Mirtazapine

Screening Patients for Bipolar Disorder

Agranulocytosis

Serotonin Syndrome

The development of a potentially life-threatening serotonin syndrome has been reported with SNRIs and SSRIs, including mirtazapine, alone but particularly with concomitant use of other serotonergic drugs (including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, tryptophan, buspirone, and 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 and intravenous methylene blue).

Serotonin syndrome 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/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome.

The concomitant use of mirtazapine with MAOIs intended to treat psychiatric disorders is contraindicated. Mirtazapine should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue. All reports with methylene blue that provided information on the route of administration involved intravenous administration in the dose range of 1 mg/kg to 8 mg/kg. No reports involved the administration of methylene blue by other routes (such as oral tablets or local tissue injection) or at lower doses. There may be circumstances when it is necessary to initiate treatment with an MAOI such as linezolid or intravenous methylene blue in a patient taking mirtazapine. Mirtazapine should be discontinued before initiating treatment with the MAOI (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).

If concomitant use of mirtazapine with other serotonergic drugs, including triptans, tricyclic antidepressants, fentanyl, lithium, tramadol, buspirone, tryptophan, and St. John's wort, is clinically warranted, be aware of a potential increased risk for serotonin syndrome, particularly during treatment initiation and dose increases.

Treatment with mirtazapine and any concomitant serotonergic agents should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated.

PRECAUTIONS

General

Discontinuation Symptoms

Akathisia/Psychomotor Restlessness

Hyponatremia

Somnolence

Dizziness

Increased Appetite/Weight Gain

Cholesterol/Triglycerides

Transaminase Elevations

Activation of Mania/Hypomania

Seizure

Use in Patients with Concomitant Illness

Information for Patients

Clinical Worsening and Suicide Risk

Agranulocytosis

Interference with Cognitive and Motor Performance

Completing Course of Therapy

Concomitant Medication

Alcohol

Pregnancy

Nursing

Laboratory Tests

Drug Interactions

Monoamine Oxidase Inhibitors

Serotonergic Drugs

Drugs Affecting Hepatic Metabolism

Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes

CYP Enzyme Inhibitors

Other Drug-Drug Interactions

Alcohol

Diazepam

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Mutagenesis

Impairment of Fertility

Pregnancy

Teratogenic Effects

Nursing Mothers

Pediatric Use

Geriatric Use

MIRTAZAPINE ADVERSE REACTIONS

Associated with Discontinuation of Treatment

Commonly Observed Adverse Events in U.S. Controlled Clinical Trials

Adverse Events Occurring at an Incidence of 1% or More Among Mirtazapine-Treated Patients

ECG Changes

Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine

Other Adverse Events Observed During Postmarketing Evaluation of Mirtazapine

DRUG ABUSE AND DEPENDENCE

Controlled Substance Class

Physical and Psychological Dependence

OVERDOSAGE

Human Experience

Overdose Management

MIRTAZAPINE DOSAGE AND ADMINISTRATION

Initial Treatment

Elderly and Patients with Renal or Hepatic Impairment

Maintenance/Extended Treatment

Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Intended to Treat Psychiatric Disorders

At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and initiation of therapy with mirtazapine tablets. Conversely, at least 14 days should be allowed after stopping mirtazapine tablets before starting an MAOI intended to treat psychiatric disorders (see CONTRAINDICATIONS).

Use of Mirtazapine Tablets With Other MAOIs, Such as Linezolid or Methylene Blue

Do not start mirtazapine tablets in a patient who is being treated with linezolid or intravenous methylene blue because there is an increased risk of serotonin syndrome. In a patient who requires more urgent treatment of a psychiatric condition, other interventions, including hospitalization, should be considered (see CONTRAINDICATIONS).

In some cases, a patient already receiving therapy with mirtazapine tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of serotonin syndrome in a particular patient, mirtazapine tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for symptoms of serotonin syndrome for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with mirtazapine tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue (see WARNINGS).

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with mirtazapine tablets is unclear. The clinician should, nevertheless, be aware of the possibility of emergent symptoms of serotonin syndrome with such use (see WARNINGS).

Discontinuation of Mirtazapine Tablets Treatment

HOW SUPPLIED

Medication Guide

• Mirtazapine tablets and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.
• Depression or other serious mental illnesses are the most important causes of suicidal thoughts or actions.
• Watch for these changes and call your healthcare provider right away if you notice:
  • New or sudden changes in mood, behavior, actions, thoughts, or feelings, especially if severe.
  • Pay particular attention to such changes when mirtazapine tablets are started or when the dose is changed.

