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ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Remeron® may be confused with Premarin®, ramelteon, Rozerem®, Zemuron®
International issues:
Avanza® [Australia] may be confused with Albenza® which is a brand name for albendazole in the U.S.
Avanza® [Australia] may be confused with Avandia® which is a brand name for rosiglitazone in the U.S.
Remeron® my be confused with Reneuron® which is a brand name for fluoxetine in Spain
Pronunciation
(mir TAZ a peen)
U.S. Brand Names
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Treatment of depression
Use: Unlabeled/Investigational
Post-traumatic stress disorder (PTSD)
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events were observed in some animal studies; therefore, the manufacturer classifies mirtazapine as pregnancy category C. A significant increase in major teratogenic effects has not been observed in humans following exposure to mirtazapine during pregnancy; however, some nonteratogenic adverse events (similar to those observed with SSRI agents) have been reported. Mirtazapine was found to cross the placenta following a maternal overdose. Pregnancy itself does not provide “protection” against depression. Women treated for major depression and who are euthymic prior to pregnancy are more likely to experience a relapse when medication is discontinued as compared to pregnant women who continue taking antidepressant medications. The ACOG recommends that therapy with antidepressants during pregnancy be individualized. According to their recommendations, treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary care provider, and pediatrician. If treatment during pregnancy is required, consider tapering therapy during the third trimester in order to prevent withdrawal symptoms in the infant. If this is done, and the woman is considered to be at risk of relapse from her major depressive disorder, the medication can be restarted following delivery, although the dose should be readjusted to that required before pregnancy. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers, 2009).
Lactation
Excreted in breast milk/use caution
Breast-Feeding Considerations
Mirtazapine and its active metabolite are found in breast milk, with higher levels in the hindmilk than foremilk. Adverse events have not been observed in nursing infants. The manufacturer recommends that caution be used if administered to a breast-feeding woman.
Contraindications
Hypersensitivity to mirtazapine or any component of the formulation; use of MAO inhibitors within 14 days
Warnings/Precautions
Boxed warnings:
• Suicidal thinking/behavior: See “Major psychiatric warnings” below.
Major psychiatric warnings:
• [U.S. Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18-24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ?65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1-2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription. Mirtazapine is not FDA approved for use in children.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Patients treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes, either 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 or psychosis occur.
• 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. Patients presenting with depressive symptoms should be screened for bipolar disorder. Mirtazapine is not FDA approved for the treatment of bipolar depression.
Concerns related to adverse effects:
• Anticholinergic effects: May cause anticholinergic effects (constipation, xerostomia, blurred vision, urinary retention); use with caution in patients with decreased gastrointestinal motility, paralytic ileus, urinary retention, BPH, xerostomia, or visual problems. The degree of anticholinergic blockade produced by this agent is low relative to other antidepressants.
• Blood dyscrasias: Discontinue immediately if signs and symptoms of neutropenia/agranulocytosis occur.
• Hyperlipidemia: May increase serum cholesterol and triglyceride levels.
• Orthostatic hypotension: May cause orthostatic hypotension (risk is low relative to other antidepressants); use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (cerebrovascular disease, cardiovascular disease, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).
• Sedation: May cause sedation, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). The degree of sedation is moderate to high relative to other antidepressants.
• Sexual dysfunction: The incidence of sexual dysfunction with mirtazapine is generally lower than with SSRIs.
• Weight gain: 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).
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
• Seizure disorder: Use with caution in patients at risk of seizures, including those with a history of seizures, head trauma, brain damage, alcoholism, or concurrent therapy with medications which may lower seizure threshold.
Concurrent drug therapy issues:
• MAO inhibitors: Potential for severe reaction when used with MAO inhibitors; autonomic instability, coma, death, delirium, diaphoresis, hyperthermia, mental status changes/agitation, muscular rigidity, myoclonus, neuroleptic malignant syndrome features, and seizures may occur.
• Sedatives: Effects may be potentiated when used with other sedative drugs or ethanol.
Special populations:
• Elderly: Use with caution in the elderly.
Dosage form specific issues:
• Phenylalanine: SolTab® formulation contains phenylalanine.
