Version July 2025
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.
Dosage guidance:
Dosing: Some experts suggest a lower starting dose of 7.5 mg daily, particularly in patients with anxiety who are sensitive to antidepressant-associated overstimulation effects (eg, anxiety, jitteriness, nervousness, dizziness, headache, nausea) (Ref).
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 (Ref).
Panic disorder (alternative agent) (off-label use):
Note: For patients nonresponsive to selective serotonin reuptake inhibitors (SSRIs) (Ref).
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 (Ref). Average doses in clinical trials were ~30 mg/day; doses up to 60 mg/day have been evaluated (Ref).
Sexual dysfunction associated with selective serotonin reuptake inhibitors (off-label use):
Note: May switch to mirtazapine to mitigate sexual adverse effects. Prior to switching, may trial watchful waiting for a limited time (eg, 2 to 8 weeks), as treatment-onset sexual dysfunction may remit spontaneously (Ref).
Oral: Switch from selective serotonin reuptake inhibitor using an appropriate schedule (eg, cross-taper over 1 to 2 weeks or may immediately switch). Initiate and titrate mirtazapine to a therapeutic dose appropriate for the appropriate indication and based upon tolerability and response (Ref).
Discontinuation of therapy: When discontinuing antidepressant treatment that has lasted for ≥4 weeks, gradually taper the dose (eg, over 2 to 4 weeks) to minimize withdrawal symptoms and detect reemerging symptoms (Ref). For brief treatment (eg, 2 to 3 weeks), may taper over 1 to 2 weeks; <2 weeks of treatment generally does not warrant tapering (Ref). Reasons for a slower taper (eg, over 4 weeks) include prior history of antidepressant withdrawal symptoms or high doses of antidepressants (Ref). If intolerable withdrawal symptoms occur, resume the previously prescribed dose and/or decrease dose at a more gradual rate (Ref). Select patients (eg, those with a history of discontinuation syndrome) on long-term treatment (>6 months) may benefit from tapering over >3 months (Ref). Evidence supporting ideal taper rates is limited (Ref).
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 (Ref).
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.
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 (Ref). Use with caution.
eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary (Ref).
eGFR <30 mL/minute/1.73 m2: Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
Hemodialysis, intermittent (thrice weekly): Unlikely to be significantly dialyzed due to high protein binding and large Vd (Ref):
Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
Peritoneal dialysis : Unlikely to be significantly dialyzed due to high protein binding and large Vd (Ref):
Initiate at 7.5 to 15 mg once daily and titrate slowly with close monitoring for adverse effects (Ref).
CRRT: Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
PIRRT (eg, sustained, low-efficiency diafiltration): Initial: 7.5 to 15 mg once daily; titrate slowly with close monitoring for adverse effects (Ref).
The liver dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Matt Harris, PharmD, MHS, BCPS, FAST, FCCP; Jeong Park, PharmD, MS, BCTXP, FCCP, FAST; Arun Jesudian, MD; Sasan Sakiani, MD.
Note: A single dose pharmacokinetic study in mild to moderate cirrhosis demonstrated that the half-life of mirtazapine is increased by 39% and clearance is decreased by ~33%, which may result in dose limiting sedation; especially in decompensated cirrhosis (Ref). There is no data in patients with severe liver impairment (has not been studied).
Liver impairment prior to treatment initiation:
Initial or dose titration in patients with preexisting liver cirrhosis:
Child-Turcotte-Pugh class A and B: Oral: Initial: Administer 50% of the normal indication-specific starting dose; may titrate with close monitoring of adverse effects to a maximum dose of 30 mg/day (Ref).
Child-Turcotte-Pugh class C: Oral: Initial: Consider alternative agents; if use is required administer 50% of the indication-specific starting dose; may titrate with close monitoring of adverse effects to a maximum dose of 30 mg/day (Ref).
Liver impairment developing in patients already receiving mirtazapine:
Chronic disease progression (eg, outpatient):
Progression to Child-Turcotte-Pugh class A or B: Oral: No dosage adjustment necessary (Ref).
