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Mirtazapine: Drug information

Mirtazapine: Drug information
(For additional information see "Mirtazapine: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
ALERT: US Boxed Warning
Suicidality and antidepressant drugs:

Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors. Mirtazapine is not approved for use in pediatric patients.

Brand Names: US
  • Remeron;
  • Remeron SolTab
Brand Names: Canada
  • APO-Mirtazapine;
  • Auro-Mirtazapine;
  • Auro-Mirtazapine OD;
  • DOM-Mirtazapine;
  • JAMP-Mirtazapine;
  • MYLAN-Mirtazapine;
  • PMS-Mirtazapine;
  • PRO-Mirtazapine;
  • Remeron;
  • Remeron RD;
  • RIVA-Mirtazapine [DSC];
  • SANDOZ Mirtazapine;
  • TEVA-Mirtazapine;
  • TEVA-Mirtazapine OD [DSC]
Pharmacologic Category
  • Antidepressant, Alpha-2 Antagonist
Dosing: Adult
Headache, chronic tension-type, prophylaxis

Headache, chronic tension-type, prophylaxis (alternative agent) (off-label use): Oral: Initial: 15 mg once daily at bedtime; may increase after 1 week to 30 mg/day based on response and tolerability (Bendtsen 2004)

Major depressive disorder

Major depressive disorder (unipolar): Oral: Initial: 15 mg once daily at bedtime; increase dose in 15 mg increments at intervals no less than every 1 to 2 weeks based on response and tolerability. Maximum dose: 45 mg/day (product labeling); however, doses up to 60 mg/day have been used in clinical trials (VA/DoD 2016; Watanabe 2011).

Panic disorder

Panic disorder (alternative agent) (off-label use):

Note: As monotherapy or adjunctive therapy in patients nonresponsive to SSRIs.

Oral: Initial: 15 mg once daily at bedtime; may increase in increments of 15 mg at intervals of no less than 1 week based on response and tolerability, up to a usual maximum of 45 mg once daily (product labeling). Average doses in clinical trials were ~30 mg/day; doses up to 60 mg/day have been evaluated (Boshuisen 2001; Montañés-Rada 2005; Ribeiro 2001).

Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for >3 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (APA 2010; WFSBP [Bauer 2015]). Reasons for a slower taper (eg, over 4 weeks) include use of a drug with a half-life <24 hours (eg, paroxetine, venlafaxine), prior history of antidepressant withdrawal symptoms, or high doses of antidepressants (APA 2010; Hirsch 2021a). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Shelton 2001). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (WFSBP [Bauer 2015]). Evidence supporting ideal taper rates is limited (Shelton 2001; WFSBP [Bauer 2015]).

Switching antidepressants: Evidence for ideal antidepressant switching strategies is limited; strategies include cross-titration (gradually discontinuing the first antidepressant while at the same time gradually increasing the new antidepressant) and direct switch (abruptly discontinuing the first antidepressant and then starting the new antidepressant at an equivalent dose or lower dose and increasing it gradually). Cross-titration (eg, over 1 to 4 weeks depending upon sensitivity to discontinuation symptoms and adverse effects) is standard for most switches, but is contraindicated when switching to or from an MAOI. A direct switch may be an appropriate approach when switching to another agent in the same or similar class (eg, when switching between two SSRIs), when the antidepressant to be discontinued has been used for <1 week, or when the discontinuation is for adverse effects. When choosing the switch strategy, consider the risk of discontinuation symptoms, potential for drug interactions, other antidepressant properties (eg, half-life, adverse effects, and pharmacodynamics), and the degree of symptom control desired (WFSBP [Bauer 2013]; Hirsch 2021b; Ogle 2013).

Switching to or from an MAOI:

Allow 14 days to elapse between discontinuing an MAOI and initiation of mirtazapine.

Allow 14 days to elapse between discontinuing mirtazapine and initiation of an MAOI.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Altered kidney function:

There are no dosage adjustments provided in the manufacturer's labeling; however, clearance is decreased in kidney impairment (manufacturer's labeling). Use with caution.

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary (Nagler 2012).

eGFR <30 mL/minute/1.73 m2: Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Nagler 2012; expert opinion).

Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzed due to high protein binding and large Vd (expert opinion):

Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Gholyaf 2020; Mehrpooya 2020; Nagler 2012; Raymond 2008).

Peritoneal dialysis : Unlikely to be significantly dialyzed due to high protein binding and large Vd (expert opinion):

Initiate at 7.5 to 15 mg once daily and titrate slowly with close monitoring for adverse effects (Nagler 2012; expert opinion).

CRRT: Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (expert opinion).

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer’s labeling; however, dosage reductions may be necessary in patients with moderate to severe hepatic impairment (clearance may be decreased). Some experts recommend reducing initial dose by 50% and a maximum dose of 30 mg in patients with hepatic impairment (Mauri 2014; Mullish 2014). Use with caution.

Dosing: Older Adult

Major depressive disorder (unipolar): Oral: Initial starting doses of 7.5 mg once daily at bedtime have been suggested (VA/DoD 2016). Use with caution; clearance may be reduced; refer to adult dosing. Note: Some experts consider mirtazapine to be useful for stimulating appetite in older adults with depression and weight loss (Ritchie 2018).

Discontinuation of therapy: Refer to adult dosing.

Switching antidepressants: Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Remeron: 15 mg [DSC] [scored]

Remeron: 15 mg [scored; contains corn starch]

Remeron: 30 mg [DSC] [scored]

Remeron: 30 mg [scored; contains corn starch]

Generic: 7.5 mg, 15 mg, 30 mg, 45 mg

Tablet Disintegrating, Oral:

Remeron SolTab: 15 mg, 30 mg, 45 mg [contains aspartame]

Generic: 15 mg, 30 mg, 45 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Remeron: 30 mg [contains corn starch]

Generic: 15 mg, 30 mg, 45 mg

Tablet Disintegrating, Oral:

Remeron RD: 15 mg, 30 mg, 45 mg [contains aspartame]

Generic: 15 mg, 30 mg, 45 mg

Medication Guide and/or Vaccine Information Statement (VIS)

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Remeron, Remeron SolTab: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/020415s038,021208s028lbl.pdf#page=23

Administration: Adult

Oral: Administer without regard to meals.

Orally disintegrating tablet: Do not remove tablet from blister pack until ready to administer; peel back foil to expose tablet; use dry hands to remove tablet and place immediately on tongue. Tablet dissolves rapidly in saliva; water is not needed. Do not chew, crush, or split tablet.

Use: Labeled Indications

Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder (MDD)

Use: Off-Label: Adult

Headache, chronic tension-type, prophylaxis; Panic disorder

Medication Safety Issues
Sound-alike/look-alike issues:

Remeron may be confused with Premarin, ramelteon, Rozerem, Zemuron

Geriatric Patients: High-Risk Medication:

Beers Criteria: Mirtazapine is identified in the Beers Criteria as a potentially inappropriate medication to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2019]).

International issues:

Avanza [Australia] may be confused with Albenza brand name for albendazole [US]; Avandia brand name for rosiglitazone [US, Canada, and multiple international markets]

Remeron [US, Canada, and multiple international markets] may be confused with Reneuron which is a brand name for fluoxetine [Spain]

Adverse Reactions (Significant): Considerations
Activation of mania or hypomania

Antidepressants (when used without a mood stabilizer) may precipitate a mixed/manic episode in patients with bipolar disorder. Treatment-emergent mania or hypomania in patients with unipolar major depressive disorder (MDD) treated with mirtazapine have been reported rarely. Although some of these cases occurred in patients receiving monotherapy at a therapeutic antidepressant dose, a number of the reports occurred in patients also receiving selective serotonin reuptake inhibitors (SSRIs) (or without a period of washout from a previous SSRI) or had potential risk factors for switching (Ref). It has also been suggested that mirtazapine-induced mania may present with atypical features, consisting of dysphoria, irritability, insomnia, psychomotor agitation, and abnormal gait (Ref).

Mechanism: Unclear to what extent mood switches represent an uncovering of unrecognized bipolar disorder or a more direct pharmacologic effect independent of diagnosis (Ref). Mirtazapine induced-mania has been attributed to central norepinephrine hyperactivity through its unique mechanism of action of blocking central alpha-2 adrenergic autoreceptors and heteroreceptors, resulting in increased serotonin and norepinephrine neurotransmitter release while blocking postsynaptic 5-HT2 and 5-HT3 receptors (Ref).

Onset: Varied; among the limited case reports involving mirtazapine, the average time until onset of mania/hypomania following mirtazapine initiation or a dose increase was 15.7 days (median, 7 days) (Ref).

Risk factors:

• Higher doses (Ref)

• Underlying brain dysfunction (Ref)

• Coadministration with certain SSRIs (Ref)

• Family history of bipolar disorder (Ref)

• Depressive episode with psychotic symptoms (Ref)

• Younger age at onset of depression (Ref)

• Antidepressant resistance (Ref)

Drug-induced movement disorders

Mirtazapine has been associated with several hyperkinetic movement disorders. Most case reports describe akathisia, acute dystonia, and restless leg syndrome (RLS). Mirtazapine-induced dyskinesia (including gradual onset, transient, and acute reversible) has also been reported rarely. Mirtazapine-induced akathisia is usually reported in the presence of higher mirtazapine doses (30 mg/day), whereas dystonia and dyskinesia are usually reported at lower doses (15 mg/day). Akathisia may also occur rarely at lower doses (15 mg/day) in select patients (Ref).

Mechanism:

Akathisia: Dose-related (likely). Mechanism has not been clearly defined, although limited data attributes akathisia to blockade of alpha-2 adrenoreceptors from higher therapeutic dosages (ie, 30 mg/day) of mirtazapine, while lower dosage may be beneficial in the treatment of akathisia due to serotonin (5-HT2A) receptor blockade (Ref).

Dystonia: Unknown, but has been attributed to antidopaminergic action due to 5-HT2 receptor inhibition associated with a central noradrenergic effect producing a noradrenergic-dopaminergic imbalance (Ref).

RLS: Unknown, but mirtazapine’s 5-HT1 stimulating properties and 5-HT2/5-HT3 receptor blocking properties have been suggested (Ref).

Dyskinesia: Unknown, but mediation by 5-HT2 receptor antagonism has been suggested, which has been shown to have some activity promoting motor function in states of reduced dopamine release (Ref).

Onset: Varied; among the case reports of mirtazapine hyperkinetic movement disorders, symptom onset occurred within 9 days, with some cases following a single dose (Ref); however, there is also a case report of mirtazapine-induced akathisia following 20 years of continuous treatment (Ref).

Risk factors:

Hyperkinetic movement disorders:

• History of drug-induced movement disorders/extrapyramidal symptoms (Ref)

Dyslipidemia

Mirtazapine commonly causes increased serum cholesterol and, less commonly, increased serum triglycerides. Cases of severe hypertriglyceridemia and acute pancreatitis have also been reported rarely (some of the acute pancreatitis cases occurred in a setting of new-onset diabetes and/or diabetic ketoacidosis, making it difficult to determine whether hypertriglyceridemia was the cause) (Ref).

Mechanism: Unknown; in one study, increases in weight were linearly associated with changes in total cholesterol; however, the clinical significance is unclear, since increased cholesterol might be due to an improvement in depressive symptoms resulting in increased appetite, caloric intake, and weight (Ref).

Onset: Intermediate; increases in total cholesterol have been observed during the first 4 weeks of treatment (Ref).

Hematologic abnormalities

Neutropenia, leukopenia, and agranulocytosis have been reported rarely with mirtazapine (Ref). Mirtazapine is also associated with drug-induced immune thrombocytopenia (DITP) (Ref).

Mechanism:

Leukopenia: Unclear and poorly understood; hypersensitivity/immune mediated mechanisms have been suggested (Ref).

DITP: Non-dose-related; immunologic; mechanism is attributed to drug-dependent antibodies that react with the glycoprotein IIb/IIIa complex on the platelet surface resulting in accelerated platelet destruction (Ref).

Onset: Varied; in general, drug-induced neutropenia usually manifests after 1 or 2 weeks of exposure and agranulocytosis usually appears 3 to 4 weeks following initiation of therapy; however, the onset may be delayed (Ref). Drug-induced thrombocytopenia generally occurs 5 to 10 days after initial drug exposure (Ref).

Orthostatic hypotension

Mirtazapine may cause orthostatic hypotension. The actual prevalence is unknown but is likely not common (Ref).

Mechanism: Orthostatic hypotension is likely caused by antagonism of alpha-1 adrenergic receptors; mirtazapine has weak peripheral alpha-1-blocking activity (Ref), although some authors have classified it as having moderate activity (Ref).

Risk factors:

• Cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities) or cerebrovascular disease

• Known predisposing conditions (hypovolemia/dehydration)

• Concurrent medications predisposing patient to orthostatic hypotension (eg, antihypertensives)

• Older adults (≥65 years of age) (Ref)

Sedation

Sedation (drowsiness) is very common with initial use and may cause nonadherence, dizziness, and confusion, particularly in older adults (Ref). However, the dose relationship with mirtazapine is unique, in that lower doses (≤15 mg) are associated with significant sedation compared to less sedation with higher doses (>15 mg) (Ref). Tolerance appears to develop to the sedative effect (Ref).

Mechanism: Dose-related (inverse relationship). Somnolence is primarily attributed to potent histamine H1 antagonism at lower doses; higher doses are less sedating due to increased noradrenergic transmission which partially offsets the antihistamine activity (Ref).

Onset: Rapid; however, tolerance appears to develop quickly (within a few days) to the sedative effect (Ref).

Risk factors:

• Concomitant use of benzodiazepines or alcohol

Serotonin syndrome

Serotonin syndrome has been reported rarely with mirtazapine and typically occurs with coadministration of multiple serotonergic drugs, but can occur following a single serotonergic agent at high therapeutic doses or supratherapeutic doses (Ref). Only a few cases of serotonin syndrome have been reported with mirtazapine monotherapy at therapeutic doses (Ref). Of note, some clinicians have questioned whether serotonin syndrome attributed to mirtazapine is an accurate characterization or if symptoms described are due to other causes, such as extrapyramidal symptoms (Ref). The diagnosis of serotonin syndrome is made based on the Hunter Serotonin Toxicity Criteria (Ref) and may result in a spectrum of symptoms, such as anxiety, agitation, confusion, delirium, hyperreflexia, muscle rigidity, myoclonus, tachycardia, tachypnea, and tremor. Severe cases may cause hyperthermia, significant autonomic instability (ie, rapid and severe changes in blood pressure and pulse), coma, and seizures (Ref).

Mechanism: Dose-related; mirtazapine, which does not inhibit the reuptake of serotonin, is sometimes classified as a noradrenergic and specific serotonergic antidepressant (NaSSA), and acts as an antagonist of presynaptic alpha-2 adrenergic receptors and postsynaptic 5-HT2 and 5-HT3 serotonin receptors, therefore leading to an increase in norepinephrine and 5-HT1A-mediated serotonin activity. Serotonin syndrome has been attributed to the serotonergic activity from stimulation of 5-HT1A receptors (Ref); however, some clinicians have argued that the receptor pharmacology of mirtazapine is not consistent with it being able to cause serotonin toxicity, as it does not cause serotonin (5-HT) excess in the brain (Ref).

Onset: Varied; in most serotonin-syndrome cases (74%) (predominantly involving selective serotonin reuptake inhibitors, tricyclic antidepressants, and/or monoamine oxidase inhibitors [MAOIs]), onset occurred within 24 hours of treatment initiation, overdose, or change in dose (Ref). In the few cases involving mirtazapine, most occurred within 24 hours or several days following initiation or a dose increase (Ref).

Risk factors:

• Concomitant use of drugs that increase serotonin synthesis, block serotonin reuptake and/or impair serotonin metabolism (eg, MAOIs). Of note, concomitant use of some serotonergic agents, such as MAOIs, are contraindicated.

Sexual dysfunction

Antidepressants, primarily the selective serotonin reuptake inhibitors, are commonly associated with sexual disorders in patients of any sex. Mirtazapine, however, is generally associated with having less risk for sexual adverse reactions and may also have some beneficial effects on sexual functioning in depressed patients (Ref). One meta-analysis also found no significant difference in treatment-emergent sexual dysfunction with mirtazapine compared to placebo (Ref).

