Mirtazapine

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

(mir TAZ a peen)

U.S. Brand Names

Remeron®; Remeron SolTab®

Generic Available

Yes

Canadian Brand Names

Remeron®

Use

Treatment of depression

Pregnancy Risk Factor

Pregnancy Implications

Animal studies did not show teratogenic effects, however, there was an increase in fetal loss and decrease in birth weight; use during pregnancy only if clearly needed.

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to mirtazapine or any component of the formulation; use of MAO inhibitors within 14 days

Warnings/Precautions

Discontinue immediately if signs and symptoms of neutropenia/agranulocytosis occur. 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 moderate-high relative to other antidepressants. May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. The risks of orthostatic hypotension or anticholinergic effects are low relative to other antidepressants. The incidence of sexual dysfunction with mirtazapine is generally lower than with SSRIs.

May increase appetite and stimulate weight gain. Weight gain of >7% of body weight reported in 7.5% of patients treated with mirtazapine compared to 0% for placebo; 8% of patients receiving mirtazapine discontinued treatment due to the weight gain. In an 8-week pediatric clinical trial, 49% of mirtazapine-treated patients had a weight gain of at least 7% (mean increase 4 kg) as compared to 5.7% of placebo-treated patients (mean increase 1 kg).

May increase serum cholesterol and triglyceride levels. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occur.

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. Mirtazapine is not FDA approved for use in children.

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 patients with hepatic or renal dysfunction and in elderly patients.

SolTab® formulation contains phenylalanine

Adverse Reactions

>10%:

Central nervous system: Somnolence (54%)

Endocrine & metabolic: Cholesterol increased

Gastrointestinal: Constipation (13%), xerostomia (25%), appetite increased (17%), weight gain (12%; weight gain of >7% reported in 8% of adults, 49% of pediatric patients)

1% to 10%:

Cardiovascular: Hypertension, vasodilatation, peripheral edema (2%), edema (1%)

Central nervous system: Dizziness (7%), abnormal dreams (4%), abnormal thoughts (3%), confusion (2%), malaise

Endocrine & metabolic: Triglycerides increased

Gastrointestinal: Vomiting, anorexia, abdominal pain

Genitourinary: Urinary frequency (2%)

Neuromuscular & skeletal: Myalgia (2%), back pain (2%), arthralgia, tremor (2%), weakness (8%)

Respiratory: Dyspnea (1%)

Miscellaneous: Flu-like symptoms (5%), thirst

<1%: Abdomen enlarged, abnormal ejaculation, accommodation abnormality, acne, agitation, agranulocytosis, akathisia, alopecia, amenorrhea, amnesia, anemia, angina pectoris, anxiety, apathy, aphasia, aphthous stomatitis, arthrosis, arthritis, asphyxia, asthma, ataxia, atrial arrhythmia, bigeminy, blepharitis, bone pain, bradycardia, breast engorgement, breast enlargement, breast pain, bronchitis, bursitis, cardiomegaly, cellulitis, cerebral ischemia, chest pain, chills, cholecystitis, cirrhosis, colitis, conjunctivitis, coordination abnormal, cough, cystitis, deafness, dehydration, delirium, delusions, dementia, depersonalization, depression, diabetes mellitus, diplopia, drug dependence, dry skin, dysarthria, dyskinesia, dysmenorrhea, dystonia, dysuria, ear pain, emotional lability, epistaxis, eructation, euphoria, exfoliative dermatitis, extrapyramidal syndrome, eye pain, facial edema, fever, fracture, gastritis, gastroenteritis, glaucoma, glossitis, goiter, gout, grand mal seizure, gum hemorrhage, hallucinations, hematuria, herpes simplex, herpes zoster, hiccup, hostility, hypokinesia, hyperacusis, hyperkinesias, hypesthesia, hypotension, hypothyroidism, hypotonia, impotence, increased salivation, intestinal obstruction, keratoconjunctivitis, kidney calculus, lacrimation disorder, laryngitis, left heart failure, leukopenia, leukorrhea, libido increased, liver function tests abnormal, lymphadenopathy, lymphocytosis, manic reaction, menorrhagia, metrorrhagia, migraine, MI, myoclonus, myositis, nausea, neck pain, neck rigidity, neurosis, nystagmus, oral moniliasis, osteoporosis, otitis media, pancreatitis, pancytopenia, paralysis, paranoid reaction, paresthesia, parosmia, petechia, phlebitis, photosensitivity reaction, pneumonia, pneumothorax, polyuria, pruritus, psychotic depression, pulmonary embolus, rash, reflexes increased, salivary gland enlargement, seborrhea, sinusitis, skin hypertrophy, skin ulcer, stomatitis, stupor, syncope, taste loss, tendon rupture, tenosynovitis, thrombocytopenia, tongue discoloration, tongue edema, twitching, ulcer, ulcerative stomatitis, urethritis, urinary incontinence, urinary retention, urinary tract infection, urinary urgency, urticaria, vaginitis, vascular headache, ventricular extrasystoles, vertigo, weight loss, withdrawal syndrome

