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REMERON
(mirtazapine) Tablets
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 REMERON®^ (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. REMERON ®^ is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use)
DESCRIPTION
REMERON®^ (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 C 17 H 19 N 3. 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.
REMERON®^ is supplied for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine, and unscored film-coated tablets containing 45 mg of mirtazapine. Each tablet also contains corn starch, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose, and other inactive ingredients.
CLINICAL PHARMACOLOGY
Pharmacodynamics
The mechanism of action of REMERON®^ (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 2 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 2 and 5-HT 3 receptors. Mirtazapine has no significant affinity for the 5-HT (^) 1A and 5-HT (^) 1B receptors.
Mirtazapine is a potent antagonist of histamine (H 1 ) receptors, a property that may explain its prominent sedative effects.
Mirtazapine is a moderate peripheral α 1 adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use.
Special Populations
Geriatric
Following oral administration of REMERON®^ (mirtazapine) Tablets 20 mg/day for 7 days to subjects of varying ages (range, 25–74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering REMERON® to elderly patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Pediatrics
Safety and effectiveness of mirtazapine in the pediatric population have not been established (see PRECAUTIONS).
Gender
The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20–40 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) (see Pharmacokinetics).
Race
There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of REMERON®^.
Renal Insufficiency
The disposition of mirtazapine was studied in patients with varying degrees of renal function. Elimination of mirtazapine is correlated with creatinine clearance. Total body clearance of mirtazapine was reduced approximately 30% in patients with moderate (Clcr = 11–39 mL/min/1. m^2 ) and approximately 50% in patients with severe (Clcr = < 10 mL/min/1.73 m^2 ) renal impairment
when compared to normal subjects. Caution is indicated in administering REMERON®^ to patients with compromised renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Hepatic Insufficiency
Following a single 15 mg oral dose of REMERON ®^ , the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering REMERON®^ to patients with compromised hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Clinical Trials Showing Effectiveness
The efficacy of REMERON ®^ (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 a 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– 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 8–12 weeks of acute treatment on REMERON®^ were randomized to continuation of REMERON®^ or placebo for up to 40 weeks of observation for relapse. Response
CONTRAINDICATIONS
REMERON®^ (mirtazapine) Tablets are contraindicated in patients with a known hypersensitivity to mirtazapine.
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.
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 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.
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
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.
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.
In premarketing clinical trials, two (one with Sjögren’s Syndrome) out of 2796 patients treated with REMERON®^ (mirtazapine) Tablets developed agranulocytosis [absolute neutrophil count (ANC) < 500/mm 3 with associated signs and symptoms, e.g., fever, infection, etc.] and a third patient developed severe neutropenia (ANC < 500/mm^3 without any associated symptoms). For these three patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. All three patients recovered after REMERON® 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 1000. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with REMERON®^ 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, 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 REMERON® (mirtazapine) Tablets, it is recommended that REMERON®^ not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI.
PRECAUTIONS
General
Somnolence
In US controlled studies, somnolence was reported in 54% of patients treated with REMERON® (mirtazapine) Tablets, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of REMERON®^ -treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of REMERON®^. Because of REMERON®^ ’s potentially significant effects on impairment of performance, patients should be cautioned about engaging in activities requiring alertness until they have been able to assess the drug’s effect on their own psychomotor performance (see Information for Patients).
Dizziness
In US controlled studies, dizziness was reported in 7% of patients treated with REMERON®^ , compared to 3% for placebo and 14% for amitriptyline. It is unclear whether or not tolerance develops to the dizziness observed in association with the use of REMERON®^.
Increased Appetite/Weight Gain
In US controlled studies, appetite increase was reported in 17% of patients treated with REMERON®^ , compared to 2% for placebo and 6% for amitriptyline. 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 and 5.9% for amitriptyline. In a pool of premarketing US studies, including many patients for long-term, open-label treatment, 8% of patients receiving REMERON® discontinued for weight gain. In an 8-week long pediatric clinical trial of doses between 15– mg/day, 49% of REMERON®^ -treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients (see PRECAUTIONS: Pediatric Use).
