OVERDOSAGE SECTION.

10 OVERDOSAGE Human Experience: In premarketing clinical studies, there were reports of mirtazapine overdose alone or in combination with other pharmacological agents. Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia. Based on postmarketing reports, serious outcomes (including fatalities) may occur at dosages higher than the recommended doses, especially with mixed overdoses. In these cases, QT prolongation and Torsades de Pointes have also been reported [see Warnings and Precautions (5.5), Adverse Reactions (6.2), and Drug Interactions (7)]. Overdose Management: No specific antidotes for mirtazapine are known. Contact Poison Control (1-800-222-1222) for the latest recommendations.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 15 mg NDC 0378-3515-93MirtazapineTablets, USP15 mgPHARMACIST: Dispense the accompanyingMedication Guide to each patient.Rx only 30 TabletsEach film-coated tablet contains:Mirtazapine, USP 15 mgDispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Keep this and all medicationout of the reach of children.Store at 20 to 25C (68 to 77F).[See USP Controlled RoomTemperature.]Protect from light and moisture.Usual Dosage: See accompanyingprescribing information.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Made in AustraliaMylan.comRALP3515H22827/2. Mirtazapine Tablets 15 mg Bottle Label.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information: oHypersensitivity [see Contraindications (4)] oSuicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] oAgranulocytosis [see Warnings and Precautions (5.2)] oSerotonin Syndrome [see Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7)] oAngle-Closure Glaucoma [see Warnings and Precautions (5.4)] oQT Prolongation and Torsades de Pointes [see Warnings and Precautions (5.5)] oDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] oIncreased Appetite and Weight Gain [see Warnings and Precautions (5.7)] oSomnolence [see Warnings and Precautions (5.8)] oActivation of Mania or Hypomania [see Warnings and Precautions (5.9)] oSeizures [see Warnings and Precautions (5.10)] oElevated Cholesterol and Triglycerides [see Warnings and Precautions (5.11)] oHyponatremia [see Warnings and Precautions (5.12)] oTransaminase Elevations [see Warnings and Precautions (5.13)] oDiscontinuation Syndrome [see Warnings and Precautions (5.14)] oUse in Patients with Concomitant Illness [see Warnings and Precautions (5.15)] oHypersensitivity [see Contraindications (4)] oSuicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] oAgranulocytosis [see Warnings and Precautions (5.2)] oSerotonin Syndrome [see Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7)] oAngle-Closure Glaucoma [see Warnings and Precautions (5.4)] oQT Prolongation and Torsades de Pointes [see Warnings and Precautions (5.5)] oDrug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] oIncreased Appetite and Weight Gain [see Warnings and Precautions (5.7)] oSomnolence [see Warnings and Precautions (5.8)] oActivation of Mania or Hypomania [see Warnings and Precautions (5.9)] oSeizures [see Warnings and Precautions (5.10)] oElevated Cholesterol and Triglycerides [see Warnings and Precautions (5.11)] oHyponatremia [see Warnings and Precautions (5.12)] oTransaminase Elevations [see Warnings and Precautions (5.13)] oDiscontinuation Syndrome [see Warnings and Precautions (5.14)] oUse 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 Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 tablets were administered to 2796 patients in phase and 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 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 MDDMirtazapine(n 453)Placebo(n 361)Somnolence10.4%2.2%Nausea1.5%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 MDDMirtazapine(n 453)Placebo(n 361)Somnolence54%18%Increased Appetite17%2%Weight Gain12%2%Dizziness7%3%Table 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 range of to 60 mg/day. This table shows the percentage of patients in each group who had at least 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 MDDMirtazapine(n 453)Placebo(n 361)Body as Whole Asthenia8%5% Flu Syndrome5%3% Back Pain2%1%Digestive System Dry Mouth25%15% Increased Appetite17%2% Constipation13%7%Metabolic and Nutritional Disorders Weight Gain12%2% Peripheral Edema2%1% Edema1%0%Musculoskeletal System Myalgia2%1%Nervous System Somnolence54%18% Dizziness7%3% Abnormal Dreams4%1% Thinking Abnormal3%1% Tremor2%1% Confusion2%0%Respiratory System Dyspnea1%0%Urogenital System Urinary Frequency2%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 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 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 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 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.. 6.2Postmarketing Experience The following adverse reactions have been identified during post-approval use of mirtazapine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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: priapismSkin and Subcutaneous Tissue Disorders: severe skin reactions, including DRESS, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis.

BOXED WARNING SECTION.

