Mirtazapine Information
Mirtazapine () 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 , , and
Mirtazapine () Description
Mirtazapine () tablets are an orally administered drug. 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] benzazepine and has the empirical formula of CHN. Its molecular weight is 265.36. The structural formula is the following and it is the racemic mixture:
Mirtazapine () is a white to creamy white crystalline powder which is slightly soluble in water.
Mirtazapine () tablets are supplied for oral administration as scored film-coated tablets containing 15 or 30 mg of Mirtazapine () , 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.
Mirtazapine () Clinical Pharmacology
The mechanism of action of Mirtazapine () tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown.
Evidence gathered in preclinical studies suggests that Mirtazapine () enhances central noradrenergic and serotonergic activity. These studies have shown that Mirtazapine () acts as an antagonist at central presynaptic α adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity.
Mirtazapine () is a potent antagonist of 5-HT and 5-HT receptors. Mirtazapine () has no significant affinity for the 5-HT and 5-HT receptors.
Mirtazapine () is a potent antagonist of histamine (H) receptors, a property that may explain its prominent sedative effects.
Mirtazapine () is a moderate peripheral α adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use.
Mirtazapine () is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use.
Mirtazapine () tablets are rapidly and completely absorbed following oral administration and have a half-life of about 20 to 40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of food in the stomach has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment.
Mirtazapine () is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation.
In vitro
data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of Mirtazapine () , whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine () has an absolute bioavailability of about 50%. It is eliminated predominantly via urine (75%) with 15% in feces. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (-) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about three times as high as that of the (+) enantiomer.
Plasma levels are linearly related to dose over a dose range of 15 to 80 mg. 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). Steady state plasma levels of Mirtazapine () are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5).
Mirtazapine () is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/mL.
The efficacy of Mirtazapine () tablets as a treatment for major depressive disorder was established in four placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with Mirtazapine () from dose range of 5 mg up to 35 mg/day. Overall, these studies demonstrated Mirtazapine () to be superior to placebo on at least three of the following four 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 () over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor. The mean Mirtazapine () dose for patients who completed these four studies ranged from 21 to 32 mg/day. A fifth study of similar design utilized a higher dose (up to 50 mg) per day and also showed effectiveness.
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 () were randomized to continuation of Mirtazapine () 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 two 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 () 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 () Indications And Usage
Mirtazapine () tablets are indicated for the treatment of major depressive disorder.
The efficacy of Mirtazapine () in the treatment of major depressive disorder was established in six week controlled trials of outpatients whose diagnoses corresponded most closely to the Diagnostic and Statistical Manual of Mental Disorders-3rd edition (DSM-III) category of major depressive disorder (see ).
A major depressive episode (DSM-IV) implies a prominent and relatively persistent (nearly every day for at least 2 weeks) depressed or dysphoric mood that usually interferes with daily functioning, and includes at least five of the following nine symptoms: depressed mood, loss of interest in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
The effectiveness of Mirtazapine () in hospitalized depressed patients has not been adequately studied.
The efficacy of Mirtazapine () in maintaining a response in patients with major depressive disorder for up to 40 weeks following 8 to 12 weeks of initial open-label treatment was demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects to use Mirtazapine () for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient (see )
Mirtazapine () Contraindications
Mirtazapine () tablets are contraindicated in patients with a known hypersensitivity to Mirtazapine () .
Mirtazapine () Warnings
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.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied.
There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1.
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
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.
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.
In premarketing clinical trials, two (one with Sjögren’s Syndrome) out of 2,796 patients treated with Mirtazapine () tablets developed agranulocytosis
[absolute neutrophil count (ANC)
] and a third patient developed severe neutropenia (ANC
was stopped. These three 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.
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.
Mirtazapine () Precautions
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 () .
As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see
CLINICAL PHARMACOLOGY
Safety and effectiveness in the pediatric population have not been established (see and ). 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 ).
Mirtazapine () Adverse Reactions
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 one 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 non-drug factors to the side effect incidence rate in the population studied.
During its premarketing assessment, multiple doses of Mirtazapine () tablets were administered to 2,796 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 2,796 patients exposed to multiple doses of Mirtazapine () who experienced an event of the type cited on at least one occasion while receiving Mirtazapine () . All reported events are included except those already listed in the previous table, 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 Mirtazapine () , 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 one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 patients. Only those events not already listed in the previous table appear in this listing. Events of major clinical importance are also described in the and 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.
Musculoskeletal System:
frequent:
myasthenia, arthralgia;
infrequent:
arthritis, tenosynovitis;
rare:
pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthosis, 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, stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal 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, 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.
Mirtazapine () Overdosage
Treatment should consist of those general measures employed in the management of overdose with any drugs effective in the treatment of major depressive disorder. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion, or in symptomatic patients.
Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the treatment of Mirtazapine () overdosage. No specific antidotes for Mirtazapine () are known.
In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control center are listed in the PDR).
Mirtazapine () Dosage And Administration
It is generally agreed that acute episodes of depression require several months or longer of sustained pharmacological therapy beyond response to the acute episode. Systematic evaluation of Mirtazapine () tablets has demonstrated that its efficacy in major depressive disorder is maintained for periods of up to 40 weeks following 8 to 12 weeks of initial treatment at a dose of 15 to 45 mg/day (see
CLINICAL PHARMACOLOGY
). Based on these limited data, it is unknown whether or not the dose of Mirtazapine () needed for maintenance treatment is identical to the dose needed to achieve an initial response. Patients should be periodically reassessed to determine the need for maintenance treatment and the appropriate dose for such treatment.
Mirtazapine () How Supplied
Mirtazapine () tablets, USP are supplied as:
– Yellow, biconvex, capsule shaped film coated tablets with a score line in between “0” and “8” on one side and “A” debossed on the other side.
Bottles of 30 NDC 21695-081-30
Bottles of 60 NDC 21695-081-60
Bottles of 90 NDC 21695-081-90
Bottles of 100 NDC 21695-081-00
– Reddish Brown, biconvex, capsule shaped film coated tablets with a score line in between “0” and “9” on one side and “A” debossed on the other side.
Bottles of 30 NDC 21695-082-30
Bottles of 60 NDC 21695-082-60
Bottles of 100 NDC 216995-082-00
– White, biconvex, capsule shaped film coated tablets with “10” debossed on one side and “A” debossed on the other side.
Bottles of 30 NDC 21695-083-30
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 for:
2400 Route 130 North
Dayton, NJ 08810
Manufactured by:
Hyderabad–500 072, India
Repackaged by:
Thousand Oaks, CA 91320
Revised: 03/2009
Mirtazapine () Medication Guide
Read the Medication Guide that comes with you or your family member’s antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.
Manufactured for:
2400 Route 130 North
Dayton, NJ 08810
Manufactured by:
Hyderabad-500 072, India
Repackaged by:
Thousand Oaks, CA 91320
Revised: 03/2009
Mirtazapine () Principal Display Panel
Mirtazapine () Principal Display Panel
Mirtazapine () Principal Display Panel
