Drug Facts
Composition & Profile
Identifiers & Packaging
16 HOW SUPPLIED/STORAGE AND HANDLING Mirtazapine tablets are supplied as: Mirtazapine Tablets, USP 15 mg are available for oral administration as pale yellow, oval-shaped, scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “15” on the other side. They are supplied as follows: Boxes of 10x10 UD 100 count NDC 63739-098-10 Mirtazapine Tablets, USP 30 mg are available for oral administration as light pink, oval-shaped, scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “30” on the other side. They are supplied as follows: Boxes of 10x10 UD 100 count NDC 63739-099-10 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.; MIRTAZAPINE Mirtazapine
- 16 HOW SUPPLIED/STORAGE AND HANDLING Mirtazapine tablets are supplied as: Mirtazapine Tablets, USP 15 mg are available for oral administration as pale yellow, oval-shaped, scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “15” on the other side. They are supplied as follows: Boxes of 10x10 UD 100 count NDC 63739-098-10 Mirtazapine Tablets, USP 30 mg are available for oral administration as light pink, oval-shaped, scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “30” on the other side. They are supplied as follows: Boxes of 10x10 UD 100 count NDC 63739-099-10 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.
- MIRTAZAPINE Mirtazapine
Overview
Mirtazapine tablets 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. Mirtazapine tablets are available for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine. Each tablet contains the following inactive ingredients: croscarmellose sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. In addition, mirtazapine tablets, USP 15 mg and 30 mg contains iron oxide yellow and mirtazapine tablets, USP 30 mg contains iron oxide red 11 DESCRIPTION
Indications & Usage
Mirtazapine Tablets are indicated for the treatment of major depressive disorder (MDD) in adults [see Clinical Studies (14)]. Mirtazapine Tablets is indicated for the treatment of major depressive disorder (MDD) in adults. (1)
Dosage & Administration
• Starting dose: 15-mg once daily; may increase up to maximum recommended dose of 45 mg once daily. (2.1) • Administer orally once daily, preferably in the evening prior to sleep. (2.1) • Reduce dose gradually when discontinuing mirtazapine tablets. (2.6, 5.14) 2.1 Recommended Dosage The recommended starting dose for mirtazapine tablets is 15 mg once daily, administered orally, preferably in the evening prior to sleep. If patients do not have an adequate response to the initial 15 mg dose, increase the dose up to a maximum of 45 mg per day. Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response to a given dose [see Clinical Pharmacology (12.3)]. 2.3 Screen for Bipolar Disorder Prior to Starting Mirtazapine Tablets Prior to initiating treatment with mirtazapine tablets or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania [see Warnings and Precautions (5.8)]. 2.4 Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of mirtazapine tablets. In addition, at least 14 days must elapse after stopping mirtazapine tablets before starting an MAOI antidepressant [ see Contraindications (4) and Warnings and Precautions (5.3)]. 2.5 Dosage Modifications Due to Drug Interactions Strong CYP3A Inducers An increase in dosage of mirtazapine tablets may be needed with concomitant strong CYP3A inducer (e.g., carbamazepine, phenytoin, rifampin) use. Conversely, a decrease in dosage of mirtazapine tablets may be needed if the CYP3A inducer is discontinued [see Drug Interactions (7)]. Strong CYP3A Inhibitors A decrease in dosage of mirtazapine tablets may be needed with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin). Conversely, an increase in dosage of mirtazapine tablets may be needed if the CYP3A inhibitor is discontinued [see Drug Interactions (7)]. Cimetidine A decrease in dosage of mirtazapine tablets may be needed with concomitant use of cimetidine. Conversely, an increase in dosage of mirtazapine tablets may be needed if cimetidine is discontinued [see Drug Interactions (7)]. 2.6 Discontinuation of Mirtazapine Tablets Treatment Adverse reactions may occur upon discontinuation or dose reduction of mirtazapine tablets [see Warnings and Precautions (5.13)]. Gradually reduce the dosage of mirtazapine tablets rather than stopping abruptly whenever possible.
Warnings & Precautions
• Agranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with mirtazapine tablets 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 tablets and initiate supportive treatment. (2.4, 4, 5.3, 7) • Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.4) • QT Prolongation: Use mirtazapine tablets with caution in patients with risk factors for QT prolongation. (5.5, 7) • Drug Reaction with Eosinophilia and System Symptoms (DRESS): Discontinue Mirtazapine tablets if DRESS is suspected. (5.6) • Increased Appetite/Weight Gain: Mirtazapine tablets have been associated with increased appetite and weight gain. (5.7) • Somnolence: May impair judgment, thinking and/or motor skills. Use with caution when engaging in activities requiring alertness, such as driving or operating machinery. (5.8, 7) • Activation of Mania/Hypomania: Screen patients for bipolar disorder prior to initiating treatment. (2.3, 5.9) • Seizures: Use with caution in patients with a seizure disorder. (5.10) • Elevated Cholesterol/Triglycerides: Has been reported with mirtazapine tablet use. (5.11) • Hyponatremia: May occur as a result of treatment with serotonergic antidepressants, including mirtazapine tablets. (5.12) • Transaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function. (5.13) 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients and 4,500 pediatric patients, the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. There were differences in absolute risk of suicidal thoughts and behaviors across the different indications, with the highest incidence in patients with MDD. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients with Suicidal Thoughts and Behavior in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients Age Range Drug-placebo Difference in Number of Patients with Suicidal Thoughts and Behaviour in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients 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 patients ≥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 tablets, 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 tablets 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 mirtazapine tablets were 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 tablets should be discontinued and the patient should be closely monitored. 5.3 Serotonin Syndrome Serotonergic antidepressants, including mirtazapine tablets, 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 tablets with MAOIs is contraindicated. In addition, do not initiate mirtazapine tablets 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 tablets, discontinue mirtazapine tablets before initiating treatment with the MAOI [see Contraindications (4), Drug Interactions (7)]. Monitor all patients taking mirtazapine tablets for the emergence of serotonin syndrome. Discontinue treatment with mirtazapine tablets and any concomitant serotonergic agents immediately if the above symptoms occur and initiate supportive symptomatic treatment. If concomitant use of mirtazapine tablets 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 tablets, 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 tablets 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 tablets is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other drugs thought to prolong the QTc interval. 5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) 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 mirtazapine immediately if DRESS is suspected and institute appropriate treatment [see Contraindications (4), Adverse Reactions (6.2)]. 5.7 Increased Appetite and Weight Gain In U.S. controlled clinical studies, appetite increase was reported in 17% of patients treated with mirtazapine tablets, 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 mirtazapine tablets discontinued for weight gain. In an 8-week-long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine tablets-treated pediatric patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. The safety and effectiveness of mirtazapine tablets in pediatric patients with MDD have not been established [see Use in Specific Populations (8.4)]. 5.8 Somnolence In U.S. controlled studies, somnolence was reported in 54% of patients treated with mirtazapine tablets, compared to 18% for placebo. In these studies, somnolence resulted in discontinuation for 10.4% of mirtazapine tablets-treated patients, compared to 2.2% for placebo. It is unclear whether tolerance develops to the somnolent effects of mirtazapine tablets. Because of the potentially significant effects of mirtazapine tablets 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 mirtazapine does not affect them adversely. The concomitant use of benzodiazepines and alcohol with mirtazapine tablets should be avoided [see Drug Interactions (7)]. 5.9 Activation of Mania or Hypomania In patients with bipolar disorder, treating a depressive episode with mirtazapine tablets 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 mirtazapine tablets. Prior to initiating treatment with mirtazapine tablets, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. 5.10 Seizures Mirtazapine tablets have 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 mirtazapine tablets. Mirtazapine tablets should be prescribed with caution in patients with a seizure disorder. 5.11 Elevated Cholesterol and Triglycerides In U.S. controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine tablets, compared to 7% for placebo. In these same studies, nonfasting triglyceride increases to ≥500 mg/dL were observed in 6% of patients treated with mirtazapine tablets, compared to 3% for placebo. 5.12 Hyponatremia Hyponatremia may occur as a result of treatment with serotonergic antidepressants, including mirtazapine tablets. 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 mirtazapine tablets and institute appropriate medical intervention. Elderly patients, patients taking diuretics, and those who are volume- depleted may be at greater risk of developing hyponatremia [see Use in Specific Populations (8.5)]. 5.13 Transaminase Elevations Clinically significant ALT (SGPT) elevations ((≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients treated with mirtazapine tablets 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 mirtazapine treatment. Mirtazapine tablets should be used with caution in patients with impaired hepatic function [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 5.14 Discontinuation Syndrome There have been reports of adverse reactions upon the discontinuation of mirtazapine tablets (particularly when abrupt), including but not limited to the following: dizziness, abnormal dreams, sensory disturbances (including paresthesia and electric shock sensations), agitation, anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating, or other symptoms which may be of clinical significance. A gradual reduction in the dosage, rather than an abrupt cessation, is recommended [see Dosage and Administration (2.6)]. 5.15 Use in Patients with Concomitant Illness Mirtazapine tablets have not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine tablets were 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)]. Mirtazapine tablets 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).
Boxed Warning
SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning . Increased risk of suicidal thoughts and behavior in pediatric and young adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors. Mirtazapine tablets is not approved for use in pediatric patients. (5.1, 8.4)
Contraindications
Mirtazapine tablets are contraindicated in patients: • Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome [see Warnings and Precautions (5.3), Drug Interactions (7)]. • With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine tablets. Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of mirtazapine tablets [see Warnings and Precautions (5.6), Adverse Reactions (6.2)]. • Concomitant use of monoamine oxidase inhibitors (MAOIs) or use within 14 days of stopping MAOIs. (2.4, 4,7) • Known hypersensitivity to mirtazapine or any of the excipients in mirtazapine tablets. (4)
Adverse Reactions
The following adverse reactions are described in more detail in other sections of the prescribing information: • Hypersensitivity [see Contraindications (4)] • Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)] • Agranulocytosis [see Warnings and Precautions (5.2)] • Serotonin Syndrome [see Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7)] • Angle-Closure Glaucoma [see Warnings and Precautions (5.4)] • QT Prolongation and Torsades de Pointes [see Warnings and Precautions (5.5)] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)] • Increased Appetite and Weight Gain [see Warnings and Precautions (5.6)] • 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 Apotex Corp. at, at 1-800-706-5575 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 tablets were 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 tablets in US 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 (>= 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 Tablets (n=453 ) Placebo (n=3 61) 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 tablets 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 Tablets (n=453) Placebo (n=3 61) 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 tablets-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 Tablets (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 tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Mirtazapine tablets 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 Events Observed During the Premarketing Evaluation of Mirtazapine Tablets 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 patient. Body as a Whole Frequent : malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare : cellulitis, chest pain substernal. Cardiovascular System Frequent : hypertension, vasodilatation; infrequent : angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare : atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure. Digestive System Frequent : vomiting, anorexia; infrequent : eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare : tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema. Endocrine System Rare: goiter, hypothyroidism. Hemic and Lymphatic System Rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia. Metabolic and Nutritional Disorders Frequent : thirst; infrequent : dehydration, weight loss; rare : gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia. Musculoskeletal System Frequent : myasthenia, arthralgia; infrequent : arthritis, tenosynovitis; rare : pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis. Nervous System Frequent : hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent : ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome. Respiratory System Frequent : cough increased, sinusitis; infrequent : epistaxis, bronchitis, asthma, pneumonia; rare : asphyxia, laryngitis, pneumothorax, hiccup. Skin and Appendages Frequent : pruritus, rash; infrequent : acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare : urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer. Special Senses Infrequent : eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia. Urogenital System Frequent : urinary tract infection; infrequent : kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare : polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of mirtazapine tablets. 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 disorder: priapism Skin and subcutaneous tissue disorders: severe skin reactions, including DRESS, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis
Drug Interactions
Table 5 includes clinically important drug interactions with Mirtazapine Tablets [see Clinical Pharmacology (12.3)]. • Strong CYP3A inducers: Dosage increase may be needed for mirtazapine tablets with concomitant use of strong CYP3A inducers. (2.5, 7) • Strong CYP3A inhibitors: Dosage decrease may be needed when mirtazapine tablets are coadministered with strong CYP3A inhibitors. (2.5, 7) • Cimetidine: Dosage decrease may be needed when mirtazapine tablets are coadministered with cimetidine. (2.5, 7) • Warfarin: Monitor INR during concomitant use. (7) Table 5: Clinically Important Drug Interactions with Mirtazapine Tablets Monoamine Oxidase Inhibitors (MAOIs) Clinical Impact The concomitant use of serotonergic drugs, including Mirtazapine Tablets, and MAOIs increases the risk of serotonin syndrome. Intervention Mirtazapine tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3)] Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue Other Serotonergic Drugs Clinical Impact The concomitant use of serotonergic drugs with mirtazapine tablets increases the risk of serotonin syndrome. Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of mirtazapine tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.3)] Examples SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St. John’s Wort, tramadol, tryptophan, buspirone Strong CYP3A Inducers Clinical Impact The concomitant use of strong CYP3A inducers with mirtazapine tablets decreases the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)]. Intervention Increase the dose of mirtazapine tablets if needed with concomitant CYP3A inducer use. Conversely, a decrease in dosage of Mirtazapine Tablets may be needed if the CYP3A inducer is discontinued [see Dosage and Administration (2.5)]. Examples phenytoin, carbamazepine, rifampin Strong CYP3A Inhibitors Clinical Impact The concomitant use of strong CYP3A inhibitors with mirtazapine tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)]. Intervention Decrease the dose of mirtazapine tablets if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine tablets may be needed if the CYP3A inhibitor is discontinued [see Dosage and Administration (2.5)]. Examples itraconazole, ritonavir, nefazodone Cimetidine Clinical Impact The concomitant use of cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, with mirtazapine tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)] Intervention Decrease the dose of mirtazapine tablets if needed with concomitant cimetidine use. Conversely, an increase in dosage of mirtazapine tablets may be needed if cimetidine is discontinued [see Dosage and Administration (2.5)]. Benzodiazepines and Alcohol Clinical Impact The concomitant use of benzodiazepines or alcohol with mirtazapine tablets increases the impairment of cognitive and motor skills produced by mirtazapine tablets alone. Intervention Avoid concomitant use of benzodiazepines and alcohol with mirtazapine tablets [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)]. Examples diazepam, alprazolam, alcohol Drugs that Prolong QTc Interval Clinical Impact The concomitant use of other drugs which prolong the QTc interval with mirtazapine tablets, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes). Intervention Use caution when using mirtazapine tablets concomitantly with drugs that prolong the QTc interval [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)]. Warfarin Clinical Impact The concomitant use of warfarin with mirtazapine tablets may result in an increase in INR [see Clinical Pharmacology (12.3)]. Intervention Monitor INR during concomitant use of warfarin with mirtazapine tablets
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