Progression to Child-Turcotte-Pugh class C: Oral: No dosage adjustment necessary; consider discontinuation in decompensated cirrhosis unless the benefits outweigh the risks (eg, sedation) (Ref).
Acute worsening of liver function (eg, requiring hospitalization):
Child-Turcotte-Pugh class A through C: Oral:
Patients with compensated cirrhosis: No dosage adjustment necessary (Ref).
Patients with decompensated cirrhosis: Consider discontinuation of therapy unless benefits outweigh the risks; continue at lowest effective dose (Ref).
Major depressive disorder (unipolar): Oral: Initial starting doses of 7.5 mg once daily at bedtime have been suggested (Ref). Use with caution; clearance may be reduced; refer to adult dosing.
Discontinuation of therapy: Refer to adult dosing.
Switching antidepressants: Refer to adult dosing.
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)
• Female sex (Ref)
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)
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).
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).
Mirtazapine may cause orthostatic hypotension (eg, dizziness). 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 (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 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.
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)
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)
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 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 dose taper) or tapering the antidepressant too quickly (Ref)
• Drugs with a half-life <24 hours (eg, paroxetine, venlafaxine) (Ref)
• Higher doses (Ref)
• Longer duration of treatment (eg, ≥4 weeks) (Ref)
• Prior history of antidepressant withdrawal symptoms (Ref)
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) (Ref)
|
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 |
|
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%)
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
|---|---|---|---|
|
17% |
2% |
453 |
361 |
Nervous system: Drowsiness (54%) (table 4)
|
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, skin rash
Endocrine & metabolic: Increased serum triglycerides (6%) (table 5), increased thirst
|
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, asthenia (8%), confusion (2%) (table 6), dizziness (7%) (table 7), hypoesthesia, malaise, myasthenia, paresthesia, psychomotor agitation, tremor (2%), twitching, vertigo
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
|---|---|---|---|
|
2% |
0% |
453 |
361 |
|
Drug (Mirtazapine) |
Placebo |
Number of Patients (Mirtazapine) |
Number of Patients (Placebo) |
|---|---|---|---|
|
7% |
3% |
453 |
361 |
Neuromuscular & skeletal: Arthralgia, back pain (2%), hyperkinetic muscle activity, hypokinesia, myalgia (2%)
Respiratory: Dyspnea (1%), flu-like symptoms (5%)
<1%:
Cardiovascular: Acute myocardial infarction, angina pectoris, atrial arrhythmia, bigeminy, bradycardia, cardiomegaly, chest pain, 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, 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: Facial edema, tongue edema
Nervous system: Akathisia, altered sense of smell, aphasia, ataxia, cerebral ischemia, chills, delirium, delusion, dementia, depersonalization, drug dependence, dysarthria, emotional lability, euphoria, extrapyramidal reaction, hallucination, hostility, hyperacusis, hyperreflexia, hypomania, hypotonia, mania, migraine, myoclonus, neurosis, paranoid ideation, seizure, serotonin syndrome, stupor, tonic-clonic seizure, vascular headache, withdrawal syndrome
Neuromuscular & skeletal: Arthritis, bone fracture (osteoporotic), dyskinesia, dystonia (including Pisa syndrome) (Ref), gout, 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 (Ref), torsades de pointes, ventricular tachycardia
Dermatologic: Bullous dermatitis, erythema multiforme, excoriation of skin (Ref), hyperpigmentation (Ref), toxic epidermal necrolysis
Endocrine & metabolic: Hyperglycemia (Ref), hyperprolactinemia, hypertriglyceridemia (Ref)
Genitourinary: Priapism, sexual disorder (Ref)
Hematologic & oncologic: Immune thrombocytopenia (Ref)
Hepatic: Hepatotoxicity (Ref), liver steatosis (Ref)
Hypersensitivity: Drug reaction with eosinophilia and systemic symptoms
Infection: Neutropenic sepsis (Ref)
Nervous system: Complex sleep-related disorder (Ref), nightmares (Ref), restless leg syndrome (precipitation or exacerbation) (Ref), somnambulism (Ref), suicidal ideation, suicidal tendencies
Neuromuscular & skeletal: Rhabdomyolysis (Ref)
Hypersensitivity (eg, severe skin reactions, including drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme, and toxic epidermal necrolysis) to mirtazapine or any component of the formulation; use of monoamine oxidase inhibitors (MAOIs), including IV methylene blue (concurrently or within 14 days of stopping an MAOI).