Mechanism: The mechanism attributed to mirtazapine’s role (if any) in sexual dysfunction is unknown, and because a large portion of sexual dysfunction is thought to be mediated via stimulation of the postsynaptic 5-HT2A receptor, the blockade of this receptor by mirtazapine should lead to a reduced incidence of these side effects (Ref).

Risk factors:

• Depression (sexual dysfunction is commonly associated with depression; antidepressant-induced sexual dysfunction may be difficult to differentiate in treated patients) (Ref)

Suicidal thinking and behavior

Antidepressants are associated with an increased risk of suicidal ideation and suicidal tendencies in pediatric and young adult patients (18 to 24 years of age) in short-term studies. In adults >24 years of age, short-term studies did not show an increased risk of suicidal thinking and behavior and in older adults ≥65 years of age, a decreased risk was observed. Although data have yielded inconsistent results regarding the association of antidepressants and risk of suicide, particularly among adults, collective evidence shows a trend of an elevated risk of suicidality in younger age groups (Ref). Of note, the risk of a suicide attempt is inherent in major depression and may persist until remission occurs.

Mechanism: Not established; one of several postulated mechanisms is antidepressants may energize suicidal patients to act on impulses; another suggests that antidepressants may produce a worsening of depressive symptoms leading to the emergence of suicidal thoughts and actions (Ref).

Onset: Varied; increased risk observed in short-term studies (ie, <4 months) in pediatric and young adults; it is unknown whether this risk extends to long-term use (ie, >4 months).

Risk factors:

• Children and adolescents (Ref)

• Depression (risk of suicide is associated with major depression and may persist until remission occurs)

Weight gain

Mirtazapine commonly causes significant weight gain (increase of ≥7% of body weight) following short and long-term use (Ref). Mirtazapine also commonly causes increased appetite (Ref).

Mechanism: Antidepressants may induce weight gain by interacting with central mechanisms regulating food intake and appetite, with differences in weight gain between agents attributed to actions on serotonergic, dopaminergic, noradrenergic, histaminergic, and cholinergic systems. Mirtazapine's weight gain has been attributed to its alpha-2 adrenoreceptor antagonism, its high affinity for antagonizing histamine (H1) receptors, and its effects on 5-HT2c receptors, as well as its low affinity for dopaminergic D1 and D2 receptors. In addition, some of the weight gain may also reflect improvement in mood (Ref).

Onset: Varied; significant increases in weight have been observed after the first week of treatment (Ref). In one meta-analysis, mirtazapine was associated with significant weight gain during acute treatment (4 to 12 weeks), and maintained significant associations with weight gain over longer periods of use (≥8 months) (Ref).

Risk factors:

• Psychiatric disorders (regardless of medication) are associated with a higher risk for obesity compared to the general population (Ref)

Withdrawal syndrome

Withdrawal syndrome following mirtazapine discontinuation has been reported, primarily following abrupt discontinuation, although it has also occurred following gradual tapering. Reported symptoms include dizziness, nausea, vomiting, paresthesia, hypotension, insomnia, reduced need of sleep, anxiety, panic attacks, restlessness, irritability, elated mood, pressure of speech, increased energy, and nightmares (Ref). There is also a single case report of mirtazapine-withdrawal associated pruritus following abrupt discontinuation (Ref). In addition, there are several case reports describing withdrawal-induced mania or hypomania following both abrupt and gradual mirtazapine discontinuation. Some of the reports occurred in patients with bipolar disorder and some reports did not mention a preexisting diagnosis of bipolar disorder (Ref).

Mechanism: Withdrawal; mechanism of withdrawal symptoms is unknown, but has been attributed, in part, to the sudden removal of the blockade of 5-HT receptors, as stimulation of 5-HT2 and 5-HT3 receptors has been associated with nausea, anxiety, and insomnia. In addition, the sudden removal of histamine (H1) blockade may contribute to dizziness (Ref).

Onset: Varied; case reports describe an onset of withdrawal symptoms between 1 to 7 days (following either abrupt or tapered discontinuation) (Ref).

Risk factors:

• Abrupt discontinuation (rather than gradual dosage reduction) of an antidepressant treatment that has lasted >3 weeks, particularly a drug with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)

• Prior history of antidepressant withdrawal symptoms (Ref)

• High dose (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Endocrine & metabolic: Increased serum cholesterol (15% (table 1)), weight gain (12%; ≥7% of body weight: 8%; literature suggests that incidence of significant weight gain may be as high as 77% after 13.5 months of use) (table 2) (Uguz 2015)

Mirtazapine: Adverse Reaction: Increased Serum Cholesterol

Drug (Mirtazapine)

Placebo

Number of Patients (Mirtazapine)

Number of Patients (Placebo)

Comments

15%

7%

N/A

N/A

Nonfasting cholesterol increases to ≥20% above the upper limits

Mirtazapine: Adverse Reaction: Weight Gain

Drug (Mirtazapine)

Placebo

Number of Patients (Mirtazapine)

Number of Patients (Placebo)

Comments

12%

2%

453

361

N/A

≥7% of body weight: 8%

0%

N/A

N/A

Gastrointestinal: Constipation (13%), increased appetite (17%) (table 3), xerostomia (25%)

Mirtazapine: Adverse Reaction: Increased Appetite

Drug (Mirtazapine)

Placebo

Number of Patients (Mirtazapine)

Number of Patients (Placebo)

17%

2%

453

361

Nervous system: Drowsiness (54%) (table 4)

Mirtazapine: Adverse Reaction: Drowsiness

Drug (Mirtazapine)

