Mirtazapine

INDICATIONS AND USAGE Mirtazapine tablets, USP are indicated for the treatment of major depressive disorder. The efficacy of mirtazapine tablets, USP in the treatment of major depressive disorder was established in six week controlled trials of outpatients whose diagnoses corresponded most closely to the Diagnostic and Statistical Manual of Mental Disorders – 3rd edition (DSM-III) category of major depressive disorder (see CLINICAL PHARMACOLOGY ). A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation. The effectiveness of mirtazapine tablets, USP in hospitalized depressed patients has not been adequately studied. The efficacy of mirtazapine tablets, USP in maintaining a response in patients with major depressive disorder for up to 40 weeks following 8 to 12 weeks of initial open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use mirtazapine tablets, USP for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see CLINICAL PHARMACOLOGY ).

DOSAGE AND ADMINISTRATION Initial Treatment The recommended starting dose for mirtazapine tablets is 15 mg/day, administered in a single dose, preferably in the evening prior to sleep. In the controlled clinical trials establishing the efficacy of mirtazapine in the treatment of major depressive disorder, the effective dose range was generally 15 to 45 mg/day. While the relationship between dose and satisfactory response in the treatment of major depressive disorder for mirtazapine tablets has not been adequately explored, patients not responding to the initial 15 mg dose may benefit from dose increases up to a maximum of 45 mg/day. Mirtazapine tablets has an elimination half-life of approximately 20 to 40 hours; therefore, dose changes should not be made at intervals of less than one to two weeks in order to allow sufficient time for evaluation of the therapeutic response to a given dose. Elderly and Patients with Renal or Hepatic Impairment The clearance of mirtazapine is reduced in elderly patients and in patients with moderate to severe renal or hepatic impairment. Consequently, the prescriber should be aware that plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in younger adults without renal or hepatic impairment (see PRECAUTIONS and CLINICAL PHARMACOLOGY ). Maintenance/Extended Treatment It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of mirtazapine tablets has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8 to 12 weeks of initial treatment at a dose of 15 to 45 mg/day (see CLINICAL PHARMACOLOGY ). Based on these limited data, it is unknown whether or not the dose of mirtazapine tablets needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment. Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with mirtazapine tablets. Conversely, at least 14 days should be allowed after stopping mirtazapine tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS ). Use of Mirtazapine Tablets With Other MAOIs, Such as Linezolid or Methylene Blue Do not start mirtazapine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS ). In some cases, a patient already receiving therapy with mirtazapine may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, Mirtazapine tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with mirtazapine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS ). The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with mirtazapine tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS ). Discontinuation of Mirtazapine Tablets, USP Treatment Symptoms associated with the discontinuation or dose reduction of mirtazapine tablets have been reported. Patients should be monitored for these and other symptoms when discontinuing treatment or during dosage reduction. A gradual reduction in the dose over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient’s clinical response (see PRECAUTIONS and ADVERSE REACTIONS ). Information for Patients Patients should be advised that taking mirtazapine tablets can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre- existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

WARNINGS AND PRECAUTIONS • Agranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with mirtazapine should be discontinued and the patient should be closely monitored. ( 5.2 ) • Serotonin Syndrome: Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue mirtazapine and initiate supportive treatment. ( 2.4 , 4 , 5.3 , 7 ) • Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. ( 5.4 ) • QTc Prolongation: Use mirtazapine with caution in patients with risk factors for QTc prolongation. ( 5.5 , 7 ) • Increased Appetite/Weight Gain: mirtazapine 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 mirtazapine use. ( 5.10 ) • Hyponatremia: May occur as a result of treatment with serotonergic antidepressants, including mirtazapine. ( 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 to 24 years old 5 additional patients Decreases Compared to Placebo 25 to 64 years old 1 fewer patient ≥65 years old 6 fewer patients It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression and that depression itself is a risk factor for suicidal thoughts and behaviors. Monitor all antidepressant-treated patients for any indication of clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing mirtazapine, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors. 5.2 Agranulocytosis In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2796 patients treated with mirtazapine developed agranulocytosis [absolute neutrophil count (ANC) <500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm 3 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 mirtazapine 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 mirtazapine should be discontinued and the patient should be closely monitored. 5.3 Serotonin Syndrome Serotonergic antidepressants, including mirtazapine, 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 mirtazapine with MAOIs is contraindicated. In addition, do not initiate mirtazapine 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 mirtazapine, discontinue mirtazapine before initiating treatment with the MAOI [see Contraindications (4) , Drug Interactions (7) ]. Monitor all patients taking mirtazapine for the emergence of serotonin syndrome. Discontinue treatment with mirtazapine and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of mirtazapine 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 mirtazapine, 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 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 mirtazapine is prescribed in patients with known cardiovascular disease or family history of QT pr

CONTRAINDICATIONS Mirtazapine orally disintegrating tablets are contraindicated in patients: • Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3) , Drug Interactions (7) ]. • With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine orally disintegrating tablets. Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine orally disintegrating tablets [see Warnings and Precautions (5.6) , Adverse Reactions (6.2) ]. • Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs. ( 2.4 , 4 , 7 ) • Known hypersensitivity to mirtazapine or any of the excipients in mirtazapine orally disintegrating tablets. ( 4 )

Information for Patients Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with mirtazapine tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for mirtazapine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document. Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking mirtazapine tablets. Clinical Worsening and Suicide Risk Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient's prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication. Agranulocytosis Patients who are to receive mirtazapine tablets should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection. Interference with Cognitive and Motor Performance Mirtazapine tablets may impair judgment, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient’s ability to drive, use machines or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that mirtazapine tablet therapy does not adversely affect their ability to engage in such activities. Completing Course of Therapy While patients may notice improvement with mirtazapine tablet therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Concomitant Medication Patients should be advised to inform their physician if they are taking, or intend to take, any prescription or over-the-counter drugs, since there is a potential for mirtazapine tablets to interact with other drugs. Patients should be made aware of a potential increased risk for serotonin syndrome if concomitant use of mirtazapine tablets with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan and St. John's wort, is clinically warranted, particularly during treatment initiation and dose increases. Alcohol The impairment of cognitive and motor skills produced by mirtazapine tablets has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine. Pregnancy Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during mirtazapine tablets therapy. Nursing Patients should be advised to notify their physician if they are breastfeeding an infant. Laboratory Tests There are no routine laboratory tests recommended. Drug Interactions As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY). Monoamine Oxidase Inhibitors (See CONTRAINDICATIONS , WARNINGS , and DOSAGE AND ADMINISTRATION .) Serotonergic Drugs (See CONTRAINDICATIONS and WARNINGS .) Drugs Affecting Hepatic Metabolism The metabolism and pharmacokinetics of mirtazapine tablets may be affected by the induction or inhibition of drug-metabolizing enzymes. Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes CYP Enzyme Inducers (these studies used both drugs at steady state) Phenytoin: In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. Carbamazepine: In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%. When phenytoin, carbamazepine, or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose. CYP Enzyme Inhibitors Cimetidine: In healthy male patients (n=12), when cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued. Ketoconazole: In healthy, male, Caucasian patients (n=24), coadministration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30-mg dose of mirtazapine by approximately 40% and 50%, respectively. Caution should be exercised when coadministering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or nefazodone. Paroxetine : In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor. Other Drug-Drug Interactions Amitriptyline In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes in the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. Warfarin In healthy male subjects (n=16), mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalized Ratio (INR) in subjects treated with warfarin. As at a higher dose of mirtazapine, a more pronounced effect cannot be excluded, it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine. Lithium No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of lithium (600 mg/day for 10 days) at steady state and a single 30-mg dose of mirtazapine. The effects of higher dose

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 Rising Health, LLC at 1-833-395-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below are from clinical trials in which mirtazapine was administered to 2796 patients in phase 2 and 3 clinical studies. The trials consisted of double-blind controlled and open-label studies, inpatient and outpatient studies, fixed dose, and titration studies. Adverse Reactions Leading to Discontinuation of Treatment Approximately 16% of the 453 patients who received mirtazapine in U.S. 6-week placebo-controlled clinical trials discontinued treatment due to an adverse reaction, compared to 7% of the 361 placebo-treated patients in those studies. The most common reactions leading to discontinuation (≥1% and at a rate at least twice that of placebo) are included in Table 2. Table 2: Adverse Reactions (≥1% and at least twice placebo) Leading to Discontinuation of Mirtazapine in 6-Week Clinical Trials in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0% Common Adverse Reactions The most common adverse reactions (≥5% and twice placebo) associated with the use of mirtazapine are listed in Table 3. Table 3: Adverse Reactions (≥5% and twice placebo) in 6-Week U.S. Clinical Trials of Mirtazapine in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Somnolence 54% 18% Increased Appetite 17% 2% Weight Gain 12% 2% Dizziness 7% 3% Table 4 enumerates adverse reactions that occurred in ≥1% of mirtazapine -treated patients, and were more frequent than the placebo-treated patients, who participated in 6-week, U.S. placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an adverse reaction at some time during their treatment. Table 4: Adverse Reactions (≥1% and greater than placebo) in 6-Week U.S. Clinical Studies of Mirtazapine in Patients with MDD Mirtazapine (n=453) Placebo (n=361) Body as a Whole Asthenia 8% 5% Flu Syndrome 5% 3% Back Pain 2% 1% Digestive System Dry Mouth 25% 15% Increased Appetite 17% 2% Constipation 13% 7% Metabolic and Nutritional Disorders Weight Gain 12% 2% Peripheral Edema 2% 1% Edema 1% 0% Musculoskeletal System Myalgia 2% 1% Nervous System Somnolence 54% 18% Dizziness 7% 3% 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 mirtazapine and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Mirtazapine 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 Mirtazapine 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

