Mirtazapine

Pregnancy category: C

Lactation: Avoid

Pregnancy Categories

A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA:Information not available.

Associated With Discontinuation Of Treatment

Approximately 16% of the 453 patients who received REMERON (mirtazapine) Tablets in US 6-week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7% of the 361 placebo-treated patients in those studies. The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) are included in Table 2.

Table 2: Common Adverse Events Associated With Discontinuation of Treatment in 6-Week US REMERON Trials

Commonly Observed Adverse Events In US Controlled Clinical Trials

The most commonly observed adverse events associated with the use of REMERON (mirtazapine) Tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (REMERON incidence at least twice that for placebo) are listed in Table 3.

Table 3: Common Treatment-Emergent Adverse Events Associated With the Use of REMERON in 6-Week US Trials

Adverse Events Occurring At An Incidence Of 1% Or More Among REMERON-Treated Patients

Table 4 enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among REMERON (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.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied.

Table 4: Incidence of Adverse Clinical Experiences* ( ≥ 1%) in Short-Term US Controlled Studies

ECG Changes

The electrocardiograms for 338 patients who received REMERON (mirtazapine) Tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed. Prolongation in QTc ≥ 500 msec was not observed among mirtazapine-treated patients; mean change in QTc was +1.6 msec for mirtazapine and - 3.1 msec for placebo. Mirtazapine 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.

The effect of REMERON (mirtazapine) on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis. This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45 mg (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine was not at a level generally considered to be clinically meaningful.

Other Adverse Events Observed During The Premarketing Evaluation Of REMERON

During its premarketing assessment, multiple doses of REMERON (mirtazapine) Tablets were administered to 2796 patients in clinical studies. The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology. The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of REMERON who experienced an event of the type cited on at least 1 occasion while receiving REMERON. All reported events are included except those already listed in Table 4, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote.

It is important to emphasize that, although the events reported occurred during treatment with REMERON, they were not necessarily caused by it.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients. Only those events not already listed in Table 4 appear in this listing. Events of major clinical importance are also described in the WARNINGS and PRECAUTIONS sections.

Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, chest pain substernal.

Cardiovascular System: frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure.

Digestive System: frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema.

Endocrine System: rare: goiter, hypothyroidism.

Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.

Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia.

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

Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome.

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

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

Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia.

Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence; rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency.

Other Adverse Events Observed During Postmarketing Evaluation Of REMERON

Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include cases of the ventricular arrhythmia Torsades de Pointes. In the majority of these cases, however, concomitant drugs were implicated. Cases of severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported. Increased creatine kinase blood levels and rhabdomyolysis have also been reported.

Drug Abuse And Dependence

REMERON (mirtazapine) Tablets are not a controlled substance.

REMERON (mirtazapine) Tablets have not been systematically studied in animals or humans for its potential for abuse, tolerance, or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of REMERON misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

• Antidepressants
• Depression
• Prescription Anxiety Medications

Mirtazapine and other antidepressant medicines may cause serious side effects, including:

• 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 is started or when the dose is changed.
  
  Keep all follow-up visits with your healthcare provider and call between visits if you are worried about symptoms.
  Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency, especially if they are new, worse, or worry you:
  • 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

Call your healthcare provider right away if you have any of the following symptoms, or call 911 if an emergency. Mirtazapine may be associated with these serious side effects:

• trouble breathing, swelling of the face, tongue, eyes or mouth

• 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

Do not stop mirtazapine without first talking to your healthcare provider. Stopping mirtazapine too quickly may cause potentially serious symptoms including:

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

Do not take mirtazapine if you:

• are allergic to mirtazapine or any of the ingredients in it. 
• 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. It is recommended that mirtazapine not be used in combination with an MAOI within 14 days of initiating or discontinuing therapy with an MAOI. People who take mirtazapine close in time to an MAOI may have serious or even life-threatening side effects. Get medical help right away if you have any of these symptoms:

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

Tell your healthcare provider if you 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.

Usual Adult Dose for Depression:

Initial dose: 15 mg orally once a day at bedtime
Maintenance dose: 15 to 45 mg orally once a day
Maximum dose: 45 mg/day

Comments:
-May increase the dose every 1 to 2 weeks to a maximum 45 mg/day according to patient response.
-Patients should be periodically reassessed to determine the need for continued use of this drug.

Use: Treatment of major depressive disorder

Taking this medicine with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking mirtazepine with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with mirtazepine, especially:

• cimetidine (Tagamet);

• diazepam (Valium);

• ketoconazole;

• St. John's wort;

• tramadol;

• tryptophan (sometimes called L-tryptophan);

• medicine to treat mood disorders, thought disorders, or mental illness--such as lithium, other antidepressants, or antipsychotics;

• migraine headache medicine--sumatriptan, zolmitriptan, and others; or

• seizure medicine--carbamazepine, phenytoin.

Other drugs may interact with mirtazepine, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

Contraindications

• Known hypersensitivity to mirtazapine or any ingredient in the formulation.a b

Warnings/Precautions

Warnings

Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality); may persist until clinically important remission occurs with therapy.19 a b Closely supervise patients with major depressive disorder or other psychiatric illness with comorbid depression during initiation of therapy and during periods of dosage adjustments.19 a b (See Boxed Warning.)

If anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and/or mania occur, consider changing or discontinuing therapy, particularly if severe, abrupt in onset, or not a part of patient’s presenting symptoms.19 a b

Prescribe in smallest quantity consistent with good patient management to reduce risk of overdosage.1 19 b

Observe these precautions for patients with psychiatric (e.g., major depressive disorder, obsessive-compulsive disorder) or nonpsychiatric disorders.19 a b

May unmask bipolar disorder.19 a b (See Activation of Mania or Hypomania under Cautions.)

Screen for risk of bipolar disorder by obtaining detailed psychiatric history (e.g., family history of suicide, bipolar disorder, depression) prior to initiating therapy.19 a b

Agranulocytosis or severe neutropenia (with or without infection) reported rarely.a b If signs of infection (e.g., sore throat, fever, stomatitis) and low WBC counts occur, discontinue therapy and monitor patient closely.a b

Concomitant use with an MAO inhibitor associated with serious, sometimes fatal reactions, including manifestations resembling serotonin syndrome (e.g., hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes) or neuroleptic malignant syndrome. (See Specific Drugs under Interactions.)a b

General Precautions

Risk of impaired mental alertness or physical coordination required for performing hazardous tasks (e.g., driving, operating machinery).a b

Possible dizziness.a b

Possible increased appetite and weight gain.a b

Clinically important increases in serum cholesterol (e.g., >20% ULN) and serum triglyceride (e.g., 500 mg/dL) concentrations reported.a b

Potentially clinically important elevations (e.g., 3 times ULN) in serum ALT concentrations; not usually associated with impaired hepatic function.a b

Possible activation of mania or hypomania; use with caution in patients with a history of mania or hypomania.a b (See Bipolar Disorder under Cautions.)

Risk of seizures; use with caution in patients with a history of seizures.a b

Experience in patients with concomitant diseases is limited.a b

Use with caution in patients with concomitant illnesses affecting metabolism or hemodynamic response.a b

Safety in patients with recent history of MI or those with unstable heart disease not established.a b

Orthostatic hypotension reported infrequently.a b Use with caution in patients with known cardiovascular or cerebrovascular disease and in patients with conditions that predispose them to hypotension (e.g., dehydration, hypovolemia, concurrent antihypertensive therapy).a b

Possible increased heart rate and changes in ECG; clinical significance not known.a b

Remeron SolTab orally disintegrating tablets contain aspartame (e.g., NutraSweet), which is metabolized in the GI tract to provide 2.6, 5.2, and 7.8 mg of phenylalanine per 15, 30, and 45 mg tablet, respectively.b

Specific Populations

Category C.b

Not known whether mirtazapine is distributed into milk.a b Caution if used in nursing women.a b

Safety and efficacy not established.1 a b

No substantial differences in adverse effects relative to younger adults; however, increased sensitivity to sedative effects possible in some geriatric individuals.a b

Use with caution in patients >65 years of age.a b

Decreased clearance; use with caution.a b

Decreased clearance in patients with moderate to severe renal impairment; use with caution.a b

Common Adverse Effects

Somnolence, increased appetite, weight gain, dizziness.a b

Metabolized by CYP2D6, CYP3A4, and CYP1A2; a b not a potent inhibitor of CYP2D6, CYP3A4, and CYP1A2.a b

Drugs Affecting Hepatic Microsomal Enzymes

Potential pharmacokinetic interaction (decreased mirtazapine metabolism) with inhibitors of CYP2D6, CYP3A4, or CYP1A2.a b