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.1)]. Mirtazapine tablets are not approved for use in pediatric patients [see Use in Specific Populations (8.4)].. WARNING: SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning.Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Mirtazapine tablets are not approved for use in pediatric patients. (5.1, 8.4).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day, based on body surface area (mg/m2) in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose.. Mutagenesis. Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells. Impairment of Fertility. In 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/m2)]. Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were or more times the MRHD, and pre-implantation losses occurred at 20 times the MRHD.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear. However, its efficacy could be mediated through its activity as an antagonist at central presynaptic 2-adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.. 12.2 Pharmacodynamics In preclinical studies, mirtazapine acts as an antagonist at 2-adrenergic inhibitory autoreceptors and heteroreceptors and as an antagonist at serotonin 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors. Mirtazapine also acts as an antagonist of histamine (H1) receptors, peripheral 1-adrenergic receptors, and muscarinic receptors. Actions at these receptors may explain some of the other clinical effects of mirtazapine (e.g., its prominent somnolent effects and orthostatic hypotension may be explained by its inhibition of histamine (H1) receptors and peripheral 1-adrenergic receptors, respectively). Cardiac Electrophysiology. The effect of mirtazapine on QTc interval was assessed in healthy subjects. At dose of 75 mg (1.67 times the maximum recommended dosage), mirtazapine does not prolong the QTc interval to clinically meaningful extent. 12.3 Pharmacokinetics Plasma levels of mirtazapine are linearly related to dose over dose range of 15 to 80 mg (1.78 times the maximum recommended dose). Steady state plasma levels of mirtazapine are attained within 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 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 hours post dose. Food Effect The presence of food in the stomach has minimal effect on both the rate and extent of absorption. Distribution. Mirtazapine is approximately 85% bound to plasma proteins over concentration range of 0.01 to 10 mcg/mL. Elimination. Mirtazapine has half-life of about 20 to 40 hours following oral administration of mirtazapine tablets. 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 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 11-39 mL/min/1.73 m2 and approximately 50% in renal impaired patients with GFR < 10 mL/min/1.73 m2) [see Warnings and Precautions (5.15) Use in Specific Populations (8.6)]. Patients with Hepatic Impairment Following 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 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 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 day, at steady state) increased mirtazapine (15 mg twice day, at steady state) clearance about 2-fold, resulting in decrease in average plasma mirtazapine concentrations of 60% [see Drug Interactions (7)]. Cimetidine In healthy male subjects (n 12), when cimetidine, 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 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), 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 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 mg twice 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 minimal effect on plasma levels of mirtazapine (15 mg) in 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES The efficacy of mirtazapine as treatment for major depressive disorder was established in placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from dose range of mg to 35 mg/day. The mean mirtazapine dose for patients who completed these studies ranged from 21 to 32 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least of the following 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 longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 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 HAM-D 17 total score of <= and CGI-Improvement score of or at consecutive visits beginning with week of the 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Mirtazapine tablets are contraindicated in patients: oTaking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3), Drug Interactions (7)]. oWith 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 Warnings and Precautions (5.6), Adverse Reactions (6.2)]. oTaking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3), Drug Interactions (7)]. oWith 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 Warnings and Precautions (5.6), Adverse Reactions (6.2)]. oConcomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs. (2.4, 4, 7) oKnown hypersensitivity to mirtazapine or any of the excipients in mirtazapine tablets. (4) oConcomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs. (2.4, 4, 7) oKnown hypersensitivity to mirtazapine or any of the excipients in mirtazapine tablets. (4).

DESCRIPTION SECTION.

