Mirtazapine (mirtazapine)

An increase in the dosage of mirtazapine may be needed when used concomitantly with a strong cytochrome P-450 (CYP) 3A inducer (e.g., carbamazepine, phenytoin, rifampin). Conversely, a decrease in the dosage of mirtazapine may be needed if the CYP3A inducer is discontinued.

A decrease in the dosage of mirtazapine may be needed when used concomitantly with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin). Conversely, an increase in the dosage of mirtazapine may be needed if the CYP3A4 inhibitor is discontinued.

A decrease in the dosage of mirtazapine may be needed when used concomitantly with cimetidine. Conversely, an increase in the dosage of mirtazapine may be needed if cimetidine is discontinued.

Mirtazapine is administered orally as conventional or orally disintegrating tablets. The drug is administered once daily, usually at bedtime. Since food does not appear to substantially affect GI absorption of mirtazapine, the drug generally can be administered without regard to meals.

Patients receiving mirtazapine orally disintegrating tablets (ODT) should be instructed not to remove a tablet from the blister until just prior to dosing; once removed, it cannot be stored. With dry hands, the blister backing should be peeled completely off the blister. The tablet should then be gently removed and immediately placed on the tongue to dissolve and be swallowed with the saliva without chewing or crushing; administration with liquid is not necessary. In addition, patients should be advised not to break the tablet.

Store mirtazapine tablets and orally disintegrating tablets at 20-25degreesC; excursions permitted between 15-30degreesC.

Mirtazapine is metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP3A; in vitro studies indicate that CYP2D6 and CYP1A2 are also involved.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antidepressants/Sibutramine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Sibutramine has demonstrated antidepressant effects. (1)

CLINICAL EFFECTS: Concurrent use of sibutramine and an antidepressant may result in additive or synergistic central nervous system (CNS) effects.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The Australian,(2) Canadian,(1) and UK(3) manufacturers of sibutramine formerly stated that concurrent use with antidepressants is contraindicated. The Canadian manufacturer also states that concurrent use of St. John's wort is contraindicated.(1)

DISCUSSION: Sibutramine has been removed from the market by the European Medicines Agency and by regulatory agencies in a number of countries including Australia, Canada, Hong Kong, India, Thailand, United Kingdom and the United States. The use of sibutramine with other CNS-active agents has not been evaluated.(1-3)

Tricyclic; Tetracyclic Compounds/Maois

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Some MAO inhibitors may enhance the effects of tricyclic and tetracyclic compounds indirectly through inhibition of microsomal enzymes.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Similarity between cyclobenzaprine and TCAs warrants consideration of TCA interactions for cyclobenzaprine.(6) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(7)

CLINICAL EFFECTS: Concurrent use may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1,3-10) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(11)

PREDISPOSING FACTORS: High doses of tricyclics or tetracyclics, or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The concurrent use of tricyclic antidepressants, cyclobenzaprine or mirtazapine and MAO inhibitors is contraindicated by the manufacturers of tricyclic antidepressants, cyclobenzaprine, mirtazapine, and tranylcypromine.(1,3-10) The manufacturers of tricyclic antidepressants, cyclobenzaprine and mirtazapine recommend at least 14 days between switching therapies.(1,3-9) The manufacturer of tranylcypromine recommends a medication-free interval of at least a week when initiating tranylcypromine in patients who have previously received a tricyclic antidepressant, then initiating tranylcypromine at a reduced dosage of 50% for one week.(10) The US manufacturer of phenelzine states that at least 14 days should elapse between the discontinuation of phenelzine and the initiation of another antidepressant. If phenelzine is used concurrently with or within 10 days of another antidepressant, the patient should be cautioned regarding the possibility of an adverse drug interaction.(8) The US manufacturer of selegiline states that at least 14 days should elapse between the discontinuation of selegiline and the initiation of a tricyclic antidepressant.(9) In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to methylene blue against the risk of serotonin syndrome. If methylene blue therapy is required, the patient's tricyclic, cyclobenzaprine or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of methylene blue, whichever comes first.(12) In non-emergency situations in patients maintained on tricyclics, cyclobenzaprine or tetracyclics when methylene blue therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of methylene blue therapy. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid or methylene blue.(12) Do not initiate tricyclic, cyclobenzaprine or tetracyclic therapy in patients receiving methylene blue until 24 hours after the last dose of these agents.(12) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing the MAOI. The interaction has been reported with tricyclic antidepressants and selegiline.(9) Methylene blue, when administered intravenously, has been shown to reach sufficient concentrations to be a potent inhibitor of MAO-A.(14,15) Metaxalone is a weak inhibitor of MAO.(34,35) The FDA AERS contains reports of serotonin syndrome with concurrent injectable methylene blue and citalopram, clomipramine, escitalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(13) One or more of the drug pairs linked to this monograph have been included in a list of interactions that should be considered "high-priority" for inclusion and should not be inactivated in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Agents That May Cause Respiratory Depression/Sodium Oxybate

