Mirtazapine (Monograph)
Brand name: Remeron
Drug class: Antidepressants, Miscellaneous
- Tetracyclic Antidepressants
VA class: CN609
Chemical name: 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido [2,3-c][2]benzazepine
Molecular formula: C17H19N3
CAS number: 61337-67-5
Warning
- Suicidality in Children and Adolescents
-
Antidepressants may increase risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders (See Pediatric Use under Cautions); balance this risk with clinical need.a b Mirtazapine is not approved for use in pediatric patients.a b
-
Closely monitor pediatric patients who are started on mirtazapine therapy for clinical worsening, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process. (See Worsening of Depression and Suicidality Risk under Cautions.)a b
Introduction
Tetracyclic antidepressant;1 2 3 4 5 6 7 8 9 10 a piperazinoazepine-derivative.1 4
Uses for Mirtazapine
Major Depressive Disorder
Treatment of major depressive disorder.13 5 6 10 11 a
Mirtazapine Dosage and Administration
General
-
Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of mirtazapine, and vice versa.a b
-
Monitor for possible worsening of depression or suicidality, especially at the beginning of therapy or during periods of dosage adjustments.19 b (See Worsening of Depression and Suicidality Risk under Cautions.)
-
Sustained therapy may be required; monitor periodically for need for continued therapy.a b
-
Maximum antidepressant effects of therapy may not be evident until ≥4 weeks of treatment.1 b
Administration
Oral Administration
Administer orally as conventional tablets and orally disintegrating tablets once daily (at bedtime) without regard to meals.1 11
Do not break orally disintegrating tablets.11
Just prior to administration of orally disintegrating tablet, remove tablet from blister package; peel open blister package, place tablet on tongue to dissolve, and swallow with saliva; administration with liquid is not necessary.11
Dosage
Adults
Major Depressive Disorder
Oral
Initially, 15 mg daily.1 11 If no improvement, dosage may be increased up to a maximum of 45 mg daily at intervals of not less than 1–2 weeks.1 11 a b
Prescribing Limits
Adults
Major Depressive Disorder
Oral
Special Populations
Hepatic Impairment
Decreased clearance; however, no special population dosage recommendations at this time.1 11 (See Hepatic Impairment under Cautions.)
Renal Impairment
Decreased clearance in patients with moderate to severe renal impairment; however, no special population dosage recommendations at this time.1 11 (See Renal Impairment under Cautions.)
Geriatric Patients
Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.a b
Cautions for Mirtazapine
Contraindications
Warnings/Precautions
Warnings
Worsening of Depression and Suicidality Risk
Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality); may persist until clinically important remission occurs with therapy.19 a b Closely supervise patients with major depressive disorder or other psychiatric illness with comorbid depression during initiation of therapy and during periods of dosage adjustments.19 a b (See Boxed Warning.)
If anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and/or mania occur, consider changing or discontinuing therapy, particularly if severe, abrupt in onset, or not a part of patient’s presenting symptoms.19 a b
Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.1 19 b
Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder) or nonpsychiatric disorders.19 a b
Bipolar Disorder
May unmask bipolar disorder.19 a b (See Activation of Mania or Hypomania under Cautions.)
Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.19 a b
Hematologic Effects
Agranulocytosis or severe neutropenia (with or without infection) reported rarely.a b If signs of infection (e.g., sore throat, fever, stomatitis) and low WBC counts occur, discontinue therapy and monitor patient closely.a b
Drug Interactions
Concomitant use with an MAO inhibitor associated with serious, sometimes fatal reactions, including manifestations resembling serotonin syndrome (e.g., hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes) or neuroleptic malignant syndrome. (See Specific Drugs under Interactions.)a b
General Precautions
CNS Effects
Risk of impaired mental alertness or physical coordination required for performing hazardous tasks (e.g., driving, operating machinery).a b
Altered Appetite and Weight
Possible increased appetite and weight gain.a b
Hyperlipidemia
Clinically important increases in serum cholesterol (e.g., >20% ULN) and serum triglyceride (e.g., 500 mg/dL) concentrations reported.a b
Hepatic Effects
Potentially clinically important elevations (e.g., 3 times ULN) in serum ALT concentrations; not usually associated with impaired hepatic function.a b
Activation of Mania or Hypomania
Possible activation of mania or hypomania; use with caution in patients with a history of mania or hypomania.a b (See Bipolar Disorder under Cautions.)
