Mirtazapine (Page 3 of 9)

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 tablets 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).

6 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 (5.7)]
• 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)]

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 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 Tablets in 6-Week Clinical Trials in Patients with MDD

	Mirtazapine Tablets (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 tablets are listed in Table 3.

Table 3: Adverse Reactions (≥5% and twice placebo) in 6-Week U.S. Clinical Trials of Mirtazapine Tablets in Patients with MDD

	Mirtazapine Tablets (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 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 Tablets 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 were 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 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 patients.

Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal.

Cardiovascular System: frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare : atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure.

Digestive System: frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema.

Endocrine System: rare: goiter, hypothyroidism.

Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.

Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia.

Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis.

Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome.

Respiratory System: frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup.

Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer.

Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia.

Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency.