These Highlights Do Not Include All The Information Needed To Use Remeron/remeronsoltab Safely And Effectively. See Full Prescribing Information For Remeron/remeronsoltab.

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)].

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:

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.

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.

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.

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 C₁₇H₁₉N₃. 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).

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)].

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)].

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 (5.7)].

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 (5.12), (5.15) and Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The efficacy of REMERON as a treatment for major depressive disorder was established in 4 placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with REMERON from a dose range of 5 mg to 35 mg/day. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21 to 32 mg/day. Overall, these studies demonstrated REMERON to be superior to placebo on at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of REMERON over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor.

Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings.

In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on REMERON were randomized to continuation of REMERON or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8 to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued REMERON treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients.

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)].

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.

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)]

Table 5 includes clinically important drug interactions with REMERON/REMERONSolTab [see Clinical Pharmacology (12.3)].

In preclinical studies, mirtazapine acts as an antagonist at α₂-adrenergic inhibitory autoreceptors and heteroreceptors and as an antagonist at serotonin 5-HT₂ and 5-HT₃ receptors. Mirtazapine has no significant affinity for the 5-HT_1A and 5-HT_1B receptors.

Mirtazapine also acts as an antagonist of histamine (H₁) receptors, peripheral α₁-adrenergic receptors, and muscarinic receptors. Actions at these receptors may explain some of the other clinical effects of mirtazapine (e.g., its prominent somnolent effects and orthostatic hypotension may be explained by its inhibition of histamine (H₁) receptors and peripheral α₁-adrenergic receptors, respectively).

Plasma levels of mirtazapine are linearly related to dose over a dose range of 15 to 80 mg (1.78 times the maximum recommended dose). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio=1.5). The (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer.

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)].

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.

REMERON/REMERONSolTab are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)].

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 α₂-adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

• 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)
• Drug Reaction with Eosinophilia and System Symptoms (DRESS): Discontinue REMERON/REMERONSolTab if DRESS is suspected. (5.6)
• Increased Appetite/Weight Gain: REMERON/REMERONSolTab 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 REMERON use. (5.11)
• Hyponatremia: May occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab. (5.12)
• Transaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. (5.13)

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.

• 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)

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

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)].

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 DRESS, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis

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)].

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.

• 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)

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 (5.13), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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 (5.16)].

• 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.

REMERON tablets are supplied as:

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.

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)].

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)].

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.

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.

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.

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).

NDC 78206-160-01

REMERON ^®

(mirtazapine)Tablets

15 mg

Rx only

30 Tablets

Must be dispensed with Medication Guide.

Manuf. for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manuf. by: Organon Pharma (UK) Limited

Cramlington, Northumberland, UK NE23 3JU

Mirtazapine (active ingred.) made in The Netherlands.

Formulated in UK.

NDC 78206-161-01

REMERON ^®

(mirtazapine)Tablets

30 mg

Rx only

30 Tablets

Must be dispensed with Medication Guide.

Manuf. for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manuf. by: Organon Pharma (UK) Limited

Cramlington, Northumberland, UK NE23 3JU

Mirtazapine (active ingred.) made in The Netherlands.

Formulated in UK.

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.

NDC 78206-156-01

30 Tablets

ONCE-A-DAY

REMERONSolTab ^®

(mirtazapine) Orally Disintegrating Tablets

Rx only

15 mg

Dispense the accompanying

Medication Guide to each patient.

Manufactured for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manufactured by: Anesta LLC, Salt Lake City, UT 84116, USA

NDC 78206-158-01

30 Tablets

ONCE-A-DAY

REMERONSolTab ^®

(mirtazapine) Orally Disintegrating Tablets

Rx only

30 mg

Dispense the accompanying Medication Guide to each patient.

Manufactured for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manufactured by: Anesta LLC, Salt Lake City, UT 84116, USA

NDC 78206-159-01

30 Tablets

ONCE-A-DAY

REMERONSolTab ^®

(mirtazapine) Orally Disintegrating Tablets

Rx only

45 mg

Dispense the accompanying Medication Guide to each patient.

Manufactured for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manufactured by: Anesta LLC, Salt Lake City, UT 84116, USA

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with postmarketing use of mirtazapine. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue REMERON/REMERONSolTab immediately if DRESS is suspected and institute appropriate treatment [see Contraindications (4), Adverse Reactions (6.2)].

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.

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.

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)].

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)].

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)].

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:

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.