11 DESCRIPTION Mirtazapine tablets, USP contain mirtazapine. Mirtazapine has tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. It is designated 1,2,3,4,10,14b-Hexahydro-2-methylpyrazino[2,1-a]pyrido[2,3-c]benzazepine and has the molecular formula of C17H19N3. Its molecular weight is 265.36. The structural formula is the following and it is the racemic mixture:Mirtazapine, USP is white to creamy white crystalline powder which is slightly soluble in water.Mirtazapine tablets are available for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine, and unscored film-coated tablets containing 45 mg of mirtazapine. Each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No. Aluminum Lake, FD&C Yellow No. Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate, titanium dioxide and triacetin.. Mirtazapine Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oStarting dose: 15-mg once daily; may increase up to maximum recommended dose of 45 mg once daily. (2.1) oAdminister orally once daily, preferably in the evening prior to sleep. (2.1) oReduce dose gradually when discontinuing mirtazapine tablets. (2.6, 5.14) oStarting dose: 15-mg once daily; may increase up to maximum recommended dose of 45 mg once daily. (2.1) oAdminister orally once daily, preferably in the evening prior to sleep. (2.1) oReduce dose gradually when discontinuing mirtazapine tablets. (2.6, 5.14) 2.1Recommended Dosage The 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 maximum of 45 mg per day. Dose changes should not be made in intervals of less than to weeks to allow sufficient time for evaluation of response to given dose [see Clinical Pharmacology (12.3)].. 2.3Screen for Bipolar Disorder Prior to Starting Mirtazapine Tablets Prior to initiating treatment with mirtazapine tablets or another antidepressant, screen patients for personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.9) ]. 2.4Switching Patients to or from Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of 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)]. 2.5Dosage 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, decrease in dosage of mirtazapine tablets may be needed if the CYP3A inducer is discontinued [see Drug Interactions (7)]. Strong CYP3A Inhibitors. 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. 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)]. 2.6Discontinuation 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Mirtazapine Tablets, USP are available containing 15 mg, 30 mg or 45 mg of mirtazapine, USP.oThe 15 mg tablets are beige, film-coated, round, scored tablets debossed with over 515 on one side of the tablet and bisected by score on the other side.oThe 30 mg tablets are beige, film-coated, round, scored tablets debossed with over 530 on one side of the tablet and bisected by score on the other side.oThe 45 mg tablets are beige, film-coated, round, unscored tablets debossed with over 545 on one side of the tablet and blank on the other side.. oThe 15 mg tablets are beige, film-coated, round, scored tablets debossed with over 515 on one side of the tablet and bisected by score on the other side.. oThe 30 mg tablets are beige, film-coated, round, scored tablets debossed with over 530 on one side of the tablet and bisected by score on the other side.. oThe 45 mg tablets are beige, film-coated, round, unscored tablets debossed with over 545 on one side of the tablet and blank on the other side.. oTablets: 15 mg scored, 30 mg scored and 45 mg unscored. (3) oTablets: 15 mg scored, 30 mg scored and 45 mg unscored. (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS Table includes clinically important drug interactions with mirtazapine tablets [see Clinical Pharmacology (12.3)]. Table 5: Clinically Important Drug Interactions with Mirtazapine TabletsMonoamine Oxidase Inhibitors (MAOIs)Clinical ImpactThe concomitant use of serotonergic drugs, including mirtazapine tablets, and MAOIs increases the risk of serotonin syndrome. InterventionMirtazapine tablets are 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 blueOther Serotonergic DrugsClinical ImpactThe concomitant use of serotonergic drugs with mirtazapine tablets 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 tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.3)].ExamplesSSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St. Johns Wort, tramadol, tryptophan, buspironeStrong CYP3A InducersClinical ImpactThe concomitant use of strong CYP3A inducers with mirtazapine tablets decreases the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].InterventionIncrease the dose of mirtazapine tablets if needed with concomitant CYP3A inducer use. Conversely, decrease in dosage of mirtazapine tablets may be needed if the CYP3A inducer is discontinued [see Dosage and Administration (2.5)].Examplesphenytoin, carbamazepine, rifampinStrong CYP3A Inhibitors Clinical ImpactThe concomitant use of strong CYP3A inhibitors with mirtazapine tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].InterventionDecrease the dose of mirtazapine tablets if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine tablets may be needed if the CYP3A inhibitor is discontinued [see Dosage and Administration (2.5)].Examplesitraconazole, ritonavir, nefazodoneCimetidineClinical ImpactThe concomitant use of cimetidine, CYP1A2, CYP2D6, and CYP3A inhibitor, with mirtazapine tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].InterventionDecrease the dose of mirtazapine tablets if needed with concomitant cimetidine use. Conversely, an increase in dosage of mirtazapine tablets 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 tablets increases the impairment of cognitive and motor skills produced by mirtazapine tablets alone.InterventionAvoid concomitant use of benzodiazepines and alcohol with mirtazapine tablets [see Warnings and Precautions (5.8) Clinical Pharmacology (12.3)].Examplesdiazepam, alprazolam, alcoholDrugs that Prolong QTc IntervalClinical ImpactThe concomitant use of other drugs which prolong the QTc interval with mirtazapine tablets, increases the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes).InterventionUse caution when using mirtazapine tablets 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 tablets may result in an increase in INR [see Clinical Pharmacology (12.3)].InterventionMonitor INR during concomitant use of warfarin with mirtazapine tablets.. oStrong CYP3A Inducers: Dosage increase may be needed for mirtazapine tablets with concomitant use of strong CYP3A inducers. (2.5, 7) oStrong CYP3A Inhibitors: Dosage decrease may be needed when mirtazapine tablets are coadministered with strong CYP3A inhibitors. (2.5, 7) oCimetidine: Dosage decrease may be needed when mirtazapine tablets are coadministered with cimetidine. (2.5, 7) oWarfarin: Monitor INR during concomitant use. (7) oStrong CYP3A Inducers: Dosage increase may be needed for mirtazapine tablets with concomitant use of strong CYP3A inducers. (2.5, 7) oStrong CYP3A Inhibitors: Dosage decrease may be needed when mirtazapine tablets are coadministered with strong CYP3A inhibitors. (2.5, 7) oCimetidine: Dosage decrease may be needed when mirtazapine tablets are coadministered with cimetidine. (2.5, 7) oWarfarin: Monitor INR during concomitant use. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use Approximately 190 patients >= 65 years of age participated in clinical studies with mirtazapine. Mirtazapine tablets are 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 decreased clearance of mirtazapine in the elderly [see Clinical Pharmacology (12.3)]. Sedating drugs, including mirtazapine tablets, 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 tablets 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Mirtazapine Tablets, USP are available containing 15 mg, 30 mg or 45 mg of mirtazapine, USP.The 15 mg tablets are beige, film-coated, round, scored tablets debossed with over 515 on one side of the tablet and bisected by score on the other side. They are available as follows:NDC 0378-3515-93bottles of 30 tabletsNDC 0378-3515-01bottles of 100 tabletsNDC 0378-3515-10bottles of 1000 tabletsThe 30 mg tablets are beige, film-coated, round, scored tablets debossed with over 530 on one side of the tablet and bisected by score on the other side. They are available as follows:NDC 0378-3530-93bottles of 30 tabletsNDC 0378-3530-01bottles of 100 tabletsNDC 0378-3530-05bottles of 500 tabletsThe 45 mg tablets are beige, film-coated, round, unscored tablets debossed with over 545 on one side of the tablet and blank on the other side. They are available as follows:NDC 0378-3545-93bottles of 30 tabletsNDC 0378-3545-01bottles of 100 tabletsNDC 0378-3545-05bottles of 500 tabletsStorage: Store at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect from light and moisture.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.PHARMACIST: Dispense Medication Guide with each prescription.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Mirtazapine tablets are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)]. Mirtazapine tablets are indicated for the treatment of major depressive disorder (MDD) in adults. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Suicidal Thoughts and Behaviors: Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)]. Agranulocytosis: Advise patients to contact their physician if they experience fever, chills, sore throat, mucous membrane ulceration, flu-like complaints, or other symptoms that might suggest infection [see Warnings and Precautions (5.2)]. Serotonin Syndrome: Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of mirtazapine tablets with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. Johns Wort, and with drugs that impair metabolism of serotonin (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 tablets 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 tablets 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 motor vehicle, until they are reasonably certain that mirtazapine tablets 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 tablets [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 tablets and to discuss any tapering regimen with their healthcare provider. Adverse reactions can occur when mirtazapine tablets are 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: oAdvise patients to notify their physician if they become pregnant or intend to become pregnant during mirtazapine tablets therapy.oAdvise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mirtazapine tablets 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 risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible [see Warnings and Precautions (5.4)]. oAdvise patients to notify their physician if they become pregnant or intend to become pregnant during mirtazapine tablets therapy.. oAdvise patients that there is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to mirtazapine tablets during pregnancy [see Use in Specific Populations (8.1)].