• attempts to commit suicide
• acting on dangerous impulses
• acting aggressive or violent
• thoughts about suicide or dying
• new or worse depression
• new or worse anxiety or panic attacks
• feeling agitated, restless, angry or irritable
• trouble sleeping
• an increase in activity or talking more than what is normal for you
• other unusual changes in behavior or mood

• greatly increased energy
• severe trouble sleeping
• racing thoughts
• reckless behavior
• unusually grand ideas
• excessive happiness or irritability
• talking more or faster than usual

• agitation, hallucinations, coma or other changes in mental status
• coordination problems or muscle twitching (overactive reflexes)
• racing heartbeat, high or low blood pressure
• sweating or fever
• nausea, vomiting, or diarrhea
• muscle rigidity

• headache
• weakness or feeling unsteady
• confusion, problems concentrating or thinking or memory problems

• severe rash with skin swelling (including on the palms of the hands and soles of the feet)
• painful reddening of the skin and/or blisters/ulcers on the body or in the mouth

• rash, itchy welts (hives) or blisters, alone or with fever or joint pain

• dizziness
• abnormal dreams
• agitation
• anxiety
• fatigue
• confusion
• headache
• shaking
• tingling sensation
• nausea, vomiting
• sweating

Who should not take mirtazapine tablets?

Do not take mirtazapine tablets:

• 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.
• if you take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.
• Do not take an MAOI within 2 weeks of stopping mirtazapine tablets unless directed to do so by your physician.
• Do not start mirtazapine tablets if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your physician.

• high fever
• uncontrolled muscle spasms
• stiff muscles
• rapid changes in heart rate or blood pressure
• confusion
• loss of consciousness (pass out)

• Are taking certain drugs such as:
  • Triptans used to treat migraine headache
  • Medicines used to treat mood, anxiety, psychotic or thought disorders, including tricyclics, lithium, SSRIs, SNRIs, or antipsychotics
  • Tramadol used to treat pain
  • Over-the-counter supplements such as tryptophan or St. John’s wort
  • Phenytoin, carbamazepine, or rifampicin (these drugs can decrease your blood level of mirtazapine)
  • Cimetidine or ketoconazole (these drugs can increase your blood level of mirtazapine)
• Have or had:
  • liver problems
  • kidney problems
  • heart problems
  • seizures or convulsions
  • bipolar disorder or mania
  • a tendency to get dizzy or faint
• are pregnant or plan to become pregnant. It is not known if mirtazapine tablets will harm your unborn baby. Talk to your healthcare provider about the benefits and risks of treating depression during pregnancy
• are breastfeeding or plan to breastfeed. Some mirtazapine may pass into your breast milk. Talk to your healthcare provider about the best way to feed your baby while taking mirtazapine tablets

• Take mirtazapine tablets exactly as prescribed. Your healthcare provider may need to change the dose of mirtazapine tablets until it is the right dose for you.
• Take mirtazapine tablets at the same time each day, preferably in the evening at bedtime.
• Swallow mirtazapine tablets as directed.
• It is common for antidepressant medicines such as mirtazapine tablets to take up to a few weeks before you start to feel better. Do not stop taking mirtazapine tablets if you do not feel results right away.
• Do not stop taking or change the dose of mirtazapine tablets without first talking to your doctor, even if you feel better.
• Mirtazapine tablets may be taken with or without food.
• If you miss a dose of mirtazapine tablets, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of mirtazapine tablets at the same time.
• If you take too much mirtazapine, call your healthcare provider or poison control center right away, or get emergency treatment.

• Mirtazapine tablets can cause sleepiness or may affect your ability to make decisions, think clearly, or react quickly. You should not drive, operate heavy machinery, or do other dangerous activities until you know how mirtazapine tablets affect you.
• Avoid drinking alcohol or taking diazepam (a medicine used for anxiety, insomnia and seizures, for example)or similar medicines while taking mirtazapine tablets. If you are uncertain about whether certain medication can be taken with mirtazapine tablets, please discuss with your doctor.

• sleepiness
• increased appetite, weight gain
• dry mouth
• constipation
• dizziness
• abnormal dreams

• Store at  25° C (77° F); excursions permitted to 15° to 30° C (59° to 86° F) [see USP Controlled Room Temperature].
• Protect from light and moisture.

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 7.5 mg (100 Tablet Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 15 mg (100 Tablet Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 15 mg Unit-of-Use Pack (30 Tablets)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 30 mg (100 Tablet Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 30 mg Unit-of-Use Pack (30 Tablets)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 45 mg (100 Tablet Bottle)

PACKAGE LABEL-PRINCIPAL DISPLAY PANEL - 45 mg Unit-of-Use Pack (30 Tablets)