Adverse Reactions
>10%:
Central nervous system: Somnolence (54%)
Endocrine & metabolic: Cholesterol increased
Gastrointestinal: Xerostomia (25%), appetite increased (17%), constipation (13%), weight gain (12%; weight gain of >7% reported in 8% of adults, ?49% of pediatric patients)
1% to 10%:
Cardiovascular: Peripheral edema (2%), edema (1%), hypertension, vasodilatation
Central nervous system: Dizziness (7%), abnormal dreams (4%), abnormal thoughts (3%), confusion (2%), malaise
Endocrine & metabolic: Triglycerides increased
Gastrointestinal: Abdominal pain, anorexia, vomiting
Genitourinary: Urinary frequency (2%)
Neuromuscular & skeletal: Weakness (8%), back pain (2%), myalgia (2%), tremor (2%), arthralgia
Respiratory: Dyspnea (1%)
Miscellaneous: Flu-like syndrome (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, hypoesthesia, 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)
Metabolism/Transport Effects
Substrate of CYP1A2 (major), 2C9 (minor), 2D6 (major), 3A4 (major); Inhibits CYP1A2 (weak), 3A4 (weak)
Drug Interactions
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alpha2-Agonists: Antidepressants (Alpha2-Antagonist) may diminish the hypotensive effect of Alpha2-Agonists. Exceptions: Apraclonidine; Brimonidine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
CYP1A2 Inducers (Strong): May increase the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Moderate): May decrease the metabolism of CYP1A2 Substrates. Risk C: Monitor therapy
CYP1A2 Inhibitors (Strong): May decrease the metabolism of CYP1A2 Substrates. Risk D: Consider therapy modification
CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Risk C: Monitor therapy
CYP2D6 Inhibitors (Strong): May decrease the metabolism of CYP2D6 Substrates. Risk D: Consider therapy modification
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Risk D: Consider therapy modification
Darunavir: May increase the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Risk C: Monitor therapy
MAO Inhibitors: May enhance the neurotoxic (central) effect of Mirtazapine. Risk X: Avoid combination
MAO Inhibitors: May enhance the orthostatic effect of Orthostasis Producing Agents. Risk C: Monitor therapy
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Risk D: Consider therapy modification
Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Risk C: Monitor therapy
Serotonin Modulators: May enhance the adverse/toxic effect of other Serotonin Modulators. The development of serotonin syndrome may occur. Risk D: Consider therapy modification
Sibutramine: May enhance the serotonergic effect of Serotonin Modulators. This may cause serotonin syndrome. Risk X: Avoid 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).
Storage
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
Absorption: Rapid and complete
Distribution: 4.5 L/kg
Protein binding: 85%
Metabolism: Extensively hepatic via CYP1A2, 2C9, 2D6, 3A4 and via demethylation (forms demethylmirtazapine, an active metabolite) and hydroxylation (forms inactive metabolites)
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
Oral:
Adults:
Treatment of depression: 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
Post-traumatic stress disorder (PTSD) (unlabeled use): 30-60 mg/day
Elderly: Decreased clearance seen (40% males, 10% females); no specific dosage adjustment recommended by manufacturer
Alzheimer's dementia-related depression: Initial: 7.5 mg at bedtime; may increase at 7.5-15 mg increments to 45-60 mg/day
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: Oral
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
Some products may contain phenylalanine.
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 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.
Geriatric Considerations
Limited published data specifically in the elderly or addressing in vivo drug interactions.
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.
Nursing: Physical Assessment/Monitoring
Assess other medications patient may be taking for effectiveness and interactions. Has potential for psychological or physiological dependence, abuse, or tolerance. Monitor therapeutic effectiveness and adverse reactions at beginning of therapy and periodically with long-term use. Monitor for CNS depression/sedation. Monitor for clinical worsening and suicidal ideation. Taper dosage slowly when discontinuing. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet: 7.5 mg, 15 mg, 30 mg, 45 mg
Remeron®: 15 mg, 30 mg, 45 mg
Tablet, orally disintegrating: 15 mg, 30 mg, 45 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]
Pricing: U.S. (www.drugstore.com)
Tablet, orally-disintegrating (Mirtazapine)
15 mg (30): $70.38
30 mg (30): $69.99
45 mg (30): $71.49
Tablet, orally-disintegrating (Remeron SolTab)
15 mg (30): $97.24
30 mg (30): $101.30
45 mg (30): $108.04
Tablets (Mirtazapine)
15 mg (30): $50.00
30 mg (30): $45.99
45 mg (30): $45.99
Tablets (Remeron)
15 mg (30): $116.32
30 mg (30): $117.99
45 mg (30): $133.63
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.
Bandelow B, Zohar J, Hollander E, et al, “World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders -- First Revision,” World J Biol Psychiatry, 2008, 9(4): 248-312. Available at http://www.wfsbp.org/fileadmin/pdf/guides/Guidelines_Anxiety_revision.pdf
Benedek DM, Friedman MJ, Zatzick D, et al, “Guideline Watch (March 2009): Practice Guideline for the Treatment of Patients With Acute Stress Disorder and Posttraumatic Stress Disorder.” Available at http://www.psychiatryonline.com/pracGuide/loadGuidelinePdf.aspx?file=AcuteStressDisorder-PTSD_GuidelineWatch
“Mirtazapine - A New Antidepressant,” Med Lett Drugs Ther, 1996, 38(990):113-4.
Pass SE and Simpson RW, “Discontinuation and Reinstitution of Medications During the Perioperative Period,” Am J Health Syst Pharm, 2004, 61(9):899-912.
Rabins PV, Blacker D, Rovner BW, et al, “Practice Guidelines for the Treatment of Patients With Alzheimer's Disease and Other Dementias,” October, 2007. Available at http://www.psych.org/psych_pract/treatg/pg/prac_guide.cfm.
Stimmel GL, Dopheide JA, and Stahl SM, “Mirtazapine: An Antidepressant With Noradrenergic and Specific Serotonergic Effects,” Pharmacotherapy, 1997, 17(1):10-21.
Yonkers KA, Wisner KL, Stewart DE, et al, “The Management of Depression During Pregnancy: A Report From the American Psychiatric Association and the American College of Obstetricians and Gynecologists,” Obstet Gynecol, 2009, 114(3):703-13.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2009
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