Mechanism of Action The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear. However, its efficacy could be mediated through its activity as an antagonist at central presynaptic α2-adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity. 12.2 Pharmacodynamics 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-HT1A and 5-HT1B 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). Cardiac Electrophysiology The effect of mirtazapine on QTc interval was assessed in healthy subjects. At a dose of 75 mg (1.67 times the maximum recommended dosage), mirtazapine does not prolong the QTc interval to a clinically meaningful extent. 12.3 Pharmacokinetics 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. Absorption Mirtazapine has an absolute bioavailability of about 50% following oral administration. Peak plasma concentrations of mirtazapine are reached within about 2 hours post dose. Food Effect The presence of food in the stomach has a minimal effect on both the rate and extent of absorption. Distribution Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/mL. Elimination Mirtazapine has a half-life of about 20 to 40 hours following oral administration of mirtazapine. Metabolism Mirtazapine is extensively metabolized after oral administration. Major pathways of bio-transformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that CYP2D6 and CYP1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas CYP3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. Excretion Mirtazapine and its metabolites are eliminated predominantly (75%) via urine with 15% in feces. Specific Populations Geriatric Patients Following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range 25 to 74 years old), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The clearance in elderly males was 40% lower compared to younger males, while the clearance was 10% lower in elderly females compared to younger females [see Warnings and Precautions (5.15), Use in Specific Populations (8.5)]. Male and Female Patients The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20 to 40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Race There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine. Patients with Renal Impairment When compared to subjects with normal renal function, total body clearance of mirtazapine was reduced approximately 30% in renal impaired patients with GFR=11 to 39 mL/min/1.73 m2 and approximately 50% in renal impaired patients with GFR=<10 mL/min/1.73 m2) [see Warnings and Precautions (5.15), Use in Specific Populations (8.6)]. Patients with Hepatic Impairment Following a single 15 mg oral dose of mirtazapine, the oral clearance of mirtazapine in patients with hepatic impairment was decreased by approximately 30%, compared to subjects with normal hepatic function [see Warnings and Precautions (5.13, 5.15), Use in Specific Populations (8.6)]. Drug Interactions Studies Warfarin Mirtazapine (30 mg daily) at steady state caused a statistically significant increase (0.2) in the International Normalized Ratio (INR) in subjects treated with warfarin [see Drug Interactions (7)]. QTc-Prolonging Drugs The risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g., some antipsychotics and antibiotics) and in mirtazapine overdose [see Warnings and Precautions (5.5), Adverse Reactions (6.1, 6.2), Drug Interactions (7), and Overdosage (10)]. Phenytoin In healthy male subjects (n=18), phenytoin (200 mg daily, at steady state) increased mirtazapine (30 mg daily, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45% [see Drug Interactions (7)]. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. Carbamazepine In healthy male subjects (n=24), carbamazepine (400 mg twice a day, at steady state) increased mirtazapine (15 mg twice a day, at steady state) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60% [see Drug Interactions (7)]. Cimetidine In healthy male subjects (n=12), when cimetidine, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50% [see Drug Interactions (7)]. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. Ketoconazole In healthy male Caucasian subjects (n=24), coadministration of the strong CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30 mg dose of mirtazapine by approximately 40% and 50%, respectively [see Drug Interactions (7)]. Amitriptyline In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes to the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline. Paroxetine In healthy CYP2D6 extensive metabolizer subjects (n=24), mirtazapine (30 mg/day), at steady state, did not cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor. Lithium No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with lithium 600 mg/day for 10 days at steady state and a single 30 mg dose of mirtazapine. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown. Risperidone Mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg twice a day) in subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug. Alcohol Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by mirtazapine were shown to be additive with those produced by alcohol. Diazepam Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy su