Mirtazapine (Page 3 of 9)
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 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 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)]. 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).
6 ADVERSE REACTIONS
The following adverse reactions are described in more detail in other sections of the prescribing information:
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- Hypersensitivity [see Contraindications (4)]
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- Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.1)]
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- Agranulocytosis [see Warnings and Precautions (5.2)]
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- Serotonin Syndrome [see Contraindications (4), Warnings and Precautions (5.3), Drug Interactions (7)]
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- Angle-Closure Glaucoma [see Warnings and Precautions (5.4)]
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- QT Prolongation and Torsades de Pointes [see Warnings and Precautions (5.5)]
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- Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.6)]
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- Increased Appetite and Weight Gain [see Warnings and Precautions (5.7)]
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- Somnolence [see Warnings and Precautions (5.8)]
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- Activation of Mania or Hypomania [see Warnings and Precautions (5.9)]
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- Seizures [see Warnings and Precautions (5.10)]
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- Elevated Cholesterol and Triglycerides [see Warnings and Precautions (5.11)]
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- Hyponatremia [see Warnings and Precautions (5.12)]
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- Transaminase Elevations [see Warnings and Precautions (5.13)]
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- Discontinuation Syndrome [see Warnings and Precautions (5.14)]
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- Use in Patients with Concomitant Illness [see Warnings and Precautions (5.15)]
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 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.
| 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.
| 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.
| 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% |
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