Potential pharmacokinetic interaction (increased mirtazapine metabolism) with inducers of CYP2D6, CYP3A4, or CYP1A2.a b

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP2D6, CYP3A4, or CYP1A2: potential pharmacokinetic interaction (decreased plasma substrate concentrations).a b However, mirtazapine is not a potent inhibitor of these enzymes and clinically important interaction is unlikely.a b

Specific Drugs

Take mirtazapine exactly as directed by your doctor in order to improve your condition as much as possible. Do not take more of it, do not take it more often, and do not take it for a longer time than your doctor ordered.

mirtazapine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

To use the orally disintegrating tablet:

• Make sure your hands are dry before you handle the tablet.
• Do not open the blister pack that contains the tablet until you are ready to take it.
• Do not push the tablet through the foil backing of the package. Instead, gently peel back the foil backing and remove the tablet.
• Immediately place the tablet on top of the tongue. Do not break or split the tablet.
• The tablet will dissolve in seconds, and you may swallow it with your saliva. You do not need to drink water or other liquids to swallow the tablet.

Dosing

The dose of mirtazapine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of mirtazapine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage forms (orally disintegrating tablets, tablets):
  • For depression:
    • Adults—At first, 15 milligrams (mg) once a day, preferably in the evening just before sleep. Your doctor may adjust your dose if needed. However, the dose is usually not more than 45 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of mirtazapine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep the orally disintegrating tablet in the original package until you are ready to take it.

• Antidepressant, Alpha-2 Antagonist

Clearance is reduced ~30% in patients with moderate (CrCl 11 to 39 mL/minute) and ~50% in patients with severe (CrCl less than 10 mL/minute) renal impairment

Clearance is reduced 40% in elderly men and 10% in elderly women

Hypersensitivity to mirtazapine or any component of the formulation; use of MAO inhibitors intended to treat psychiatric disorders (concurrently or within 14 days of discontinuing either mirtazapine or the MAO inhibitor); initiation of mirtazapine in a patient receiving linezolid or intravenous methylene blue

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light and moisture. Use orally disintegrating tablets immediately upon opening individual tablet blister; once removed it cannot be stored.

Antidepressants increased the risk compared with 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 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 with placebo in adults older than 24 years; there was a reduction in risk with antidepressants compared with placebo in adults 65 years and older. Depression and certain other psychiatric disorders are associated with increases in suicide risk. Appropriately monitor and closely observe patients of all ages who are started on antidepressant therapy for clinical worsening, suicidality, or unusual changes in behavior. Advise families and caregivers of the need for close observation and communication with the health care provider. Mirtazapine is not approved for use in pediatric patients.

Adverse events were observed in some animal reproduction studies. A significant increase in major teratogenic effects has not been observed in humans following exposure to mirtazapine during pregnancy; however, some nonteratogenic adverse events (similar to those observed with SSRI agents) have been reported (Djulus 2006; Einarson 2009; Lennestål, 2007). Mirtazapine was found to cross the placenta following a maternal overdose (Hatzidaki 2008).

The ACOG recommends that therapy with antidepressants during pregnancy be individualized; treatment of depression during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. According to the American Psychiatric Association (APA), the risks of medication treatment should be weighed against other treatment options and untreated depression. Consideration should be given to using agents with safety data in pregnancy. For women who discontinue antidepressant medications during pregnancy and who may be at high risk for postpartum depression, the medications can be restarted following delivery. Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (ACOG 2008; APA 2010; Yonkers 2009).

Pregnant women exposed to antidepressants during pregnancy are encouraged to enroll in the National Pregnancy Registry for Antidepressants (NPRAD). Women 18 to 45 years of age or their health care providers may contact the registry by calling 844-405-6185. Enrollment should be done as early in pregnancy as possible.

Usual Adult Dose for Depression:

Initial dose: 15 mg orally once a day at bedtime.
Maintenance dose: 15 to 45 mg per day.

Initial dose: 15 mg orally once a day at bedtime
Maintenance dose: 15 to 45 mg orally once a day
Maximum dose: 45 mg/day

Comments:
-May increase the dose every 1 to 2 weeks to a maximum 45 mg/day according to patient response.
-Patients should be periodically reassessed to determine the need for continued use of this drug.

Use: Treatment of major depressive disorder