Seizures
Risk of seizures; use with caution in patients with a history of seizures.a b
Concomitant Illnesses
Experience in patients with concomitant diseases is limited.a b
Use with caution in patients with concomitant illnesses affecting metabolism or hemodynamic response.a b
Cardiovascular Effects
Safety in patients with recent history of MI or those with unstable heart disease not established.a b
Orthostatic hypotension reported infrequently.a b Use with caution in patients with known cardiovascular or cerebrovascular disease and in patients with conditions that predispose them to hypotension (e.g., dehydration, hypovolemia, concurrent antihypertensive therapy).a b
Possible increased heart rate and changes in ECG; clinical significance not known.a b
Phenylketonuria
Remeron SolTab orally disintegrating tablets contain aspartame (e.g., NutraSweet), which is metabolized in the GI tract to provide 2.6, 5.2, and 7.8 mg of phenylalanine per 15, 30, and 45 mg tablet, respectively.b
Specific Populations
Pregnancy
Category C.b
Lactation
Not known whether mirtazapine is distributed into milk.a b Caution if used in nursing women.a b
Pediatric Use
Safety and efficacy not established.1 a b
Geriatric Use
No substantial differences in adverse effects relative to younger adults; however, increased sensitivity to sedative effects possible in some geriatric individuals.a b
Use with caution in patients >65 years of age.a b
Hepatic Impairment
Decreased clearance; use with caution.a b
Renal Impairment
Decreased clearance in patients with moderate to severe renal impairment; use with caution.a b
Common Adverse Effects
Somnolence, increased appetite, weight gain, dizziness.a b
Drug Interactions
Metabolized by CYP2D6, CYP3A4, and CYP1A2; a b not a potent inhibitor of CYP2D6, CYP3A4, and CYP1A2.a b
Drugs Affecting Hepatic Microsomal Enzymes
Potential pharmacokinetic interaction (decreased mirtazapine metabolism) with inhibitors of CYP2D6, CYP3A4, or CYP1A2.a b
Potential pharmacokinetic interaction (increased mirtazapine metabolism) with inducers of CYP2D6, CYP3A4, or CYP1A2.a b
Drugs Metabolized by Hepatic Microsomal Enzymes
Substrates of CYP2D6, CYP3A4, or CYP1A2: potential pharmacokinetic interaction (decreased plasma substrate concentrations).a b However, mirtazapine is not a potent inhibitor of these enzymes and clinically important interaction is unlikely.a b
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Alcohol |
||
Benzodiazepines (diazepam) |
||
MAO inhibitors |
Concomitant use is not recommendeda b Allow at least 2 weeks to elapse between discontinuance of an MAO inhibitor and initiation of mirtazapine, or vice versaa b |
Mirtazapine Pharmacokinetics
Absorption
Bioavailability
Well absorbed from the GI tract following oral administration, with peak plasma concentration usually attained within 2 hours.a b
Bioavailability is approximately 50%.a
Food
Food does not appear to affect absorption.1 11
Distribution
Extent
Not known whether distributed into milk.a
Plasma Protein Binding
Elimination
Metabolism
Extensively metabolized in the liver, via CYP2D6 and CYP1A2 to the 8-hydroxy metabolite, and via CYP3A4 to the N-desmethyl and N-oxide metabolitea .b
Elimination Route
Excreted in urine (75%) and feces (15%).a b
Half-life
Special Populations
Renal impairment may reduce clearance.1 11 a b
Hepatic impairment may reduce clearance.1 11 a b
Stability
Storage
Oral
Tablets and Orally Disintegrating Tablets
25°C in the original container;a protect from light and moisture.b
Actions
-
Mechanism of action as an antidepressant is unclear, but is presumed to be linked to potentiation of noradrenergic and serotonergic activity in the CNS resulting from its antagonism at central presynaptic α2-adrenergic autoreceptors and heteroreceptors.1 2 7 8 9 10 11
-
Exhibits potent antagonism of serotonin type 2 (5-HT2) and type 3 (5-HT3) receptors;1 2 7 10 11 does not exhibit high affinity for serotonin type 1A (5-HT1A) or type 1B (5-HT1B) receptors.1 2 7 11
-
Exhibits moderate peripheral α1-adrenergic blocking activity and moderate antagonism at muscarinic receptors.1 11
Advice to Patients
-
Risks of suicidality; importance of patients, caregivers, and families immediately reporting emergence of suicidality, worsening depression, or other manifestations associated with increased risk of worsening depression or suicidality.19 25 b
-
Importance of considering possible impaired ability to perform hazardous activities (e.g., operating machinery, driving a motor vehicle); avoid driving or operating machinery until effects on individual are known.a b
-
Importance of avoiding alcohol-containing beverages or products.a b
-
Importance of continuing therapy even if improvement is evident within 1–4 weeks, unless directed otherwise.1 11 b Importance of patients not discontinuing therapy without first consulting clinician.17 18
-
Importance of not breaking orally disintegrating tablets.11
-
Importance of informing patients with phenylketonuria that orally disintegrating tablets contain aspartame.b
-
Importance of patients informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.b
-
Importance of women notifying clinicians if they are or plan to become pregnant or plan to breast-feed.
