Highlights Of Prescribing Information

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

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.

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.

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.

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.

Mirtazapine tablets contain mirtazapine. Mirtazapine has a tetracyclic chemical structure and

belongs to the piperazino-azepine group of compounds. It is designated

1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c][2] benzazepine and has the

empirical formula of C17H19N3. Its molecular weight is 265.35. The structural formula is the

following and it is the racemic mixture:

Mirtazapine is a white to creamy white crystalline powder which is practically insoluble in water.

Mirtazapine tablets are available for oral administration as scored film-coated tablets containing 15

or 30 mg of mirtazapine. Each tablet contains the following inactive ingredients: croscarmellose

sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, polyethylene glycol and titanium dioxide. In addition, mirtazapine tablets,

USP 15 mg and 30 mg contains iron oxide yellow and mirtazapine tablets, USP 30 mg contains iron

oxide red

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)].

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.

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.

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.

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.

Rare: goiter, hypothyroidism.

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.

Mirtazapine Tablets, USP

(mir taz’ a peen)

Medication Guide available at www1.apotex.com/products/us

What is the most important information I should know

about mirtazapine tablets?

Mirtazapine tablets may cause serious side effects, including:

• Increased risk of suicidal thoughts or actions in

some children and young adults. Mirtazapine tablets,

and other antidepressant medicines may increase

suicidal thoughts or actions in some people 24 years of

age and younger, especially within the first few

months of treatment or when the dose is changed.

Mirtazapine tablets are not for use in children.

° Depression or other serious mental illnesses are

the most important causes of suicidal thoughts or

How can I watch for and try to prevent suicidal

thoughts and actions?

° Pay close attention to any changes, especially sudden

changes in mood, behavior, thoughts, or feelings, or if

you develop suicidal thoughts or actions. This is very

important when an antidepressant medicine is started

or when the dose is changed.

° Call your healthcare provider right away to report new

or sudden changes in mood, behavior, thoughts, or

feelings.

° Keep all follow-up visits with your healthcare provider

as scheduled. Call your healthcare provider between

visits as needed, especially if you have concerns

about symptoms.

Call your healthcare provider or get emergency medical

help right away if you or your family member have any

of the following symptoms, especially if they are new,

worse, or worry you:

• attempts to commit suicide

• acting aggressive, being angry or violent

• new or worse depression

• panic attacks

• new or worse irritability

• an extreme increase in activity or talking (mania)

• acting on dangerous impulses

• thoughts about suicide or dying

• new or worse anxiety

• feeling very agitated or restless

• trouble sleeping

• other unusual changes in behavior or mood

What are mirtazapine tablets?

Mirtazapine tablets are prescription medicines used to treat

a certain type of depression called Major Depressive

Disorder (MDD) in adults.

It is not known if mirtazapine tablets are safe and effective

for use to treat MDD in children.

Who should not take mirtazapine tablets? Do not take

mirtazapine tablets if you:

• take a Monoamine Oxidase Inhibitor (MAOI)

• have stopped taking an MAOI in the last 14 days

• are being treated with the antibiotic linezolid or

intravenous methylene blue

• if you are allergic to mirtazapine or any of the ingredients

in mirtazapine tablets. See the end of this Medication

Guide for a complete list of ingredients in mirtazapine

tablets

Ask your healthcare provider or pharmacist if you are not

sure if you take an MAOI, including the antibiotic linezolid or

intravenous methylene blue.

Do not start taking an MAOI for at least 14 days after

you stop treatment with mirtazapine tablets.

Before taking mirtazapine tablets, tell your healthcare

provider about all your medical conditions, including if you:​

• have a history of suicide or depression

• have a history or family history of bipolar disorder, mania

or hypomania

• have a low white blood cell count

• have glaucoma (high pressure in the eye)

• have or had heart problems or stroke

• have an abnormal heart beat called QT prolongation or a

family history of QT prolongation

• have seizures

• have high cholesterol or triglyceride levels

• have low sodium levels in your blood

• have or had kidney or liver problems

• have low blood pressure

• are pregnant or plan to become pregnant. It is not known

if mirtazapine tablets will harm your unborn baby.

• Talk to your healthcare provider if you become pregnant

or think you may be pregnant during treatment with

mirtazapine tablets.

• If you become pregnant while taking mirtazapine tablets,

talk to your healthcare provider about registering with

the National Pregnancy Registry for Antidepressants. You

can register by calling 1-844-405-6185 or visiting online

at http://womensmentalhealth.org/clinical-and-researchprograms/

pregnancyregistry/antidepressants/. The

purpose of this registry is to monitor the pregnancy

outcomes in women who have been treated with

mirtazapine tablets at any time during pregnancy.

• are breastfeeding or plan to breastfeed. Mirtazapine may

pass into your breast milk. Talk to your healthcare

provider about the best way to feed your baby during

treatment with mirtazapine tablets.

Tell your healthcare provider about all the medicines

you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

Mirtazapine tablets and other medicines may affect each

other causing possible serious side effects.