Note: Although mirtazapine is contraindicated per the manufacturer labeling when used in combination with linezolid, new evidence suggests that the combination is unlikely to cause serotonin syndrome (0.06% to 3% risk), and therefore these agents can be administered concomitantly when necessary. Monitor patients on this combination; average duration of serotonin toxicity is ~4 days; however, risks may be greater with longer durations of concurrent therapy. Educate patients on the signs and symptoms of serotonin syndrome (Bai 2022; Butterfield 2012; Karkow 2017; Kufel 2023; Narita 2007; Taylor 2006).
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
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.
• 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 (Leach 2017; Rabenda 2013; Rizzoli 2012).
• 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.
Disease-related concerns:
• Bariatric surgery: Presurgical assessment of the indication for use, symptoms, and goals of therapy should be documented to enable postsurgical assessment. A small pharmacokinetic study shows wide interpatient variability in plasma concentrations following bariatric surgery (Wallerstedt 2021). Monitor for continued efficacy after bariatric surgery and consider switching to an alternate medication if symptoms worsen. Mirtazapine can cause significant weight gain in the general population (Uguz 2015); an alternate medication may be preferred in patients attempting weight loss with bariatric surgery.
• 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.
• 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, alcohol use disorder, or concurrent therapy with medications that may lower seizure threshold.
Dosage form specific issues:
• Lactose: Tablets may contain lactose.
• Phenylalanine: SolTab formulation may contain phenylalanine.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Remeron: 15 mg [DSC] [contains corn starch]
Remeron: 15 mg [scored; contains corn starch]
Remeron: 30 mg [DSC] [contains corn starch]
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
Yes
Tablet, orally-disintegrating (Mirtazapine Oral)
15 mg (per each): $2.35 - $2.36
30 mg (per each): $2.42 - $2.43
45 mg (per each): $2.58 - $2.59
Tablet, orally-disintegrating (Remeron SolTab Oral)
15 mg (per each): $6.16
30 mg (per each): $6.35
45 mg (per each): $6.76
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): $7.74
30 mg (per each): $7.97
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.
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
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.
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
Major depressive disorder (unipolar): Treatment of unipolar major depressive disorder (MDD) in adults.
Headache, chronic tension-type, prophylaxis; Methamphetamine use disorder; Panic disorder; Sexual dysfunction associated with selective serotonin reuptake inhibitors
Remeron may be confused with Premarin, ramelteon, Rozerem, Zemuron
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 2023]).
Mirtazapine is identified in the Screening Tool of Older Person's Prescriptions (STOPP) criteria as a potentially inappropriate medication in older adults (≥65 years of age) with a history of recurrent falls due to an increased risk of falls (O'Mahony 2023).
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]
Substrate of CYP1A2 (Minor), CYP2C9 (Minor), CYP2D6 (Minor), CYP3A4 (Major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential;
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.