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Oxybate by itself may be associated with severe somnolence or respiratory depression. Concurrent use with other CNS depressants may further increase the risk for respiratory depression or loss of consciousness.(1-3)

CLINICAL EFFECTS: Concurrent use of sodium oxybate and sedative hypnotics or alcohol may further increase the risk for profound sedation, respiratory depression, coma, and/or death.(1,2) Fatalities have been reported.(3)

PREDISPOSING FACTORS: Based upon FDA evaluation of deaths in patients taking sodium oxybate, risk factors may include: use of multiple drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Note that in oxybate clinical trials for narcolepsy 78% - 85% of patients were also receiving concomitant CNS stimulants.(1-3)

PATIENT MANAGEMENT: Avoid use of concomitant opioids, benzodiazepines, sedating antidepressants, sedating antipsychotics, general anesthetics, or muscle relaxants, particularly when predisposing risk factors are present. If combination use is required, dose reduction or discontinuation of one or more CNS depressants should be considered. If short term use of an opioid or general anesthetic is required, consider interruption of sodium oxybate treatment.(1,2) Respiratory depression can occur at any time during opioid therapy, especially during therapy initiation and following dosage increases. The risk of opioid-related overdose or overdose-related death is increased with higher opioid doses, and this risk persists over the course of therapy. Consider these risks when using concurrently with other agents that may cause CNS depression.(4) Discuss opioid reversal agents (e.g., naloxone, nalmefene) with all patients when prescribing or renewing an opioid analgesic or medicine to treat opioid use disorder (OUD). Consider prescribing an opioid reversal agent (e.g., naloxone, nalmefene) to patients prescribed medicines to treat OUD or opioid analgesics who are at increased risk of opioid overdose (such as those taking CNS depressants) and when a patient has household members/close contacts at risk for accidental overdose. Discuss the options for obtaining an opioid reversal agent (e.g., prescription, over-the-counter, or as part of a community-based program).(5)

DISCUSSION: The FDA evaluated sodium oxybate postmarket fatal adverse event reports from the FDA Adverse Event Reporting System(AERS)and from the manufacturer. Although report documentation was not always optimal or complete, useful information was obtained. Factors which may have contributed to fatal outcome: concomitant use of one or more drugs which depress the CNS, more rapid than recommended oxybate dose titration, exceeding the maximum recommended oxybate dose, and prescribing for unapproved uses such as fibromyalgia, insomnia or migraine. Many deaths occurred in patients with serious psychiatric disorders such as depression and substance abuse. Other concomitant diseases may have also contributed to respiratory and CNS depressant effects of oxybate.(3)

Tricyclic; Tetracyclic Agents; Carbamazepine/Linezolid

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Linezolid is a weak, reversible inhibitor of monoamine oxidase.(1) Tricyclic and tetracyclic compounds may sensitize post-synaptic receptors to amines that are accumulating extraneuronally as a result of MAO inhibition.(2) Carbamazepine is structurally related to the tricyclic antidepressants.(3) Similarity between cyclobenzaprine and tricyclics warrants consideration of tricyclic interactions for cyclobenzaprine.(4) Mirtazapine, a tetracyclic antidepressant, should also be considered for this interaction.(5)

CLINICAL EFFECTS: Concurrent use with linezolid may result in a severe reaction including hyperpyrexia, convulsions, excitability, fluctuations in blood pressure, convulsions, grand mal seizures, serotonin syndrome, coma, and death.(1) Symptoms of serotonin syndrome may include tremor, agitation, diaphoresis, hyperreflexia, clonus, tachycardia, hyperthermia, and muscle rigidity.(6)

PREDISPOSING FACTORS: High doses of tricyclics or tetracyclics, or concurrent use of multiple drugs which increase CNS serotonin levels may increase risk for serotonin syndrome.