Mirtazapine tablets may affect the way other medicines

work and other medicines may affect the way mirtazapine

tablets work.

Especially tell your healthcare provider if you take:

• MAOIs

• medicines to treat migraine headaches known as

triptans

• tricyclic antidepressants

• fentanyl

• lithium

• tramadol

• tryptophan

• buspirone

• amphetamines

• benzodiazepines

• St. John’s Wort

• medicines used to treat mood, anxiety, psychotic or

thought disorders, including selective serotonin reuptake

inhibitors (SSRIs) and serotonin norepinephrine reuptake

inhibitors (SNRIs)

• medicines that may affect your heart rhythm (such as

certain antibiotics and some antipsychotics)

Ask your healthcare provider if you are not sure if you are

taking any of these medicines. Your healthcare provider can

tell you if it is safe to take mirtazapine tablets with your

other medicines.

Do not start or stop any other medicines during treatment

with mirtazapine tablets without talking to your healthcare

provider first. Stopping mirtazapine tablets suddenly may

cause you to have serious side effects. See, "What are the

possible side effects of mirtazapine tablets?"

Know the medicines you take. Keep a list of them to show

to your healthcare provider and pharmacist when you get a

new medicine.

How should I take mirtazapine tablets?

• Take mirtazapine tablets exactly as your healthcare

provider tells you to. Do not change your dose or stop

taking mirtazapine tablets without first talking to your

healthcare provider.

• Your healthcare provider may need to change the dose of

mirtazapine tablets until it is the right dose for you

• Take mirtazapine tablets 1 time each day, preferably in

the evening at bedtime

• If you take too much mirtazapine tablets call your

healthcare provider or poison control center at

1-800-222-1222 right away or go to the nearest hospital

emergency room.

What should I avoid while taking mirtazapine tablets?

• Do not drive, operate heavy machinery, or do other

dangerous activities until you know how mirtazapine

tablets affects you. Mirtazapine tablets can cause

sleepiness or may affect your ability to make decisions,

think clearly, or react quickly.

• Avoid drinking alcohol during treatment with mirtazapine

tablets.

• Avoid taking medicines used to treat anxiety, insomnia,

and seizures, called benzodiazepines, during treatment

with mirtazapine tablets. Ask your healthcare provider if

you are not sure if you take one of these medicines.

What are the possible side effects of mirtazapine tablets?

Mirtazapine tablets may cause serious side effects,

including:

• See, "What is the most important information I

should know about mirtazapine?"

• Low white blood cell count. Tell your healthcare

provider right away if you develop any signs or

symptoms of a low white blood cell count, including:

° fever

° sore throat

° flu-like symptoms

° chills

° mouth and nose sores

° infections

• Serotonin syndrome. A potentially

life-threatening problem called serotonin syndrome can

happen when you take mirtazapine tablets with certain

other medicines. See, "Who should not take

mirtazapine tablets?" Stop taking mirtazapine tablets

and call your healthcare provider or go to the nearest

hospital emergency room right away if you have any of

the following signs and symptoms of serotonin

syndrome:

° agitation

° confusion

° fast heart beat

° dizziness

° flushing

° tremors, stiff muscles, or muscle twitching

° seizures

° seeing or hearing things that are not real

(hallucinations)

° coma

° blood pressure changes

° sweating

° high body temperature (hyperthermia)

° loss of coordination nausea,

° vomiting, diarrhea

• Eye problems (angle-closure glaucoma). Mirtazapine

tablets may cause a certain type of eye problem called

angle-closure glaucoma. Call your healthcare provider if

you have eye pain, changes in your vision, or swelling or

redness in or around the eye. Only some people are at

risk for these problems. You may want to undergo an eye

examination to see if you are at risk and receive

preventative treatment if you are.

• Heart rhythm problems.

• Severe skin reaction. Mirtazapine tablets may cause a

severe skin reaction that may include rash, fever, swollen

glands, and other organ involvement such as liver,

kidney, lung and heart. The reaction may sometimes be

fatal. Tell your healthcare provider right away if you

experience any of these signs.

• Increased appetite and weight gain.

• Sleepiness. See, "What should I avoid while taking

mirtazapine tablets?"

• Mania or hypomania (manic episodes) in people who

have a history of bipolar disorder. Symptoms may

include:

° greatly increased energy

° racing thoughts

° unusually grand ideas

° talking more or faster than usual

° severe trouble sleeping

° reckless behavior

° excessive happiness or irritability

• Seizures (convulsions).

• Increased fat levels (cholesterol and triglycerides) in

your blood.

• Low sodium levels in your blood (hyponatremia). Low

sodium levels in your blood may be serious and may

cause death. Elderly people may be at greater risk for

this. Signs and Symptoms of low sodium levels in your

blood may include:

° headache

° memory changes

° weakness and unsteadiness on your feet which can

lead to falls

° difficulty concentrating

° confusion

In severe or more sudden cases, signs and symptoms

include:

° hallucinations (seeing or hearing things that are not

real)

° seizures

° respiratory arrest

° fainting

° coma

° death

• Changes in liver function tests.