Acrivastine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Alcohol (Ethyl): May increase CNS depressant effects of Mirtazapine. Risk X: Avoid
Alizapride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Almotriptan: May increase serotonergic effects 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
Alosetron: May increase serotonergic effects 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
Alpha2-Agonists: Mirtazapine may decrease antihypertensive effects 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
Amisulpride (Oral): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Amphetamines: May increase serotonergic effects 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
Antiemetics (5HT3 Antagonists): May increase serotonergic effects 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
Antipsychotic Agents: Serotonergic Agents (High Risk) may increase adverse/toxic effects of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Articaine: May increase CNS depressant effects of CNS Depressants. Management: Consider reducing the dose of articaine if possible when used in patients who are also receiving CNS depressants. Monitor for excessive CNS depressant effects with any combined use. Risk D: Consider Therapy Modification
Azelastine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Benperidol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Blonanserin: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects of Brexanolone. Risk C: Monitor
Brimonidine (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromopride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Bromperidol: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Buclizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Buprenorphine: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects of CNS Depressants. Risk C: Monitor
BusPIRone: May increase serotonergic effects 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
Cannabinoid-Containing Products: CNS Depressants may increase CNS depressant effects of Cannabinoid-Containing Products. Risk C: Monitor
Cetirizine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk D: Consider Therapy Modification
Chloral Hydrate/Chloral Betaine: CNS Depressants may increase CNS depressant effects of Chloral Hydrate/Chloral Betaine. Management: Consider alternatives to the use of chloral hydrate or chloral betaine and additional CNS depressants. If combined, consider a dose reduction of either agent and monitor closely for enhanced CNS depressive effects. Risk D: Consider Therapy Modification
Chlormethiazole: May increase CNS depressant effects 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 increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cimetidine: May increase serum concentration of Mirtazapine. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CNS Depressants: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Cyclobenzaprine: May increase serotonergic effects 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
CYP3A4 Inducers (Strong): May decrease serum concentration of Mirtazapine. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of Mirtazapine. Risk C: Monitor
Dantrolene: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dapoxetine: May increase serotonergic effects 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
Daridorexant: May increase CNS depressant effects 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
DexmedeTOMIDine: CNS Depressants may increase CNS depressant effects of DexmedeTOMIDine. Management: Monitor for increased CNS depression during coadministration of dexmedetomidine and CNS depressants, and consider dose reductions of either agent to avoid excessive CNS depression. Risk D: Consider Therapy Modification
Dexmethylphenidate-Methylphenidate: May increase serotonergic effects 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
Dextromethorphan: May increase serotonergic effects 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
Difelikefalin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Difenoxin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dihydralazine: CNS Depressants may increase hypotensive effects of Dihydralazine. Risk C: Monitor
Dimethindene (Topical): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Dothiepin: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Doxylamine: CNS Depressants may increase CNS depressant effects of Doxylamine. Risk C: Monitor
DroPERidol: May increase CNS depressant effects 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 increase serotonergic effects 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
Emedastine (Systemic): May increase CNS depressant effects of CNS Depressants. Management: Consider avoiding this combination if possible. If required, monitor for excessive sedation or CNS depression, limit the dose and duration of combination therapy, and consider CNS depressant dose reductions. Risk C: Monitor
Entacapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ergot Derivatives: May increase serotonergic effects 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
Esketamine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Fenfluramine: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Flunarizine: CNS Depressants may increase CNS depressant effects of Flunarizine. Risk X: Avoid
Flunitrazepam: CNS Depressants may increase CNS depressant effects 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 serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Gepirone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects of Haloperidol. Risk C: Monitor
HydrOXYzine: May increase CNS depressant effects of CNS Depressants. Management: Consider a decrease in the CNS depressant dose, as appropriate, when used together with hydroxyzine. Increase monitoring of signs/symptoms of CNS depression in any patient receiving hydroxyzine together with another CNS depressant. Risk D: Consider Therapy Modification
Ixabepilone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kava Kava: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Ketotifen (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Kratom: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Lasmiditan: May increase serotonergic effects 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
Lemborexant: May increase CNS depressant effects 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
Levocetirizine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Linezolid: May increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid
Lisuride: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Lofepramine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Loxapine: CNS Depressants may increase CNS depressant effects of Loxapine. Management: Consider reducing the dose of CNS depressants administered concomitantly with loxapine due to an increased risk of respiratory depression, sedation, hypotension, and syncope. Risk D: Consider Therapy Modification
Magnesium Sulfate: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Melitracen [INT]: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Mequitazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metaxalone: May increase serotonergic effects 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
Metergoline: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methotrimeprazine: CNS Depressants may increase CNS depressant effects of Methotrimeprazine. Methotrimeprazine may increase CNS depressant effects 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
Methoxyflurane: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Methylene Blue: Serotonergic Non-Opioid CNS Depressants may increase serotonergic effects of Methylene Blue. This could result in serotonin syndrome. Risk X: Avoid
Metoclopramide: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Metoclopramide: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Consider monitoring 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
MetyroSINE: CNS Depressants may increase sedative effects of MetyroSINE. Risk C: Monitor
Minocycline (Systemic): May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Monoamine Oxidase Inhibitors (Antidepressant): Serotonergic Non-Opioid CNS Depressants may increase serotonergic effects of Monoamine Oxidase Inhibitors (Antidepressant). This could result in serotonin syndrome. Risk X: Avoid
Nabilone: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Nalfurafine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Nefazodone: Mirtazapine may increase serotonergic effects of Nefazodone. This could result in serotonin syndrome. Nefazodone may increase 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
Noscapine: CNS Depressants may increase adverse/toxic effects of Noscapine. Risk X: Avoid
Olopatadine (Nasal): May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Ondansetron: May increase serotonergic effects 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
Opicapone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opioid Agonists: CNS Depressants may increase CNS depressant effects 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
Opipramol: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Opipramol: May increase serotonergic effects 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
Orphenadrine: CNS Depressants may increase CNS depressant effects of Orphenadrine. Risk X: Avoid
Oxitriptan: Serotonergic Agents (High Risk) may increase serotonergic effects 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
Oxomemazine: May increase CNS depressant effects of CNS Depressants. Risk X: Avoid
Oxybate Salt Products: CNS Depressants may increase CNS depressant effects 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 increase CNS depressant effects 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
Paliperidone: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Paraldehyde: CNS Depressants may increase CNS depressant effects of Paraldehyde. Risk X: Avoid
Perampanel: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Periciazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pipamperone: May increase adverse/toxic effects of CNS Depressants. Risk C: Monitor
Piribedil: CNS Depressants may increase CNS depressant effects of Piribedil. Risk C: Monitor
Pitolisant: Mirtazapine may decrease therapeutic effects of Pitolisant. Risk X: Avoid
Pizotifen: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Pramipexole: CNS Depressants may increase sedative effects of Pramipexole. Risk C: Monitor
Procarbazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Psilocybin: Antidepressants may decrease therapeutic effects of Psilocybin. Risk C: Monitor
QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may increase QTc-prolonging effects 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
Ramosetron: May increase serotonergic effects 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
Rasagiline: May increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid
Ropeginterferon Alfa-2b: CNS Depressants may increase adverse/toxic effects 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 increase sedative effects of ROPINIRole. Risk C: Monitor
Rotigotine: CNS Depressants may increase sedative effects of Rotigotine. Risk C: Monitor
Safinamide: May increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid
Selective Serotonin Reuptake Inhibitor: May increase serotonergic effects 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
Selegiline: May increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Risk X: Avoid
Serotonergic Agents (High Risk, Miscellaneous): May increase serotonergic effects 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
Serotonergic Opioids (High Risk): Serotonergic Non-Opioid CNS Depressants may increase serotonergic effects of Serotonergic Opioids (High Risk). This could result in serotonin syndrome. Serotonergic Non-Opioid CNS Depressants may increase CNS depressant effects of Serotonergic Opioids (High Risk). 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 increase serotonergic effects 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
Serotonin/Norepinephrine Reuptake Inhibitor: Mirtazapine may increase serotonergic effects of Serotonin/Norepinephrine Reuptake Inhibitor. 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
