Desipramine

Special Alerts

Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, 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). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.

Pronunciation

(des IP ra meen)

U.S. Brand Names

Norpramin®

Synonyms

Desipramine Hydrochloride; Desmethylimipramine Hydrochloride

Generic Available

Yes

Canadian Brand Names

Alti-Desipramine; Apo-Desipramine®; Norpramin®; Novo-Desipramine; Nu-Desipramine; PMS-Desipramine

Use

Treatment of depression

Use - Unlabeled/Investigational

Analgesic adjunct in chronic pain; peripheral neuropathies; substance-related disorders; attention-deficit/hyperactivity disorder (ADHD)

Pregnancy Risk Factor

Lactation

Enters breast milk/not recommended (AAP rates "of concern")

Contraindications

Hypersensitivity to desipramine, drugs of similar chemical class, or any component of the formulation; use of MAO inhibitors within 14 days; use in a patient during the acute recovery phase of MI

Warnings/Precautions

May cause sedation, resulting in impaired performance of tasks requiring alertness (eg, operating machinery or driving). Sedative effects may be additive with other CNS depressants and/or ethanol. The degree of sedation is low-moderate relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. May cause hyponatremia/SIADH. May increase the risks associated with electroconvulsive therapy. This agent should be discontinued, when possible, prior to elective surgery. Therapy should not be abruptly discontinued in patients receiving high doses for prolonged periods.

May cause orthostatic hypotension (risk is moderate relative to other antidepressants) - use with caution in patients at risk of hypotension or in patients where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). The degree of anticholinergic blockade produced by this agent is low relative to other cyclic antidepressants - however, caution should be used in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or a history of bowel obstruction.

The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Desipramine is FDA approved for the treatment of depression in adolescents.

Use with caution in patients with a history of cardiovascular disease (including previous MI, stroke, tachycardia, or conduction abnormalities). The risk conduction abnormalities with this agent is moderate relative to other antidepressants. Use caution in patients with a previous seizure disorder or condition predisposing to seizures such as brain damage, alcoholism, or concurrent therapy with other drugs which lower the seizure threshold. Use with caution in hyperthyroid patients or those receiving thyroid supplementation. Use with caution in patients with hepatic or renal dysfunction and in elderly patients.

Adverse Reactions

Frequency not defined.

Cardiovascular: Arrhythmias, hyper-/hypotension, palpitation, heart block, tachycardia

Central nervous system: Dizziness, drowsiness, headache, confusion, delirium, hallucinations, nervousness, restlessness, parkinsonian syndrome, insomnia, disorientation, anxiety, agitation, hypomania, exacerbation of psychosis, incoordination, seizure, extrapyramidal symptoms

Dermatologic: Alopecia, photosensitivity, skin rash, urticaria

Endocrine & metabolic: Breast enlargement, galactorrhea, SIADH

Gastrointestinal: Xerostomia, decreased lower esophageal sphincter tone may cause GE reflux, constipation, nausea, unpleasant taste, weight gain/loss, anorexia, abdominal cramps, diarrhea, heartburn

Genitourinary: Difficult urination, sexual dysfunction, testicular edema

Hematologic: Agranulocytosis, eosinophilia, purpura, thrombocytopenia

Hepatic: Cholestatic jaundice, increased liver enzyme

Neuromuscular & skeletal: Fine muscle tremor, weakness, numbness, tingling, paresthesia of extremities, ataxia

Ocular: Blurred vision, disturbances of accommodation, mydriasis, increased intraocular pressure

Miscellaneous: Diaphoresis (excessive), allergic reactions

Overdosage/Toxicology

Symptoms of overdose include agitation, confusion, hallucinations, hyperthermia, urinary retention, CNS depression, cyanosis, dry mucous membranes, cardiac arrhythmias, and seizures. Treatment is supportive. Ventricular arrhythmias and ECG changes (eg, QRS widening) often respond with concurrent systemic alkalinization (sodium bicarbonate 0.5-2 mEq/kg I.V. or hyperventilation). Arrhythmias unresponsive to phenytoin 15-20 mg/kg (adults) may respond to lidocaine. Physostigmine (1-2 mg I.V. slowly for adults) may be indicated for reversing life-threatening cardiac arrhythmias.

Drug Interactions

Substrate of CYP1A2 (minor), 2D6 (major); Inhibits CYP2A6 (moderate), 2B6 (moderate), 2D6 (moderate), 2E1 (weak), 3A4 (moderate)

Altretamine: Concurrent use may cause orthostatic hypertension

Amphetamines: TCAs may enhance the effect of amphetamines; monitor for adverse CV effects

Anticholinergics: Combined use with TCAs may produce additive anticholinergic effects

Antihypertensives: TCAs inhibit the antihypertensive response to bethanidine, clonidine, debrisoquin, guanadrel, guanethidine, guanabenz, guanfacine; monitor BP; consider alternate antihypertensive agent

Beta-agonists: When combined with TCAs may predispose patients to cardiac arrhythmias

Bupropion: May increase the levels of tricyclic antidepressants; based on limited information; monitor response

Carbamazepine: Tricyclic antidepressants may increase carbamazepine levels; monitor

Cholestyramine and colestipol: May bind TCAs and reduce their absorption; monitor for altered response

Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis; amitriptyline may enhance the response

CNS depressants: Sedative effects may be additive with TCAs; monitor for increased effect; includes benzodiazepines, barbiturates, antipsychotics, ethanol, and other sedative medications

CYP2A6 substrates: Desipramine may increase the levels/effects of CYP2A6 substrates. Example substrates include dexmedetomidine and ifosfamide.

CYP2B6 substrates: Desipramine may increase the levels/effects of CYP2B6 substrates. Example substrates include bupropion, promethazine, propofol, selegiline, and sertraline.

CYP2D6 inhibitors: May increase the levels/effects of desipramine. Example inhibitors include chlorpromazine, delavirdine, fluoxetine, miconazole, paroxetine, pergolide, quinidine, quinine, ritonavir, and ropinirole.

CYP2D6 substrates: Desipramine may increase the levels/effects of CYP2D6 substrates. Example substrates include amphetamines, selected beta-blockers, dextromethorphan, fluoxetine, lidocaine, mirtazapine, nefazodone, paroxetine, risperidone, ritonavir, thioridazine, tricyclic antidepressants, and venlafaxine.

CYP2D6 prodrug substrates: Desipramine may decrease the levels/effects of CYP2D6 prodrug substrates. Example prodrug substrates include codeine, hydrocodone, oxycodone, and tramadol.

CYP3A4 substrates: Desipramine may increase the levels/effects of CYP3A4 substrates. Example substrates include benzodiazepines, calcium channel blockers, cyclosporine, mirtazapine, nateglinide, nefazodone, sildenafil (and other PDE-5 inhibitors), tacrolimus, and venlafaxine. Selected benzodiazepines (midazolam and triazolam), cisapride, ergot alkaloids, selected HMG-CoA reductase inhibitors (lovastatin and simvastatin), and pimozide are generally contraindicated with strong CYP3A4 inhibitors.

Epinephrine (and other direct alpha-agonists): Pressor response to I.V. epinephrine, norepinephrine, and phenylephrine may be enhanced in patients receiving TCAs ( Note: Effect is unlikely with epinephrine or levonordefrin dosages typically administered as infiltration in combination with local anesthetics)

Fenfluramine: May increase tricyclic antidepressant levels/effects

Hypoglycemic agents (including insulin): TCAs may enhance the hypoglycemic effects of tolazamide, chlorpropamide, or insulin; monitor for changes in blood glucose levels; reported with chlorpropamide, tolazamide, and insulin

Levodopa: Tricyclic antidepressants may decrease the absorption (bioavailability) of levodopa; rare hypertensive episodes have also been attributed to this combination

Linezolid: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported with agents which inhibit MAO (serotonin syndrome); this combination should be avoided

Lithium: Concurrent use with a TCA may increase the risk for neurotoxicity

MAO inhibitors: Hyperpyrexia, hypertension, tachycardia, confusion, seizures, and deaths have been reported (serotonin syndrome); this combination should be avoided

Methylphenidate: Metabolism of TCAs may be decreased

Phenothiazines: Serum concentrations of some TCAs may be increased; in addition, TCAs may increase concentration of phenothiazines; monitor for altered clinical response

QTc-prolonging agents: Concurrent use of tricyclic agents with other drugs which may prolong QTc interval may increase the risk of potentially fatal arrhythmias; includes type Ia and type III antiarrhythmics agents, selected quinolones (sparfloxacin, gatifloxacin, moxifloxacin, grepafloxacin), cisapride, and other agents

Ritonavir: Combined use of high-dose tricyclic antidepressants with ritonavir may cause serotonin syndrome in HIV-positive patients; monitor

Sucralfate: Absorption of tricyclic antidepressants may be reduced with coadministration

Sympathomimetics, indirect-acting: Tricyclic antidepressants may result in a decreased sensitivity to indirect-acting sympathomimetics; includes dopamine and ephedrine; also see interaction with epinephrine (and direct-acting sympathomimetics)

Tramadol: Tramadol's risk of seizures may be increased with TCAs

Valproic acid: May increase serum concentrations/adverse effects of some tricyclic antidepressants

Warfarin (and other oral anticoagulants): TCAs may increase the anticoagulant effect in patients stabilized on warfarin; monitor INR

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Grapefruit juice may inhibit the metabolism of some TCAs and clinical toxicity may result.

