Mirtazapine
FULL PRESCRIBING INFORMATION: CONTENTS*
- Suicidality and Antidepressant Drugs
- MIRTAZAPINE DESCRIPTION
- CLINICAL PHARMACOLOGY
- INDICATIONS & USAGE
- MIRTAZAPINE CONTRAINDICATIONS
- WARNINGS
- PRECAUTIONS
- MIRTAZAPINE ADVERSE REACTIONS
- Associated with Discontinuation of Treatment
- Commonly Observed Adverse Events in US 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
- OVERDOSAGE
- DOSAGE & ADMINISTRATION
- HOW SUPPLIED
- Medication Guide
- PACKAGE LABEL-PRINCIPAL DISPLAY PANEL-30 mg 500 Tablets Bottle
FULL PRESCRIBING INFORMATION
Suicidality and Antidepressant Drugs
Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of mirtazapine tablets or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Mirtazapine is not approved for use in pediatric patients. (See Warnings: Clinical Worsening and Suicide Risk, Precautions: Information for Patients, and Precautions: Pediatric Use)
MIRTAZAPINE DESCRIPTION
17193
Mirtazapine tablets are supplied for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine USP, and unscored film-coated tablets containing 7.5 or 45 mg of mirtazapine. Each tablet also contains corn starch, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose monohydrate, hypromellose and titanium dioxide. In addition, the 15 mg contains iron oxide yellow and 30 mg contains iron oxide red, iron oxide black and iron oxide yellow.
CLINICAL PHARMACOLOGY
Pharmacodynamics
2
2 31A1B
1
1
Pharmacokinetics
In vitro
Special Populations
Geriatric
PRECAUTIONSDOSAGE AND ADMINISTRATION
Pediatrics
PRECAUTIONS
Gender
Pharmacokinetics
Race
Renal Insufficiency
22PRECAUTIONSDOSAGE AND ADMINISTRATION
Hepatic Insufficiency
PRECAUTIONSDOSAGE AND ADMINISTRATION
Clinical Trials Showing Effectiveness
INDICATIONS & USAGE
CLINICAL PHARMACOLOGY
CLINICAL PHARMACOLOGY
MIRTAZAPINE CONTRAINDICATIONS
Hypersensitivity
Monoamine Oxidase Inhibitors
WARNINGSPRECAUTIONS: Drug InteractionsDOSAGE AND ADMINISTRATION
WARNINGS
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
| Table 1 | |
|---|---|
| Age Range |
Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
| |
Increases Compared to Placebo |
| <18 |
14 additional cases |
| 18-24 |
5 additional cases |
| |
Decreases Compared to Placebo |
| 25-64 |
1 fewer case |
| ≥65 |
6 fewer cases |
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for mirtazapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder:
Agranulocytosis
In premarketing clinical trials, 2 (1 with Sjögren’s Syndrome) out of 2,796 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 was stopped. These 3 cases yield a crude incidence of severe neutropenia (with or without associated infection) of approximately 1.1 per thousand patients exposed, with a very wide 95% confidence interval i.e., 2.2 cases per 10,000 to 3.1 cases per 1,000. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with mirtazapine should be discontinued and the patient should be closely monitored.
MAO Inhibitors
In patients receiving other drugs for major depressive disorder in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued a drug for major depressive disorder and then are started on an MAOI, there have been reports of serious, and sometimes fatal, reactions, e.g., including nausea, vomiting, flushing, dizziness, tremor, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability with rapid fluctuations of vital signs, seizures, and mental status changes ranging from agitation to coma. Although there are no human data pertinent to such an interaction with mirtazapine tablets, it is recommended that mirtazapine not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI.
Serotonin Syndrome
CONTRAINDICATIONSPRECAUTIONS: Drug Interactions
PRECAUTIONS
General
Discontinuation Symptoms
Akathisia/Psychomotor Restlessness
Hyponatremia
Somnolence
Information for Patients
Dizziness
Increased Appetite/Weight Gain
PRECAUTIONS: Pediatric Use
Cholesterol/Triglycerides
Transaminase Elevations
CLINICAL PHARMACOLOGYDOSAGE AND ADMINISTRATION
Activation of Mania/Hypomania
Seizure
Use in Patients with Concomitant Illness
22CLINICAL PHARMACOLOGYDOSAGE AND ADMINISTRATION
Information for Patients
Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with mirtazapine and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions” is available for mirtazapine. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking mirtazapine.