St John's Wort: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. St John's Wort may decrease 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
Suvorexant: CNS Depressants may increase CNS depressant effects 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 increase serotonergic effects 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
Thalidomide: CNS Depressants may increase CNS depressant effects of Thalidomide. Risk X: Avoid
Tobacco (Smoked): May decrease serum concentration of Mirtazapine. Risk C: Monitor
TraZODone: May increase serotonergic effects of Mirtazapine. This could result in serotonin syndrome. TraZODone may increase CNS depressant effects 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 CNS depression when these agents are combined. Risk C: Monitor
Tricyclic Antidepressants: May increase serotonergic effects of Serotonergic Non-Opioid CNS Depressants. This could result in serotonin syndrome. Tricyclic Antidepressants may increase CNS depressant effects of Serotonergic Non-Opioid CNS Depressants. 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
Trimeprazine: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Valerian: May increase CNS depressant effects of CNS Depressants. Risk C: Monitor
Warfarin: Mirtazapine may increase anticoagulant effects of Warfarin. Risk C: Monitor
Ziprasidone: May increase serotonergic effects of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Risk C: Monitor
Zolpidem: CNS Depressants may increase CNS depressant effects 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
Zuranolone: May increase CNS depressant effects of CNS Depressants. Management: Consider alternatives to the use of zuranolone with other CNS depressants or alcohol. If combined, consider a zuranolone dose reduction and monitor patients closely for increased CNS depressant effects. Risk D: Consider Therapy Modification
Evaluate pregnancy status prior to initiating treatment in patients who could become pregnant. Treatment should not be withheld, but pharmacologic management may vary based on reproductive status, severity of illness, and history of antidepressant response (ACOG 2023; WFSBP [Dodd 2018]). When treating depression, mirtazapine is not a first–line medication for use prior to conception in patients who are treatment naive or who do not have a history of effective treatment. Patients effectively treated may continue their current medication when planning a pregnancy unless contraindications exist (BAP [McAllister-Williams 2017]). Management of mental health conditions in patients who could become pregnant should be based on a shared decision-making process that considers the possibility of pregnancy during treatment (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]).
Product labeling notes menstrual disorders, including amenorrhea and dysmenorrhea, have been reported following use of mirtazapine. Depression is also associated with menstrual changes (Padda 2021).
Mirtazapine crosses the placenta (Hatzidaki 2008).
Outcome data following maternal use of mirtazapine during pregnancy are available (Biswas 2003; Gentile 2005; Ostenfeld 2022; Smit 2016; Winterfeld 2015). A significant increased risk of major teratogenic effects has not been observed following exposure to mirtazapine during pregnancy; however, data are limited (CANMAT [MacQueen 2016]).
Untreated and undertreated mental health conditions are associated with adverse pregnancy outcomes. Untreated or undertreated depression is associated with preterm birth, low birth weight, preeclampsia, postpartum depression, and impaired infant attachment (associated with long-term developmental effects). Discontinuing effective medications during pregnancy increases the risk of relapse. Management should be made as part of a shared decision-making process (ACOG 2023).
Patients effectively treated for depression prepregnancy may use the same medication during pregnancy unless contraindications exist (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). Treatment should not be withheld or discontinued based only on pregnancy status (ACOG 2023). Mirtazapine is not first–line medication for pregnant patients who are treatment naive or who do not have a history of effective treatment with another medication (ACOG 2023; BAP [McAllister-Williams 2017]; CANMAT [MacQueen 2016]). When medications are used, the lowest effective dose of a single agent is recommended. Optimize dosing prior to changing a medication or adding additional agents whenever possible. Monthly monitoring for symptom improvement with a validated screening tool during pregnancy is recommended. Manage side effects as needed (ACOG 2023).
Mirtazapine may have some efficacy for the management of treatment–resistant hyperemesis gravidarum in patients with mood disorders. However, use should only be considered in patients with ongoing psychiatric care when preferred treatments are not effective (SOGC [Campbell 2016]; Spinosa 2020).
Data collection to monitor pregnancy and infant outcomes following exposure to antidepressant medications is ongoing. Pregnant patients ≤45 years of age with a history of psychiatric illness are encouraged to enroll in the National Pregnancy Registry for Antidepressants (1-866-961-2388 or https://womensmentalhealth.org/research/pregnancyregistry/antidepressants).
Mirtazapine and its active metabolite are present in breast milk.
Multiple case reports summarize data related to the presence of mirtazapine in breast milk:
• Breast milk was sampled in one patient following use of mirtazapine 30 mg once daily. Maternal plasma and breast milk were obtained twice after the patient was at steady state. Mirtazapine concentrations 22 hours after the maternal dose were 7 ng/mL (maternal plasma), 7 ng/mL (foremilk), and 18 ng/mL (hindmilk). The next day, mirtazapine concentrations 15 hours after the dose were 25 ng/mL (maternal plasma), 28 ng/mL (foremilk), and 34 ng/mL (hindmilk). Mirtazapine concentrations in the infant plasma were 0.2 ng/mL. Psychomotor development in the breastfed infant was reported to be normal (Aichhorn 2004).
