Mirtazapine

RECENT MAJOR CHANGES Contraindications ( 4 ) 11/2021 Warnings and Precautions ( 5.6 ) 11/2021

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

2 DOSAGE AND ADMINISTRATION • Starting dose: 15 mg once daily; may increase up to maximum recommended dose of 45 mg once daily. ( 2.1 ) • Administer orally once daily, preferably in the evening prior to sleep. ( 2.1 ) • Administer mirtazapine orally disintegrating tablets immediately after removal from blister pack or container pack. ( 2.2 ) • Reduce dose gradually when discontinuing mirtazapine orally disintegrating tablets. ( 2.6 , 5.14 ) 2.1 Recommended Dosage The recommended starting dose of mirtazapine orally disintegrating tablets is 15 mg once daily, administered orally, preferably in the evening prior to sleep. If patients do not have an adequate response to the initial 15 mg dose, increase the dose up to a maximum of 45 mg per day. Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response to a given dose [see Clinical Pharmacology (12.3) ]. 2.2 Administration of Mirtazapine Orally Disintegrating Tablets • The tablet should remain in the blister pack or container pack until the patient is ready to take it. • The patient or caregiver should use dry hands to open the blister or container. • As soon as the blister or container is opened, the tablet should be removed and placed on the patient’s tongue. • Use mirtazapine orally disintegrating tablets immediately after removal from its blister or container; once removed, it cannot be stored. • The whole tablet should be placed on the tongue and allowed to disintegrate without chewing or crushing. Do not attempt to split the tablet. • The tablet will disintegrate in saliva so that it can be swallowed. 2.3 Screen for Bipolar Disorder Prior to Starting Mirtazapine Orally Disintegrating Tablets Prior to initiating treatment with mirtazapine orally disintegrating tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.9) ]. 2.4 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of mirtazapine orally disintegrating tablets. In addition, at least 14 days must elapse after stopping mirtazapine orally disintegrating tablets before starting an MAOI antidepressant [see Contraindications (4) and Warnings and Precautions (5.3) ]. 2.5 Dosage Modifications Due to Drug Interactions Strong CYP3A Inducers An increase in dosage of mirtazapine orally disintegrating tablets may be needed with concomitant strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampin) use. Conversely, a decrease in dosage of mirtazapine orally disintegrating tablets may be needed if the CYP3A inducer is discontinued [see Drug Interactions (7) ]. Strong CYP3A Inhibitors A decrease in dosage of mirtazapine orally disintegrating tablets may be needed with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin). Conversely, an increase in dosage of mirtazapine orally disintegrating tablets may be needed if the CYP3A4 inhibitor is discontinued [see Drug Interactions (7) ]. Cimetidine A decrease in dosage of mirtazapine orally disintegrating tablets may be needed with concomitant use of cimetidine. Conversely, an increase in dosage of mirtazapine orally disintegrating tablets may be needed if cimetidine is discontinued [see Drug Interactions (7) ]. 2.6 Discontinuation of Mirtazapine Orally Disintegrating Tablets Treatment Adverse reactions may occur upon discontinuation or dose reduction of mirtazapine orally disintegrating tablets [see Warnings and Precautions (5.14) ]. Gradually reduce the dosage of mirtazapine orally disintegrating tablets rather than stopping abruptly whenever possible.

3 DOSAGE FORMS AND STRENGTHS Mirtazapine orally disintegrating tablets, USP are supplied as: 15 mg orally disintegrating tablets: White to off-white colored, round shaped, beveled edged, uncoated tablets, debossed with '677' on upper face and plain on other side. 30 mg orally disintegrating tablets: White to off-white colored, round shaped, beveled edged, uncoated tablets, debossed with '676' on upper face and plain on other side. 45 mg orally disintegrating tablets: White to off-white colored, round shaped, beveled edged, uncoated tablets, debossed with '679' on upper face and plain on other side. Orally disintegrating tablets : 15 mg, 30 mg, and 45 mg. ( 3 )