• Discontinuation syndrome. Suddenly stopping

mirtazapine tablets may cause you to have serious side

effects. Your healthcare provider may want to decrease

your dose slowly. Symptoms may include:

° dizziness

° irritability and agitation

° anxiety

° sweating

° seizures

° ringing in your ears (tinnitus)

° nausea and vomiting

° problems sleeping

° tiredness

° confusion

° electric shock sensation (paresthesia)

° shaking (tremor)

° headache

° abnormal dreams

° changes in your mood

° hypomania

The most common side effects of mirtazapine tablets

include:

• sleepiness

• increased appetite

• weight gain

• dizziness

These are not all the possible side effects of mirtazapine

tablets.

Call your doctor for medical advice about side effects. You

may report side effects to FDA at 1-800-FDA-1088.

How should I store mirtazapine tablets?

• Store mirtazapine tablets at room temperature between

68°F to 77°F (20°C to 25°C).

• Keep mirtazapine tablets away from light and moisture.

Keep mirtazapine tablets, and all medicines out of the

reach of children.

General information about the safe and effective use of

mirtazapine tablets.

Medicines are sometimes prescribed for purposes other

than those listed in a Medication Guide. Do not use

mirtazapine tablets for a condition for which it was not

prescribed. Do not give mirtazapine tablets to other people,

even if they have the same symptoms that you have. It may

harm them. You can ask your healthcare provider or

pharmacist for information about mirtazapine tablets that is

written for healthcare professionals.

What are the ingredients in mirtazapine tablets?

Active ingredient: mirtazapine

Inactive ingredients:

15 mg tablets: Croscarmellose sodium, hydroxypropyl

cellulose, hypromellose, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, polyethylene glycol,

titanium dioxide and iron oxide yellow.

30 mg tablets: Croscarmellose sodium, hydroxypropyl

cellulose, hypromellose, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, polyethylene glycol,

titanium dioxide and iron oxide yellow and iron oxide red.

Distributed By:

McKesson Corporation dba SKY Packaging

Memphis, TN 38141

Manufactured By:

Apotex Inc.

Toronto, Ontario

Canada M9L 1T9

Revised: 02/2024

21495-2

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)].

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)].

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.

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.

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

The efficacy of mirtazapine tablets as a treatment for major depressive disorder was established in

4 placebo- controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major

depressive disorder. Patients were titrated with mirtazapine tablets from a dose range of 5 mg to

35 mg/day. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21

to 32 mg/day. Overall, these studies demonstrated mirtazapine tablets to be superior to placebo on

at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total

score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression

Rating Scale (MADRS). Superiority of mirtazapine tablets over placebo was also found for certain

factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor.

Examination of age and gender subsets of the population did not reveal any differential

responsiveness on the basis of these subgroupings.

In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had

responded during an initial 8 to 12 weeks of acute treatment on mirtazapine tablets were

randomized to continuation of mirtazapine tablets or placebo for up to 40 weeks of observation for

relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score

of

≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8

to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was

determined by the individual investigators. Patients receiving continued mirtazapine tablets

treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to

those receiving placebo. This pattern was demonstrated in both male and female patients.

Mirtazapine tablets are contraindicated in patients:

• Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous

methylene blue) because of an increased risk of serotonin syndrome [see Warnings and

Precautions (5.3), Drug Interactions (7)].

• With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine

tablets. Severe skin reactions, including drug reaction with eosinophilia and systemic

symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and

toxic epidermal necrolysis have been reported following the use of mirtazapine tablets [see

Warnings and Precautions (5.6), Adverse Reactions (6.2)].

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.

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 (5.6)]

• Somnolence [see Warnings and Precautions (5.7)]

• Activation of Mania or Hypomania [see Warnings and Precautions (5.8)]

• Seizures [see Warnings and Precautions (5.9)]

• Elevated Cholesterol and Triglycerides [see Warnings and Precautions (5.10)]

• Hyponatremia [see Warnings and Precautions (5.11)]

• Transaminase Elevations [see Warnings and Precautions (5.12)]

• Discontinuation Syndrome [see Warnings and Precautions (5.13)]

• Use in Patients with Concomitant Illness [see Warnings and Precautions (5.14)]

Table 5 includes clinically important drug interactions with Mirtazapine Tablets [see Clinical

Pharmacology (12.3)].

No specific antidotes for mirtazapine are known.

Contact Poison Control (1-800-222-1222) for the latest recommendations.

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

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.

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.

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.

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)].

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.

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

Mirtazapine Tablets are indicated for the treatment of major depressive disorder (MDD) in adults

[see Clinical Studies (14)].

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.

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.

Rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.

Mirtazapine Tablets, USP 15 mg are available for oral administration as pale yellow, oval-shaped,

scored, film-coated tablets imprinted "APO" on one side and "MI" bisect "15" on the other side.

Mirtazapine Tablets, USP 30 mg are available for oral administration as light pink, oval-shaped,

scored, film-coated tablets imprinted "APO" on one side and "MI" bisect "30" on the other side.

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)].

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

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)].

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

• Geriatric Use: Use with caution in elderly patients. (5.12, 5.15, 8.5)

• Renal impairment: Dosage decrease may be needed in patients with moderate to severe renal

impairment. (8.6)

• Hepatic impairment: Dosage decrease may be needed in patients with hepatic impairment. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Revised: 02/2024

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)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during

treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms

to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Agranulocytosis

Advise patients to contact their physician if they experience fever, chills, sore throat, mucous

membrane ulceration, flu-like complaints, or other symptoms that might suggest infection [see

Warnings and Precautions (5.2)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of

mirtazapine tablets with other serotonergic drugs including triptans, tricyclic antidepressants,

fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs

that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric

disorders and also others, such as linezolid). Advise patients to contact their healthcare provider or

report to the emergency room if they experience signs or symptoms of serotonin syndrome [see

Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3), Drug

Interactions (7)].

QT Prolongation and Torsades de Pointes

Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have

heart palpitations [see Warnings and Precautions (5.5), Drug Interactions (7), Overdosage (10)].

Advise patients to inform physicians that they are taking mirtazapine tablets before any new drug is

taken.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Advise patients to report to their healthcare provider at the earliest onset of fever, rash, swollen

lymph nodes, or other signs and symptoms suggestive of Drug Reaction with Eosinophilia and

Systemic Symptoms (DRESS) [see Contraindications (4), Warnings and Precautions (5.6)].

Somnolence

Advise patients that mirtazapine tablets may impair judgment, thinking, and particularly, motor

skills, because of its prominent sedative effect. Caution patients about performing activities

requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle,

until they are reasonably certain that mirtazapine tablets therapy does not adversely affect their

ability to engage in such activities. [see Warnings and Precautions (5.7)].

Alcohol

Advise patients to avoid alcohol while taking mirtazapine tablets [see Warnings and Precautions

(5.7), Drug Interactions (7)].

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and

instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions

(5.8)].

Discontinuation Syndrome

Advise patients not to abruptly discontinue mirtazapine tablets and to discuss any tapering regimen

with their healthcare provider. Adverse reactions can occur when mirtazapine tablets are

discontinued [see Dosage and Administration (2.6), Warnings and Precautions (5.13)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash,

hives, swelling, or difficulty breathing [see Contraindications (4), Adverse Reactions (6.2)].

Pregnancy

• Advise patients to notify their physician if they become pregnant or intend to become pregnant

during mirtazapine tablets therapy.

• Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes

in women exposed to mirtazapine tablets during pregnancy [see Use in Specific Populations

(8.2)].

Lactation

Advise patients to notify their physician if they are breastfeeding an infant [see Use in Specific

Populations (8.2)].

Angle-Closure Glaucoma

Patients should be advised that taking mirtazapine can cause mild pupillary dilation, which in

susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is

almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be

treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure

glaucoma. Patients may wish to be examined to determine whether they are susceptible to

angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see

Warnings and Precautions (5.4).]

Dispense with Medication Guide available at www1.apotex.com/products/us

Distributed By:

McKesson Corporation dba SKY Packaging

Memphis, TN 38141

Manufactured by:

Apotex Inc

Toronto, Ontario

Canada M9L 1T9

Revised: 02/2024

21495-2

Frequent : thirst; infrequent : dehydration, weight loss; rare : gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia.

Mirtazapine tablets are supplied as:

Mirtazapine Tablets, USP 15 mg are available for oral administration as pale yellow, oval-shaped,

scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “15” on the other side.

They are supplied as follows:

Boxes of 10x10 UD 100 count NDC 63739-098-10

Mirtazapine Tablets, USP 30 mg are available for oral administration as light pink, oval-shaped,

scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “30” on the other side.

They are supplied as follows:

Boxes of 10x10 UD 100 count NDC 63739-099-10

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see

USP Controlled Room Temperature]. Protect from light and moisture.

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.

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)].

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.

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.

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).

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)].

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.

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.

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)].

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.

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)].

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)].

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.

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

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.

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.

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.

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.

Mirtazapine tablets contain mirtazapine. Mirtazapine has a tetracyclic chemical structure and

belongs to the piperazino-azepine group of compounds. It is designated

1,2,3,4,10,14b-hexahydro-2-methylpyrazino [2,1-a] pyrido [2,3-c][2] benzazepine and has the

empirical formula of C17H19N3. Its molecular weight is 265.35. The structural formula is the

following and it is the racemic mixture:

Mirtazapine is a white to creamy white crystalline powder which is practically insoluble in water.

Mirtazapine tablets are available for oral administration as scored film-coated tablets containing 15

or 30 mg of mirtazapine. Each tablet contains the following inactive ingredients: croscarmellose

sodium, hydroxypropyl cellulose, hypromellose, lactose monohydrate, magnesium stearate,

microcrystalline cellulose, polyethylene glycol and titanium dioxide. In addition, mirtazapine tablets,

USP 15 mg and 30 mg contains iron oxide yellow and mirtazapine tablets, USP 30 mg contains iron

oxide red

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)].

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.

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.

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.

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.

Rare: goiter, hypothyroidism.

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.

Mirtazapine Tablets, USP

(mir taz’ a peen)

Medication Guide available at www1.apotex.com/products/us

What is the most important information I should know

about mirtazapine tablets?

Mirtazapine tablets may cause serious side effects, including:

• Increased risk of suicidal thoughts or actions in

some children and young adults. Mirtazapine tablets,

and other antidepressant medicines may increase

suicidal thoughts or actions in some people 24 years of

age and younger, especially within the first few

months of treatment or when the dose is changed.

Mirtazapine tablets are not for use in children.

° Depression or other serious mental illnesses are

the most important causes of suicidal thoughts or

How can I watch for and try to prevent suicidal

thoughts and actions?

° Pay close attention to any changes, especially sudden

changes in mood, behavior, thoughts, or feelings, or if

you develop suicidal thoughts or actions. This is very

important when an antidepressant medicine is started

or when the dose is changed.

° Call your healthcare provider right away to report new

or sudden changes in mood, behavior, thoughts, or

feelings.

° Keep all follow-up visits with your healthcare provider

as scheduled. Call your healthcare provider between

visits as needed, especially if you have concerns

about symptoms.

Call your healthcare provider or get emergency medical

help right away if you or your family member have any

of the following symptoms, especially if they are new,

worse, or worry you:

• attempts to commit suicide

• acting aggressive, being angry or violent

• new or worse depression

• panic attacks

• new or worse irritability

• an extreme increase in activity or talking (mania)

• acting on dangerous impulses

• thoughts about suicide or dying

• new or worse anxiety

• feeling very agitated or restless

• trouble sleeping

• other unusual changes in behavior or mood

What are mirtazapine tablets?

Mirtazapine tablets are prescription medicines used to treat

a certain type of depression called Major Depressive

Disorder (MDD) in adults.

It is not known if mirtazapine tablets are safe and effective

for use to treat MDD in children.

Who should not take mirtazapine tablets? Do not take

mirtazapine tablets if you:

• take a Monoamine Oxidase Inhibitor (MAOI)

• have stopped taking an MAOI in the last 14 days

• are being treated with the antibiotic linezolid or

intravenous methylene blue

• if you are allergic to mirtazapine or any of the ingredients

in mirtazapine tablets. See the end of this Medication

Guide for a complete list of ingredients in mirtazapine

tablets

Ask your healthcare provider or pharmacist if you are not

sure if you take an MAOI, including the antibiotic linezolid or

intravenous methylene blue.

Do not start taking an MAOI for at least 14 days after

you stop treatment with mirtazapine tablets.

Before taking mirtazapine tablets, tell your healthcare

provider about all your medical conditions, including if you:​

• have a history of suicide or depression

• have a history or family history of bipolar disorder, mania

or hypomania

• have a low white blood cell count

• have glaucoma (high pressure in the eye)

• have or had heart problems or stroke

• have an abnormal heart beat called QT prolongation or a

family history of QT prolongation

• have seizures

• have high cholesterol or triglyceride levels

• have low sodium levels in your blood

• have or had kidney or liver problems

• have low blood pressure

• are pregnant or plan to become pregnant. It is not known

if mirtazapine tablets will harm your unborn baby.

• Talk to your healthcare provider if you become pregnant

or think you may be pregnant during treatment with

mirtazapine tablets.

• If you become pregnant while taking mirtazapine tablets,

talk to your healthcare provider about registering with

the National Pregnancy Registry for Antidepressants. You

can register by calling 1-844-405-6185 or visiting online

at http://womensmentalhealth.org/clinical-and-researchprograms/

pregnancyregistry/antidepressants/. The

purpose of this registry is to monitor the pregnancy

outcomes in women who have been treated with

mirtazapine tablets at any time during pregnancy.

• are breastfeeding or plan to breastfeed. Mirtazapine may

pass into your breast milk. Talk to your healthcare

provider about the best way to feed your baby during

treatment with mirtazapine tablets.

Tell your healthcare provider about all the medicines

you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements.

Mirtazapine tablets and other medicines may affect each

other causing possible serious side effects.

Mirtazapine tablets may affect the way other medicines

work and other medicines may affect the way mirtazapine

tablets work.

Especially tell your healthcare provider if you take:

• MAOIs

• medicines to treat migraine headaches known as

triptans

• tricyclic antidepressants

• fentanyl

• lithium

• tramadol

• tryptophan

• buspirone

• amphetamines

• benzodiazepines

• St. John’s Wort

• medicines used to treat mood, anxiety, psychotic or

thought disorders, including selective serotonin reuptake

inhibitors (SSRIs) and serotonin norepinephrine reuptake

inhibitors (SNRIs)

• medicines that may affect your heart rhythm (such as

certain antibiotics and some antipsychotics)

Ask your healthcare provider if you are not sure if you are

taking any of these medicines. Your healthcare provider can

tell you if it is safe to take mirtazapine tablets with your

other medicines.

Do not start or stop any other medicines during treatment

with mirtazapine tablets without talking to your healthcare

provider first. Stopping mirtazapine tablets suddenly may

cause you to have serious side effects. See, "What are the

possible side effects of mirtazapine tablets?"

Know the medicines you take. Keep a list of them to show

to your healthcare provider and pharmacist when you get a

new medicine.

How should I take mirtazapine tablets?

• Take mirtazapine tablets exactly as your healthcare

provider tells you to. Do not change your dose or stop

taking mirtazapine tablets without first talking to your

healthcare provider.

• Your healthcare provider may need to change the dose of

mirtazapine tablets until it is the right dose for you

• Take mirtazapine tablets 1 time each day, preferably in

the evening at bedtime

• If you take too much mirtazapine tablets call your

healthcare provider or poison control center at

1-800-222-1222 right away or go to the nearest hospital

emergency room.

What should I avoid while taking mirtazapine tablets?

• Do not drive, operate heavy machinery, or do other

dangerous activities until you know how mirtazapine

tablets affects you. Mirtazapine tablets can cause

sleepiness or may affect your ability to make decisions,

think clearly, or react quickly.

• Avoid drinking alcohol during treatment with mirtazapine

tablets.

• Avoid taking medicines used to treat anxiety, insomnia,

and seizures, called benzodiazepines, during treatment

with mirtazapine tablets. Ask your healthcare provider if

you are not sure if you take one of these medicines.

What are the possible side effects of mirtazapine tablets?

Mirtazapine tablets may cause serious side effects,

including:

• See, "What is the most important information I

should know about mirtazapine?"

• Low white blood cell count. Tell your healthcare

provider right away if you develop any signs or

symptoms of a low white blood cell count, including:

° fever

° sore throat

° flu-like symptoms

° chills

° mouth and nose sores

° infections

• Serotonin syndrome. A potentially

life-threatening problem called serotonin syndrome can

happen when you take mirtazapine tablets with certain

other medicines. See, "Who should not take

mirtazapine tablets?" Stop taking mirtazapine tablets

and call your healthcare provider or go to the nearest

hospital emergency room right away if you have any of

the following signs and symptoms of serotonin

syndrome:

° agitation

° confusion

° fast heart beat

° dizziness

° flushing

° tremors, stiff muscles, or muscle twitching

° seizures

° seeing or hearing things that are not real

(hallucinations)

° coma

° blood pressure changes

° sweating

° high body temperature (hyperthermia)

° loss of coordination nausea,

° vomiting, diarrhea

• Eye problems (angle-closure glaucoma). Mirtazapine

tablets may cause a certain type of eye problem called

angle-closure glaucoma. Call your healthcare provider if

you have eye pain, changes in your vision, or swelling or

redness in or around the eye. Only some people are at

risk for these problems. You may want to undergo an eye

examination to see if you are at risk and receive

preventative treatment if you are.

• Heart rhythm problems.

• Severe skin reaction. Mirtazapine tablets may cause a

severe skin reaction that may include rash, fever, swollen

glands, and other organ involvement such as liver,

kidney, lung and heart. The reaction may sometimes be

fatal. Tell your healthcare provider right away if you

experience any of these signs.

• Increased appetite and weight gain.

• Sleepiness. See, "What should I avoid while taking

mirtazapine tablets?"

• Mania or hypomania (manic episodes) in people who

have a history of bipolar disorder. Symptoms may

include:

° greatly increased energy

° racing thoughts

° unusually grand ideas

° talking more or faster than usual

° severe trouble sleeping

° reckless behavior

° excessive happiness or irritability

• Seizures (convulsions).

• Increased fat levels (cholesterol and triglycerides) in

your blood.

• Low sodium levels in your blood (hyponatremia). Low

sodium levels in your blood may be serious and may

cause death. Elderly people may be at greater risk for

this. Signs and Symptoms of low sodium levels in your

blood may include:

° headache

° memory changes

° weakness and unsteadiness on your feet which can

lead to falls

° difficulty concentrating

° confusion

In severe or more sudden cases, signs and symptoms

include:

° hallucinations (seeing or hearing things that are not

real)

° seizures

° respiratory arrest

° fainting

° coma

° death

• Changes in liver function tests.

• Discontinuation syndrome. Suddenly stopping

mirtazapine tablets may cause you to have serious side

effects. Your healthcare provider may want to decrease

your dose slowly. Symptoms may include:

° dizziness

° irritability and agitation

° anxiety

° sweating

° seizures

° ringing in your ears (tinnitus)

° nausea and vomiting

° problems sleeping

° tiredness

° confusion

° electric shock sensation (paresthesia)

° shaking (tremor)

° headache

° abnormal dreams

° changes in your mood

° hypomania

The most common side effects of mirtazapine tablets

include:

• sleepiness

• increased appetite

• weight gain

• dizziness

These are not all the possible side effects of mirtazapine

tablets.

