium dioxide. The 25 mg, 50 mg, 75 mg, and 100 mg tablets also contain FD&C Blue No. 1 Aluminum Lake.

Indications and Usage

Desipramine hydrochloride tablets are indicated for the treatment of depression. Off label uses include the treatment of anxiety, ADHD, cataplexy, chronic itching, bulimia, neuropathic pain, panic attacks, and depression caused by traumatic brain injury. Desipramine may also be used for purposes not listed in this medication guide. Talk to your doctor about the possible risks of using this medication for your condition.

The physician who elects to use Desipramine for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient.

Contraindications

Desipramine hydrochloride should not be given in conjunction with, or within 2 weeks of, treatment with an MAO inhibitor drug; hyperpyretic crises, severe convulsions, and death have occurred in patients taking MAO inhibitors and tricyclic antidepressants. When desipramine hydrochloride is substituted for an MAO inhibitor, at least 2 weeks should elapse between treatments. Desipramine hydrochloride should then be started cautiously and should be increased gradually.

Desipramine hydrochloride 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.

Common Side Effects

Gastrointestinal: Constipation, Xerostomia
Neurologic: Dizziness, Somnolence
Ophthalmic: Blurred vision
Other: Fatigue

Serious Side Effects

Cardiovascular: Cardiac dysrhythmia, Electrocardiogram abnormal, Myocardial infarction, Myocarditis, Prolonged QT interval, Sudden cardiac death
Hematologic: Agranulocytosis, Drug-induced eosinophilia, Purpuric disorder, Thrombocytopenia
Hepatic: Hepatic necrosis, Hepatitis, Jaundice
Immunologic: Immune hypersensitivity reaction
Neurologic: Cerebrovascular accident, Neuroleptic malignant syndrome, Seizure
Psychiatric: Depression, worsening, Suicidal thoughts, Suicide

Get emergency medical help if you have any of these signs of an allergic reaction: skin rash or hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Suicidality and Antidepressant Drugs

Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of desipramine hydrochloride or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Desipramine hydrochloride is not approved for use in pediatric patients.

Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.  Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers.

General

Extreme caution should be used when this drug is given in the following situations:

• In patients with cardiovascular disease, because of the possibility of conduction defects, arrhythmias, tachycardias, strokes, and acute myocardial infarction.

• In patients who have a family history of sudden death, cardiac dysrhythmias, or cardiac conduction disturbances

• In patients with a history of urinary retention or glaucoma, because of the anticholinergic properties of the drug.

• In patients with thyroid disease or those taking thyroid medication, because of the possibility of cardiovascular toxicity, including arrhythmias.

• In patients with a history of seizure disorder, because this drug has been shown to lower the seizure threshold. Seizures precede cardiac dysrhythmias and death in some patients.

This drug is capable of blocking the antihypertensive effect of guanethidine and similarly acting compounds. The patient should be cautioned that this drug may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. In patients who may use alcohol excessively, it should be borne in mind that the potentiation may increase the danger inherent in any suicide attempt or overdosage.

Screening Patients for Bipolar Disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that desipramine hydrochloride is not approved for use in treating bipolar depression.

Overdose

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. The oral median lethal dose of desipramine is 290 mg/kg in male mice and 320 mg/kg in female rats. 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, and hyperpyrexia, among others. See the official Desipramine medication guide.

Call 911 or the Poison Help line at 1-800-222-1222 for all suspected overdose cases.

Pregnancy

Pregnancy Category N (Not Assigned)
Safe use of desipramine hydrochloride during pregnancy and lactation has not been established; therefore, if it is to be given to pregnant patients, nursing mothers, or women of childbearing potential, the possible benefits must be weighed against the possible hazards to mother and child. Animal reproductive studies have been inconclusive.

Geriatric Use

Clinical studies of desipramine 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 has not identified differences in responses between the elderly and younger patients. Lower doses are recommended for elderly patients. The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.  Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. Desipramine hydrochloride use in the elderly has been associated with a proneness to falling as well as confusional states.

Detailed Summary

Desipramine hydrochloride, USP is an antidepressant drug of the tricyclic type, and is chemically: 5H-Dibenz[b,f]azepine-5-propanamine,10,11-dihydro-N-methyl-, monohydrochloride. The following inactive ingredients are contained in all dosage strengths: croscarmellose sodium, hypromellose, anhydrous lactose, magnesium stearate, polyethylene glycol, polysorbate 80, povidone, sodium lauryl sulfate and titanium dioxide. The 25 mg, 50 mg, 75 mg, and 100 mg tablets also contain FD&C Blue No. 1 Aluminum Lake.

Mechanism of Action

Available evidence suggests that many depressions have a biochemical basis in the form of a relative deficiency of neurotransmitters such as norepinephrine and serotonin. Norepinephrine deficiency may be associated with relatively low urinary 3-methoxy- 4-hydroxyphenyl glycol (MHPG) levels, while serotonin deficiencies may be associated with low spinal fluid levels of 5-hydroxyindoleacetic acid. While the precise mechanism of action of the tricyclic antidepressants is unknown, a leading theory suggests that they restore normal levels of neurotransmitters by blocking the re-uptake of these substances from the synapse in the central nervous system. Evidence indicates that the secondary amine tricyclic antidepressants, including desipramine hydrochloride, may have greater activity in blocking the re-uptake of norepinephrine. Tertiary amine tricyclic antidepressants, such as amitriptyline, may have greater effect on serotonin re-uptake. Desipramine hydrochloride is not a monoamine oxidase (MAO) inhibitor and does not act primarily as a central nervous system stimulant. It has been found in some studies to have a more rapid onset of action than imipramine. Earliest therapeutic effects may occasionally be seen in 2 to 5 days, but full treatment benefit usually requires 2 to 3 weeks to obtain.

Metabolism

Tricyclic antidepressants, such as desipramine hydrochloride, are rapidly absorbed from the gastrointestinal tract. Tricyclic antidepressants or their metabolites are to some extent excreted through the gastric mucosa and reabsorbed from the gastrointestinal tract. Desipramine is metabolized in the liver, and approximately 70% is excreted in the urine. The rate of metabolism of tricyclic antidepressants varies widely from individual to individual, chiefly on a genetically determined basis. Up to a 36-fold difference in plasma level may be noted among individuals taking the same oral dose of desipramine. The ratio of 2-hydroxydesipramine to desipramine may be increased in the elderly, most likely due to decreased renal elimination with aging. Certain drugs, particularly the psychostimulants and the phenothiazines, increase plasma levels of concomitantly administered tricyclic antidepressants through competition for the same metabolic enzyme systems. Concurrent administration of cimetidine and tricyclic antidepressants can produce clinically significant increases in the plasma concentrations of the tricyclic antidepressants.  Conversely, decreases in plasma levels of the tricyclic antidepressants have been reported upon discontinuation of cimetidine, which may result in the loss of the therapeutic efficacy of the tricyclic antidepressant. Other substances, particularly barbiturates and alcohol, induce liver enzyme activity and thereby reduce tricyclic antidepressant plasma levels. Similar effects have been reported with tobacco smoke. Research on the relationship of plasma level to therapeutic response with the tricyclic antidepressants has produced conflicting results. While some studies report no correlation, many studies cite therapeutic levels for most tricyclics in the range of 50 to 300 nanograms per milliliter. The therapeutic range is different for each tricyclic antidepressant. For desipramine, an optimal range of therapeutic plasma levels has not been established.

Drug-Drug Interactions Including P450 Interactions

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 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.

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 desipramine hydrochloride 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 desipramine 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 desipramine.

