Mirtazapine (Page 2 of 9)

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)].

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