PATIENT MANAGEMENT: The manufacturers of the tricyclic antidepressants, carbamazepine, cyclobenzaprine and mirtazapine state that coadministration with MAO inhibitors is contraindicated. Concurrent linezolid is specifically contraindicated by the manufacturers of clomipramine, desipramine, mirtazapine, nortriptyline, and trimipramine.(1,3-5,7-12) The manufacturer of linezolid does not contraindicate the use of serotonergic agents but states that they should not be coadministered unless clinically appropriate and the patient is closely monitored.(1) This recommendation is consistent with the 2011 FDA Drug Safety Communication on linezolid and serotonergic psychiatric medications.(13,14) In non-emergency situations in patients maintained on tricyclics or tetracyclics when linezolid therapy is planned, discontinue the patient's tricyclic or tetracyclic at least 2 weeks in advance of linezolid therapy. In emergency situations in patients maintained on tricyclics or tetracyclics, weigh the availability and safety of alternatives to linezolid against the risk of serotonin syndrome. If linezolid therapy is required, the patient's tricyclic or tetracyclic should be immediately discontinued. Patients should be monitored for serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid, whichever comes first. The patient's tricyclic or tetracyclic therapy may be resumed 24 hours after the last dose of linezolid.(13) Clinical studies have found a low incidence of serotonin syndrome in patients on concomitant linezolid and serotonergic agents, ranging from 0.24% to 4%, depending on the quality and size of the study. While linezolid-associated serotonin syndrome is potentially serious and fatal, if treated early, it is quickly reversible with discontinuation of offending agents and supportive care. Therefore, some authors suggest that use of serotonergic medications should not preclude the use of linezolid but that the clinical situation should be assessed. If concurrent use or use of linezolid without a washout is warranted, the patient should be closely monitored.(15-20) If concurrent therapy is warranted, patients should be monitored for signs and symptoms of serotonin syndrome. Instruct patients to report muscle twitching, tremors, shivering and stiffness, fever, heavy sweating, heart palpitations, restlessness, confusion, agitation, trouble with coordination, or severe diarrhea.

DISCUSSION: It should be noted that if this interaction occurs, the consequences will be immediate and severe. Effects may continue to be seen for several days after discontinuing linezolid. The FDA FAERS contains reports of serotonin syndrome with the concurrent use of linezolid and citalopram, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, and venlafaxine. The risk of serotonin syndrome with other psychiatric drugs is unclear.(14)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Selected Antidepressants/Bupropion

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Depending upon the antidepressant, one or two mechanisms may be involved. Both bupropion and antidepressants are known to lower the seizure threshold.(1,2) Bupropion, a strong inhibitor of CYP2D6 may increase systemic exposure (AUC, area-under-curve) to antidepressants metabolized by this pathway. The tricyclic antidepressants, the SSRIs, and the SNRIs are the most sensitive to CYP2D6 inhibition and are addressed in separate monographs. Antidepressants which are metabolized by CYP2D6 but less susceptible to CYP2D6 inhibition are: mianserin, mirtazapine, nefazodone active metabolite (mCPP), and trazodone active metabolite (mCPP).(3)

CLINICAL EFFECTS: Concurrent use of bupropion and an antidepressant may result in additive effects on the seizure threshold, increasing the risk of seizures.(1,2) Concurrent use may also increase levels of and side effects from antidepressants metabolized by CYP2D6, such as mianserin, mirtazepine, nefazodone, and trazodone.(3)

PREDISPOSING FACTORS: The risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants an anorectics; a total daily dose of bupropion greater than 450 mg or single doses greater than 150 mg; rapid escalation of bupropion dosage; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids).(1,2)

PATIENT MANAGEMENT: The concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) Single doses should not exceed 150 mg.(1,2) The maximum daily dose of bupropion should not exceed 300 mg for smoking cessation(2) or 450 mg for depression.(1)

DISCUSSION: Because of the risk of seizure from concurrent bupropion and other agents that lower seizure threshold, the manufacturer of bupropion states that the concurrent use of bupropion and antidepressants should be undertaken only with extreme caution and with low initial bupropion dosing and small gradual dosage increases.(1,2) In a study in 15 male subjects who were extensive metabolizers of CYP2D6, bupropion (150 mg twice daily) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of desipramine (50 mg) by 2-fold, 5-fold, and 2-fold, respectively.(1,2)

Tricyclic Compounds; Mirtazapine/Clonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Clonidine decreases blood pressure via alpha-2 agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2, which may result in a loss of effect of clonidine.