Cholesterol/Triglycerides
In US controlled studies, nonfasting cholesterol increases to ≥ 20% above the upper limits of normal were observed in 15% of patients treated with REMERON®^ , compared to 7% for placebo and 8% for amitriptyline. In these same studies, nonfasting triglyceride increases to ≥ 500 mg/dL
REMERON®^ has not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. REMERON®^ was associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. REMERON®^ 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).
Mirtazapine clearance is decreased in patients with moderate [glomerular filtration rate (GFR) = 11–39 mL/min/1.73 m^2 ] and severe [GFR < 10 mL/min/1.73 m^2 ] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering REMERON®^ to such patients (see CLINICAL PHARMACOLOGY and DOSAGE 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 REMERON®^ (mirtazapine) Tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for REMERON®^. 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 REMERON®^.
Clinical Worsening and Suicide Risk
Patients, their families, and their caregivers should be encouraged to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Families and caregivers of patients should be advised to look for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Agranulocytosis
Patients who are to receive REMERON®^ should be warned about the risk of developing agranulocytosis. Patients should be advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration or other possible signs of infection. Particular attention should be paid to any flu-like complaints or other symptoms that might suggest infection.
Interference with Cognitive and Motor Performance
REMERON®^ may impair judgement, thinking, and particularly, motor skills, because of its prominent sedative effect. The drowsiness associated with mirtazapine use may impair a patient’s ability to drive, use machines or perform tasks that require alertness. Thus, patients should be cautioned about engaging in hazardous activities until they are reasonably certain that REMERON®^ therapy does not adversely affect their ability to engage in such activities.
Completing Course of Therapy
While patients may notice improvement with REMERON®^ therapy in 1–4 weeks, they should be advised to continue therapy as directed.
Many drugs are metabolized by and/or inhibit various cytochrome P450 enzymes, e.g., 2D6, 1A2, 3A4, etc. In vitro studies have shown that mirtazapine is a substrate for several of these enzymes, including 2D6, 1A2, and 3A4. While in vitro studies have shown that mirtazapine is not a potent inhibitor of any of these enzymes, an indication that mirtazapine is not likely to have a clinically significant inhibitory effect on the metabolism of other drugs that are substrates for these cytochrome P450 enzymes, the concomitant use of REMERON ®^ with most other drugs metabolized by these enzymes has not been formally studied. Consequently, it is not possible to make any definitive statements about the risks of coadministration of REMERON®^ with such drugs.
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 REMERON®^ were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON®^.
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 REMERON®^ has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON®^.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 on a mg/m^2 basis 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. The data suggest that the above effects could possibly be mediated by non-genotoxic mechanisms, the relevance of which to humans is not known.
The doses used in the mouse study may not have been high enough to fully characterize the carcinogenic potential of REMERON®^ (mirtazapine) Tablets.
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) on a mg/m^2 basis]. 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.
Pregnancy
Teratogenic Effects – Pregnancy Category C
Reproduction studies in pregnant rats and rabbits at doses up to 100 mg/kg and 40 mg/kg, respectively [20 and 17 times the maximum recommended human dose (MRHD) on a mg/m^2 basis, respectively], have revealed no evidence of teratogenic effects. However, in rats, there was an increase in post-implantation losses in dams treated with mirtazapine. There was an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. The effects occurred at doses that were 20 times the MRHD, but not at 3 times
revealed a decreased clearance in the elderly. Caution is indicated in administering REMERON®^ to elderly patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Approximately 16 percent 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 percent 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) included:
Common Adverse Events Associated with Discontinuation of Treatment in 6-Week US REMERON®^ Trials Percentage of Patients Adverse Event Discontinuing with Adverse Event REMERON® (n=453)
Placebo (n=361) Somnolence 10.4% 2.2% Nausea 1.5% 0%
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) were:
Common Treatment-Emergent Adverse Events Associated with the Use of REMERON®^ in 6-Week US Trials Percentage of Patients Adverse Event Reporting Adverse Event REMERON® (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 REMERON®-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 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 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