Call your doctor for medical advice about side effects. You

may report side effects to FDA at 1-800-FDA-1088.

How should I store mirtazapine tablets?

• Store mirtazapine tablets at room temperature between

68°F to 77°F (20°C to 25°C).

• Keep mirtazapine tablets away from light and moisture.

Keep mirtazapine tablets, and all medicines out of the

reach of children.

General information about the safe and effective use of

mirtazapine tablets.

Medicines are sometimes prescribed for purposes other

than those listed in a Medication Guide. Do not use

mirtazapine tablets for a condition for which it was not

prescribed. Do not give mirtazapine tablets to other people,

even if they have the same symptoms that you have. It may

harm them. You can ask your healthcare provider or

pharmacist for information about mirtazapine tablets that is

written for healthcare professionals.

What are the ingredients in mirtazapine tablets?

Active ingredient: mirtazapine

Inactive ingredients:

15 mg tablets: Croscarmellose sodium, hydroxypropyl

cellulose, hypromellose, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, polyethylene glycol,

titanium dioxide and iron oxide yellow.

30 mg tablets: Croscarmellose sodium, hydroxypropyl

cellulose, hypromellose, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, polyethylene glycol,

titanium dioxide and iron oxide yellow and iron oxide red.

Distributed By:

McKesson Corporation dba SKY Packaging

Memphis, TN 38141

Manufactured By:

Apotex Inc.

Toronto, Ontario

Canada M9L 1T9

Revised: 02/2024

21495-2

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)].

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)].

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.

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.

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

The efficacy of mirtazapine tablets as a treatment for major depressive disorder was established in

4 placebo- controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major

depressive disorder. Patients were titrated with mirtazapine tablets from a dose range of 5 mg to

35 mg/day. The mean mirtazapine dose for patients who completed these 4 studies ranged from 21

to 32 mg/day. Overall, these studies demonstrated mirtazapine tablets to be superior to placebo on

at least 3 of the following 4 measures: 21-Item Hamilton Depression Rating Scale (HDRS) total

score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression

Rating Scale (MADRS). Superiority of mirtazapine tablets over placebo was also found for certain

factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor.

Examination of age and gender subsets of the population did not reveal any differential

responsiveness on the basis of these subgroupings.

In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had

responded during an initial 8 to 12 weeks of acute treatment on mirtazapine tablets were

randomized to continuation of mirtazapine tablets or placebo for up to 40 weeks of observation for

relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score

of

≤8 and a CGI-Improvement score of 1 or 2 at 2 consecutive visits beginning with week 6 of the 8

to 12 weeks in the open-label phase of the study. Relapse during the double-blind phase was

determined by the individual investigators. Patients receiving continued mirtazapine tablets

treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to

those receiving placebo. This pattern was demonstrated in both male and female patients.

Mirtazapine tablets are contraindicated in patients:

• Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous

methylene blue) because of an increased risk of serotonin syndrome [see Warnings and

Precautions (5.3), Drug Interactions (7)].

• With a known hypersensitivity to mirtazapine or to any of the excipients in mirtazapine

tablets. Severe skin reactions, including drug reaction with eosinophilia and systemic

symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and

toxic epidermal necrolysis have been reported following the use of mirtazapine tablets [see

Warnings and Precautions (5.6), Adverse Reactions (6.2)].

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.

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 (5.6)]

• Somnolence [see Warnings and Precautions (5.7)]

• Activation of Mania or Hypomania [see Warnings and Precautions (5.8)]

• Seizures [see Warnings and Precautions (5.9)]

• Elevated Cholesterol and Triglycerides [see Warnings and Precautions (5.10)]

• Hyponatremia [see Warnings and Precautions (5.11)]

• Transaminase Elevations [see Warnings and Precautions (5.12)]

• Discontinuation Syndrome [see Warnings and Precautions (5.13)]

• Use in Patients with Concomitant Illness [see Warnings and Precautions (5.14)]

Table 5 includes clinically important drug interactions with Mirtazapine Tablets [see Clinical

Pharmacology (12.3)].

No specific antidotes for mirtazapine are known.

Contact Poison Control (1-800-222-1222) for the latest recommendations.

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

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.

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.

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.

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)].

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.

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

Mirtazapine Tablets are indicated for the treatment of major depressive disorder (MDD) in adults

[see Clinical Studies (14)].

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.

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.

Rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.

Mirtazapine Tablets, USP 15 mg are available for oral administration as pale yellow, oval-shaped,

scored, film-coated tablets imprinted "APO" on one side and "MI" bisect "15" on the other side.

Mirtazapine Tablets, USP 30 mg are available for oral administration as light pink, oval-shaped,

scored, film-coated tablets imprinted "APO" on one side and "MI" bisect "30" on the other side.

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)].

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

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)].