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

6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information: Hypersensitivity [see Contraindications (4) ] Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1) ] Agranulocytosis [see Warnings and Precautions (5.2) ] Serotonin Syndrome [see Contraindications (4) , Warnings and Precautions (5.3) , Drug Interactions (7) ] Angle-Closure Glaucoma [see Warnings and Precautions (5.4) ] QT Prolongation and Torsades de Pointes [see Warnings and Precautions (5.5) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6) ] Increased Appetite and Weight Gain [see Warnings and Precautions (5.7) ] Somnolence [see Warnings and Precautions (5.8) ] Activation of Mania or Hypomania [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Elevated Cholesterol and Triglycerides [see Warnings and Precautions (5.11) ] Hyponatremia [see Warnings and Precautions (5.12) ] Transaminase Elevations [see Warnings and Precautions (5.13) ] Discontinuation Syndrome [see Warnings and Precautions (5.14) ] Use in Patients with Concomitant Illness [see Warnings and Precautions (5.15) ] Most common adverse reactions (≥5% or greater and twice placebo) were somnolence, increased appetite, weight gain, and dizziness. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below are from clinical trials in which mirtazapine orally disintegrating tablets were administered to 2796 patients in phase 2 and 3 clinical studies. The trials consisted of double-blind controlled and open-label studies, inpatient and outpatient studies, fixed dose, and titration studies. Adverse Reactions Leading to Discontinuation of Treatment Approximately 16% of the 453 patients who received mirtazapine in U.S. 6-week placebo-controlled clinical trials discontinued treatment due to an adverse reaction, compared to 7% of the 361 placebo-treated patients in those studies. The most common reactions leading to discontinuation (≥1% and at a rate at least twice that of placebo) are included in Table 2. Table 2: Adverse Reactions (≥1% and at least twice placebo) Leading to Discontinuation of Mirtazapine in 6-Week Clinical Trials in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0% Common Adverse Reactions The most common adverse reactions (≥5% and twice placebo) associated with the use of mirtazapine are listed in Table 3. Table 3: Adverse Reactions (≥5% and twice placebo) in 6-Week U.S. Clinical Trials of Mirtazapine in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Somnolence 54% 18% Increased Appetite 17% 2% Weight Gain 12% 2% Dizziness 7% 3% Table 4 enumerates adverse reactions that occurred in ≥1% of mirtazapine-treated patients, and were more frequent than the placebo-treated patients, who participated in 6-week, U.S. placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an adverse reaction at some time during their treatment. Table 4: Adverse Reactions (≥1% and greater than placebo) in 6-Week U.S. Clinical Studies of Mirtazapine in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back Pain 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% Constipation 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Nervous System Somnole …

7 DRUG INTERACTIONS Table 5 includes clinically important drug interactions with mirtazapine orally disintegrating tablets [see Clinical Pharmacology (12.3) ]. Table 5: Clinically Important Drug Interactions with Mirtazapine Orally Disintegrating Tablets Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of serotonergic drugs, including mirtazapine orally disintegrating tablets, and MAOIs increases the risk of serotonin syndrome. Intervention Mirtazapine orally disintegrating 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) ]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with mirtazapine orally disintegrating tablets increase the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of mirtazapine orally disintegrating tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.3) ]. Examples SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St. John’s Wort, tramadol, tryptophan, buspirone Strong CYP3A Inducers Clinical Impact The concomitant use of strong CYP3A inducers with mirtazapine orally disintegrating tablets decrease the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ]. Intervention Increase the dose of mirtazapine orally disintegrating tablets if needed with concomitant CYP3A inducer use. Conversely, a decrease in dosage of mirtazapine orally disintegrating tablets may be needed if the CYP3A inducer is discontinued [see Dosage and Administration (2.5) ]. Examples phenytoin, carbamazepine, rifampin Strong CYP3A Inhibitors Clinical Impact The concomitant use of strong CYP3A inhibitors with mirtazapine orally disintegrating tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ]. Intervention Decrease the dose of mirtazapine orally disintegrating tablets if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine orally disintegrating tablets may be needed if the CYP3A inhibitor is discontinued [see Dosage and Administration (2.5) ]. Examples itraconazole, ritonavir, nefazodone Cimetidine Clinical Impact The concomitant use of cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, with mirtazapine orally disintegrating tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ]. Intervention Decrease the dose of mirtazapine orally disintegrating tablets if needed with concomitant cimetidine use. Conversely, an increase in dosage of mirtazapine orally disintegrating tablets may be needed if cimetidine is discontinued [see Dosage and Administration (2.5) ]. Benzodiazepines and Alcohol Clinical Impact The concomitant use of benzodiazepines or alcohol with mirtazapine orally disintegrating tablets increase the impairment of cognitive and motor skills produced by mirtazapine orally disintegrating tablets alone. Intervention Avoid concomitant use of benzodiazepines and alcohol with mirtazapine orally disintegrating tablets [see Warnings and Precautions (5.8) , Clinical Pharmacology (12.3) ]. Examples diazepam, alprazolam, alcohol Drugs that Prolong QTc Interval Clinical Impact The concomitant use of other drugs which prolong the QTc interval with mirtazapine orally disintegrating tablets, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes). Intervention Use caution when using mirtazapine orally disintegrating tablets concomitantly with drugs that prolong the QTc interval [see Warnings and Precautions (5.5) , Clinical Ph …

