Mirtazapine Prescribing Information
Mirtazapine tablets are indicated for the treatment of major depressive disorder (MDD) in adults
The efficacy of mirtazapine as a treatment for major depressive disorder was established in 4 placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from a dose range of 5 mg to 35 mg/day. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21 to 32 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of mirtazapine over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor.
Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings.
In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on mirtazapine were randomized to continuation of mirtazapine or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8 to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued mirtazapine treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients.
- Starting dose: 15 mg once daily; may increase up to maximum recommended dose of 45 mg once daily. ()
2.1 Recommended DosageThe recommended starting dose of mirtazapine tablets is 15 mg once daily, administered orally, preferably in the evening prior to sleep. If patients do not have an adequate response to the initial 15 mg dose, increase the dose up to a maximum of 45 mg per day. Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response to a given dose
[see Clinical Pharmacology (12.3)]. - Administer orally once daily, preferably in the evening prior to sleep. ()
2.1 Recommended DosageThe recommended starting dose of mirtazapine tablets is 15 mg once daily, administered orally, preferably in the evening prior to sleep. If patients do not have an adequate response to the initial 15 mg dose, increase the dose up to a maximum of 45 mg per day. Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response to a given dose
[see Clinical Pharmacology (12.3)]. - Reduce dose gradually when discontinuing mirtazapine tablets. (,
2.6 Discontinuation of Mirtazapine Tablets TreatmentAdverse reactions may occur upon discontinuation or dose reduction of mirtazapine tablets
[see Warnings and Precautions (5.14)].Gradually reduce the dosage of mirtazapine tablets rather than stopping abruptly whenever possible.)5.14 Discontinuation SyndromeThere have been reports of adverse reactions upon the discontinuation of mirtazapine (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance.
A gradual reduction in the dosage, rather than an abrupt cessation, is recommended
[see Dosage and Administration (2.6)].
Mirtazapine tablets USP are supplied as:
- 7.5 mg tablets: White, biconvex, capsule shaped film coated tablets with “11” debossed on one side and “A” debossed on the other side.
- 15 mg tablets: Yellow, biconvex, capsule shaped film coated tablets with a score line in between “0” and “8” on one side and “A” debossed on the other side.
- 30 mg tablets: Reddish brown, biconvex, capsule shaped film coated tablets with a score line in between “0” and “9” on one side and “A” debossed on the other side.
- 45 mg tablets: White, biconvex, capsule shaped film coated tablets with “10” debossed on one side and “A” debossed on the other side.
- Geriatric Use: Use with caution in elderly patients. (,
5.12 HyponatremiaHyponatremia may occur as a result of treatment with serotonergic antidepressants, including mirtazapine. Cases with serum sodium lower than 110 mmol/L have been reported.
Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH).
In patients with symptomatic hyponatremia, discontinue mirtazapine and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume-depleted may be at greater risk of developing hyponatremia
[see Use in Specific Populations (8.5)].,5.15 Use in Patients with Concomitant IllnessMirtazapine has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients
[see Adverse Reactions (6.1)].Mirtazapine should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication).)8.5 Geriatric UseApproximately 190 patients ≥65 years of age participated in clinical studies with mirtazapine. Mirtazapine is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Pharmacokinetic studies revealed a decreased clearance of mirtazapine in the elderly
[see Clinical Pharmacology (12.3)].Sedating drugs, including mirtazapine, may cause confusion and over-sedation in the elderly. Elderly patients may be at greater risk of developing hyponatremia. Caution is indicated when administering mirtazapine to elderly patients
[see Warnings and Precautions (5.12), (5.15)and Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. - Renal impairment:Dosage decrease may be needed in patients with moderate to severe renal impairment. ()
8.6 Renal or Hepatic ImpairmentThe clearance of mirtazapine is reduced in patients with moderate to severe renal or hepatic impairment. Consequently, plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in patients without renal or hepatic impairment. Dosage decrease may be necessary when administering mirtazapine to patients with moderate to severe renal or hepatic impairment
[see Warnings and Precautions (5.13), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)]. - Hepatic impairment: Dosage decrease may be needed in patients with hepatic impairment. ()
8.6 Renal or Hepatic ImpairmentThe clearance of mirtazapine is reduced in patients with moderate to severe renal or hepatic impairment. Consequently, plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in patients without renal or hepatic impairment. Dosage decrease may be necessary when administering mirtazapine to patients with moderate to severe renal or hepatic impairment
[see Warnings and Precautions (5.13), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].