Placebo

Number of Patients (Mirtazapine)

Number of Patients (Placebo)

54%

18%

453

361

1% to 10%:

Cardiovascular: Edema (1%), hypertension, peripheral edema (2%), vasodilation

Dermatologic: Pruritus (may be withdrawal-associated, which is rare: <1%) (Spitznogle 2019), skin rash

Endocrine & metabolic: Increased serum triglycerides (6%) (table 5), increased thirst

Mirtazapine: Adverse Reaction: Increased Serum Triglycerides

Drug (Mirtazapine)

Placebo

Number of Patients (Mirtazapine)

Number of Patients (Placebo)

Comments

6%

3%

N/A

N/A

Nonfasting triglyceride increases to ≥500 mg/dL

Gastrointestinal: Abdominal pain, anorexia, vomiting

Genitourinary: Urinary frequency (2%), urinary tract infection

Hepatic: Increased serum alanine aminotransferase (≥3 times ULN: 2%)

Nervous system: Abnormal dreams (4%), abnormality in thinking (3%), amnesia, anxiety, apathy, confusion (2%) (table 6), dizziness (7%) (table 7), hypoesthesia, malaise, myasthenia, paresthesia, psychomotor agitation, twitching, vertigo

Mirtazapine: Adverse Reaction: Confusion

Drug (Mirtazapine)

Placebo

Number of Patients (Mirtazapine)

Number of Patients (Placebo)

2%

0%

453

361

Mirtazapine: Adverse Reaction: Dizziness

Drug (Mirtazapine)

Placebo

Number of Patients (Mirtazapine)

Number of Patients (Placebo)

7%

3%

453

361

Neuromuscular & skeletal: Arthralgia, asthenia (8%), back pain (2%), hyperkinetic muscle activity, hypokinesia, myalgia (2%), tremor (2%)

Respiratory: Dyspnea (1%), flu-like symptoms (5%)

<1%:

Cardiovascular: Acute myocardial infarction, angina pectoris, atrial arrhythmia, bigeminy, bradycardia, cardiomegaly, cerebral ischemia, chest pain, facial edema, hypotension, left ventricular failure, phlebitis, pulmonary embolism, syncope, ventricular premature contractions

Dermatologic: Alopecia, cellulitis, exfoliative dermatitis, skin photosensitivity, Stevens-Johnson syndrome, urticaria, xeroderma

Endocrine & metabolic: Amenorrhea, dehydration, diabetes mellitus, goiter, gout, heavy menstrual bleeding, hyponatremia, hypothyroidism, increased acid phosphatase, increased libido, weight loss

Gastrointestinal: Ageusia, cholecystitis, colitis, enlargement of abdomen, enlargement of salivary glands, eructation, gastritis, gastroenteritis, gingival hemorrhage, glossitis, intestinal obstruction, nausea, oral candidiasis, pancreatitis, sialorrhea, stomatitis, tongue discoloration

Genitourinary: Breast engorgement, breast hypertrophy, cystitis, dysmenorrhea, dysuria, ejaculatory disorder, hematuria, impotence, leukorrhea, mastalgia, urethritis, urinary incontinence, urinary retention, urinary urgency, uterine hemorrhage, vaginitis

Hematologic & oncologic: Agranulocytosis, anemia, leukopenia, pancytopenia, petechia, severe neutropenia, thrombocytopenia

Hepatic: Hepatic cirrhosis, increased serum aspartate aminotransferase

Hypersensitivity: Tongue edema

Nervous system: Akathisia, aphasia, ataxia, chills, delirium, delusion, dementia, depersonalization, drug dependence, dysarthria, dystonia, emotional lability, euphoria, extrapyramidal reaction, hallucination, hostility, hyperacusis, hyperreflexia, hypomania (may be withdrawal-associated) (MacCall 1999), hypotonia, mania (may be withdrawal-associated) (Pombo 2017), migraine, myoclonus, neurosis, paranoid ideation, seizure, serotonin syndrome, stupor, tonic clonic epilepsy, vascular headache, withdrawal syndrome

Neuromuscular & skeletal: Arthritis, bone fracture (osteoporosis), dyskinesia, myositis, neck pain, neck stiffness, ostealgia, rupture of tendon, tenosynovitis

Ophthalmic: Abnormal lacrimation, accommodation disturbance, angle-closure glaucoma, blepharitis, conjunctivitis, diplopia, eye pain, nystagmus disorder

Otic: Deafness, otalgia

Renal: Nephrolithiasis, polyuria

Respiratory: Epistaxis

Miscellaneous: Abnormal healing, fever, ulcer

Frequency not defined: Cardiovascular: Orthostatic hypotension

Postmarketing:

Cardiovascular: Increased serum creatine kinase, prolonged QT interval on ECG (Matsuda 2020), torsades de pointes, ventricular tachycardia

Dermatologic: Bullous dermatitis, erythema multiforme, hyperpigmentation (Sukhdeo 2018), toxic epidermal necrolysis

Endocrine & metabolic: Hyperprolactinemia, hypertriglyceridemia (Chen 2003, Duncan 2015)

Genitourinary: Priapism, sexual disorder (Lee 2010)

Hematologic: Immune thrombocytopenia (Stuhec 2014)

Hepatic: Steatosis (Thomas 2017)

Immunologic: Drug reaction with eosinophilia and systemic symptoms

Nervous system: Complex sleep-related disorder (Shinith 2018), somnambulism (Yeh 2009), suicidal ideation, suicidal tendencies

Neuromuscular & skeletal: Restless leg syndrome (precipitation or exacerbation) (Kolla 2018, Kim 2008), rhabdomyolysis (Khandat 2004)

Contraindications

Hypersensitivity to mirtazapine or any component of the formulation; use of monoamine oxidase inhibitors (MAOIs) including linezolid or methylene blue IV (concurrently or within 14 days of stopping an MAOI).

Warnings/Precautions

Major psychiatric warnings:

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 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 health care 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. 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.

Concerns related to adverse effects:

• Akathisia/psychomotor restlessness: Most likely to occur within first few weeks of treatment and characterized by unpleasant or distressing restlessness and need to move often accompanied by an inability to sit or stand still. Increasing the dose in these patients may be detrimental.

• 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.

• Arrhythmias: QT prolongation, torsade de pointes, and ventricular fibrillation have been reported (rarely); case reports are mostly associated with mirtazapine overdose (although one case series of single-agent mirtazapine overdose in 84 patients did not identify any cases of QT prolongation [Berling 2014]) or patients with risk factors for QT prolongation or receiving concomitant QT-prolonging agents. Use caution in patients with cardiovascular disease, history of QT prolongation, or receiving concomitant QT-prolonging agents.

• Blood dyscrasias: Discontinue immediately if signs and symptoms of neutropenia/agranulocytosis occur.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). The degree of sedation is moderate to high relative to other antidepressants.

• Dizziness: Dizziness may occur; it is unclear whether or not tolerance may develop to dizziness.

• Fractures: Bone fractures have been associated with antidepressant treatment. Consider the possibility of a fragility fracture if an antidepressant-treated patient presents with unexplained bone pain, point tenderness, swelling, or bruising (Rabenda 2013; Rizzoli 2012).

• Hyperlipidemia: May increase serum cholesterol and triglyceride levels.

• Hyponatremia: May cause hyponatremia. Use caution in patients at risk, such as elderly or patients who are volume depleted or concomitantly treated with medications known to cause hyponatremia. Discontinue treatment if symptoms occur.

• Ocular effects: May cause mild pupillary dilation which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.

• 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, dehydration, hypovolemia, or concurrent medication use which may predispose to hypotension/bradycardia).

• Serotonin syndrome: Potentially life-threatening serotonin syndrome (SS) has occurred with serotonergic agents (eg, SSRIs, SNRIs), particularly when used in combination with other serotonergic agents (eg, triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John's wort, tryptophan) or agents that impair metabolism of serotonin (eg, MAO inhibitors intended to treat psychiatric disorders, other MAO inhibitors [ie, linezolid and intravenous methylene blue]). Monitor patients closely for signs of SS such as mental status changes (eg, agitation, hallucinations, delirium, coma); autonomic instability (eg, tachycardia, labile blood pressure, diaphoresis); neuromuscular changes (eg, tremor, rigidity, myoclonus); GI symptoms (eg, nausea, vomiting, diarrhea); and/or seizures. Discontinue treatment (and any concomitant serotonergic agent) immediately if signs/symptoms arise.

• Weight gain: May increase appetite and stimulate weight gain.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; clearance is decreased and half-life and plasma concentrations are increased in mild to moderate impairment. Clinically significant transaminase elevations have been observed.

• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer may be effective for acute treatment of bipolar major depressive episodes, but should be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Mirtazapine is not FDA approved for the treatment of bipolar depression.

• Renal impairment: Use with caution in patients with renal impairment; clearance is decreased with moderate and severe 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.

Dosage form specific issues:

• Lactose: Tablets may contain lactose.

• Phenylalanine: SolTab formulation may contain phenylalanine.

Other warnings/precautions:

• Discontinuation syndrome: Abrupt discontinuation or interruption of antidepressant therapy has been associated with a discontinuation syndrome. Symptoms arising may vary with antidepressant however commonly include nausea, vomiting, diarrhea, headaches, lightheadedness, dizziness, diminished appetite, sweating, chills, tremors, paresthesias, fatigue, somnolence, and sleep disturbances (eg, vivid dreams, insomnia). Less common symptoms include electric shock-like sensations, cardiac arrhythmias (more common with tricyclic antidepressants), myalgias, parkinsonism, arthralgias, and balance difficulties. Psychological symptoms may also emerge such as agitation, anxiety, akathisia, panic attacks, irritability, aggressiveness, worsening of mood, dysphoria, mood lability, hyperactivity, mania/hypomania, depersonalization, decreased concentration, slowed thinking, confusion, and memory or concentration difficulties. Greater risks for developing a discontinuation syndrome have been associated with antidepressants with shorter half-lives, longer durations of treatment, and abrupt discontinuation. For antidepressants of short or intermediate half-lives, symptoms may emerge within 2 to 5 days after treatment discontinuation and last 7 to 14 days (APA 2010; Fava 2006; Haddad 2001; Shelton 2001; Warner 2006).

Metabolism/Transport Effects

Substrate of CYP1A2 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential

Drug Interactions

Alcohol (Ethyl): May enhance the CNS depressant effect of Mirtazapine. Risk X: Avoid combination

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Almotriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Alosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Alpha2-Agonists: Mirtazapine may diminish the antihypertensive effect of Alpha2-Agonists. Management: Consider avoiding concurrent use. If the combination cannot be avoided, monitor for decreased effects of alpha2-agonists if mirtazapine is initiated/dose increased, or increased effects if mirtazapine is discontinued/dose decreased. Risk D: Consider therapy modification

Amphetamines: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability). Initiate amphetamines at lower doses, monitor frequently, and adjust doses as needed. Risk C: Monitor therapy

Antiemetics (5HT3 Antagonists): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Antipsychotic Agents: Serotonergic Agents (High Risk) may enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification

BusPIRone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of Mirtazapine. Risk C: Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy

Cyclobenzaprine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Mirtazapine. Risk C: Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Mirtazapine. Risk C: Monitor therapy

Dapoxetine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Do not use serotonergic agents (high risk) with dapoxetine or within 7 days of serotonergic agent discontinuation. Do not use dapoxetine within 14 days of monoamine oxidase inhibitor use. Dapoxetine labeling lists this combination as contraindicated. Risk X: Avoid combination

Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Dexmethylphenidate-Methylphenidate: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Dextromethorphan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification

Eletriptan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy

Ergot Derivatives: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Fenfluramine: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Risk C: Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy

Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Lasmiditan: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification

Linezolid: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination

Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Lorcaserin (Withdrawn From US Market): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Metaxalone: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. 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 the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification

Methylene Blue: Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid combination

Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Monoamine Oxidase Inhibitors (Antidepressant): Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid combination

Nefazodone: Mirtazapine may enhance the serotonergic effect of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase the serum concentration of Mirtazapine. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and for increased mirtazapine toxicities when these agents are combined. Risk C: Monitor therapy

Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Ondansetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination

Oxitriptan: Serotonergic Agents (High Risk) may enhance the serotonergic effect of Oxitriptan. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Risk D: Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification

Ozanimod: May enhance the adverse/toxic effect of Serotonergic Agents (High Risk). Risk C: Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy

Pitolisant: Mirtazapine may diminish the therapeutic effect of Pitolisant. Risk X: Avoid combination

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Risk C: Monitor therapy

Ramosetron: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Rasagiline: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination

Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy

Safinamide: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination

Selective Serotonin Reuptake Inhibitors: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Selegiline: May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid combination

Serotonergic Agents (High Risk, Miscellaneous): May enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Serotonergic Opioids (High Risk): Serotonergic Non-Opioid CNS Depressants may enhance the CNS depressant effect of Serotonergic Opioids (High Risk). Serotonergic Non-Opioid CNS Depressants may enhance the serotonergic effect of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity and CNS depression. Risk D: Consider therapy modification

Serotonin 5-HT1D Receptor Agonists (Triptans): May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Serotonin/Norepinephrine Reuptake Inhibitors: Mirtazapine may enhance the serotonergic effect of Serotonin/Norepinephrine Reuptake Inhibitors. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

St John's Wort: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease the serum concentration of Serotonergic Agents (High Risk). Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification

Syrian Rue: May enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Risk C: Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination

Tobacco (Smoked): May decrease the serum concentration of Mirtazapine. Risk C: Monitor therapy

TraZODone: May enhance the CNS depressant effect of Mirtazapine. TraZODone may enhance the serotonergic effect of Mirtazapine. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor therapy

Tricyclic Antidepressants: May enhance the CNS depressant effect of Serotonergic Non-Opioid CNS Depressants. Tricyclic Antidepressants may enhance the serotonergic effect of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) and CNS depression when these agents are combined. Risk C: Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy

Warfarin: Mirtazapine may enhance the anticoagulant effect of Warfarin. Risk C: Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification

Reproductive Considerations

If treatment for major depressive disorder is initiated for the first time in females planning a pregnancy, agents other than mirtazapine are preferred (use of mirtazapine is not preferred in pregnant women) (Larsen 2015).

The incidence of sexual dysfunction with mirtazapine is generally lower than with selective serotonin reuptake inhibitors (WFSBP [Bauer 2013]).

Pregnancy Considerations

Mirtazapine crosses the placenta (Hatzidaki 2008).

A significant increase in major teratogenic effects has not been observed following exposure to mirtazapine during pregnancy; however, information is limited (CANMAT [MacQueen 2016]; Larsen 2015).

Untreated or inadequately treated psychiatric illness may lead to poor compliance with prenatal care. Therapy with antidepressants during pregnancy should be individualized (ACOG 92 2008; CANMAT [MacQueen 2016]). Psychotherapy or other nonmedication therapies may be considered for some women; however, antidepressant medication should be considered for pregnant women with moderate to severe major depressive disorder (MDD) (APA 2010). If treatment for MDD is initiated for the first time during pregnancy, mirtazapine is not recommended (CANMAT [MacQueen 2016]; Larsen 2015; WFSBP [Bauer 2013]); mirtazapine is considered a third-line agent for the treatment of mild to moderate depression during pregnancy (CANMAT [MacQueen 2016]).

Data collection to monitor pregnancy and infant outcomes following exposure to antidepressants is ongoing. Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Breastfeeding Considerations

Mirtazapine and its active metabolite are present in breast milk.

The highest relative infant dose (RID) of mirtazapine located in the literature is 4.4%. Authors of the study calculated the RID following maternal administration of mirtazapine 22.5 mg/day to a woman at 6 weeks' postpartum; metabolite concentrations were not evaluated. Breast milk was sampled 4 hours after the maternal dose (Klier 2007). Desmethylmirtazpine can also be detected in breast milk (Kristensen 2007).

In general, breastfeeding is considered acceptable when the RID of a medication is <10% (Anderson 2016; Ito 2000). However, some sources note breastfeeding should only be considered if the RID is <5% for psychotropic agents (Larsen 2015).

Mirtazapine can be detected in the serum of breastfed infants; adverse events have generally not been observed, although possible sedation and weight gain was noted in one case report (Kristensen 2007; Smit 2015; Tonn 2009).

