REMERONSOLTAB

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

1 INDICATIONS AND USAGE REMERON/REMERONSolTab are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14) ] . REMERON/REMERONSolTab is 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 REMERONSolTab immediately after removal from blister pack. ( 2.2 ) Reduce dose gradually when discontinuing REMERON/REMERONSolTab. ( 2.6 , 5.14 ) 2.1 Recommended Dosage The recommended starting dose of REMERON/REMERONSolTab 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 REMERONSolTab The tablet should remain in the blister pack until the patient is ready to take it. The patient or caregiver should use dry hands to open the blister. As soon as the blister is opened, the tablet should be removed and placed on the patient's tongue. Use REMERONSolTab immediately after removal from its blister; 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 REMERON/REMERONSolTab Prior to initiating treatment with REMERON/REMERONSolTab 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 REMERON/REMERONSolTab. In addition, at least 14 days must elapse after stopping REMERON/REMERONSolTab 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 REMERON/REMERONSolTab may be needed with concomitant strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampin) use. Conversely, a decrease in dosage of REMERON/REMERONSolTab may be needed if the CYP3A inducer is discontinued [see Drug Interactions (7) ]. Strong CYP3A Inhibitors A decrease in dosage of REMERON/REMERONSolTab may be needed with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin). Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if the CYP3A4 inhibitor is discontinued [see Drug Interactions (7) ]. Cimetidine A decrease in dosage of REMERON/REMERONSolTab may be needed with concomitant use of cimetidine. Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if cimetidine is discontinued [see Drug Interactions (7) ]. 2.6 Discontinuation of REMERON/REMERONSolTab Treatment Adverse reactions may occur upon discontinuation or dose reduction of REMERON/REMERONSolTab [see Warnings and Precautions (5.14) ] . Gradually reduce the dosage of REMERON/REMERONSolTab rather than stopping abruptly whenever possible.

3 DOSAGE FORMS AND STRENGTHS REMERON is supplied as: 15 mg tablets: Oval, scored, yellow, with "MSD" debossed on one side and " T 3 Z " on the other side, on both sides of the score line 30 mg tablets: Oval, scored, red-brown, with "MSD" debossed on one side and " T 5 Z " on the other side, on both sides of the score line REMERONSolTab is supplied as: 15 mg orally disintegrating tablets: Round, white, with " T 1 Z " debossed on one side 30 mg orally disintegrating tablets: Round, white, with " T 2 Z " debossed on one side 45 mg orally disintegrating tablets: Round, white, with " T 4 Z " debossed on one side Tablets : 15 mg scored and 30 mg scored. ( 3 ) Orally disintegrating tablets : 15 mg, 30 mg, and 45 mg. ( 3 )

4 CONTRAINDICATIONS REMERON/REMERONSolTab is 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 REMERON/REMERONSolTab . 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 REMERON/REMERONSolTab [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 REMERON/REMERONSolTab. ( 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 Organon USA LLC, a subsidiary of Organon & Co., at 1-844-674-3200 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 REMERON/REMERONSolTab was administered to 2796 patients in phase 2 and 3 clinical studies. The trials consisted of double-blind controlled and open-label studies, inpatient and outpatient studies, fixed dose, and titration studies. Adverse Reactions Leading to Discontinuation of Treatment Approximately 16% of the 453 patients who received REMERON 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 REMERON in 6-Week Clinical Trials in Patients with MDD REMERON (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 REMERON are listed in Table 3. Table 3: Adverse Reactions (≥5% and twice placebo) in 6-Week U.S. Clinical Trials of REMERON in Patients with MDD REMERON (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 REMERON-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 Remeron in Patients with MDD REMERON (n=453) Placebo (n=361) Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back Pain 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% Constipation 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Nervous System Somnolence 54% 18% Dizziness 7% 3% Abnormal …

7 DRUG INTERACTIONS Table 5 includes clinically important drug interactions with REMERON/REMERONSolTab [see Clinical Pharmacology (12.3) ]. Table 5: Clinically Important Drug Interactions with REMERON/REMERONSolTab Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of serotonergic drugs, including REMERON/REMERONSolTab, and MAOIs increases the risk of serotonin syndrome. Intervention REMERON/REMERONSolTab is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.4) , Contraindications (4) , Warnings and Precautions (5.3) ]. Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with REMERON/REMERONSolTab increases 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 REMERON/REMERONSolTab 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 REMERON/REMERONSolTab decreases the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ] . Intervention Increase the dose of REMERON/REMERONSolTab if needed with concomitant CYP3A inducer use. Conversely, a decrease in dosage of REMERON/REMERONSolTab 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 REMERON/REMERONSolTab may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ] . Intervention Decrease the dose of REMERON/REMERONSolTab if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of REMERON/REMERONSolTab 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 REMERON/REMERONSolTab may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3) ]. Intervention Decrease the dose of REMERON/REMERONSolTab if needed with concomitant cimetidine use. Conversely, an increase in dosage of REMERON/REMERONSolTab 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 REMERON/REMERONSolTab increases the impairment of cognitive and motor skills produced by REMERON/REMERONSolTab alone. Intervention Avoid concomitant use of benzodiazepines and alcohol with REMERON/REMERONSolTab [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 REMERON/REMERONSolTab, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes). Intervention Use caution when using REMERON/REMERONSolTab concomitantly with drugs that prolong the QTc interval [see Warnings and Precautions (5.5) , Clinical Pharmacology (12.3) ]. Warfarin Clinical Impact The concomitant use of warfarin with REMERON/REMERONSolTab may result in an increase in INR [see Clinical Pharmacology (12.3) ] . Intervention Monitor INR during concomitant use of warfarin with REMERON/REMERONSolTab. Strong CYP3A inducers: Dosage increase may be needed for REMERON/REMERONSolTab with concomitant use of strong CYP3A inducers. ( 2. …

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 : REMERONSolTab 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 maternal weight-adjusted dose (se …

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 REMERON and REMERONSolTab contain mirtazapine. 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 empirical 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 is a white to creamy white crystalline powder which is practically insoluble in water. REMERON is available for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine Each tablet contains the following inactive ingredients: colloidal silicon dioxide anhydrous, corn starch, ferric oxide (yellow), hydroxypropyl cellulose, hypromellose, magnesium stearate, lactose monohydrate, polyethylene glycol 8000, and titanium dioxide. The 30 mg tablets also contain ferric oxide (red). REMERONSolTab is available for oral administration as an orally disintegrating tablet containing 15, 30, or 45 mg of mirtazapine. REMERONSolTab also contains the following inactive ingredients: aspartame, citric acid anhydrous fine granular, crospovidone, hypromellose, magnesium stearate, mannitol, granular mannitol 2080, microcrystalline cellulose, natural and artificial orange flavor, polymethacrylate (Eudragit E100), povidone, sodium bicarbonate, and sugar spheres (composed of starch and sucrose). Chemical Structure

10 OVERDOSAGE Human Experience In premarketing clinical studies, there were reports of REMERON 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 REMERON tablets are supplied as: Tablet Strength Tablet Color/Shape Tablet Markings Package Configuration NDC Code 15 mg Yellow, oval tablet Scored with "MSD" debossed on one side and " T 3 Z " on other side, on both sides of score line Bottle / 30 count 78206-160-01 30 mg Red-brown, oval tablet Scored with "MSD" debossed on one side and " T 5 Z " on other side, on both sides of score line Bottle / 30 count 78206-161-01 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. REMERONSolTab orally disintegrating tablets are supplied as: Tablet Strength Tablet Color/Shape Tablet Markings Package Configuration NDC Code 15 mg White, round tablet " T 1 Z " debossed on one side. Box of 5 × 6-unit dose blister packs/ 30 count 78206-156-01 30 mg White, round tablet " T 2 Z " debossed on one side. Box of 5 × 6-unit dose blister packs/30 count 78206-158-01 45 mg White, round tablet " T 4 Z " debossed on one side Box of 5 × 6-unit dose blister packs/30 count 78206-159-01 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from light and moisture. Use immediately upon opening individual tablet blister.