8 USE IN SPECIFIC POPULATIONS Geriatric Use : Use with caution in elderly patients. ( 5.12 , 5.15 , 8.5 ) Renal impairment : Dosage decrease may be needed in patients with moderate to severe renal impairment. ( 8.6 ) Hepatic impairment : Dosage decrease may be needed in patients with hepatic impairment. ( 8.6 ) Patients with Phenylketonuria : Mirtazapine orally disintegrating tablets contains phenylalanine. ( 5.16 , 8.7 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a 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 a 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/m 2 body surface area. However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m 2 body surface area. Oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth weights at doses 20 times the MRHD based on mg/m 2 body surface area ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Data Animal Data Mirtazapine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day, respectively, which are up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg based on mg/m 2 body surface area, respectively. No evidence of teratogenic effects was observed. However, in rats, there was an increase in postimplantation loss in dams treated with mirtazapine at 100 mg/kg/day which is 20 times the MRHD based on mg/m 2 body surface area. Oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/kg/day to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights at 20 times the MRHD based on mg/m 2 body surface area. The cause of these deaths is not known. The no effect dose level is 3 times the MRHD based on mg/m 2 body surface area. 8.2 Lactation Risk Summary Data from published literature report the presence of mirtazapine in human milk at low levels with relative infant doses for mirtazapine ranging between 0.6 and 2.8% of the mat …

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 α 2 - adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

11 DESCRIPTION Mirtazapine orally disintegrating tablet, USP contains mirtazapine, USP. Mirtazapine has a 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][2] benzazepine and has the molecular formula of C 17 H 19 N 3 . Its molecular weight is 265.35. The structural formula is the following and it is the racemic mixture: Mirtazapine, USP is a white or slightly yellow powder which is practically insoluble in water. Mirtazapine orally disintegrating tablet is available for oral administration as an orally disintegrating tablet containing 15, 30, or 45 mg of mirtazapine. Mirtazapine orally disintegrating tablet also contains the following inactive ingredients: Mannitol USP, Microcrystalline Cellulose NF, Crospovidone NF, Povidone USP, Aspartame NF, alpha-tocopherol , maltodextrin, Colloidal Silicon Dioxide NF, Anhydrous Citric Acid USP, Magnesium stearate NF, Sodium Stearyl Fumarate NF Image

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Mirtazapine orally disintegrating tablets, USP are supplied as: 15 mg Tablets – White , round tablets debossed with ‘36’ on one side and ‘A’ on the other side with an embossed circular edge. Box of 30 5 x 6 Unit dosage forms NDC 65862-021-06 Bottles of 30 NDC 65862-021-30 Bottles of 60 NDC 65862-021-60 Bottles of 90 NDC 65862-021-90 Bottles of 100 NDC 65862-021-01 30 mg Tablets – White, round tablets debossed with ‘37’ on one side and ‘A’ on the other side with an embossed circular edge. Box of 30 5 x 6 Unit dosage forms NDC 65862-022-06 Bottles of 30 NDC 65862-022-30 Bottles of 60 NDC 65862-022-60 Bottles of 90 NDC 65862-022-90 Bottles of 100 NDC 65862-022-01 45 mg Tablets – White, round tablets debossed with ‘38’ on one side and ‘A’ on the other side with an embossed circular edge. Box of 30 5 x 6 Unit dosage forms NDC 65862-023-06 Bottles of 30 NDC 65862-023-30 Bottles of 60 NDC 65862-023-60 Bottles of 90 NDC 65862-023-90 Bottles of 100 NDC 65862-023-01 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. The tablet should be used immediately after removal from its blister or container. Keep the container tightly closed.