Mirtazapine

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 )

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 ) Reduce dose gradually when discontinuing mirtazapine tablets. ( 2.6 , 5.14 ) 2.1 Recommended 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 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) ]. 2.3 Screen for Bipolar Disorder Prior to Starting Mirtazapine Tablets Prior to initiating treatment with mirtazapine 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 tablets. In addition, at least 14 days must elapse after stopping mirtazapine tablets before starting an MAOI antidepressant [see Contraindications (4) and Warnings and Precautions (5.3) ]. 2.5 Dosage Modifications Due to Drug Interactions Strong CYP3A Inducers An increase in dosage of mirtazapine tablets may be needed with concomitant strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampin) use. Conversely, a decrease in dosage of mirtazapine tablets may be needed if the CYP3A inducer is discontinued [see Drug Interactions (7) ]. Strong CYP3A Inhibitors A decrease in dosage of mirtazapine tablets may be needed with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin). Conversely, an increase in dosage of mirtazapine tablets may be needed if the CYP3A4 inhibitor is discontinued [see Drug Interactions (7) ]. Cimetidine A decrease in dosage of mirtazapine tablets may be needed with concomitant use of cimetidine. Conversely, an increase in dosage of mirtazapine tablets may be needed if cimetidine is discontinued [see Drug Interactions (7) ]. 2.6 Discontinuation of Mirtazapine Tablets Treatment Adverse reactions may occur upon discontinuation or dose reduction of mirtazapine tablets [see Warnings and Precautions (5.14) ]. Gradually reduce the dosage of mirtazapine tablets rather than stopping abruptly whenever possible.

5 WARNINGS AND PRECAUTIONS Agranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with mirtazapine should be discontinued and the patient should be closely monitored. ( 5.2 ) Serotonin 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 and initiate supportive treatment. ( 2.4 , 4 , 5.3 , 7 ) Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.4 ) QT Prolongation: Use mirtazapine with caution in patients with risk factors for QT prolongation. ( 5.5 , 7 ) Drug Reaction with Eosinophilia and System Symptoms (DRESS) : Discontinue mirtazapine if DRESS is suspected. ( 5.6 ) Increased Appetite/Weight Gain: mirtazapine has been associated with increased appetite and weight gain. ( 5.7 ) Somnolence: 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 ) Activation of Mania/Hypomania: Screen patients for bipolar disorder prior to initiating treatment. ( 2.3 , 5.9 ) Seizures: Use with caution in patients with a seizure disorder. ( 5.10 ) Elevated Cholesterol/Triglycerides: Has been reported with mirtazapine use. ( 5.11 ) Hyponatremia: May occur as a result of treatment with serotonergic antidepressants, including mirtazapine. ( 5.12 ) Transaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. ( 5.13 ) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-Placebo Difference in Number of Patients with Suicidal Thoughts or Behaviors per 1000 Patients Treated Increases Compared to Placebo <18 years old 14 additional patients 18 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing mirtazapine, in patients whose depression is persistently worse, or who are experiencing emergent…

4 CONTRAINDICATIONS Mirtazapine tablets are contraindicated in patients: Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3) , Drug Interactions (7) ]. With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine tablets. Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine tablets [see 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 tablets. ( 4 )

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

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 mirtazpine to pregnant rats and rabbits during the period of organogenesis revealed no evidence of teratogenic effects up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg, respectively, based on mg/m 2 body surface area. However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m 2 body surface area. Oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth weights at doses 20 times the MRHD based on mg/m 2 body surface area (see Data). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum. Data Animal Data Mirtazapine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day, respectively, which are up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg based on mg/m 2 body surface area, respectively. No evidence of teratogenic effects was observed. However, in rats, there was an increase in postimplantation loss in dams treated with mirtazapine at 100 mg/kg/day which is 20 times the MRHD based on mg/m 2 body surface area. Oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/kg/day to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights at 20 times the MRHD based on mg/m 2 body surface area. The cause of these deaths is not known. The no effect dose level is 3 times the MRHD based on mg/m 2 body surface area.

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 Rising Pharma Holdings, Inc. at 1-844-874-7464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below are from clinical trials in which mirtazapine was administered to 2796 patients in phase 2 and 3 clinical studies. The trials consisted of double-blind controlled and open-label studies, inpatient and outpatient studies, fixed dose, and titration studies. Adverse Reactions Leading to Discontinuation of Treatment Approximately 16% of the 453 patients who received mirtazapine in U.S. 6-week placebo-controlled clinical trials discontinued treatment due to an adverse reaction, compared to 7% of the 361 placebo-treated patients in those studies. The most common reactions leading to discontinuation (≥1% and at a rate at least twice that of placebo) are included in Table 2. Table 2: Adverse Reactions (≥1% and at least twice placebo) Leading to Discontinuation of Mirtazapine in 6-Week Clinical Trials in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0% Common Adverse Reactions The most common adverse reactions (≥5% and twice placebo) associated with the use of mirtazapine are listed in Table 3. Table 3: Adverse Reactions (≥5% and twice placebo) in 6-Week U.S. Clinical Trials of Mirtazapine in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Somnolence 54% 18% Increased Appetite 17% 2% Weight Gain 12% 2% Dizziness 7% 3% Table 4 enumerates adverse reactions that occurred in ≥1% of mirtazapine-treated patients, and were more frequent than the placebo-treated patients, who participated in 6-week, U.S. placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an adverse reaction at some time during their treatment. Table 4: Adverse Reactions (≥1% and greater than placebo) in 6-Week U.S. Clinical Studies of Mirtazapine in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back Pain 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% Constipation 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Nervous System Somnolence 54% 18% Dizziness 7% 3% A…