According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Infants of mothers using psychotropic medications should be monitored daily for changes in sleep, feeding patterns, and behavior (WFSBP [Bauer 2013]) as well as infant growth and neurodevelopment (ABM [Sriraman 2015]; Sachs 2013). When first initiating an antidepressant in a breastfeeding female, agents other than mirtazapine are preferred (Berle 2011; CANMAT [MacQueen 2016]).

Dietary Considerations

Some products may contain phenylalanine.

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; renal and hepatic function; mental status for depression, suicide ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks; signs/symptoms of serotonin syndrome; lipid profile; weight gain

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.

Pharmacokinetics

Onset of action:

Anxiety disorders (panic disorder): Initial effects may be observed within 2 weeks of treatment, with continued improvements through 4 to 6 weeks (WFSBP [Bandelow 2012]); some experts suggest up to 12 weeks of treatment may be necessary for response (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2012]).

Depression: Initial effects may be observed within 1 to 2 weeks of treatment, with continued improvements through 4 to 6 weeks (Papakostas 2006; Posternak 2005; Szegedi 2009).

Absorption: Rapid and complete.

Protein binding: ~85%.

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

Bioavailability: ~50%.

Half-life elimination: ~20 to 40 hours; increased with renal or hepatic impairment.

Time to peak, serum: ~2 hours.

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

Pharmacokinetics: Additional Considerations

Renal function impairment: Clearance is reduced ~30% in patients with moderate (GFR 11 to 39 mL/minute/1.73 m2) and ~50% in patients with severe (GFR <10 mL/minute/1.73 m2) kidney impairment.

Hepatic function impairment: Clearance decreased by 33% and half-life and serum concentration increased by 39% and 55%, respectively, following a single dose of mirtazapine in elderly patients with mild or moderate hepatic impairment (Mauri 2014).

Geriatric: Clearance is reduced 40% in elderly men and 10% in elderly women.

Gender: Women have a longer elimination half-life (37 hours) than men (26 hours).

Pricing: US

Tablet, orally-disintegrating (Mirtazapine Oral)

15 mg (per each): $2.36

30 mg (per each): $2.43

45 mg (per each): $2.59

Tablet, orally-disintegrating (Remeron SolTab Oral)

15 mg (per each): $5.10

30 mg (per each): $5.26

45 mg (per each): $5.59

Tablets (Mirtazapine Oral)

7.5 mg (per each): $2.63

15 mg (per each): $2.70 - $2.72

30 mg (per each): $2.77 - $2.80

45 mg (per each): $2.83 - $2.85

Tablets (Remeron Oral)

15 mg (per each): $6.41

30 mg (per each): $6.60

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • Afloyan (ES);
  • Amirel (CL);
  • Aurozapine (VN);
  • Avanza (AU, NZ);
  • Avanza Soltab (AU);
  • Axit (AU);
  • Azapin (GR);
  • Beron (ZA);
  • Calixia (RU);
  • Calixta (HR);
  • Ciblex (CL, PY);
  • Combar (DK);
  • Comentor (VE);
  • Comment (CR, DO, GT, HN, NI, PA, SV);
  • Espirtal (UA);
  • Esprital (CZ);
  • Maz (IN);
  • Menelat (PH, TZ);
  • Mi Er Ning (CN);
  • Minelat (BR);
  • Minelza (TR);
  • Mirap (IE);
  • Mirastad (HK);
  • Mirazep (IN, LK, PH, UA);
  • Mirez (BD);
  • Miro (IL);
  • Mirta TD (MT);
  • Mirtapav (FI);
  • Mirtapax (CO, EC);
  • Mirtaron (AT);
  • Mirtaz (LK);
  • Mirtazap (CH);
  • Mirtazelon (DE);
  • Mirtazon (AU);
  • Mirtel (AT, UA);
  • Mirtimash (EG);
  • Mirtin (DK, SE);
  • Mirtor (PL);
  • Mirzap (ID);
  • Mirzasna (NL);
  • Mirzaten (PL);
  • Mitabor (NL);
  • Mitrapil (LK);
  • Mizapia (HK);
  • Mytra (ZA);
  • Nassa (IN);
  • Norset (FR);
  • Noxibel (EC, PY);
  • Odonazin (HR);
  • Psidep (PT);
  • Rapine (BD);
  • Razapina (BR);
  • Reflex (JP);
  • Remergil (DE);
  • Remergon (BE, LU);
  • Remeron (AE, AR, AT, BB, BH, BR, CH, CN, CO, CY, CZ, DK, EC, EE, EG, FI, GR, HK, HU, ID, IL, IQ, IR, IS, IT, JO, JP, KR, KW, LB, LT, LV, LY, MX, MY, NL, NO, OM, PE, PK, PL, PT, QA, RO, RU, SA, SE, SG, SI, SK, SY, TR, TW, UY, VE, VN, YE, ZA);
  • Remeron SolTab (CO, HK, PH, SG);
  • Remeron Soltab (TH);
  • Remirta (BG, MT);
  • Remixil ODT (KR);
  • Resant (BD);
  • Rexer (ES);
  • Sinmaron (TW);
  • Tazeurin (VN);
  • Trazapin (BD);
  • Trovia (VE);
  • U-Mirtaron (TW);
  • Yarocen (HU);
  • Zapex (CR, DO, GT, HN, NI, PA, SV);
  • Zapimet (EG);
  • Zismirt (IE);
  • Zispin (GB, IE);
  • Zulin (RO)


For country abbreviations used in Lexicomp (show table)

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