onsider discontinuation of mirtazapine and/or concomitant serotonergic drugs [see warnings and precautions (5.3) ]. examples ssris, snris, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, st. john’s wort, tramadol, tryptophan, buspirone strong cyp3a inducers clinical impact the concomitant use of strong cyp3a inducers with mirtazapine decreases the plasma concentration of mirtazapine [see clinical pharmacology (12.3) ]. intervention increase 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) ]. examples phenytoin, carbamazepine, rifampin strong cyp3a inhibitors clinical impact the concomitant use of strong cyp3a inhibitors with mirtazapine may increase the plasma concentration of mirtazapine [see clinical pharmacology (12.3) ]. intervention decrease 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) ]. examples itraconazole, ritonavir, nefazodone cimetidine clinical impact the concomitant use of cimetidine, a cyp1a2, cyp2d6, and cyp3a inhibitor, with mirtazapine may increase the plasma concentration of mirtazapine [see clinical pharmacology (12.3) ]. intervention decrease 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 alcohol clinical impact the concomitant use of benzodiazepines or alcohol with mirtazapine increases the impairment of cognitive and motor skills produced by mirtazapine alone. intervention avoid concomitant use of benzodiazepines and alcohol with mirtazapine [see warnings and precautions (5.8) , clinical pharmacology (12.3) ]. examples diazepam, alprazolam, alcohol drugs that prolong qtc interval clinical impact the 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). intervention use caution when using mirtazapine concomitantly with drugs that prolong the qtc interval [see warnings and precautions (5.5) , clinical pharmacology (12.3) ]. warfarin clinical impact the concomitant use of warfarin with mirtazapine may result in an increase in inr [see clinical pharmacology (12.3) ]. intervention monitor inr during concomitant use of warfarin with mirtazapine. strong cyp3a inducers : dosage increase may be needed for mirtazapine with concomitant use of strong cyp3a inducers. ( 2.5 , 7 ) strong cyp3a inhibitors: dosage decrease may be needed when mirtazapine is coadministered with strong cyp3a inhibitors. ( 2.5 , 7 ) cimetidine: dosage decrease may be needed when mirtazapine is coadministered with cimetidine. ( 2.5 , 7 ) warfarin: monitor inr during concomitant use. ( 7 )

ir judgment, thinking and/or motor skills. use with caution when engaging in activities requiring alertness, such as driving or operating machinery. ( 5.8 , 7 ) activation of mania/hypomania: screen patients for bipolar disorder prior to initiating treatment. ( 2.3 , 5.9 ) seizures: use with caution in patients with a seizure disorder. ( 5.10 ) elevated cholesterol/triglycerides: has been reported with mirtazapine use. ( 5.11 ) hyponatremia: may occur as a result of treatment with serotonergic antidepressants, including mirtazapine. ( 5.12 ) transaminase elevations: clinically significant elevations have occurred. use with caution in patients with impaired hepatic function. ( 5.13 ) 5.1 suicidal thoughts and behaviors in adolescents and young adults in pooled analyses of placebo-controlled trials of antidepressant drugs (ssris and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. there was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. there were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with mdd. the drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in table 1. table 1: risk differences of the number of patients with suicidal thoughts and behavior in the pooled placebo-controlled trials of antidepressants in pediatric and adult patients age range drug-placebo difference in number of patients with suicidal thoughts or behaviors per 1000 patients treated increases compared to placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients decreases compared to placebo 25 to 64 years old 1 fewer patient ?65 years old 6 fewer patients it is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. however, there is substantial evidence from placebo-controlled maintenance trials in adults with mdd that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. consider changing the therapeutic regimen, including possibly discontinuing mirtazapine, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 agranulocytosis in premarketing clinical trials, 2 (1 with sjögren’s syndrome) out of 2796 patients treated with mirtazapine developed agranulocytosis [absolute neutrophil count (anc) <500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (anc <500/mm 3 without any associated symptoms). for these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. all 3 patients recovered after mirtazapine was stopped. if a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low white blood cell (wbc) count, treatment with mirtazapine should be discontinued and the patient should be closely monitored. 5.3 serotonin syndrome serotonergic 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. 5.4 angle-closure glaucoma the pupillary dilation that occurs following use of many antidepressant drugs, including mirtazapine, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.5 qt prolongation and torsades de pointes the effect of mirtazapine on qtc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis. this trial showed a positive relationship between mirtazapine concentrations and prolongation of the qtc interval. however, the degree of qt prolongation observed with both 45 mg and 75 mg (1.67 times the maximum recommended daily dose) doses of mirtazapine was not at a level generally considered to be clinically meaningful. during postmarketing use of mirtazapine, cases of qt prolongation, torsades de pointes, ventricular tachycardia, and sudden death, have been reported [see adverse reactions (6.1 , 6.2) ]. the majority of reports occurred in association with overdose or in patients with other risk factors for qt prolongation, including concomitant use of qtc-prolonging medicines [see drug interactions (7) and overdosage (10) ]. exercise caution when mirtazapine is prescribed in patients with known cardiovascular disease or family history of qt prolongation, and in concomitant use with other drugs thought to prolong the qtc interval. 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) ] . 5.7 increased appetite and weight gain in u.s. controlled clinical studies, appetite increase was reported in 17% of patients treated with mirtazapine, compared to 2% for placebo. in these same trials, weight gain of ?7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo. in a pool of premarketing u.s. clinical studies, including many patients for long-term, open-label treatment, 8% of patients receiving mirtazapine discontinued for weight gain. in an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-treated pediatric patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. the safety and effectiveness of mirtazapine in pediatric patients with mdd have not been established [see use in specific populations (8.4) ]. 5.8 somnolence in u.s. controlled studies, somnolence was reported in 54% of patients treated with mirtazapine, compared to 18% for placebo. in these studies, somnolence resulted in discontinuation for 10.4% of mirtazapine-treated patients, compared to 2.2% for placebo. it is unclear whether tolerance develops to the somnolent effects of mirtazapine. because of the potentially significant effects of mirtazapine on impairment of performance, caution patients about engaging in activities that require alertness, including operating hazardous machinery and motor vehicles, until they are reasonably certain that mirtazapine does not affect them adversely. the concomitant use of benzodiazepines and alcohol with mirtazapine should be avoided [see drug interactions (7) ]. 5.9 activation of mania or hypomania in patients with bipolar disorder, treating a depressive episode with mirtazapine or another antidepressant may precipitate a mixed/manic episode. in controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.2% of patients treated with mirtazapine. prior to initiating treatment with mirtazapine, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.10 seizures mirtazapine has not been systematically evaluated in patients with seizure disorders. in premarketing clinical trials, 1 seizure was reported among the 2796 u.s. and non-u.s. patients treated with mirtazapine. mirtazapine should be prescribed with caution in patients with a seizure disorder. 5.11 elevated cholesterol and triglycerides in u.s. controlled studies, nonfasting cholesterol increases to ?20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine, compared to 7% for placebo. in these same studies, nonfasting triglyceride increases to ?500 mg/dl were observed in 6% of patients treated with mirtazapine, compared to 3% for placebo. 5.12 hyponatremia hyponatremia 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) ]. 5.13 transaminase elevations clinically significant alt (sgpt) elevations (?3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with mirtazapine in a pool of short-term, u.s. controlled trials, compared to 0.3% (1/328) of placebo patients. while some patients were discontinued for the alt increases, in other cases, the enzyme levels returned to normal despite continued mirtazapine treatment. mirtazapine should be used with caution in patients with impaired hepatic function [see use in specific populations (8.6) , clinical pharmacology (12.3) ]. 5.14 discontinuation syndrome there 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) ]. 5.15 use in patients with concomitant illness mirtazapine 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).

rnings and precautions (5.9) ]. 2.4 switching patients to or from a monoamine oxidase inhibitor antidepressant at least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (maoi) antidepressant and initiation of mirtazapine tablets. in addition, at least 14 days must elapse after stopping mirtazapine tablets before starting an maoi antidepressant [see contraindications (4) and warnings and precautions (5.3) ]. 2.5 dosage modifications due to drug interactions strong cyp3a inducers an increase in dosage of mirtazapine tablets may be needed with concomitant strong cyp3a inducer (e.g., carbamazepine, phenytoin, rifampin) use. conversely, a decrease in dosage of mirtazapine tablets may be needed if the cyp3a inducer is discontinued [see drug interactions (7) ]. strong cyp3a inhibitors a decrease in dosage of mirtazapine tablets may be needed with concomitant use of strong cyp3a4 inhibitors (e.g., ketoconazole, clarithromycin). conversely, an increase in dosage of mirtazapine tablets may be needed if the cyp3a4 inhibitor is discontinued [see drug interactions (7) ]. cimetidine a decrease in dosage of mirtazapine tablets may be needed with concomitant use of cimetidine. conversely, an increase in dosage of mirtazapine tablets may be needed if cimetidine is discontinued [see drug interactions (7) ]. 2.6 discontinuation of mirtazapine tablets treatment adverse 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.

utions (5.12) ] transaminase elevations [see warnings and precautions (5.13) ] discontinuation syndrome [see warnings and precautions (5.14) ] use in patients with concomitant illness [see warnings and precautions (5.15) ] most common adverse reactions (?5% or greater and twice placebo) were somnolence, increased appetite, weight gain, and dizziness. ( 6.1 ) to report suspected adverse reactions, contact aurobindo pharma usa, inc. at 1-866-850-2876 or fda at 1-800-fda-1088 or www.fda.gov/medwatch. 6.1 clinical trial experience because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. the data described below are from clinical trials in which mirtazapine was administered to 2796 patients in phase 2 and 3 clinical studies. the trials consisted of double-blind controlled and open-label studies, inpatient and outpatient studies, fixed dose, and titration studies. adverse reactions leading to discontinuation of treatment approximately 16% of the 453 patients who received mirtazapine in u.s. 6-week placebo-controlled clinical trials discontinued treatment due to an adverse reaction, compared to 7% of the 361 placebo-treated patients in those studies. the most common reactions leading to discontinuation (?1% and at a rate at least twice that of placebo) are included in table 2. table 2: adverse reactions (?1% and at least twice placebo) leading to discontinuation of mirtazapine in 6-week clinical trials in patients with mdd mirtazapine (n=453) placebo (n=361) somnolence 10.4% 2.2% nausea 1.5% 0% common adverse reactions the most common adverse reactions (?5% and twice placebo) associated with the use of mirtazapine are listed in table 3. table 3: adverse reactions (?5% and twice placebo) in 6-week u.s. clinical trials of mirtazapine in patients with mdd mirtazapine (n=453) placebo (n=361) somnolence 54% 18% increased appetite 17% 2% weight gain 12% 2% dizziness 7% 3% table 4 enumerates adverse reactions that occurred in ?1% of mirtazapine-treated patients, and were more frequent than the placebo-treated patients, who participated in 6-week, u.s. placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. this table shows the percentage of patients in each group who had at least 1 episode of an adverse reaction at some time during their treatment. table 4: adverse reactions (?1% and greater than placebo) in 6-week u.s. clinical studies of mirtazapine in patients with mdd mirtazapine (n=453) placebo (n=361) body as a whole asthenia 8% 5% flu syndrome 5% 3% back pain 2% 1% digestive system dry mouth 25% 15% increased appetite 17% 2% constipation 13% 7% metabolic and nutritional disorders weight gain 12% 2% peripheral edema 2% 1% edema 1% 0% musculoskeletal system myalgia 2% 1% nervous system somnolence 54% 18% dizziness 7% 3% abnormal dreams 4% 1% thinking abnormal 3% 1% tremor 2% 1% confusion 2% 0% respiratory system dyspnea 1% 0% urogenital system urinary frequency 2% 1% ecg changes the electrocardiograms for 338 patients who received mirtazapine and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. the clinical significance of these changes is unknown. other adverse reactions observed during the premarketing evaluation of mirtazapine the following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general or excessively specific so as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. adverse reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients. body as a whole : frequent : malaise, abdominal pain, abdominal syndrome acute; infrequent : chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare : cellulitis, chest pain substernal. cardiovascular system : frequent : hypertension, vasodilatation; infrequent : angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare : atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. digestive system : frequent : vomiting, anorexia; infrequent : eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare : tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. endocrine system : rare : goiter, hypothyroidism. hemic and lymphatic system : rare : lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. metabolic and nutritional disorders: frequent : thirst; infrequent : dehydration, weight loss; rare : gout, sgot increased, healing abnormal, acid phosphatase increased, sgpt increased, diabetes mellitus, hyponatremia. musculoskeletal system : frequent : myasthenia, arthralgia; infrequent : arthritis, tenosynovitis; rare : pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. nervous system: frequent : hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent : ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare : aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. respiratory system : frequent : cough increased, sinusitis; infrequent : epistaxis, bronchitis, asthma, pneumonia; rare : asphyxia, laryngitis, pneumothorax, hiccup. skin and appendages : frequent : pruritus, rash; infrequent : acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare : urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. special senses : infrequent : eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare : blepharitis, partial transitory deafness, otitis media, taste loss, parosmia. urogenital system : frequent : urinary tract infection; infrequent : kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare : polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. 6.2 postmarketing experience the 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 rhabdomyolysis psychiatric disorders : somnambulism (ambulation and other complex behaviors out of bed) reproductive system and breast disorders: priapism skin and subcutaneous tissue disorders : severe skin reactions, including dress, stevens-johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis

onsider discontinuation of mirtazapine and/or concomitant serotonergic drugs [see warnings and precautions (5.3) ]. examples ssris, snris, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, st. john’s wort, tramadol, tryptophan, buspirone strong cyp3a inducers clinical impact the concomitant use of strong cyp3a inducers with mirtazapine decreases the plasma concentration of mirtazapine [see clinical pharmacology (12.3) ]. intervention increase 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) ]. examples phenytoin, carbamazepine, rifampin strong cyp3a inhibitors clinical impact the concomitant use of strong cyp3a inhibitors with mirtazapine may increase the plasma concentration of mirtazapine [see clinical pharmacology (12.3) ]. intervention decrease 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) ]. examples itraconazole, ritonavir, nefazodone cimetidine clinical impact the concomitant use of cimetidine, a cyp1a2, cyp2d6, and cyp3a inhibitor, with mirtazapine may increase the plasma concentration of mirtazapine [see clinical pharmacology (12.3) ]. intervention decrease 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 alcohol clinical impact the concomitant use of benzodiazepines or alcohol with mirtazapine increases the impairment of cognitive and motor skills produced by mirtazapine alone. intervention avoid concomitant use of benzodiazepines and alcohol with mirtazapine [see warnings and precautions (5.8) , clinical pharmacology (12.3) ]. examples diazepam, alprazolam, alcohol drugs that prolong qtc interval clinical impact the 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). intervention use caution when using mirtazapine concomitantly with drugs that prolong the qtc interval [see warnings and precautions (5.5) , clinical pharmacology (12.3) ]. warfarin clinical impact the concomitant use of warfarin with mirtazapine may result in an increase in inr [see clinical pharmacology (12.3) ]. intervention monitor inr during concomitant use of warfarin with mirtazapine. strong cyp3a inducers : dosage increase may be needed for mirtazapine with concomitant use of strong cyp3a inducers. ( 2.5 , 7 ) strong cyp3a inhibitors: dosage decrease may be needed when mirtazapine is coadministered with strong cyp3a inhibitors. ( 2.5 , 7 ) cimetidine: dosage decrease may be needed when mirtazapine is coadministered with cimetidine. ( 2.5 , 7 ) warfarin: monitor inr during concomitant use. ( 7 )

. there are risks associated with untreated depression in pregnancy (see clinical considerations). in animal reproduction studies, oral administration of mirtazpine to pregnant rats and rabbits during the period of organogenesis revealed no evidence of teratogenic effects up to 20 and 17 times the maximum recommended human dose (mrhd) of 45 mg, respectively, based on mg/m 2 body surface area. however, in rats, there was an increase in postimplantation loss at 20 times the mrhd based on mg/m 2 body surface area. oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth weights at doses 20 times the mrhd based on mg/m 2 body surface area (see data). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. this finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. data animal data mirtazapine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day, respectively, which are up to 20 and 17 times the maximum recommended human dose (mrhd) of 45 mg based on mg/m 2 body surface area, respectively. no evidence of teratogenic effects was observed. however, in rats, there was an increase in postimplantation loss in dams treated with mirtazapine at 100 mg/kg/day which is 20 times the mrhd based on mg/m 2 body surface area. oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/kg/day to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights at 20 times the mrhd based on mg/m 2 body surface area. the cause of these deaths is not known. the no effect dose level is 3 times the mrhd based on mg/m 2 body surface area. 8.2 lactation risk summary data from published literature report the presence of mirtazapine in human milk at low levels with relative infant doses for mirtazapine ranging between 0.6 and 2.8% of the maternal weight-adjusted dose (see data) . no adverse effects on the breastfed infant have been reported in most cases of maternal use of mirtazapine. there are no data on the effects of mirtazapine on milk production. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mirtazapine and any potential adverse effects on the breastfed infant from mirtazapine or from the underlying maternal condition. data in a published pooled analysis of 8 breastfeeding mother-infant pairs, the mean (min, max) total relative infant doses for mirtazapine and its desmethyl metabolite were 1.5% (0.6%, 2.8%) and 0.4% (0.1%, 0.7%) of the maternal weight-adjusted dose (median (min, max) dose of 38 mg (30 mg, 120 mg), respectively). no adverse drug effects were reported for any of the infants. 8.4 pediatric use the safety and effectiveness of mirtazapine have not been established in pediatric patients with mdd. two placebo-controlled trials in 258 pediatric patients with mdd have been conducted with mirtazapine, and the data were insufficient to establish the safety and effectiveness of mirtazapine in pediatric patients with mdd. antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see boxed warning and warnings and precautions (5.1) ]. in an 8-week-long clinical trial in pediatric patients receiving doses between 15 to 45 mg per day, 49% of mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. the mean increase in weight was 4 kg (2 kg sd) for mirtazapine-treated patients versus 1 kg (2 kg sd) for placebo-treated patients [see warnings and precautions (5.7) ]. 8.5 geriatric use approximately 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. 8.6 renal or hepatic impairment the 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) ].

mended human dose (mrhd) of 45 mg, respectively, based on mg/m 2 body surface area. however, in rats, there was an increase in postimplantation loss at 20 times the mrhd based on mg/m 2 body surface area. oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth weights at doses 20 times the mrhd based on mg/m 2 body surface area (see data). the estimated background risk of major birth defects and miscarriage for the indicated population is unknown. all pregnancies have a background risk of birth defect, loss, or other adverse outcomes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. this finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. data animal data mirtazapine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day, respectively, which are up to 20 and 17 times the maximum recommended human dose (mrhd) of 45 mg based on mg/m 2 body surface area, respectively. no evidence of teratogenic effects was observed. however, in rats, there was an increase in postimplantation loss in dams treated with mirtazapine at 100 mg/kg/day which is 20 times the mrhd based on mg/m 2 body surface area. oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/kg/day to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights at 20 times the mrhd based on mg/m 2 body surface area. the cause of these deaths is not known. the no effect dose level is 3 times the mrhd based on mg/m 2 body surface area.