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.

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.

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 C₁₇H₁₉N₃. 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).

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)].

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)].

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 (5.7)].

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 (5.12), (5.15) and Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

The efficacy of REMERON as a treatment for major depressive disorder was established in 4 placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with REMERON from a dose range of 5 mg to 35 mg/day. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21 to 32 mg/day. Overall, these studies demonstrated REMERON to be superior to placebo on at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of REMERON over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor.

Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings.

In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on REMERON were randomized to continuation of REMERON or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of ≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8 to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued REMERON treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients.

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)].

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.

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)]

Table 5 includes clinically important drug interactions with REMERON/REMERONSolTab [see Clinical Pharmacology (12.3)].

In preclinical studies, mirtazapine acts as an antagonist at α₂-adrenergic inhibitory autoreceptors and heteroreceptors and as an antagonist at serotonin 5-HT₂ and 5-HT₃ receptors. Mirtazapine has no significant affinity for the 5-HT_1A and 5-HT_1B receptors.

Mirtazapine also acts as an antagonist of histamine (H₁) receptors, peripheral α₁-adrenergic receptors, and muscarinic receptors. Actions at these receptors may explain some of the other clinical effects of mirtazapine (e.g., its prominent somnolent effects and orthostatic hypotension may be explained by its inhibition of histamine (H₁) receptors and peripheral α₁-adrenergic receptors, respectively).

Plasma levels of mirtazapine are linearly related to dose over a dose range of 15 to 80 mg (1.78 times the maximum recommended dose). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio=1.5). The (–) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about 3 times as high as that of the (+) enantiomer.

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)].

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.

REMERON/REMERONSolTab are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)].

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 α₂-adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

• 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)
• Drug Reaction with Eosinophilia and System Symptoms (DRESS): Discontinue REMERON/REMERONSolTab if DRESS is suspected. (5.6)
• Increased Appetite/Weight Gain: REMERON/REMERONSolTab 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 REMERON use. (5.11)
• Hyponatremia: May occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab. (5.12)
• Transaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. (5.13)

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.

• 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)

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

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)].

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 DRESS, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis

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)].

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.

• 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)

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 (5.13), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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 (5.16)].

• 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.

REMERON tablets are supplied as:

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.

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)].

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)].

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.

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.

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.

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).

NDC 78206-160-01

REMERON ^®

(mirtazapine)Tablets

15 mg

Rx only

30 Tablets

Must be dispensed with Medication Guide.

Manuf. for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manuf. by: Organon Pharma (UK) Limited

Cramlington, Northumberland, UK NE23 3JU

Mirtazapine (active ingred.) made in The Netherlands.

Formulated in UK.

NDC 78206-161-01

REMERON ^®

(mirtazapine)Tablets

30 mg

Rx only

30 Tablets

Must be dispensed with Medication Guide.

Manuf. for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manuf. by: Organon Pharma (UK) Limited

Cramlington, Northumberland, UK NE23 3JU

Mirtazapine (active ingred.) made in The Netherlands.

Formulated in UK.

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.

NDC 78206-156-01

30 Tablets

ONCE-A-DAY

REMERONSolTab ^®

(mirtazapine) Orally Disintegrating Tablets

Rx only

15 mg

Dispense the accompanying

Medication Guide to each patient.

Manufactured for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manufactured by: Anesta LLC, Salt Lake City, UT 84116, USA

NDC 78206-158-01

30 Tablets

ONCE-A-DAY

REMERONSolTab ^®

(mirtazapine) Orally Disintegrating Tablets

Rx only

30 mg

Dispense the accompanying Medication Guide to each patient.

Manufactured for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manufactured by: Anesta LLC, Salt Lake City, UT 84116, USA

NDC 78206-159-01

30 Tablets

ONCE-A-DAY

REMERONSolTab ^®

(mirtazapine) Orally Disintegrating Tablets

Rx only

45 mg

Dispense the accompanying Medication Guide to each patient.

Manufactured for: Organon USA LLC, a subsidiary of

ORGANON & Co.,

Jersey City, NJ 07302, USA

Manufactured by: Anesta LLC, Salt Lake City, UT 84116, USA

Drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with postmarketing use of mirtazapine. DRESS may present with a cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, pneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. Discontinue REMERON/REMERONSolTab immediately if DRESS is suspected and institute appropriate treatment [see Contraindications (4), Adverse Reactions (6.2)].

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.

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.

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)].

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)].