• Breast milk was sampled 6 weeks postpartum in one patient following use of mirtazapine 22.5 mg once daily for 14 days. Four hours after the maternal dose, mirtazapine concentrations were 130 ng/mL (foremilk) and 145 ng/mL (hindmilk). Ten hours post dose, mirtazapine concentrations were 61 ng/mL (foremilk) and 90 ng/mL (hindmilk). Authors of the study calculated the relative infant dose (RID) of mirtazapine to be 3.9% to 4.4% of the weight–adjusted maternal dose. Mirtazapine was not detectable in the infant plasma when sampled 12.5 hours after the maternal dose. Sedation was not observed in the breastfed infant (Klier 2007).
• Mirtazapine breast milk was sampled in one patient 2 months after delivery following use during pregnancy and postpartum. At the time of testing, the maternal dose was 15 mg once daily. Foremilk obtained 12 hours after the dose contained mirtazapine 15 ng/mL compared to the maternal serum concentration of 27 ng/mL. Infant serum concentrations of mirtazapine were 10 ng/mL 2 hours after feeding. Authors of the study calculated the estimated infant dose of mirtazapine via breast milk to be 3 mcg/kg/day, providing a RID of 1.3% of the weight–adjusted maternal dose (224 mcg/kg/day) (Tonn 2009).
• The presence of mirtazapine and the active metabolite desmethyl mirtazapine were evaluated in 8 mother/infant pairs. Infants were 1.5 to 13 months of age (mean 6.3 months), and the maternal once–daily dose of mirtazapine was 30 to 120 mg (median 38 mg). Testing occurred following 6 to 129 days of therapy (median 32 days). Breast milk was sampled with each infant feeding over 24 hours. Authors of the study calculated the mean absolute infant dose of mirtazapine via breast milk to be 8 mcg/kg/day, providing a mean RID of 1.5% compared to the mean weight–adjusted maternal dose of 495 mcg/kg/day. In addition, the mean absolute infant dose of desmethyl mirtazapine via breast milk was calculated to be 3 mcg/kg/day, providing a mean RID of 0.4%. For individual pairs, the RID of mirtazapine + desmethyl mirtazapine ranged from 0.7% to 3.1%. Mirtazapine and desmethyl mirtazapine were detected in the plasma of some infants (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 (Anderson 2021).
Neither feeding nor sleeping problems were observed in a case series of infants exposed to mirtazapine via breast milk. Included were 24 fully breastfed infants and 20 infants who received formula and breast milk. All were exposed to mirtazapine in utero and followed for at least 2 days after birth (Smit 2015). Infants exposed to psychotropic medication via breast milk should be monitored for adverse effects (eg, over sedation, poor feeding) (BAP [McAllister-Williams 2017]).
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. Patients effectively treated for depression during pregnancy may continue their medication postpartum unless contraindications to breastfeeding exist. The presence and concentration of the drug in breast milk, efficacy of maternal treatment, and infant age should be considered when initiating a medication for the first time postpartum (ABM [Sriraman 2015]; BAP [McAllister-Williams 2017]). When first initiating an antidepressant in a patient who is treatment naive and breastfeeding, an agent other than mirtazapine may be preferred (ABM [Sriraman 2015]; CANMAT [MacQueen 2016]).
Some products may contain phenylalanine.
CBC; renal and hepatic function; lipid profile; weight; suicidality (during the initial 1 to 2 months of therapy or during periods of dosage adjustments).
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.
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 2023]); some experts suggest up to 12 weeks of treatment may be necessary for response (BAP [Baldwin 2014]; Katzman 2014; WFSBP [Bandelow 2023]).
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.
Time to peak, serum: ~2 hours.
Excretion: Urine (75%) and feces (15%) as metabolites.
Altered kidney function: 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).
Older adult: Clearance is reduced 40% in elderly men and 10% in elderly women.
Sex: Women have a longer elimination half-life (37 hours) than men (26 hours).
