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.

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.

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).

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

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

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.

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.

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

8.1 Pregnancy

Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to
antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling
the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at
https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Risk Summary
Prolonged experience with mirtazapine in pregnant women, based on published observational
studies and postmarketing reports, has not reliably identified a drug-associated risk of major birth
defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with
untreated depression in pregnancy (see Clinical Considerations).
In animal reproduction studies, oral administration of mirtazapine to pregnant rats and rabbits
during the period of organogenesis revealed no evidence of teratogenic effects up to 20 and 17
times the maximum recommended human dose (MRHD) of 45 mg, respectively, based on mg/m2
body surface area. However, in rats, there was an increase in post implantation loss at 20 times the
MRHD based on mg/m2 body surface area. Oral administration of mirtazapine to pregnant rats
during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth
weights at doses 20 times the MRHD based on mg/m2 body surface area (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population
is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse
outcomes. In the U.S. general population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Women who discontinue antidepressants during pregnancy are more likely to experience a relapse
of major depression than women who continue antidepressants. This finding is from a prospective,
longitudinal study that followed 201 pregnant women with a history of major depressive disorder
who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of
untreated depression when discontinuing or changing treatment with antidepressant medication
during pregnancy and postpartum.

Data
Animal Data
Mirtazapine was administered orally to pregnant rats and rabbits during the period of
organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day,
respectively, which are up to 20 and 17 times the maximum recommended human dose (MRHD) of
45 mg based on mg/m2 body surface area, respectively. No evidence of teratogenic effects was
observed. However, in rats, there was an increase in post implantation loss in dams treated with
mirtazapine at 100 mg/kg/day which is 20 times the MRHD based on mg/m2 body surface area.
Oral administration of mirtazapine at doses of 2.5, 15, and 100mg/kg/day to pregnant rats during
pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation
and a decrease in pup birth weights at 20 times the MRHD based on mg/m2 body surface area. The
cause of these deaths is not known. The no effect dose level is 3 times the MRHD based on mg/m2
body surface area.

8.2 Lactation

Risk Summary
Data from published literature report the presence of mirtazapine in human milk at low levels with
relative infant doses for mirtazapine ranging between 0.6 and 2.8% of the maternal
weight-adjusted dose (see Data). No adverse effects on the breastfed infant have been reported in
most cases of maternal use of mirtazapine. There are no data on the effects of mirtazapine on milk
production.
The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for mirtazapine and any potential adverse effects on the breastfed infant
from mirtazapine or from the underlying maternal condition.
Data
In a published pooled analysis of 8 breastfeeding mother-infant pairs, the mean (min, max) total
relative infant doses for mirtazapine and its desmethyl metabolite were 1.5% (0.6%, 2.8%) and
0.4% (0.1%, 0.7%) of the maternal weight-adjusted dose (median (min, max) dose of 38 mg
(30 mg, 120 mg), respectively). No adverse drug effects were reported for any of the infants.

8.4 Pediatric Use

The safety and effectiveness of mirtazapine tablets have not been established in pediatric patients
with MDD. Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted
with mirtazapine tablets, and the data were insufficient to establish the safety and effectiveness of
mirtazapine tablets in pediatric patients with MDD.
Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see
Boxed Warning and Warnings and Precautions (5.1)].
In an 8-week-long clinical trial in pediatric patients receiving doses between 15 to 45 mg per day,
49% of mirtazapine tablets-treated patients had a weight gain of at least 7%, compared to 5.7% of
placebo- treated patients. The mean increase in weight was 4 kg (2 kg SD) for mirtazapine
tablets-treated patients versus 1 kg (2 kg SD) for placebo-treated patients [see Warnings and
Precautions (5.7)].

8.5 Geriatric Use

Approximately 190 patients≥ 65 years of age participated in clinical studies with mirtazapine
tablets. Mirtazapine tablets are known to be substantially excreted by the kidney (75%), and the
risk of decreased clearance of this drug is greater in patients with impaired renal function.
Pharmacokinetic studies revealed a decreased clearance of mirtazapine in the elderly [see Clinical
Pharmacology (12.3)]
Sedating drugs, including mirtazapine tablets, may cause confusion and over-sedation in the
elderly. Elderly patients may be at greater risk of developing hyponatremia. Caution is indicated
when administering mirtazapine tablets to elderly patients [see Warnings and Precautions (5.12),
(5.15) and Clinical Pharmacology (12.3)]. In general, dose selection for an elderly patient should be
conservative, usually starting at the low end of the dosing range, reflecting the greater frequency of
decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

8.6 Renal or Hepatic Impairment

The clearance of mirtazapine is reduced in patients with moderate to severe renal or hepatic
impairment. Consequently, plasma mirtazapine levels may be increased in these patient groups,
compared to levels observed in patients without renal or hepatic impairment. Dosage decrease may
be necessary when administering mirtazapine tablets to patients with moderate to severe renal or
hepatic impairment [seeWarnings and Precautions(5.13),Use in Specific Populations(8.5), and
Clinical Pharmacology(12.3)].

Human Experience

In premarketing clinical studies, there were reports of mirtazapine tablets overdose alone or in
combination with other pharmacological agents. Signs and symptoms reported in association with
overdose included disorientation, drowsiness, impaired memory, and tachycardia.
Based on postmarketing reports, serious outcomes (including fatalities) may occur at dosages
higher than the recommended doses, especially with mixed overdoses. In these cases, QT
prolongation and Torsades de Pointes have also been reported [see Warnings and Precautions (5.5),
Adverse Reactions (6.2), and Drug Interactions (7)].

Overdose Management
No specific antidotes for mirtazapine are known.
Contact Poison Control (1-800-222-1222) for the latest recommendations.

Overdose Management

No specific antidotes for mirtazapine are known.
Contact Poison Control (1-800-222-1222) for the latest recommendations.

12.1 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 auto-receptors and heteroreceptors and enhancing central noradrenergic
and serotonergic activity.

12.2 Pharmacodynamics

In preclinical studies, mirtazapine acts as an antagonist at α2-adrenergic inhibitory auto-receptors
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 tablets on QTc interval was assessed in healthy subjects. At a dose of
75 mg (1.67 times the maximum recommended dosage), mirtazapine tablets do 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
tablets

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 (5.14), 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 tablets.
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=11–39 mL/min/1.73 m2 and
approximately 50% in renal impaired patients with GFR=<10 mL/min/1.73 m2) [see Warnings and
Precautions (5.14), Use in Specific Populations (8.6)].
Patients with Hepatic Impairment
Following a single 15-mg oral dose of mirtazapine tablets, 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 (5.12, 5.14), 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 tablets 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 subjects. However, the impairment of motor skills produced by
mirtazapine tablets has been shown to be additive with those caused by diazepam.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis
Carcinogenicity studies were conducted with mirtazapine given in the diet at doses of 2, 20, and
200 mg/kg/day to mice and 2, 20, and 60 mg/kg/day to rats. The highest doses used are
approximately 20 and 12 times the maximum recommended human dose (MRHD) of 45 mg/day,
based on body surface area (mg/m2) in mice and rats, respectively. There was an increased
incidence of hepatocellular adenoma and carcinoma in male mice at the high dose. In rats, there
was an increase in hepatocellular adenoma in females at the mid and high doses and in
hepatocellular tumors and thyroid follicular adenoma/cystadenoma and carcinoma in males at the
high dose.
Mutagenesis
Mirtazapine was not mutagenic or clastogenic and did not induce general DNA damage as
determined in several genotoxicity tests: Ames test, in vitro gene mutation assay in Chinese
hamster V 79 cells, in vitro sister chromatid exchange assay in cultured rabbit lymphocytes, in vivo
bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells.
Impairment of Fertility
In a fertility study in rats, mirtazapine was given at doses up to 100 mg/kg [20 times the maximum
recommended human dose (MRHD), based on body surface area (mg/m2)]. Mating and conception
were not affected by the drug, but estrous cycling was disrupted at doses that were 3 or more
times the MRHD, and pre-implantation losses occurred at 20 times the MRHD.