LACTATION SECTION.

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 mothers clinical need for mirtazapine and any potential adverse effects on the breastfed infant from mirtazapine or from the underlying maternal condition. Data. In published pooled analysis of 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.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear. However, its efficacy could be mediated through its activity as an antagonist at central presynaptic 2-adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis. Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and 200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day, based on body surface area (mg/m2) in mice and rats, respectively. There was an increased incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there was an increase in hepatocellular adenoma in females at the mid and high doses and in hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the high dose.. Mutagenesis. Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese hamster 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells. Impairment of Fertility. In 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/m2)]. Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were or more times the MRHD, and pre-implantation losses occurred at 20 times the MRHD.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of mirtazapine tablets 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 tablets 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 weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was kg (2 kg SD) for mirtazapine-treated patients versus kg (2 kg SD) for placebo-treated patients [see Warnings and Precautions (5.7) ].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics In preclinical studies, mirtazapine acts as an antagonist at 2-adrenergic inhibitory autoreceptors and heteroreceptors and as an antagonist at serotonin 5-HT2 and 5-HT3 receptors. Mirtazapine has no significant affinity for the 5-HT1A and 5-HT1B receptors. Mirtazapine also acts as an antagonist of histamine (H1) receptors, peripheral 1-adrenergic receptors, and muscarinic receptors. Actions at these receptors may explain some of the other clinical effects of mirtazapine (e.g., its prominent somnolent effects and orthostatic hypotension may be explained by its inhibition of histamine (H1) receptors and peripheral 1-adrenergic receptors, respectively). Cardiac Electrophysiology. The effect of mirtazapine on QTc interval was assessed in healthy subjects. At dose of 75 mg (1.67 times the maximum recommended dosage), mirtazapine does not prolong the QTc interval to clinically meaningful extent.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Plasma levels of mirtazapine are linearly related to dose over dose range of 15 to 80 mg (1.78 times the maximum recommended dose). Steady state plasma levels of mirtazapine are attained within 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 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 hours post dose. Food Effect The presence of food in the stomach has minimal effect on both the rate and extent of absorption. Distribution. Mirtazapine is approximately 85% bound to plasma proteins over concentration range of 0.01 to 10 mcg/mL. Elimination. Mirtazapine has half-life of about 20 to 40 hours following oral administration of mirtazapine tablets. 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 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 11-39 mL/min/1.73 m2 and approximately 50% in renal impaired patients with GFR < 10 mL/min/1.73 m2) [see Warnings and Precautions (5.15) Use in Specific Populations (8.6)]. Patients with Hepatic Impairment Following 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 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 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 day, at steady state) increased mirtazapine (15 mg twice day, at steady state) clearance about 2-fold, resulting in decrease in average plasma mirtazapine concentrations of 60% [see Drug Interactions (7)]. Cimetidine In healthy male subjects (n 12), when cimetidine, 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 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), 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 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 mg twice 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 minimal effect on plasma levels of mirtazapine (15 mg) in 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 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.

PREGNANCY SECTION.

8.1 Pregnancy Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.. Risk Summary. Prolonged experience with mirtazapine in pregnant women, based on published observational studies and postmarketing reports, has not reliably identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy (see Clinical Considerations).In animal reproduction studies, oral administration of mirtazapine 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/m2 body surface area. However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m2 body surface area. Oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and decrease in pup birth weights at doses 20 times the MRHD based on mg/m2 body surface area (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 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 relapse of major depression than women who continue antidepressants. This finding is from prospective, longitudinal study that followed 201 pregnant women with 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/m2 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/m2 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 days of lactation and decrease in pup birth weights at 20 times the MRHD based on mg/mg2 body surface area. The cause of these deaths is not known. The no effect dose level is times the MRHD based on mg/m2 body surface area.

RECENT MAJOR CHANGES SECTION.

Contraindications (4) 11/2021Warnings and Precautions (5.6) 11/2021.

RISKS.

Risk Summary. Prolonged experience with mirtazapine in pregnant women, based on published observational studies and postmarketing reports, has not reliably identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy (see Clinical Considerations).In animal reproduction studies, oral administration of mirtazapine 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/m2 body surface area. However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m2 body surface area. Oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and decrease in pup birth weights at doses 20 times the MRHD based on mg/m2 body surface area (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 to 4% and 15 to 20%, respectively.

SPL MEDGUIDE SECTION.