Mirtazapine tablets are contraindicated in patients:
- Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see,
5.3 Serotonin SyndromeSerotonergic antidepressants, including mirtazapine, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John’s Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs
[see Contraindications (4), Drug Interactions (7)].Serotonin syndrome can also occur when these drugs are used alone.Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
The concomitant use of mirtazapine with MAOIs is contraindicated. In addition, do not initiate mirtazapine in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking mirtazapine, discontinue mirtazapine before initiating treatment with the MAOI
[see Contraindications (4), Drug Interactions (7)].Monitor all patients taking mirtazapine for the emergence of serotonin syndrome. Discontinue treatment with mirtazapine and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of mirtazapine with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.
].7 DRUG INTERACTIONSTable 5 includes clinically important drug interactions with mirtazapine
[see Clinical Pharmacology (12.3)].Table 5: Clinically Important Drug Interactions with Mirtazapine Monoamine Oxidase Inhibitors (MAOIs)Clinical ImpactThe concomitant use of serotonergic drugs, including mirtazapine, and MAOIs increases the risk of serotonin syndrome. InterventionMirtazapine is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3)].Examplesselegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic DrugsClinical ImpactThe concomitant use of serotonergic drugs with mirtazapine increases the risk of serotonin syndrome. InterventionMonitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of mirtazapine and/or concomitant serotonergic drugs [see Warnings and Precautions (5.3)].ExamplesSSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St. John’s Wort, tramadol, tryptophan, buspirone Strong CYP3A InducersClinical ImpactThe concomitant use of strong CYP3A inducers with mirtazapine decreases the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].InterventionIncrease the dose of mirtazapine if needed with concomitant CYP3A inducer use. Conversely, a decrease in dosage of mirtazapine may be needed if the CYP3A inducer is discontinued [see Dosage and Administration (2.5)].Examplesphenytoin, carbamazepine, rifampin Strong CYP3A InhibitorsClinical ImpactThe concomitant use of strong CYP3A inhibitors with mirtazapine may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].InterventionDecrease the dose of mirtazapine if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine may be needed if the CYP3A inhibitor is discontinued [see Dosage and Administration (2.5)].Examplesitraconazole, ritonavir, nefazodone CimetidineClinical ImpactThe concomitant use of cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, with mirtazapine may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].InterventionDecrease the dose of mirtazapine if needed with concomitant cimetidine use. Conversely, an increase in dosage of mirtazapine may be needed if cimetidine is discontinued [see Dosage and Administration (2.5)].Benzodiazepines and AlcoholClinical ImpactThe concomitant use of benzodiazepines or alcohol with mirtazapine increases the impairment of cognitive and motor skills produced by mirtazapine alone. InterventionAvoid concomitant use of benzodiazepines and alcohol with mirtazapine [see Warnings and Precautions (5.8), Clinical Pharmacology (12.3)].Examplesdiazepam, alprazolam, alcohol Drugs that Prolong QTc IntervalClinical ImpactThe concomitant use of other drugs which prolong the QTc interval with mirtazapine, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes). InterventionUse caution when using mirtazapine concomitantly with drugs that prolong the QTc interval [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].WarfarinClinical ImpactThe concomitant use of warfarin with mirtazapine may result in an increase in INR [see Clinical Pharmacology (12.3)].InterventionMonitor INR during concomitant use of warfarin with mirtazapine. - Strong CYP3Ainducers: Dosage increase may be needed for mirtazapine with concomitant use of strong CYP3A inducers.
- Strong CYP3A inhibitors:Dosage decrease may be needed when mirtazapine is coadministered with strong CYP3A inhibitors.
- Cimetidine:Dosage decrease may be needed when mirtazapine is coadministered with cimetidine.
- Warfarin:Monitor INR during concomitant use.
- With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine tablets. Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine tablets [see,
5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with postmarketing use of mirtazapine. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue mirtazapine immediately if DRESS is suspected and institute appropriate treatment
[see Contraindications (4), Adverse Reactions (6.2)].].6.2 Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of mirtazapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Cardiac disorders: ventricular arrhythmia (Torsades de Pointes)Endocrine disorders: hyperprolactinemia (and related symptoms, e.g., galactorrhea and gynecomastia)Musculoskeletal and connective tissue disorders: increased creatine kinase blood levels and rhabdomyolysisPsychiatric disorders: somnambulism (ambulation and other complex behaviors out of bed)Reproductive system and breast disorders:priapismSkin and subcutaneous tissue disorders: severe skin reactions, including DRESS, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis