2.1 Recommended Dosage

The recommended starting dose of 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 (5.9)].

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 CYP3A4 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 Tablet Treatment

Adverse reactions may occur upon discontinuation or dose reduction of mirtazapine tablets [see Warnings and Precautions (5.14)] . 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/mm 3with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC <500/mm 3without 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 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 are 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 tablets 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 tablet-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 tablet-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 tablets do 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 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 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.

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 4 enumerates adverse reactions that occurred in ≥1% of mirtazapine tablet-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 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.

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 disorders: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/m 2body surface area. However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m 2body 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/m 2body 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/m 2body 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/m 2body surface area. Oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/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/m 2body surface area. The cause of these deaths is not known. The no effect dose level is 3 times the MRHD based on mg/m 2body 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 Warningand 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 tablet-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 tablet-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 [see Warnings and Precautions (5.13), Use in Specific Populations (8.5), and Clinical Pharmacology (12.3)] .

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 α 2-adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.

12.2 Pharmacodynamics

In preclinical studies, mirtazapine acts as an antagonist at α 2-adrenergic inhibitory autoreceptors and heteroreceptors and as an antagonist at serotonin 5-HT 2and 5-HT 3receptors. Mirtazapine has no significant affinity for the 5-HT 1Aand 5-HT 1Breceptors.

Mirtazapine also acts as an antagonist of histamine (H 1) receptors, peripheral α 1-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 (H 1) receptors and peripheral α 1-adrenergic receptors, respectively).

Cardiac Electrophysiology

The effect of mirtazapine on QTc interval was assessed in healthy subjects. At a dose of 75 mg (1.67 times the maximum recommended dosage), mirtazapine does 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 biotransformation 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 (5.15),  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 m 2 and approximately 50% in renal impaired patients with GFR=<10 mL/min/1.73 m 2)  [see  Warnings and Precautions (5.15),  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 (5.13,  5.15),  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 co-administered 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/m 2) 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 determine 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/m 2)]. 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.