CLINICAL EFFECTS: The concurrent use of clonidine and tricyclic compounds(1,3,4-16) and mirtazapine(3,17) may result in decreased effectiveness of clonidine and hypertensive crisis.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If possible, avoid concurrent use of clonidine with tricyclic compounds or mirtazapine. Consider using an alternative agent in patients maintained on clonidine. If concurrent administration is warranted, blood pressure should be carefully monitored, particularly in the first two weeks of therapy, when this interaction is most likely to occur. The dosage of clonidine may need to be adjusted or the tricyclic compound or mirtazapine may need to be discontinued.

DISCUSSION: This interaction has been reported in patients receiving amitriptyline,(6) clomipramine,(7,8) desipramine,(2,9-11) imipramine(12-16), and protriptyline.(11) In one patient, a hypertensive crisis resulted. Other patients experienced a decrease in blood pressure control. A controlled trial demonstrated a decrease in anti-hypertensive effect when desipramine was added to a clonidine regimen. This decrease in hypertensive-control may be overcome by increasing the dose of clonidine and monitoring blood pressure closely. Cyclobenzaprine is structurally related to the tricyclic antidepressants and, especially at higher dosages, has similar effects.(18) Therefore, it is prudent to consider cyclobenzaprine in this interaction. Hypertensive crisis has been reported during concurrent clonidine and mirtazapine therapy.(3,17) Mianserin(19,20) and maprotiline,(21) tetracyclic antidepressants, have been shown not to affect the antihypertensive effects of clonidine.

Tricyclic Compounds; Mirtazapine/Moxonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moxonidine decreases blood pressure via imidazoline-1 and alpha-2 receptor agonism.(1) Tricyclic compounds(2) and mirtazapine(3) antagonize alpha-2, which may result in a loss of effect of moxonidine.

CLINICAL EFFECTS: The concurrent use of moxonidine and tricyclic compounds and mirtazapine may result in decreased effectiveness of moxonidine and decreased blood pressure control.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of moxonidine with tricyclic compounds or mirtazapine is not recommended.(1) Consider using an alternative agent in patients maintained on moxonidine. If concurrent administration is necessary, blood pressure should be carefully monitored. The dosage of moxonidine may need to be adjusted or the tricyclic compound or mirtazapine may need to be discontinued.

DISCUSSION: Moxonidine is an imidazoline-1 and alpha-2 receptor agonist.(1) Since tricyclic antidepressants and mirtazapine may reduce the effectiveness of centrally acting antihypertensive agents, the concurrent use of moxonidine is not recommended. No studies have evaluated the current use of moxonidine with tricyclic antidepressants or mirtazapine. Loss of blood pressure control and hypertensive crisis have been reported with clonidine,(4-22) and a similar interaction may occur with moxonidine. The sedative effect of tricyclic antidepressants can be potentiated by moxonidine.

*Known hypersensitivity to mirtazapine, or to any ingredient in its formulations.

*Concurrent or recent (i.e., within 14 days) therapy with monoamine oxidase (MAO) inhibitors, including linezolid and IV methylene blue.

• Neuroleptic malignant syndrome

• Acute thromboembolic stroke
• Angle-closure glaucoma
• Bipolar disorder
• Congenital long QT syndrome
• Dehydration
• Disease of liver
• Hypovolemia
• Myopathy with CK elevation
• Prolonged QT interval
• Risk of angle-closure glaucoma due to narrow angle of anterior chamber of eye
• Suicidal ideation
• Torsades de pointes

• Acute myocardial infarction
• Akathisia
• Angina
• Cerebrovascular accident
• Cerebrovascular disorder
• Hypercholesterolemia
• Hypertriglyceridemia
• Hypomania
• Hyponatremia
• Hypotension
• Manic disorder
• Obesity
• Orthostatic hypotension
• Renal disease with moderate to severe function impairment
• Seizure disorder
• Weight gain

Adverse effects reported in >=5% of patients receiving mirtazapine include somnolence, increased appetite, weight gain, and dizziness.

Less Frequent

• Acute cognitive impairment
• Agitation
• Dyspnea
• Edema
• Flu-like symptoms
• Hyperkinesis
• Hypertension
• Hypokinesia
• Increased alanine transaminase
• Mood changes
• Orthostatic hypotension
• Skin rash

Rare or Very Rare

• Abnormal hepatic function tests
• Accommodation disorder
• Acquired dystonia
• Agranulocytosis
• Akathisia
• Amenorrhea
• Bullous dermatitis
• Delusional disorder
• Depersonalization
• DRESS syndrome
• Dysmenorrhea
• Erectile dysfunction
• Erythema multiforme
• Extrapyramidal disease
• Facial edema
• Hallucinations
• Herpes zoster
• Hostility
• Hypomania
• Hyponatremia
• Irritability
• Kidney stone
• Manic disorder
• Neutropenic disorder
• Priapism
• Prolonged QT interval
• Rhabdomyolysis
• Secondary angle-closure glaucoma
• Seizure disorder
• Serotonin syndrome
• Stevens-johnson syndrome
• Suicidal ideation
• Torsades de pointes
• Toxic epidermal necrolysis

More Frequent

• Constipation
• Dizziness
• Drowsy
• General weakness
• Hypercholesterolemia
• Increased appetite
• Weight gain
• Xerostomia

Less Frequent

• Acute abdominal pain
• Anorexia
• Arthralgia
• Back pain
• Cough
• Hypoesthesia
• Increased urinary frequency
• Indifference
• Malaise
• Memory impairment
• Muscle fasciculation
• Muscle weakness
• Myalgia
• Nausea
• Nervousness
• Paresthesia
• Peripheral edema
• Polydipsia
• Pruritus of skin
• Sinusitis
• Symptoms of anxiety
• Tremor
• Urinary tract infection
• Vasodilation of blood vessels
• Vertigo
• Vomiting

Rare or Very Rare

• Accidental fall
• Aggressive behavior
• Anticholinergic toxicity
• Breast engorgement
• Dream disorder
• Hyperprolactinemia
• Loss of taste
• Parosmia
• Sleep walking disorder

No enhanced messaging available.

The safety and effectiveness of mirtazapine in pediatric patients for the treatment of major depressive disorder have not been established; mirtazapine is not approved for use in pediatric patients. In 2 placebo-controlled trials, there were insufficient data to establish the safety and efficacy of mirtazapine for the treatment of major depressive disorder in pediatric patients. Additionally, in an 8-week-long clinical trial, 49% of pediatric patients receiving mirtazapine had a weight gain of at least 7% versus 5.7% of pediatric patients receiving placebo. The average weight increase for those in the mirtazapine group was 4 kg compared to a 1-kg weight increase in the placebo group.

An increased risk of suicidal thoughts and behaviors was observed in pediatric patients treated with antidepressants.

A National Pregnancy Registry for Antidepressants is available that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Clinicians are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or by visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregi stry/antidepressants/.

Available evidence has not reliably identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

In animal reproductive studies, no evidence of teratogenic effects were observed when oral mirtazapine was administered during the period of organogenesis at doses up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg on a mg/m2 body surface area basis in rats and rabbits, respectively. However, there was an increase in postimplantation loss at 20 times the MRHD in rats. Also, an increase in pup deaths and a decrease in pup birth weights at doses 20 times the MRHD was observed with oral administration of mirtazapine to rats during pregnancy and lactation.

There are risks associated with untreated depression in pregnancy. In a prospective, longitudinal study, women who discontinued antidepressants during pregnancy were more likely to experience a relapse in major depression than women who continued antidepressants. Consider the risk of untreated depression when discontinuing or changing antidepressants during pregnancy and postpartum.

Mirtazapine is present at low levels in human milk with relative infant doses for mirtazapine ranging from 0.6-2.8% of the maternal weight-adjusted dose. There have been no adverse effects on the breast-fed infant reported in most cases of maternal use of mirtazapine. There are no data on the effects of mirtazapine on milk production.

Consider the developmental and health benefits of breast-feeding, the mother's clinical need for mirtazapine, and any potential adverse effects on the breast-fed child from the drug or from the underlying maternal condition.

Caution should be used when administering mirtazapine to geriatric patients; dosage selection should be conservative, usually starting at the low end of the dosing range, due to age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

In clinical trials with mirtazapine, approximately 190 patients were >=65 years of age. Mirtazapine is primarily eliminated by kidney excretion; pharmacokinetic studies showed a decreased clearance of mirtazapine in geriatric patients.

Sedating drugs such as mirtazapine may cause confusion and over-sedation in geriatric patients; geriatric patients may also be at greater risk of developing hyponatremia.

Mirtazapine should be used with caution in geriatric patients. Dosage selection should be conservative in this population, starting at the low end of the dosing range to reflect the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.