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
CLINICAL PHARMACOLOGY
Monoamine Oxidase Inhibitors
CONTRAINDICATIONSWARNINGSDOSAGE AND ADMINISTRATION
Serotonergic Drugs
CONTRAINDICATIONSWARNINGS
Drugs Affecting Hepatic Metabolism
Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes
CYP Enzyme Inducers (these studies used both drugs at steady state)
Phenytoin
Carbamazepine
CYP Enzyme Inhibitors
Cimetidine
Ketoconazole
Paroxetine
in vivo
Other Drug-Drug Interactions
Amitriptyline
Warfarin
Lithium
Risperidone
in vivo
Alcohol
Diazepam
Carcinogenesis & Mutagenesis & Impairment Of Fertility
Carcinogenesis
2
Mutagenesis
in vitro in vitro in vivo
Impairment of Fertility
2
Pregnancy
Teratogenic Effects – Pregnancy Category C
22
Nursing Mothers
Pediatric Use
Safety and effectiveness in the pediatric population have not been established (see BOX WARNING and WARNINGS—Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with mirtazapine tablets, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of mirtazapine tablets in a child or adolescent must balance the potential risks with the clinical need.
In an 8-week long pediatric clinical trial of doses between 15 to 45 mg/day, 49% of mirtazapine-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-treated patients versus 1 kg (2 kg SD) for placebo-treated patients (see PRECAUTIONS-Increased Appetite/Weight Gain).
Geriatric Use
CLINICAL PHARMACOLOGYDOSAGE AND ADMINISTRATION
MIRTAZAPINE ADVERSE REACTIONS
Associated with Discontinuation of Treatment
| Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US Mirtazapine Trials |
||
| Adverse Event |
Percentage of Patients Discontinuing with Adverse Event |
|
| Mirtazapine (n=453) |
Placebo (n=361) |
|
| Somnolence |
10.4% |
2.2% |
| Nausea |
1.5% |
0% |
Commonly Observed Adverse Events in US Controlled Clinical Trials
| Common Treatment –Emergent Adverse Events Associated with the Use of Mirtazapine in 6-Week US Trials |
||
| Adverse Event |
Percentage of Patients Reporting Adverse Event |
|
| Mirtazapine (n=453) |
Placebo (n=361) |
|
| Somnolence |
54% |
18% |
| Increased Appetite |
17% |
2% |
| Weight Gain |
12% |
2% |
| Dizziness |
7% |
3% |
Adverse Events Occurring at an Incidence of 1% or More Among Mirtazapine-Treated Patients
The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among mirtazapine tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day. This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a standard COSTART-based dictionary terminology.
1
| Body System Adverse Clinical Experience | Mirtazapine (n=453) |
Placebo (n=361) |
|---|---|---|
|
1Events reported by at least 1% of patients treated with mirtazapine are included, except the following events which had an incidence on placebo grater than or equal to mirtazapine: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion |
||
|
Body as a Whole
|
||
| Asthenia |
8% |
5% |
| Flu Syndrome |
5% |
3% |
| Back Pain |
2% |
1% |
|
Digestive System
|
|
|
| Dry Mouth |
25% |
15% |
| Increased Appetite |
17% |
2% |
| Constipation |
13% |
7% |
|
Metabolic and Nutritional Disorders
|
||
| Weight Gain |
12% |
2% |
| Peripheral Edema |
2% |
1% |
| Edema |
1% |
0% |
|
Musculoskeletal System
|
||
| Myalgia |
2% |
1% |
|
Nervous System
|
||
| Somnolence |
54% |
18% |
| Dizziness |
7% |
3% |
| Abnormal Dreams |
4% |
1% |
| Thinking Abnormal |
3% |
1% |
| Tremor |
2% |
1% |
| Confusion |
2% |
0% |
|
Respiratory System
|
||
| Dyspnea |
1% |
0% |
|
Urogenital System
|
||
| Urinary Frequency |
2% |
1% |
ECG Changes
Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine
WARNINGSPRECAUTIONS
Body as a Wholefrequent:infrequent: rare:
Cardiovascular Systemfrequent: infrequent:rare:
Digestive Systemfrequent: infrequent: rare:
Endocrine Systemrare:
Hemic and Lymphatic System rare:
Metabolic and Nutritional Disordersfrequent: infrequent: rare:
Musculoskeletal System:frequent: infrequent: rare:
Nervous Systemfrequent: infrequent: rare:
Respiratory Systemfrequent: infrequent: rare:
Skin and Appendagesfrequent: infrequent: rare:
Special Sensesinfrequent: rare:
Urogenital Systemfrequent:infrequent: rare:
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
Physicians’ Desk Reference (
DOSAGE & ADMINISTRATION
Initial Treatment
Elderly and Patients with Renal or Hepatic Impairment
PRECAUTIONSCLINICAL PHARMACOLOGY
Maintenance/Extended Treatment
CLINICAL PHARMACOLOGY
Switching Patients To or From a Monoamine Oxidase Inhibitor
Discontinuation of Mirtazapine Tablets treatment
PRECAUTIONSADVERSE REACTIONS
HOW SUPPLIED
30 mg Tablets
Storage
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.
Manufactured by:
Aurolife Pharma LLC
Dayton, NJ08810
Manufactured for:
Aurobindo Pharma USA, Inc.
Dayton, NJ08810
Repacked by:
H.J. Harkins Company, Inc.
Nipomo, CA 93444
Medication Guide
Mirtazapine Tablets, USP
What is the most important information I should know about mirtazapine tablets?
Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions
Talk to your, or your family member’s, healthcare provider about:
- all risks and benefits of treatment with antidepressant medicines
- all treatment choices for depression or other serious mental illness
What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?
- Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
- Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
- How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?
- Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.
- Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
- Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.
Call a healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:
- thoughts about suicide or dying
- attempts to commit suicide
- new or worse depression
- new or worse anxiety
- feeling very agitated or restless
- panic attacks
- trouble sleeping (insomnia)
- new or worse irritability
- acting aggressive, being angry, or violent
- acting on dangerous impulses
- an extreme increase in activity and talking (mania)
- other unusual changes in behavior or mood
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
What else do I need to know about antidepressant medicines?
- Never stop an antidepressant medicine without first talking to a healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms.
- Antidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.
- Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.
- Antidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.
- Not all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your child’s healthcare provider for more information.
What are mirtazapine tablets?
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 the Medication Guide for a complete list of ingredients in mirtazapine tablets.
- currently take or have taken within the last 14 days, any medicine known as Monoamine Oxidase inhibitors (MAOI). Taking an MAOI with certain other medicines, with similar actions to mirtazapine tablets, can cause serious or even life-threatening side effects.
What should I tell my doctor before taking mirtazapine tablets?
Tell your doctor about all your medical conditions,
- have or had liver problems
- have or had kidney problems
- have or had manic episodes
- have had a seizure (convulsion)
- have any heart problems
- tend to get dizzy or faint
- are pregnant or planning to become pregnant. It is not known if mirtazapine will harm your unborn baby.
- are breastfeeding. It is not known if mirtazapine passes into your milk or if it can harm your unborn baby.
How should I take mirtazapine tablets?
- Take mirtazapine tablets exactly as prescribed by your doctor.
- 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 talking to your doctor, even if you feel better.
- If you miss a dose of mirtazapine tablets, do not take another dose to make up for the dose you forgot. Wait and take your tablet at the next regular time.
- If you take too much mirtazapine tablets, call your doctor or poison control center or go to the emergency room right away.
What should I avoid while taking mirtazapine tablets?
- Mirtazapine tablets can cause drowsiness, which 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 unsure about whether a certain medication can be taken together with mirtazapine tablets, please discuss this with your doctor.
What are the possible side effects of mirtazapine tablets?
Mirtazapine tablets may be associated with serious side effects, including:
- See the beginning of this Medication Guide - Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions
-
Serotonin Syndrome: This is a condition that can be life threatening. Call your doctor right away if you become severely ill and have some or all of these symptoms:
- stiffness
- muscle spasm
- confusion
- irritability
- agitation
- increased body temperature
- fast heart rate
- increased blood pressure
- Decreased White Blood Cells called neutrophils, which are needed to fight infections. Tell your doctor if you have any indication of infection such as fever, chills, sore throat, or mouth or nose sores, especially symptoms which are flu-like.
- Increased cholesterol and triglyceride levels in your blood
-
Symptoms when stopping
mirtazapine
(discontinuation symptoms). Side effects may occur when stopping
mirtazapine
(discontinuation symptoms), especially when therapy is stopped suddenly. Your healthcare provider may want to decrease your dose slowly to help avoid side effects. Some of these side effects may include:
- dizziness
- abnormal dreams
- agitation
- anxiety
- fatigue
- confusion
- headache
- shaking
- tingling sensation
- nausea
- vomiting
- sweating
- Mania
- Seizures
-
Low sodium levels in your blood: Call your doctor right away if you become severely ill and have some or all of these symptoms:
- headache
- feel weak
- confusion
- problems concentrating
- memory problems
- feel unsteady
The most common side effects with mirtazapine tablets include:
How should I store mirtazapine tablets?
- 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.
General information about 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 condition as you have. They may harm them.
- This Medication guide summarizes the most important information about mirtazapine tablets. If you have any concerns or would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about mirtazapine tablets that is written for health professionals.
What are the ingredients in mirtazapine tablets?
Aurolife Pharma LLC
Aurobindo Pharma USA, Inc.
PACKAGE LABEL-PRINCIPAL DISPLAY PANEL-30 mg 500 Tablets Bottle
NDC 13107-003-05
Mirtazapine Tablets, USP
30 mg
PHARMACIST: PLEASE DISPENSE WITH
MEDICATION GUIDE PROVIDED SEPARATELY
Rx only 500 Tablets
AUROBINDO
MirtazapineMirtazapine TABLET, FILM COATED
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