Postmarketing and/or case reports: Torsade de pointes (1 case reported)

Overdosage/Toxicology

Experience with overdose is limited. Signs and symptoms have included disorientation, drowsiness, impaired memory, and tachycardia. Treatment should be symptomatic and supportive. Activated charcoal should be administered. Emesis is not recommended; however, gastric lavage with airway protection may be used in symptomatic patients or if performed soon after ingestion. Consider the possibility of multiple drug involvement.

Drug Interactions

Substrate of CYP1A2 (major), 2C8/9 (minor), 2D6 (major), 3A4 (major); Inhibits CYP1A2 (weak), 3A4 (weak)

Clonidine: Antihypertensive effects of clonidine may be antagonized by mirtazapine (hypertensive urgency has been reported following addition of mirtazapine to clonidine); in addition, mirtazapine may potentially enhance the hypertensive response associated with abrupt clonidine withdrawal. Avoid this combination; consider an alternative agent.

CNS depressants: Sedative effects may be additive with other CNS depressants; monitor for increased effect; includes barbiturates, benzodiazepines, narcotic analgesics, ethanol and other sedative agents

CYP1A2 inducers: May decrease the levels/effects of mirtazapine. Example inducers include aminoglutethimide, carbamazepine, phenobarbital, and rifampin.

CYP1A2 inhibitors: May increase the levels/effects of mirtazapine. Example inhibitors include amiodarone, ciprofloxacin, fluvoxamine, ketoconazole, norfloxacin, ofloxacin, and rofecoxib.

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

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of mirtazapine. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of mirtazapine. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Linezolid: Due to MAO inhibition (see note on MAO inhibitors), this combination should be avoided

MAO inhibitors: Possibly serious or fatal reactions can occur when given with or when given within 14 days of an MAO inhibitor; use is contraindicated.

Selegiline: Interaction is less likely than with nonselective MAO inhibitors (see MAO inhibitor information), but theoretically possible; monitor

Sibutramine: Potential for serotonin syndrome when used in combination

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid St John's wort (may decrease mirtazapine levels). Avoid valerian, St John's wort, SAMe, kava kava (may increase CNS depression).

Stability

Store at controlled room temperature

SolTab®: Protect from light and moisture; use immediately upon opening tablet blister

Mechanism of Action

Mirtazapine is a tetracyclic antidepressant that works by its central presynaptic alpha2-adrenergic antagonist effects, which results in increased release of norepinephrine and serotonin. It is also a potent antagonist of 5-HT2 and 5-HT3 serotonin receptors and H1 histamine receptors and a moderate peripheral alpha1-adrenergic and muscarinic antagonist; it does not inhibit the reuptake of norepinephrine or serotonin.

Pharmacodynamics/Kinetics

Protein binding: 85%

Metabolism: Extensively hepatic via CYP1A2, 2C9, 2D6, 3A4 and via demethylation and hydroxylation

Bioavailability: 50%

Half-life elimination: 20-40 hours; hampered with renal or hepatic impairment

Time to peak, serum: 2 hours

Excretion: Urine (75%) and feces (15%) as metabolites

Dosage

Children: Safety and efficacy in children have not been established

Treatment of depression: Adults: Oral: Initial: 15 mg nightly, titrate up to 15-45 mg/day with dose increases made no more frequently than every 1-2 weeks; there is an inverse relationship between dose and sedation

Elderly: Decreased clearance seen (40% males, 10% females); no specific dosage adjustment recommended by manufacturer

Dosage adjustment in renal impairment:

Clcr 11-39 mL/minute: 30% decreased clearance

Clcr<10 mL/minute: 50% decreased clearance

Dosage adjustment in hepatic impairment: Clearance decreased by 30%

Administration

SolTab®: Open blister pack and place tablet on the tongue. Do not split tablet. Tablet is formulated to dissolve on the tongue without water.

Monitoring Parameters

Patients should be monitored for signs of agranulocytosis or severe neutropenia such as sore throat, stomatitis or other signs of infection or a low WBC; mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; lipid profile

Dietary Considerations

Remeron SolTab® contains phenylalanine: 2.6 mg per 15 mg tablet; 5.2 mg per 30 mg tablet; 7.8 mg per 45 mg tablet

Patient Education

Take exactly as directed; do not increase dose or frequency. It may take 2-3 weeks to achieve desired results. Take once-a-day dose at bedtime. Avoid alcohol, caffeine, and other prescription or OTC medications not approved by prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, or lightheadedness (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, anorexia, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); or orthostatic hypotension (use caution when climbing stairs or changing position from lying or sitting to standing). Report persistent insomnia, agitation, or confusion; suicidal ideation; muscle cramping, tremors, weakness, or change in gait; breathlessness or respiratory difficulty; chest pain, palpitations, or rapid heartbeat; change in urinary pattern; vision changes or eye pain; yellowing of eyes or skin; pale stools/dark urine; or worsening of condition.

SolTab®: Open blister pack and place tablet on the tongue. Do not split tablet. Tablet is formulated to dissolve on the tongue without water.

Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Breast-feeding is not recommended.

Additional Information

Note: At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of therapy with mirtazapine; at least 14 days should be allowed after discontinuing mirtazapine before starting an MAO inhibitor.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Significant xerostomia (normal salivary flow resumes upon discontinuation).

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

Although mirtazapine 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 mirtazapine.

Dosage Forms

Tablet (Remeron®): 15 mg, 30 mg, 45 mg

Tablet, orally-disintegrating: 15 mg, 30 mg

Remeron SolTab®:

15 mg [contains phenylalanine 2.6 mg/tablet; orange flavor]

30 mg [contains phenylalanine 5.2 mg/tablet; orange flavor]

45 mg [contains phenylalanine 7.8 mg/tablet; orange flavor]

References

Abo-Zena RA, Bobek MB, and Dweik RA, "Hypertensive Urgency Induced by an Interaction of Mirtazapine and Clonidine," Pharmacotherapy , 2000, 20(4):476-8.

"Mirtazapine - A New Antidepressant," Med Lett Drugs Ther , 1996, 38(990):113-4.

Stimmel GL, Dopheide JA, and Stahl SM, "Mirtazapine: An Antidepressant With Noradrenergic and Specific Serotonergic Effects," Pharmacotherapy , 1997, 17(1):10-21.

International Brand Names

Arintapin® (DK); Combar® (DK); MirtaLich® (DE); Mirta TAD® (DE); Mirtazapin-AbZ® (DE); Mirtazapin AL® (DE); Mirtazapin Alternova® (DK); Mirtazapin Arrow® (DK); Mirtazapin AWD® (DE); Mirtazapin beta® (DE); Mirtazapin-biomo® (DE); Mirtazapin-ct® (DE); Mirtazapin dura® (DE); Mirtazapin Gea® (DK); MIrtazapin-Heumann® (DE); Mirtazapin Hexal® (DE); Mirtazapin-Isis® (DE); Mirtazapin Kwizda® (DE); Mirtazapin-neuraxpharm® (DE); Mirtazapin-ratiopharm® (DE); Mirtazapin Sandoz® (DE); Mirtazapin Stada® (DE); Mirtazelon® (DE); Mirtaz® (IN); Mirtazon® (DK); Mirtazza® (DE); Mirzaten® (SI); Norset® (FR); Noxibel® (AR); Promyrtil® (CL); Remergil® (DE); Remergon® (BE); Remeron® (AR, AT, CA, CH, CO, CR, CY, CZ, DK, EG, FI, GT, HN, HU, ID, IL, IT, JO, KW, LB, MX, NL, NO, PL, RO, RU, SE, SG, SI, SY, TH, TR, YU, ZA); Rexer® (ES); Zispin® (GB, IE)

A.D.A.M., Inc. is accredited by URAC, also known as the American Accreditation HealthCare Commission (www.urac.org). URAC's accreditation program is the first of its kind, requiring compliance with 53 standards of quality and accountability, verified by independent audit. A.D.A.M. is among the first to achieve this important distinction for online health information and services. Learn more about A.D.A.M.'s editorial process . A.D.A.M. is also a founding member of Hi-Ethics (www.hiethics.com) and subscribes to the principles of the Health on the Net Foundation (www.hon.ch).

The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition. A licensed medical professional should be consulted for diagnosis and treatment of any and all medical conditions. Call 911 for all medical emergencies. Links to other sites are provided for information only -- they do not constitute endorsements of those other sites. © 1997-2007 A.D.A.M., Inc. Any duplication or distribution of the information contained herein is strictly prohibited.

Home > Medical Reference > Complementary Medicine