Medication Guide Mirtazapine Tablets, USP(mir taz peen)What is the most important information should know about mirtazapine tabletsMirtazapine tablets may cause serious side effects, including: oIncreased risk of suicidal thoughts or actions in some children and young adults. Mirtazapine tablets and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. Mirtazapine tablets are not for use in children.oDepression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. How can watch for and try to prevent suicidal thoughts and actionsoPay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.oCall your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. oKeep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms. Call your healthcare provider or get emergency medical help right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:oattempts to commit suicideoacting aggressive, being angry or violentonew or worse depressionopanic attacksonew or worse irritabilityoan extreme increase in activity or talking (mania)oacting on dangerous impulsesothoughts about suicide or dyingonew or worse anxietyofeeling very agitated or restlessotrouble sleepingoother unusual changes in behavior or moodWhat are mirtazapine tabletsMirtazapine tablets are prescription medicines used to treat certain type of depression called Major Depressive Disorder (MDD) in adults.It is not known if mirtazapine tablets are safe and effective for use to treat MDD in children. Who should not take mirtazapine tablets Do not take mirtazapine tablets if you: otake Monoamine Oxidase Inhibitor (MAOI)ohave stopped taking an MAOI in the last 14 daysoare being treated with the antibiotic linezolid or intravenous methylene blueoif you are allergic to mirtazapine or any of the ingredients in mirtazapine tablets. See the end of this Medication Guide for complete list of ingredients in mirtazapine tablets. Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid or intravenous methylene blue. Do not start taking an MAOI for at least 14 days after you stop treatment with mirtazapine tablets. Before taking mirtazapine tablets, tell your healthcare provider about all of your medical conditions, including if you:ohave history of suicide or depressionohave history or family history of bipolar disorder, mania or hypomaniaohave low white blood cell countohave glaucoma (high pressure in the eye)ohave or had heart problems or strokeohave an abnormal heart beat called QT prolongation or family history of QT prolongation ohave seizures ohave high cholesterol or triglyceride levelsohave low sodium levels in your bloodohave or had kidney or liver problemsohave low blood pressureoare pregnant or plan to become pregnant. It is not known if mirtazapine tablets will harm your unborn baby. oTalk to your healthcare provider if you become pregnant or think you may be pregnant during treatment with mirtazapine tablets.oIf you become pregnant while taking mirtazapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. The purpose of this registry is to monitor the pregnancy outcomes in women who have been treated with mirtazapine tablets at any time during pregnancy.oare breastfeeding or plan to breastfeed. Mirtazapine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with mirtazapine tablets.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Mirtazapine tablets and other medicines may affect each other causing possible serious side effects. Mirtazapine tablets may affect the way other medicines work and other medicines may affect the way mirtazapine tablets work. Especially tell your healthcare provider if you take:oMAOIsomedicines to treat migraine headaches knows as triptansotricyclic antidepressantsofentanylolithiumotramadolotryptophanobuspironeoamphetaminesobenzodiazepinesoSt. Johns Wortomedicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs)omedicines that may affect your heart rhythm (such as certain antibiotics and some antipsychotics)Ask your healthcare provider if you are not sure if you are taking any of these medicines. Your healthcare provider can tell you if it is safe to take mirtazapine tablets with your other medicines. Do not start or stop any other medicines during treatment with mirtazapine tablets without talking to your healthcare provider first. Stopping mirtazapine tablets suddenly may cause you to have serious side effects. See, What are the possible side effects of mirtazapine tablets Know the medicines you take. Keep list of them to show to your healthcare provider and pharmacist when you get new medicine. How should take mirtazapine tabletsoTake mirtazapine tablets exactly as your healthcare provider tells you to. Do not change your dose or stop taking mirtazapine tablets without first talking to your healthcare provider. oYour healthcare provider may need to change the dose of mirtazapine tablets until it is the right dose for you. oTake mirtazapine tablets time each day, preferably in the evening at bedtime. oIf you take too many mirtazapine tablets call your healthcare provider or poison control center at 1-800-222-1222 right away or go to the nearest hospital emergency room. What should avoid while taking mirtazapine tabletsoDo not drive, operate heavy machinery, or do other dangerous activities until you know how mirtazapine tablets affect you. Mirtazapine tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly.oAvoid drinking alcohol during treatment with mirtazapine tablets.oAvoid taking medicines used to treat anxiety, insomnia, and seizures, called benzodiazepines, during treatment with mirtazapine tablets. Ask your healthcare provider if you are not sure if you take one of these medicines.What are the possible side effects of mirtazapine tablets Mirtazapine tablets may cause serious side effects, including:oSee, What is the most important information should know about mirtazapine tabletsoLow white blood cell count. Tell your healthcare provider right away if you develop any signs or symptoms of low white blood cell count, including:ofeverosore throatoflu-like symptomsochillsomouth or nose soresoinfectionsoSerotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when you take mirtazapine tablets with certain other medicines. See, Who should not take mirtazapine tablets Stop taking mirtazapine tablets and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:oagitationoconfusionofast heart beatodizzinessoflushingotremors, stiff muscles, or muscle twitchingoseizuresoseeing or hearing things that are not real (hallucinations)ocomaoblood pressure changesosweatingohigh body temperature (hyperthermia)oloss of coordinationonausea, vomiting, diarrheaoEye problems (angle-closure glaucoma). Mirtazapine tablets may cause certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. oHeart rhythm problems.oSevere skin reaction. Mirtazapine tablets may cause severe skin reaction that may include rash, fever, swollen glands, and other organ involvement such as liver, kidney, lung and heart. The reaction may sometimes be fatal. Tell your healthcare provider right away if you experience any of these signs.oIncreased appetite and weight gain.oSleepiness. See, What should avoid while taking mirtazapine tablets oMania or hypomania (manic episodes) in people who have history of bipolar disorder. Symptoms may include: ogreatly increased energyoracing thoughtsounusually grand ideasotalking more or faster than usualosevere trouble sleepingoreckless behavioroexcessive happiness or irritabilityoSeizures (convulsions).oIncreased fat levels (cholesterol and triglycerides) in your blood.oLow sodium levels in your blood (hyponatremia). Low sodium levels in your blood may be serious and may cause death. Elderly people may be at greater risk for this. Signs and Symptoms of low sodium levels in your blood may include:oheadacheomemory changesoweakness and unsteadiness on your feet which can lead to falls odifficulty concentratingoconfusion In severe or more sudden cases, signs and symptoms include:ohallucinations (seeing or hearing things that are not real)oseizuresorespiratory arrestoChanges in liver function tests.ofaintingocoma odeathoDiscontinuation syndrome. Suddenly stopping mirtazapine tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:odizzinessoirritability and agitationoanxietyosweatingoseizuresoringing in your ears (tinnitus)onausea and vomitingoproblems sleepingotirednessoconfusionoelectric shock sensation (paresthesia)oshaking (tremor)oheadacheoabnormal dreamsochanges in your moodohypomaniaThe most common side effects of mirtazapine tablets include:osleepinessoincreased appetiteoweight gainodizzinessThese are not all the possible side effects of mirtazapine tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store mirtazapine tabletsoStore mirtazapine tablets at room temperature between 20 to 25C (68 to 77F). oKeep mirtazapine tablets away from light and moisture. Keep mirtazapine tablets and all medicines out of the reach of children.General information about the safe and effective use of mirtazapine tablets.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use mirtazapine tablets for condition for which they were not prescribed. Do not give mirtazapine tablets to other people, even if they have the same symptoms that you have. They may harm them. You can ask your healthcare provider or pharmacist for information about mirtazapine tablets that is written for healthcare professionals.What are the ingredients in mirtazapine tabletsActive ingredient: mirtazapine Inactive ingredients: anhydrous lactose, colloidal silicon dioxide, croscarmellose sodium, FD&C Blue No. Aluminum Lake, FD&C Yellow No. Aluminum Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polydextrose, polyethylene glycol, pregelatinized starch (corn), sodium lauryl sulfate, titanium dioxide and triacetin. For more information about mirtazapine tablets, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).The brands listed are trademarks of their respective owners.This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Manufactured by: ALPHAPHARM PTY LTD 15 Garnet StreetCarole Park QLD 4300AustraliaRevised: 1/2022ALP:MTZP:R21mh/ALP:MG:MTZP:R6mhPM 2847/6. oIncreased risk of suicidal thoughts or actions in some children and young adults. Mirtazapine tablets and other antidepressant medicines may increase suicidal thoughts or actions in some people 24 years of age and younger, especially within the first few months of treatment or when the dose is changed. Mirtazapine tablets are not for use in children.oDepression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. oDepression or other serious mental illnesses are the most important causes of suicidal thoughts or actions. How can watch for and try to prevent suicidal thoughts and actions. oPay close attention to any changes, especially sudden changes in mood, behavior, thoughts, or feelings, or if you develop suicidal thoughts or actions. This is very important when an antidepressant medicine is started or when the dose is changed.. oCall your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. oKeep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you have concerns about symptoms.. Call your healthcare provider or get emergency medical help right away if you or your family member have any of the following symptoms, especially if they are new, worse, or worry you:. oattempts to commit suicide. oacting aggressive, being angry or violent. onew or worse depression. opanic attacks. onew or worse irritability. oan extreme increase in activity or talking (mania). oacting on dangerous impulses. othoughts about suicide or dying. onew or worse anxiety. ofeeling very agitated or restless. otrouble sleeping. oother unusual changes in behavior or mood. otake Monoamine Oxidase Inhibitor (MAOI). ohave stopped taking an MAOI in the last 14 days. oare being treated with the antibiotic linezolid or intravenous methylene blue. oif you are allergic to mirtazapine or any of the ingredients in mirtazapine tablets. See the end of this Medication Guide for complete list of ingredients in mirtazapine tablets. ohave history of suicide or depression. ohave history or family history of bipolar disorder, mania or hypomania. ohave low white blood cell count. ohave glaucoma (high pressure in the eye). ohave or had heart problems or stroke. ohave an abnormal heart beat called QT prolongation or family history of QT prolongation ohave seizures ohave high cholesterol