1 ) receptors and peripheral ? 1 -adrenergic receptors, respectively). cardiac electrophysiology the effect of mirtazapine on qtc interval was assessed in healthy subjects. at a dose of 75 mg (1.67 times the maximum recommended dosage), mirtazapine does not prolong the qtc interval to a clinically meaningful extent. 12.3 pharmacokinetics plasma levels of mirtazapine are linearly related to dose over a dose range of 15 to 80 mg (1.78 times the maximum recommended dose). steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio=1.5). the (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer. absorption mirtazapine has an absolute bioavailability of about 50% following oral administration. peak plasma concentrations of mirtazapine are reached within about 2 hours post dose. food effect the presence of food in the stomach has a minimal effect on both the rate and extent of absorption. distribution mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/ml. elimination mirtazapine has a half-life of about 20 to 40 hours following oral administration of mirtazapine. metabolism mirtazapine is extensively metabolized after oral administration. major pathways of bio-transformation are demethylation and hydroxylation followed by glucuronide conjugation. in vitro data from human liver microsomes indicate that cyp2d6 and cyp1a2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cyp3a is considered to be responsible for the formation of the n-desmethyl and n-oxide metabolite. several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. excretion mirtazapine and its metabolites are eliminated predominantly (75%) via urine with 15% in feces. specific populations geriatric patients following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range 25 to 74 years old), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. the clearance in elderly males was 40% lower compared to younger males, while the clearance was 10% lower in elderly females compared to younger females [see warnings and precautions (5.15) , use in specific populations (8.5) ]. male and female patients the mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). race there have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine. patients with renal impairment when compared to subjects with normal renal function, total body clearance of mirtazapine was reduced approximately 30% in renal impaired patients with gfr=11 to 39 ml/min/1.73 m 2 and approximately 50% in renal impaired patients with gfr=<10 ml/min/1.73 m 2 ) [see warnings and precautions (5.15) , use in specific populations (8.6) ]. patients with hepatic impairment following a single 15 mg oral dose of mirtazapine, the oral clearance of mirtazapine in patients with hepatic impairment was decreased by approximately 30%, compared to subjects with normal hepatic function [see warnings and precautions (5.13 , 5.15) , use in specific populations (8.6) ]. drug interactions studies warfarin mirtazapine (30 mg daily) at steady state caused a statistically significant increase (0.2) in the international normalized ratio (inr) in subjects treated with warfarin [see drug interactions (7) ]. qtc-prolonging drugs the risk of qt prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) may be increased with concomitant use of medicines which prolong the qtc interval (e.g., some antipsychotics and antibiotics) and in mirtazapine overdose [see warnings and precautions (5.5) , adverse reactions (6.1 , 6.2) , drug interactions (7), and overdosage (10)]. phenytoin in healthy male subjects (n=18), phenytoin (200 mg daily, at steady state) increased mirtazapine (30 mg daily, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45% [see drug interactions (7) ]. mirtazapine did not significantly affect the pharmacokinetics of phenytoin. carbamazepine in healthy male subjects (n=24), carbamazepine (400 mg twice a day, at steady state) increased mirtazapine (15 mg twice a day, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60% [see drug interactions (7) ]. cimetidine in healthy male subjects (n=12), when cimetidine, a weak inhibitor of cyp1a2, cyp2d6, and cyp3a4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the area under the curve (auc) of mirtazapine increased more than 50% [see drug interactions (7) ]. mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. ketoconazole in healthy male caucasian subjects (n=24), coadministration of the strong cyp3a4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the auc of a single 30 mg dose of mirtazapine by approximately 40% and 50%, respectively [see drug interactions (7) ]. amitriptyline in healthy, cyp2d6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes to the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. paroxetine in healthy cyp2d6 extensive metabolizer subjects (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a cyp2d6 inhibitor. lithium no relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with lithium 600 mg/day for 10 days at steady state and a single 30 mg dose of mirtazapine. the effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown. risperidone mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg twice a day) in subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug. alcohol concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. however, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. diazepam concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. however, the impairment of motor skills produced by mirtazapine has been shown to be additive with those caused by diazepam.

mirtazapine. metabolism mirtazapine is extensively metabolized after oral administration. major pathways of bio-transformation are demethylation and hydroxylation followed by glucuronide conjugation. in vitro data from human liver microsomes indicate that cyp2d6 and cyp1a2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cyp3a is considered to be responsible for the formation of the n-desmethyl and n-oxide metabolite. several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. excretion mirtazapine and its metabolites are eliminated predominantly (75%) via urine with 15% in feces. specific populations geriatric patients following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range 25 to 74 years old), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. the clearance in elderly males was 40% lower compared to younger males, while the clearance was 10% lower in elderly females compared to younger females [see warnings and precautions (5.15) , use in specific populations (8.5) ]. male and female patients the mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). race there have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine. patients with renal impairment when compared to subjects with normal renal function, total body clearance of mirtazapine was reduced approximately 30% in renal impaired patients with gfr=11 to 39 ml/min/1.73 m 2 and approximately 50% in renal impaired patients with gfr=<10 ml/min/1.73 m 2 ) [see warnings and precautions (5.15) , use in specific populations (8.6) ]. patients with hepatic impairment following a single 15 mg oral dose of mirtazapine, the oral clearance of mirtazapine in patients with hepatic impairment was decreased by approximately 30%, compared to subjects with normal hepatic function [see warnings and precautions (5.13 , 5.15) , use in specific populations (8.6) ]. drug interactions studies warfarin mirtazapine (30 mg daily) at steady state caused a statistically significant increase (0.2) in the international normalized ratio (inr) in subjects treated with warfarin [see drug interactions (7) ]. qtc-prolonging drugs the risk of qt prolongation and/or ventricular arrhythmias (e.g., torsades de pointes) may be increased with concomitant use of medicines which prolong the qtc interval (e.g., some antipsychotics and antibiotics) and in mirtazapine overdose [see warnings and precautions (5.5) , adverse reactions (6.1 , 6.2) , drug interactions (7), and overdosage (10)]. phenytoin in healthy male subjects (n=18), phenytoin (200 mg daily, at steady state) increased mirtazapine (30 mg daily, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45% [see drug interactions (7) ]. mirtazapine did not significantly affect the pharmacokinetics of phenytoin. carbamazepine in healthy male subjects (n=24), carbamazepine (400 mg twice a day, at steady state) increased mirtazapine (15 mg twice a day, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60% [see drug interactions (7) ]. cimetidine in healthy male subjects (n=12), when cimetidine, a weak inhibitor of cyp1a2, cyp2d6, and cyp3a4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the area under the curve (auc) of mirtazapine increased more than 50% [see drug interactions (7) ]. mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. ketoconazole in healthy male caucasian subjects (n=24), coadministration of the strong cyp3a4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the auc of a single 30 mg dose of mirtazapine by approximately 40% and 50%, respectively [see drug interactions (7) ]. amitriptyline in healthy, cyp2d6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes to the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. paroxetine in healthy cyp2d6 extensive metabolizer subjects (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a cyp2d6 inhibitor. lithium no relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with lithium 600 mg/day for 10 days at steady state and a single 30 mg dose of mirtazapine. the effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown. risperidone mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg twice a day) in subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug. alcohol concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. however, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. diazepam concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. however, the impairment of motor skills produced by mirtazapine has been shown to be additive with those caused by diazepam.

in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled dna synthesis assay in hela cells. impairment of fertility in a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [20 times the maximum recommended human dose (mrhd), based on body surface area (mg/m 2 )]. mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the mrhd, and pre-implantation losses occurred at 20 times the mrhd.

ytes, in vivo bone marrow micronucleus test in rats, and unscheduled dna synthesis assay in hela cells. impairment of fertility in a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [20 times the maximum recommended human dose (mrhd), based on body surface area (mg/m 2 )]. mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more times the mrhd, and pre-implantation losses occurred at 20 times the mrhd.

udy, 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.

03-90 bottles of 100 ndc 65862-003-01 bottles of 500 ndc 65862-003-05 30 unit-of-use packaging ndc 65862-003-32 45 mg tablets – white, biconvex, capsule shaped film coated tablets with “10” debossed on one side and “a” debossed on the other side. bottles of 30 ndc 65862-032-30 bottles of 60 ndc 65862-032-60 bottles of 90 ndc 65862-032-90 bottles of 100 ndc 65862-032-01 bottles of 500 ndc 65862-032-05 30 unit-of-use packaging ndc 65862-032-32 storage store at 25°c (77°f); excursions permitted to 15° to 30°c (59° to 86°f) [see usp controlled room temperature]. protect from light and moisture.

tonin (in particular, maois, both those intended to treat psychiatric disorders and also others, such as linezolid). advise patients to contact their healthcare provider or report to the emergency room if they experience signs or symptoms of serotonin syndrome [see dosage and administration (2.4) , contraindications (4) , warnings and precautions (5.3) , drug interactions (7) ]. qt prolongation and torsades de pointes inform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations [see warnings and precautions (5.5) , drug interactions (7) , overdosage (10) ]. advise patients to inform physicians that they are taking mirtazapine before any new drug is taken. drug reaction with eosinophilia and systemic symptoms (dress) advise patients to report to their healthcare provider at the earliest onset of fever, rash, swollen lymph nodes, or other signs and symptoms suggestive of drug reaction with eosinophilia and systemic symptoms (dress) [see contraindications (4) , warnings and precautions (5.6) ]. somnolence advise patients that mirtazapine may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that mirtazapine therapy does not adversely affect their ability to engage in such activities . [see warnings and precautions (5.8) ]. alcohol advise patients to avoid alcohol while taking mirtazapine [see warnings and precautions (5.8) , drug interactions (7) ]. activation of mania/hypomania advise patients and their caregivers to observe for signs of activation of mania/hypomania and instruct them to report such symptoms to the healthcare provider [see warnings and precautions (5.9) ]. discontinuation syndrome advise patients not to abruptly discontinue mirtazapine and to discuss any tapering regimen with their healthcare provider. adverse reactions can occur when mirtazapine is discontinued [see dosage and administration (2.6) , warnings and precautions (5.14) ]. allergic reactions advise patients to notify their healthcare provider if they develop an allergic reaction such as rash, hives, swelling, or difficulty breathing [see contraindications (4) , adverse reactions (6.2) ]. pregnancy advise patients to notify their physician if they become pregnant or intend to become pregnant during mirtazapine therapy. advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mirtazapine during pregnancy [see use in specific populations (8.1) ]. lactation advise patients to notify their physician if they are breastfeeding an infant [see use in specific populations (8.2) ]. angle-closure glaucoma patients should be advised that taking mirtazapine can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. open-angle glaucoma is not a risk factor for angle-closure glaucoma. patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see warnings and precautions (5.4) .] for more information, call aurobindo pharma usa, inc. at 1-866-850-2876. dispense with medication guide available at: www.aurobindousa.com/medication-guides distributed by: aurobindo pharma usa, inc. 279 princeton-hightstown road east windsor, nj 08520 manufactured by: aurobindo pharma limited hyderabad-500 032, india revised: 12/2021