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

• Geriatric Use: Use with caution in elderly patients. (5.12, 5.15, 8.5)

• Renal impairment: Dosage decrease may be needed in patients with moderate to severe renal

impairment. (8.6)

• Hepatic impairment: Dosage decrease may be needed in patients with hepatic impairment. (8.6)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide

Revised: 02/2024

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)].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Suicidal Thoughts and Behaviors

Advise patients and caregivers to look for the emergence of suicidality, especially early during

treatment and when the dosage is adjusted up or down, and instruct them to report such symptoms

to the healthcare provider [see Boxed Warning and Warnings and Precautions (5.1)].

Agranulocytosis

Advise patients to contact their physician if they experience fever, chills, sore throat, mucous

membrane ulceration, flu-like complaints, or other symptoms that might suggest infection [see

Warnings and Precautions (5.2)].

Serotonin Syndrome

Caution patients about the risk of serotonin syndrome, particularly with the concomitant use of

mirtazapine tablets with other serotonergic drugs including triptans, tricyclic antidepressants,

fentanyl, lithium, tramadol, tryptophan, buspirone, amphetamines, St. John’s Wort, and with drugs

that impair metabolism of serotonin (in particular, MAOIs, both those intended to treat psychiatric

disorders and also others, such as linezolid). Advise patients to contact their healthcare provider or

report to the emergency room if they experience signs or symptoms of serotonin syndrome [see

Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3), Drug

Interactions (7)].

QT Prolongation and Torsades de Pointes

Inform patients to consult their physician immediately if they feel faint, lose consciousness, or have

heart palpitations [see Warnings and Precautions (5.5), Drug Interactions (7), Overdosage (10)].

Advise patients to inform physicians that they are taking mirtazapine tablets before any new drug is

taken.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)

Advise patients to report to their healthcare provider at the earliest onset of fever, rash, swollen

lymph nodes, or other signs and symptoms suggestive of Drug Reaction with Eosinophilia and

Systemic Symptoms (DRESS) [see Contraindications (4), Warnings and Precautions (5.6)].

Somnolence

Advise patients that mirtazapine tablets may impair judgment, thinking, and particularly, motor

skills, because of its prominent sedative effect. Caution patients about performing activities

requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle,

until they are reasonably certain that mirtazapine tablets therapy does not adversely affect their

ability to engage in such activities. [see Warnings and Precautions (5.7)].

Alcohol

Advise patients to avoid alcohol while taking mirtazapine tablets [see Warnings and Precautions

(5.7), Drug Interactions (7)].

Activation of Mania/Hypomania

Advise patients and their caregivers to observe for signs of activation of mania/hypomania and

instruct them to report such symptoms to the healthcare provider [see Warnings and Precautions

(5.8)].

Discontinuation Syndrome

Advise patients not to abruptly discontinue mirtazapine tablets and to discuss any tapering regimen

with their healthcare provider. Adverse reactions can occur when mirtazapine tablets are

discontinued [see Dosage and Administration (2.6), Warnings and Precautions (5.13)].

Allergic Reactions

Advise patients to notify their healthcare provider if they develop an allergic reaction such as rash,

hives, swelling, or difficulty breathing [see Contraindications (4), Adverse Reactions (6.2)].

Pregnancy

• Advise patients to notify their physician if they become pregnant or intend to become pregnant

during mirtazapine tablets therapy.

• Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes

in women exposed to mirtazapine tablets during pregnancy [see Use in Specific Populations

(8.2)].

Lactation

Advise patients to notify their physician if they are breastfeeding an infant [see Use in Specific

Populations (8.2)].

Angle-Closure Glaucoma

Patients should be advised that taking mirtazapine can cause mild pupillary dilation, which in

susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is

almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be

treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure

glaucoma. Patients may wish to be examined to determine whether they are susceptible to

angle-closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible [see

Warnings and Precautions (5.4).]

Dispense with Medication Guide available at www1.apotex.com/products/us

Distributed By:

McKesson Corporation dba SKY Packaging

Memphis, TN 38141

Manufactured by:

Apotex Inc

Toronto, Ontario

Canada M9L 1T9

Revised: 02/2024

21495-2

Frequent : thirst; infrequent : dehydration, weight loss; rare : gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia.

Mirtazapine tablets are supplied as:

Mirtazapine Tablets, USP 15 mg are available for oral administration as pale yellow, oval-shaped,

scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “15” on the other side.

They are supplied as follows:

Boxes of 10x10 UD 100 count NDC 63739-098-10

Mirtazapine Tablets, USP 30 mg are available for oral administration as light pink, oval-shaped,

scored, film-coated tablets imprinted “APO” on one side and “MI” bisect “30” on the other side.

They are supplied as follows:

Boxes of 10x10 UD 100 count NDC 63739-099-10

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see

USP Controlled Room Temperature]. Protect from light and moisture.

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.

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)].

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.

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.

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).

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)].

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.

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.

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)].

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.

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)].

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)].

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.