or triglyceride levels. ohave low sodium levels in your blood. ohave or had kidney or liver problems. ohave low blood pressure. oare pregnant or plan to become pregnant. It is not known if mirtazapine tablets will harm your unborn baby. oTalk to your healthcare provider if you become pregnant or think you may be pregnant during treatment with mirtazapine tablets.oIf you become pregnant while taking mirtazapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. The purpose of this registry is to monitor the pregnancy outcomes in women who have been treated with mirtazapine tablets at any time during pregnancy.. oTalk to your healthcare provider if you become pregnant or think you may be pregnant during treatment with mirtazapine tablets.. oIf you become pregnant while taking mirtazapine tablets, talk to your healthcare provider about registering with the National Pregnancy Registry for Antidepressants. You can register by calling 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/. The purpose of this registry is to monitor the pregnancy outcomes in women who have been treated with mirtazapine tablets at any time during pregnancy.. oare breastfeeding or plan to breastfeed. Mirtazapine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby during treatment with mirtazapine tablets.. oMAOIs. omedicines to treat migraine headaches knows as triptans. otricyclic antidepressants. ofentanyl. olithium. otramadol. otryptophan. obuspirone. oamphetamines. obenzodiazepines. oSt. Johns Wort. omedicines used to treat mood, anxiety, psychotic or thought disorders, including selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). omedicines that may affect your heart rhythm (such as certain antibiotics and some antipsychotics). oTake mirtazapine tablets exactly as your healthcare provider tells you to. Do not change your dose or stop taking mirtazapine tablets without first talking to your healthcare provider. oYour healthcare provider may need to change the dose of mirtazapine tablets until it is the right dose for you. oTake mirtazapine tablets time each day, preferably in the evening at bedtime. oIf you take too many mirtazapine tablets call your healthcare provider or poison control center at 1-800-222-1222 right away or go to the nearest hospital emergency room. oDo not drive, operate heavy machinery, or do other dangerous activities until you know how mirtazapine tablets affect you. Mirtazapine tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly.. oAvoid drinking alcohol during treatment with mirtazapine tablets.. oAvoid taking medicines used to treat anxiety, insomnia, and seizures, called benzodiazepines, during treatment with mirtazapine tablets. Ask your healthcare provider if you are not sure if you take one of these medicines.. oSee, What is the most important information should know about mirtazapine tablets. oLow white blood cell count. Tell your healthcare provider right away if you develop any signs or symptoms of low white blood cell count, including:. ofever. osore throat. oflu-like symptoms. ochills. omouth or nose sores. oinfections. oSerotonin syndrome. potentially life-threatening problem called serotonin syndrome can happen when you take mirtazapine tablets with certain other medicines. See, Who should not take mirtazapine tablets Stop taking mirtazapine tablets and call your healthcare provider or go to the nearest hospital emergency room right away if you have any of the following signs and symptoms of serotonin syndrome:. oagitation. oconfusion. ofast heart beat. odizziness. oflushing. otremors, stiff muscles, or muscle twitching. oseizures. oseeing or hearing things that are not real (hallucinations). ocoma. oblood pressure changes. osweating. ohigh body temperature (hyperthermia). oloss of coordination. onausea, vomiting, diarrhea. oEye problems (angle-closure glaucoma). Mirtazapine tablets may cause certain type of eye problem called angle-closure glaucoma. Call your healthcare provider if you have eye pain, changes in your vision, or swelling or redness in or around the eye. Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. oHeart rhythm problems.. oSevere skin reaction. Mirtazapine tablets may cause severe skin reaction that may include rash, fever, swollen glands, and other organ involvement such as liver, kidney, lung and heart. The reaction may sometimes be fatal. Tell your healthcare provider right away if you experience any of these signs.. oIncreased appetite and weight gain.. oSleepiness. See, What should avoid while taking mirtazapine tablets oMania or hypomania (manic episodes) in people who have history of bipolar disorder. Symptoms may include: ogreatly increased energy. oracing thoughts. ounusually grand ideas. otalking more or faster than usual. osevere trouble sleeping. oreckless behavior. oexcessive happiness or irritability. oSeizures (convulsions).. oIncreased fat levels (cholesterol and triglycerides) in your blood.. oLow sodium levels in your blood (hyponatremia). Low sodium levels in your blood may be serious and may cause death. Elderly people may be at greater risk for this. Signs and Symptoms of low sodium levels in your blood may include:. oheadache. omemory changes. oweakness and unsteadiness on your feet which can lead to falls odifficulty concentrating. oconfusion. In severe or more sudden cases, signs and symptoms include:. ohallucinations (seeing or hearing things that are not real). oseizures. orespiratory arrest. oChanges in liver function tests.. ofainting. ocoma odeath. oDiscontinuation syndrome. Suddenly stopping mirtazapine tablets may cause you to have serious side effects. Your healthcare provider may want to decrease your dose slowly. Symptoms may include:. odizziness. oirritability and agitation. oanxiety. osweating. oseizures. oringing in your ears (tinnitus). onausea and vomiting. oproblems sleeping. otiredness. oconfusion. oelectric shock sensation (paresthesia). oshaking (tremor). oheadache. oabnormal dreams. ochanges in your mood. ohypomania. osleepiness. oincreased appetite. oweight gain. odizziness. oStore mirtazapine tablets at room temperature between 20 to 25C (68 to 77F). oKeep mirtazapine tablets away from light and moisture.

SPL UNCLASSIFIED SECTION.

2.1Recommended Dosage The 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 maximum of 45 mg per day. Dose changes should not be made in intervals of less than to weeks to allow sufficient time for evaluation of response to given dose [see Clinical Pharmacology (12.3)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oGeriatric Use: Use with caution in elderly patients. (5.12, 5.15, 8.5) oRenal Impairment: Dosage decrease may be needed in patients with moderate to severe renal impairment. (8.6) oHepatic Impairment: Dosage decrease may be needed in patients with hepatic impairment. (8.6) oGeriatric Use: Use with caution in elderly patients. (5.12, 5.15, 8.5) oRenal Impairment: Dosage decrease may be needed in patients with moderate to severe renal impairment. (8.6) oHepatic Impairment: Dosage decrease may be needed in patients with hepatic impairment. (8.6) 8.1 Pregnancy Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.. Risk Summary. Prolonged experience with mirtazapine in pregnant women, based on published observational studies and postmarketing reports, has not reliably identified drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy (see Clinical Considerations).In animal reproduction studies, oral administration of mirtazapine 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/m2 body surface area. However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m2 body surface area. Oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and decrease in pup birth weights at doses 20 times the MRHD based on mg/m2 body surface area (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 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 relapse of major depression than women who continue antidepressants. This finding is from prospective, longitudinal study that followed 201 pregnant women with 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/m2 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/m2 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 days of lactation and decrease in pup birth weights at 20 times the MRHD based on mg/mg2 body surface area. The cause of these deaths is not known. The no effect dose level is times the MRHD based on mg/m2 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 mothers clinical need for mirtazapine and any potential adverse effects on the breastfed infant from mirtazapine or from the underlying maternal condition. Data. In published pooled analysis of 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 tablets 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 tablets 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 weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was kg (2 kg SD) for mirtazapine-treated patients versus 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 tablets are 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 decreased clearance of mirtazapine in the elderly [see Clinical Pharmacology (12.3)]. Sedating drugs, including mirtazapine tablets, 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 tablets 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. 8.6Renal 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 tablets 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oAgranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with low white blood cell count, treatment with mirtazapine tablets should be discontinued and the patient should be closely monitored. (5.2) oSerotonin Syndrome: Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue mirtazapine tablets and initiate supportive treatment. (2.4, 4, 5.3, 7) oAngle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.4) oQT Prolongation: Use mirtazapine tablets with caution in patients with risk factors for QT prolongation. (5.5, 7)oDrug Reaction with Eosinophilia and System Symptoms (DRESS): Discontinue mirtazapine tablets if DRESS is suspected. (5.6)oIncreased Appetite/Weight Gain: Mirtazapine tablets have been associated with increased appetite and weight gain. (5.7) oSomnolence: May impair judgment, thinking and/or motor skills. Use with caution when engaging in activities requiring alertness, such as driving or operating machinery. (5.8, 7) oActivation of Mania/Hypomania: Screen patients for bipolar disorder prior to initiating treatment. (2.3, 5.9) oSeizures: Use with caution in patients with seizure disorder. (5.10)oElevated Cholesterol/Triglycerides: Has been reported with mirtazapine use. (5.11) oHyponatremia: May occur as result of treatment with serotonergic antidepressants, including mirtazapine tablets. (5.12)oTransaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. (5.13) oAgranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with low white blood cell count, treatment with mirtazapine tablets should be discontinued and the patient should be closely monitored. (5.2) oSerotonin Syndrome: Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue mirtazapine tablets and initiate supportive treatment. (2.4, 4, 5.3, 7) oAngle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.4) oQT Prolongation: Use mirtazapine tablets with caution in patients with risk factors for QT prolongation. (5.5, 7). oDrug Reaction with Eosinophilia and System Symptoms (DRESS): Discontinue mirtazapine tablets if DRESS is suspected. (5.6). oIncreased Appetite/Weight Gain: Mirtazapine tablets have been associated with increased appetite and weight gain. (5.7) oSomnolence: May impair judgment, thinking and/or motor skills. Use with caution when engaging in activities requiring alertness, such as driving or operating machinery. (5.8, 7) oActivation of Mania/Hypomania: Screen patients for bipolar disorder prior to initiating treatment. (2.3, 5.9) oSeizures: Use with caution in patients with seizure disorder. (5.10). oElevated Cholesterol/Triglycerides: Has been reported with mirtazapine use. (5.11) oHyponatremia: May occur as result of treatment with serotonergic antidepressants, including mirtazapine tablets. (5.12). oTransaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. (5.13) 5.1Suicidal 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 PatientsAge RangeDrug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients TreatedIncreases Compared to Placebo< 18 years old14 additional patients18-24 years old5 additional patientsDecreases Compared to Placebo25-64 years old1 fewer patient>= 65 years old6 fewer patientsIt 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 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 tablets, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.. 5.2Agranulocytosis In premarketing clinical trials, (1 with Sjogrens Syndrome) out of 2796 patients treated with mirtazapine developed agranulocytosis [absolute neutrophil count (ANC) 500/mm3 with associated signs and symptoms, e.g., fever, infection, etc.] and third patient developed severe neutropenia (ANC 500/mm3 without any associated symptoms). For these patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All patients recovered after mirtazapine was stopped. If patient develops sore throat, fever, stomatitis, or other signs of infection, along with low white blood cell (WBC) count, treatment with mirtazapine tablets should be discontinued and the patient should be closely monitored. 5.3Serotonin Syndrome Serotonergic antidepressants, including mirtazapine tablets, can precipitate serotonin syndrome, 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. Johns 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 tablets with MAOIs is contraindicated. In addition, do not initiate mirtazapine tablets in 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 patient taking mirtazapine tablets, discontinue mirtazapine tablets before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)]. Monitor all patients taking mirtazapine tablets for the emergence of serotonin syndrome. Discontinue treatment with mirtazapine tablets and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of mirtazapine tablets with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.4Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including mirtazapine tablets, may trigger an angle-closure attack in patient with anatomically narrow angles who does not have patent iridectomy.. 5.5QT Prolongation and Torsades de Pointes The effect of mirtazapine on QTc interval was assessed in clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis. This trial showed 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 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 tablets are 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 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 tablets immediately if DRESS is suspected and institute appropriate treatment [see Contraindications (4), Adverse Reactions (6.2)] .. 5.7Increased 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 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 weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The safety and effectiveness of mirtazapine tablets in pediatric patients with MDD have not been established [see Use in Specific Populations (8.4)].. 5.8Somnolence 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 tablets. Because of the potentially significant effects of mirtazapine tablets 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 tablets do not affect them adversely. The concomitant use of benzodiazepines and alcohol with mirtazapine tablets should be avoided [see Drug Interactions (7)].. 5.9Activation of Mania or Hypomania In patients with bipolar disorder, treating depressive episode with mirtazapine tablets or another antidepressant may precipitate 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 tablets screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.10Seizures Mirtazapine tablets have not been systematically evaluated in patients with seizure disorders. In premarketing clinical trials, seizure was reported among the 2796 U.S. and non-U.S. patients treated with mirtazapine. Mirtazapine tablets should be prescribed with caution in patients with seizure disorder. 5.11Elevated 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. 5.12Hyponatremia Hyponatremia may occur as result of treatment with serotonergic antidepressants, including mirtazapine tablets. 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 tablets 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)].. 5.13Transaminase Elevations Clinically significant ALT (SGPT) elevations (>= times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with mirtazapine in 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 tablets should be used with caution in patients with impaired hepatic function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 5.14Discontinuation Syndrome There have been reports of adverse reactions upon the discontinuation of mirtazapine tablets (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. gradual reduction in the dosage, rather than an abrupt cessation, is recommended [see Dosage and Administration (2.6)]. 5.15Use in Patients with Concomitant Illness Mirtazapine tablets have not been systematically evaluated or used to any appreciable extent in patients with 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 tablets 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).