Dosage and Administration

Dosage Forms and Strengths

Desipramine hydrochloride tablets, USP are supplied as follows:

• 10 mg – Each white to off-white, round, biconvex with flat edge, film-coated tablet, debossed with 341 on one side and plain on the other side. Tablets are supplied in bottles of 100 (NDC 45963-341-02) with a non-child resistant closure.

• 25 mg – Each light blue, round, biconvex with flat edge, film-coated tablet, debossed with 342 on one side and plain on the other side. Tablets are supplied in bottles of 100 (NDC 45963-342-02) with a non-child resistant closure.

• 50 mg – Each blue, round, biconvex with flat edge, film-coated tablet, debossed with 343 on one side and plain on the other side.  Tablets are supplied in bottles of 100 (NDC 45963-343-02) with a non-child resistant closure.

• 75 mg – Each light blue, round, biconvex with flat edge, film-coated tablet, debossed with 344 on one side and plain on the other side. Tablets are supplied in bottles of 100 (NDC 45963-344-02) with a non-child resistant closure.

• 100 mg – Each blue, round, biconvex with flat edge, film-coated tablet, debossed with 345 on one side and plain on the other side. Tablets are supplied in bottles of 100 (NDC 45963-345-02) with a non-child resistant closure.

• 150 mg – Each white to off-white, round, biconvex with flat edge, film-coated tablet, debossed with 346 on one side and plain on the other side. Tablets are supplied in bottles of 50 (NDC 45963-346-50) with a non-child resistant closure.

Not recommended for use in children.

Lower dosages are recommended for elderly patients and adolescents. Lower dosages are also recommended for outpatients compared to hospitalized patients, who are closely supervised. Dosage should be initiated at a low level and increased according to clinical response and any evidence of intolerance.  Following remission, maintenance medication may be required for a period of time and should be at the lowest dose that will maintain remission.

Usual Adult Dose
The usual adult dose is 100 to 200 mg per day. In more severely ill patients, dosage may be further increased gradually to 300 mg/day if necessary. Dosages above 300 mg/day are not recommended. Dosage should be initiated at a lower level and increased according to tolerance and clinical response. Treatment of patients requiring as much as 300 mg should generally be initiated in hospitals, where regular visits by the physician, skilled nursing care, and frequent electrocardiograms (ECGs) are available. The best available evidence of impending toxicity from very high doses of desipramine is prolongation of the QRS or QT intervals on the ECG. Prolongation of the PR interval is also significant, but less closely correlated with plasma levels.  Clinical symptoms of intolerance, especially drowsiness, dizziness, and postural hypotension, should also alert the physician to the need for reduction in dosage. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance.

Adolescent and Geriatric Dose
The usual adolescent and geriatric dose is 25 to 100 mg daily. Dosage should be initiated at a lower level and increased according to tolerance and clinical response to a usual maximum of 100 mg daily. In more severely ill patients, dosage may be further increased to 150 mg/day. Doses above 150 mg/day are not recommended in these age groups. Initial therapy may be administered in divided doses or a single daily dose. Maintenance therapy may be given on a once-daily schedule for patient convenience and compliance.

This dosage information does not include all the information needed to use Desipramine safely and effectively. See full prescribing information for Desipramine. The information at DepressionHealth.net is not a substitute for medical advice. ALWAYS consult your doctor or pharmacist.
This abridged guide is not the complete medication guide, and does not act as medical advice or replace the advice of a physician.
This guide is meant to be used as an educational tool and supplement to the expert advice and judgement of a physician.
Get emergency medical help or visit your nearest hospital if you have any of the signs of an allergic reaction when taking this medication:
skin rash or hives; difficulty breathing; swelling of your face, lips, tongue, or throat.
If you overdose, seek emergency medical attention or call the Poison Help line at 1-800-222-1222. An overdose of Desipramine can be fatal.
The above information derives from the following sources: FDA Monograph Citation ANDA074430, Micromedex®, MedlinePlus, DailyMed. Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed. Disclaimer: Every effort has been made to ensure that the information provided by Depression Health Network is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive.