Maprotiline

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

(ma PROE ti leen)

Synonyms

Ludiomil; Maprotiline Hydrochloride

Generic Available

Yes

Canadian Brand Names

Novo-Maprotiline

Use

Treatment of depression and anxiety associated with depression

Use - Unlabeled/Investigational

Bulimia; duodenal ulcers; enuresis; urinary symptoms of multiple sclerosis; pain; panic attacks; tension headache; cocaine withdrawal

Pregnancy Risk Factor

Contraindications

Hypersensitivity to maprotiline 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 high relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disease. 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 moderate relative to other cyclic antidepressants, however, caution should still be used in patients with urinary retention, benign prostatic hyperplasia, narrow-angle glaucoma, xerostomia, visual problems, constipation, or 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. Maprotiline is not FDA approved for use in children.

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

>10%:

Central nervous system: Drowsiness

Gastrointestinal: Xerostomia

1% to 10%:

Central nervous system: Insomnia, nervousness, anxiety, agitation, dizziness, fatigue, headache

Gastrointestinal: Constipation, nausea

Neuromuscular & skeletal: Tremor, weakness

Ocular: Blurred vision

<1%: Abdominal cramps, accommodation disturbances, akathisia, arrhythmia, ataxia, bitter taste, breast enlargement, confusion, decreased libido, delusions, diaphoresis (excessive), diarrhea, disorientation, dysarthria, dysphagia, edema of testicles, epigastric distress, EPS, exacerbation of psychosis, hallucinations, heart block, hyperglycemia, hypertension, hypomania, hypotension, impotence, mania, motor hyperactivity, mydriasis, nightmares, numbness, palpitation, petechiae, photosensitivity, rash, restlessness, seizure, syncope, tachycardia, tingling, tinnitus, urinary retention, vomiting, weight gain/loss

Drug Interactions

Substrate of CYP2D6 (major)

Altretamine: Concurrent use may cause orthostatic hypertension

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

Anticholinergics: Combined use with cyclic antidepressants may produce additive anticholinergic effects

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

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

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

Carbamazepine: Cyclic antidepressants may increase carbamazepine levels; monitor

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

Clonidine: Abrupt discontinuation of clonidine may cause hypertensive crisis, cyclic antidepressants may enhance the response

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

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

Epinephrine (and other direct alpha-agonists): The pressor response to I.V. epinephrine, norepinephrine, and phenylephrine may be enhanced in patients receiving cyclic antidepressants; this combination is best avoided

Fenfluramine: May increase cyclic antidepressant levels/effects

Hypoglycemic agents (including insulin): Hypoglycemic effects may be enhanced, profound hypoglycemia has been reported; monitor for changes in blood glucose levels; reported with chlorpropamide, tolazamide, and insulin

Levodopa: Cyclic 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 cyclic antidepressant 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 maprotiline 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 cyclic 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

Sucralfate: Absorption of cyclic antidepressants may be reduced with coadministration.

Sympathomimetics, indirect-acting: Cyclic 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 cyclic antidepressants

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

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Mechanism of Action

Traditionally believed to increase the synaptic concentration of norepinephrine in the central nervous system by inhibition of their 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

Absorption: Slow

Protein binding: 88%

Metabolism: Hepatic to active and inactive compounds

Half-life elimination, serum: 27-58 hours (mean: 43 hours)

Time to peak, serum: Within 12 hours

Excretion: Urine (70%); feces (30%)

Dosage

Oral:

Adults: Depression/anxiety: 75 mg/day to start, increase by 25 mg every 2 weeks up to 150-225 mg/day; given in 3 divided doses or in a single daily dose

Elderly: Depression/anxiety: Initial: 25 mg at bedtime, increase by 25 mg every 3 days for inpatients and weekly for outpatients if tolerated; usual maintenance dose: 50-75 mg/day, higher doses may be necessary in nonresponders

Monitoring Parameters

Monitor blood pressure and pulse rate prior to and during initial therapy; evaluate mood and somatic complaints; monitor appetite and weight; ECG in older adults

Patient Education

Avoid alcohol ingestion; do not discontinue medication abruptly; may cause drowsiness; full effect may not occur for 3-6 weeks; dry mouth may be helped by sips of water, sugarless gum, or hard candy; rise slowly to avoid dizziness

Nursing Implications

Monitor blood pressure and pulse rate prior to and during initial therapy; evaluate mental status; monitor weight and appetite

Additional Information

Odorless, bitter tasting; seizures are rarely seen 5-30 hours postdrug ingestion.

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).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Although maprotiline is not a tricyclic antidepressant, it does block norepinephrine reuptake within CNS synapses as part of its mechanisms. It has been suggested that vasoconstrictor be administered with caution and to monitor vital signs in dental patients taking antidepressants that affect norepinephrine in this way, including maprotiline. Epinephrine, norepinephrine and levonordefrin have been shown to have an increased pressor response in combination with TCAs.

Dosage Forms

Tablet, as hydrochloride: 25 mg, 50 mg, 75 mg

References

Bergman RN and Watson WA, "Cardiac Toxicity Associated With Acute Maprotiline Self Poisoning," Am J Emerg Med , 1983, 2(2):144-6.

Boakes AJ, Laurence DR, Teoh PC, et al, "Interactions Between Sympathomimetic Amines and Antidepressant Agents in Man," Br Med J , 1973, 1(849):311-5.

Hrdina PD, Rovei V, Henry JF, et al, "Comparison of Single-Dose Pharmacokinetics of Imipramine and Maprotiline in the Elderly," Psychopharmacology , 1980, 70(1):29-34.

Jastak JT and Yagiela JA, "Vasoconstrictors and Local Anesthesia: A Review and Rationale for Use," J Am Dent Assoc , 1983, 107(4):623-30.

Larochelle P, Hamet P, and Enjalbert M, "Responses to Tyramine and Norepinephrine After Imipramine and Trazodone," Clin Pharmacol Ther , 1979, 26(1):24-30.

Mitchell JR, "Guanethidine and Related Agents. III Antagonism by Drugs Which Inhibit the Norepinephrine Pump in Man," J Clin Invest , 1970, 49(8):1596-604.

Rundegren J, van Dijken J, Mörnstad H, et al, "Oral Conditions in Patients Receiving Long-Term Treatment With Cyclic Antidepressant Drugs," Swed Dent J , 1985, 9(2):55-64.

Svedmyr N, "The Influence of a Tricyclic Antidepressive Agent (Protriptyline) on Some of the Circulatory Effects of Noradrenaline and Adrenalin in Man," Life Sci , 1968, 7(1):77-84.

Wynn RL, "New Antidepressant Medications," Gen Dent , 1997, 45(1):24-8.

Wyss PA, Serena S, and Meier PJ, "Dose-Dependency of Seizures in Maprotiline (Ludiomil®) Intoxications," Vet Hum Toxicol , 1993, 35:341.

International Brand Names

Deprilept® (DE); Epalon® (CY); Ladiomil® (HR, SI); Ludiomil® (AT, BD, BE, BG, CH, CL, CO, CZ, DE, DK, ES, FR, GB, HU, ID, IT, LU, MT, MX, NL, NZ, PL, PT, RO, RU, SE, TH, TR, ZA); Ludiomil® [inj.] (AT, BE, CH, CL, CZ, DE, HU, LU); Maludil® (DK); Maprolu® (DE, HU, LU, RO); Maprolu® [inj.] (DE); Mapromil® (CL); Maprotibene® (CZ); Maprotilin Holsten® (DE); Maprotilin Hydrochlorid 1A Pharma® (AT); Maprotilin-neuraxpharm® (DE); Maprotilin-neuraxpharm® [inj.] (DE); Maprotilin NM Pharma® (SE); Maprotilin-ratiopharm® (DE); Maprotilin® (RO, YU); Maprotilin-TEVA® (DE); maprotilin von ct® (DE, RO); Maprotil® (TR); Melodil® (IL); Novo-Maprotiline (CA); Repentil® (CL)

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