-
Importance of informing patients of other important precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Tablets, film-coated |
15 mg* |
Remeron (scored) |
Organon |
30 mg* |
Remeron (scored) |
Organon |
||
45 mg* |
Remeron |
Organon |
||
Tablets, orally disintegrating |
15 mg |
Remeron SolTab™ (with aspartame) |
Organon |
|
30 mg |
Remeron SolTab™ (with aspartame) |
Organon |
||
45 mg |
Remeron SolTab™ (with aspartame) |
Organon |
AHFS DI Essentials™. © Copyright 2024, Selected Revisions May 1, 2007. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
References
1. Organon Inc. Remeron (mirtazapine) tablets prescribing information. West Orange, NJ; 1999 Mar.
2. de Boer T, Ruigt GSF. The selectiveα2-adrenoceptor antagonist mirtazapine (Org 3770) enhances noradrenergic and 5-HT1A-mediated serotonergic neurotransmission. CNS Drugs. 1995; 4(Suppl 1):29-38.
3. Bremner JD. A double-blind comparison of Org 3770, amitriptyline, and placebo in major depression. J Clin Psychiatry. 1995; 56:519-25. http://www.ncbi.nlm.nih.gov/pubmed/7592505?dopt=AbstractPlus
4. Smith WT, Glaudin V, Panagides J et al. Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder. Psychopharmacol Bull. 1990; 26:191-6. http://www.ncbi.nlm.nih.gov/pubmed/2236455?dopt=AbstractPlus
5. Claghorn JL, Lesem MD. A double-blind placebo-controlled study of Org 3770 in depressed outpatients. J Affect Disord. 1995; 34:165-71. http://www.ncbi.nlm.nih.gov/pubmed/7560544?dopt=AbstractPlus
6. Halikas JA. Org 3770 (mirtazapine) versus trazodone: a placebo controlled trial in depressed elderly patients. Hum Psychopharmacol. 1995; 10:S125-33.
7. De Boer T, Ruigt GSF, Berendsen HHG. The α2-selective adrenoceptor antagonist Org 3770 (mirtazapine, Remeron) enhances noradrenergic and serotonergic transmission. Hum Psychopharmacol. 1995; 10(Suppl 2):S107-18.
8. de Montigny C, Haddjeri N, Mongeau R et al. The effects of mirtazapine on the interactions between central noradrenergic and serotonergic systems. CNS Drugs. 1995; 4(Suppl 1):13-7.
9. Frazer A. Pharmacology of antidepressants. J Clin Psychopharmacol. 1997; 17(Suppl 1):2-18S.
10. Burrows GD, Kremer CME. Mirtazapine: clinical advantages in the treatment of depression. J Clin Psychopharmacol. 1997; 17(Suppl 1):34-9S. http://www.ncbi.nlm.nih.gov/pubmed/9004055?dopt=AbstractPlus
11. Organon Inc. Remeron SolTab™ (mirtazapine) orally disintegrating tablets prescribing information. West Orange, NJ; 2001 Feb.
12. American Medical Association Council on Scientific Affairs. Aspartame: review of safety issues. JAMA. 1985; 254:400-2. http://www.ncbi.nlm.nih.gov/pubmed/2861297?dopt=AbstractPlus
13. Gossel TA. A review of aspartame: characteristics, safety and uses. US Pharm. 1984; 9:26,28-30.
14. Food and Drug Administration. Aspartame as an inactive ingredient in human drug products; labeling requirements. Proposed rule. [21 CFR Part 201] Fed Regist. 1983; 48:54993-5. (lDIS 178728)
15. Food and Drug Administration. Food additives permitted for direct addition to food for human consumption; aspartame. Final rule. [21 CFR Part 172] Fed Regist. 1983; 48:31376-82. (IDIS 172957)
16. Anon. Aspartame and other sweeteners. Med Lett Drugs Ther. 1982; 24:1-2. http://www.ncbi.nlm.nih.gov/pubmed/7054648?dopt=AbstractPlus
17. Anon. FDA issues public health advisory entitled: Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Talk Paper. Rockville, MD: Food and Drug Administration; 2003 Oct 27. From the FDA website: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm096293.htm
18. Anon. Reports of suicidality in pediatric patients being treated with antidepressant medications for major depressive disorder (MDD). FDA Public Health Advisory. Rockville, MD: Food and Drug Administration; 2003 Oct 27. From the FDA website:. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm168828.htm
19. Food and Drug Administration. Class suicidality labeling language for antidepressants. From the FDA website:. http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM173233.pdf
20. Food and Drug Administration. Public health advisory: suicidality in children and adolescents being treated with antidepressant medications. Rockville, MD; 2004 Oct 15. From the FDA website:. http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm096273.htm
25. Food and Drug Administration. Medication guide: about using antidepressants in children or teenagers. Rockville, MD; 2005 Jan 16. From the FDA website:. http://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/ucm100211.pdf
a. Organon Inc. Remeron (mirtazapine) tablets prescribing information. West Orange, NJ; 2005 Jun
b. Organon Inc. Remeron SolTab™ (mirtazapine) orally disintegrating tablets prescribing information. West Orange, NJ; 2005 Jun
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