This information is not for clinical use. These highlights do not include all the information needed to use Remeron safely and effectively. Before taking Remeron please consult with your doctor. See full prescribing information for Remeron.

Warning

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)]. REMERON/REMERONSolTab is 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. REMERON/REMERONSolTab is not approved for use in pediatric patients. (5.1, 8.4)

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)

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Dosage Forms And Strengths

REMERON is supplied as: 15 mg tablets: Oval, scored, yellow, with "Organon" debossed on one side and "T 3 Z" on the other side, on both sides of the score line 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 "Organon" debossed on one side and "T 5 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)

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 Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of REMERON/REMERONSolTab [see 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)

Warning and Cautions

Agranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with REMERON/REMERONSolTab 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 REMERON/REMERONSolTab 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 REMERON/REMERONSolTab with caution in patients with risk factors for QT prolongation. (5.5, 7) Increased Appetite/Weight Gain: REMERON/REMERONSolTab has been associated with increased appetite and weight gain. (5.6) Somnolence: May impair judgment, thinking and/or motor skills. Use with caution when engaging in activities requiring alertness, such as driving or operating machinery. (5.7, 7) Activation of Mania/Hypomania: Screen patients for bipolar disorder prior to initiating treatment. (2.3, 5.8) Seizures: Use with caution in patients with a seizure disorder. (5.9) Elevated Cholesterol/Triglycerides: Has been reported with REMERON use. (5.10) Hyponatremia: May occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab. (5.11) Transaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. (5.12) 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 18–24 years old 5 additional patients Decreases Compared to Placebo 25–64 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 REMERON/REMERONSolTab, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren's Syndrome) out of 2796 patients treated with REMERON developed agranulocytosis [absolute neutrophil count (ANC) <500/mm3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm3 without any associated symptoms). For these 3 patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All 3 patients recovered after REMERON was stopped. If a patient develops a sore throat, fever, stomatitis, or other signs of infection, along with a low white blood cell (WBC) count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored. 5.3 Serotonin Syndrome Serotonergic antidepressants, including REMERON/REMERONSolTab, can precipitate serotonin syndrome, a potentially life-threatening condition. The risk is increased with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, and St. John's Wort) and with drugs that impair metabolism of serotonin, i.e., MAOIs [see Contraindications (4), Drug Interactions (7)]. Serotonin syndrome can also occur when these drugs are used alone. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of REMERON/REMERONSolTab with MAOIs is contraindicated. In addition, do not initiate REMERON/REMERONSolTab in a patient being treated with MAOIs such as linezolid or intravenous methylene blue. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection). If it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking REMERON/REMERONSolTab, discontinue REMERON/REMERONSolTab before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)]. Monitor all patients taking REMERON/REMERONSolTab for the emergence of serotonin syndrome. Discontinue treatment with REMERON/REMERONSolTab and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of REMERON/REMERONSolTab with other serotonergic drugs is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms. 5.4 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs, including REMERON/REMERONSolTab, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.5 QT Prolongation and Torsades de Pointes The effect of REMERON (mirtazapine) on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45 mg and 75 mg (1.67 times the maximum recommended daily dose) doses of mirtazapine was not at a level generally considered to be clinically meaningful. During postmarketing use of mirtazapine, cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, and sudden death, have been reported [see Adverse Reactions (6.1, 6.2)]. The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc-prolonging medicines [see Drug Interactions (7) and Overdosage (10)]. Exercise caution when REMERON/REMERONSolTab is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other drugs thought to prolong the QTc interval. 5.6 Increased Appetite and Weight Gain In U.S. controlled clinical studies, appetite increase was reported in 17% of patients treated with REMERON, compared to 2% for placebo. In these same trials, weight gain of ≥7% of body weight was reported in 7.5% of patients treated with mirtazapine, compared to 0% for placebo. In a pool of premarketing U.S. clinical studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON discontinued for weight gain. In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of REMERON-treated pediatric patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The safety and effectiveness of REMERON/REMERONSolTab in pediatric patients with MDD have not been established [see Use in Specific Populations (8.4)]. 5.7 Somnolence In U.S. controlled studies, somnolence was reported in 54% of patients treated with REMERON, compared to 18% for placebo. In these studies, somnolence resulted in discontinuation for 10.4% of REMERON-treated patients, compared to 2.2% for placebo. It is unclear whether tolerance develops to the somnolent effects of REMERON/REMERONSolTab. Because of the potentially significant effects of REMERON/REMERONSolTab 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 REMERON/REMERONSolTab does not affect them adversely. The concomitant use of benzodiazepines and alcohol with REMERON/REMERONSolTab should be avoided [see Drug Interactions (7)]. 5.8 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with REMERON/REMERONSolTab or another antidepressant may precipitate a mixed/manic episode. In controlled clinical trials, patients with bipolar disorder were generally excluded; however, symptoms of mania or hypomania were reported in 0.2% of patients treated with REMERON. Prior to initiating treatment with REMERON/REMERONSolTab, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.9 Seizures REMERON/REMERONSolTab has not been systematically evaluated in patients with seizure disorders. In premarketing clinical trials, 1 seizure was reported among the 2796 U.S. and non-U.S. patients treated with REMERON. REMERON/REMERONSolTab should be prescribed with caution in patients with a seizure disorder. 5.10 Elevated Cholesterol and Triglycerides In U.S. controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with REMERON, compared to 7% for placebo. In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with REMERON, compared to 3% for placebo. 5.11 Hyponatremia Hyponatremia may occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab. 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 REMERON/REMERONSolTab 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)]. 5.12 Transaminase Elevations Clinically significant ALT (SGPT) elevations (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with REMERON in a pool of short-term, U.S. controlled trials, compared to 0.3% (1/328) of placebo patients. While some patients were discontinued for the ALT increases, in other cases, the enzyme levels returned to normal despite continued REMERON treatment. REMERON/REMERONSolTab should be used with caution in patients with impaired hepatic function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 5.13 Discontinuation Syndrome There have been reports of adverse reactions upon the discontinuation of REMERON/REMERONSolTab (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance. A gradual reduction in the dosage, rather than an abrupt cessation, is recommended [see Dosage and Administration (2.6)]. 5.14 Use in Patients with Concomitant Illness REMERON/REMERONSolTab has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. REMERON 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)]. REMERON/REMERONSolTab 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). 5.15 Risks in Patients with Phenylketonuria Phenylalanine can be harmful to patients with phenylketonuria (PKU). REMERONSolTab contains phenylalanine, a component of aspartame. REMERONSolTab contains the following amount of phenylalanine: 2.6 mg in 15 mg orally disintegrating tablet, 5.2 mg in 30 mg orally disintegrating tablet, and 7.8 mg in 45 mg orally disintegrating tablet. Before prescribing REMERONSolTab to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including REMERONSolTab.