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, kava kava (may increase risk of serotonin syndrome and/or excessive sedation).

Mechanism of Action

Traditionally believed to increase the synaptic concentration of norepinephrine (and to a lesser extent, serotonin) in the central nervous system by inhibition of its reuptake by the presynaptic neuronal membrane. However, additional receptor effects have been found including desensitization of adenyl cyclase, down regulation of beta-adrenergic receptors, and down regulation of serotonin receptors.

Pharmacodynamics/Kinetics

Onset of action: 1-3 weeks; Maximum antidepressant effect: >2 weeks

Absorption: Well absorbed

Metabolism: Hepatic

Half-life elimination: Adults: 7-60 hours

Time to peak, plasma: 4-6 hours

Excretion: Urine (70%)

Dosage

Oral (dose is generally administered at bedtime):

Children 6-12 years: Depression (unlabeled use): 10-30 mg/day or 1-3 mg/kg/day in divided doses; do not exceed 5 mg/kg/day

Adolescents: Depression: Initial: 25-50 mg/day; gradually increase to 100 mg/day in single or divided doses (maximum: 150 mg/day)

Adults:

Depression: Initial: 75 mg/day in divided doses; increase gradually to 150-200 mg/day in divided or single dose (maximum: 300 mg/day)

Cocaine withdrawal (unlabeled use): 50-200 mg/day in divided or single dose

Elderly: Depression: Initial dose: 10-25 mg/day; increase by 10-25 mg every 3 days for inpatients and every week for outpatients if tolerated; usual maintenance dose: 75-100 mg/day, but doses up to 150 mg/day may be necessary

Hemodialysis/peritoneal dialysis: Supplemental dose is not necessary

Monitoring Parameters

Monitor blood pressure and pulse rate prior to and during initial therapy evaluate mental status; monitor weight; ECG in older adults and those patients with cardiac disease; blood levels are useful for therapeutic monitoring

Reference Range

Plasma levels do not always correlate with clinical effectiveness

Timing of serum samples: Draw trough just before next dose

Therapeutic: 50-300 ng/mL

In elderly patients the response rate is greatest with steady-state plasma concentrations >115 ng/mL

Possible toxicity: >300 ng/mL

Toxic: >1000 ng/mL

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results. This medicine may cause physical and/or psychological dependence. Avoid alcohol and grapefruit juice. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause drowsiness, lightheadedness, impaired coordination, dizziness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); loss of appetite or disturbed taste (small, frequent meals, good mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); urinary retention (void before taking medication); postural hypotension (use caution climbing stairs or when changing position from lying or sitting to standing); altered sexual drive or ability (reversible); or photosensitivity (use sunscreen, wear protective clothing and eyewear, and avoid direct sunlight). Report chest pain, palpitations, or rapid heartbeat; persistent adverse CNS effects (eg, suicidal ideation, nervousness, restlessness, insomnia, anxiety, excitation, headache, agitation, impaired coordination, changes in cognition); muscle cramping, weakness, tremors, or rigidity; blurred vision or eye pain; breast enlargement or swelling; yellowing of skin or eyes; or worsening of condition. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Additional Information

Less sedation and anticholinergic effects than with amitriptyline or imipramine

Anesthesia and Critical Care Concerns/Other Considerations

Desipramine causes less sedation and anticholinergic effects than with amitriptyline or imipramine.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation), and unpleasant taste. Long-term treatment with TCAs increases the risk of caries by reducing salivation and salivary buffer capacity.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Use with caution; epinephrine, norepinephrine and levonordefrin have been shown to have an increased pressor response in combination with TCAs

Dosage Forms

Tablet, as hydrochloride: 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg

References

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International Brand Names

Alti-Desipramine (CA); Apo-Desipramine® (CA); Norpramin® (CA); Novo-Desipramine (CA); Nu-Desipramine (CA); PMS-Desipramine (CA)

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