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)] Increased Appetite and Weight Gain [see Warnings and Precautions (5.6)] Somnolence [see Warnings and Precautions (5.7)] Activation of Mania or Hypomania [see Warnings and Precautions (5.8)] Seizures [see Warnings and Precautions (5.9)] Elevated Cholesterol and Triglycerides [see Warnings and Precautions (5.10)] Hyponatremia [see Warnings and Precautions (5.11)] Transaminase Elevations [see Warnings and Precautions (5.12)] Discontinuation Syndrome [see Warnings and Precautions (5.13)] Use in Patients with Concomitant Illness [see Warnings and Precautions (5.14)] 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 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., at 1-877-888-4231 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 Dreams 4% 1% Thinking Abnormal 3% 1% Tremor 2% 1% Confusion 2% 0% Respiratory System Dyspnea 1% 0% Urogenital System Urinary Frequency 2% 1% ECG Changes The electrocardiograms for 338 patients who received REMERON and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. REMERON was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown. Other Adverse Reactions Observed During the Premarketing Evaluation of REMERON The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) for which a drug cause was remote, 3) which were so general or excessively specific so as to be uninformative, 4) which were not considered to have significant clinical implications, or 5) which occurred at a rate equal to or less than placebo. Adverse reactions are categorized by body system according to the following definitions: frequent adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer than 1/1000 patients. Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal. Cardiovascular System: frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. Digestive System: frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. Endocrine System: rare: goiter, hypothyroidism. Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia. Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. Respiratory System: frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup. Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia. Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of REMERON. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Cardiac disorders: ventricular arrhythmia (Torsades de Pointes) Endocrine disorders: hyperprolactinemia (and related symptoms, e.g., galactorrhea and gynecomastia) Musculoskeletal and connective tissue disorders: increased creatine kinase blood levels and rhabdomyolysis Psychiatric disorders: somnambulism (ambulation and other complex behaviors out of bed) Reproductive system and breast disorders: priapism Skin and subcutaneous tissue disorders: severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis

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 (5.7), 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. (2.5, 7) Strong CYP3A inhibitors: Dosage decrease may be needed when REMERON/REMERONSolTab is coadministered with strong CYP3A inhibitors. (2.5, 7) Cimetidine: Dosage decrease may be needed when REMERON/REMERONSolTab is coadministered with cimetidine. (2.5, 7) Warfarin: Monitor INR during concomitant use. (7)

Use In Specific Populations

Geriatric Use: Use with caution in elderly patients. (5.11, 5.14, 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. (5.15, 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/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 a 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 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/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 3 days of lactation and a decrease in pup birth weights at 20 times the MRHD based on mg/m2 body surface area. The cause of these deaths is not known. The no effect dose level is 3 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 mother’s clinical need for mirtazapine and any potential adverse effects on the breastfed infant from mirtazapine or from the underlying maternal condition. Data In a published pooled analysis of 8 breastfeeding mother-infant pairs, the mean (min, max) total relative infant doses for mirtazapine and its desmethyl metabolite were 1.5% (0.6%, 2.8%) and 0.4% (0.1%, 0.7%) of the maternal weight-adjusted dose (median (min, max) dose of 38 mg (30 mg, 120 mg), respectively). No adverse drug effects were reported for any of the infants. 8.4 Pediatric Use The safety and effectiveness of REMERON/REMERONSolTab have not been established in pediatric patients with MDD. Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with REMERON, and the data were insufficient to establish the safety and effectiveness of REMERON/REMERONSolTab 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 REMERON-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The mean increase in weight was 4 kg (2 kg SD) for REMERON-treated patients versus 1 kg (2 kg SD) for placebo-treated patients [see Warnings and Precautions (5.6)]. 8.5 Geriatric Use Approximately 190 patients ≥65 years of age participated in clinical studies with REMERON. REMERON/REMERONSolTab is known to be substantially excreted by the kidney (75%), and the risk of decreased clearance of this drug is greater in patients with impaired renal function. Pharmacokinetic studies revealed a decreased clearance of mirtazapine in the elderly [see Clinical Pharmacology (12.3)]. Sedating drugs, including REMERON/REMERONSolTab, may cause confusion and over-sedation in the elderly. Elderly patients may be at greater risk of developing hyponatremia. Caution is indicated when administering REMERON/REMERONSolTab to elderly patients [see Warnings and Precautions (5.11), (5.14) and Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. 8.6 Renal or Hepatic Impairment The clearance of mirtazapine is reduced in patients with moderate to severe renal or hepatic impairment. Consequently, plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in patients without renal or hepatic impairment. Dosage decrease may be necessary when administering REMERON/REMERONSolTab to patients with moderate to severe renal or hepatic impairment [see Warnings and Precautions (5.12), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)]. 8.7 Patients with Phenylketonuria REMERONSolTab contains phenylalanine, a component of aspartame. REMERONSolTab contains the following amount of phenylalanine: 2.6 mg in 15 mg orally disintegrating tablet, 5.2 mg in 30 mg orally disintegrating tablet, and 7.8 mg in 45 mg orally disintegrating tablet [see Warnings and Precautions (5.15)].