Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/742
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Remeron (Tablet, Orally Disintegrating)
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Medication Guide:<br/>Antidepressant Medicines,
Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions: 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. Talk to your, or your family
member's healthcare provider about:<br/>What is the most important
information I should know about antidepressant medicines, depression and other
serious mental illnesses, and suicidal thoughts or actions?:<br/>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::<br/>What else do I need to know
about antidepressant medicines?: This Medication Guide
has been approved by the U.S. Food and Drug Administration for all
antidepressants.
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Initial Treatment: The recommended starting
dose for REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets is 15 mg/day,
administered in a single dose, preferably in the evening prior to sleep. In the
controlled clinical trials establishing the efficacy of REMERON' in the treatment
of major depressive disorder, the effective dose range was generally 15���45 mg/day.
While the relationship between dose and satisfactory response in the treatment of
major depressive disorder for REMERON' has not been adequately explored, patients
not responding to the initial 15 mg dose may benefit from dose increases up to a
maximum of 45 mg/day. REMERON' has an elimination half-life of approximately 20���40
hours; therefore, dose changes should not be made at intervals of less than one to
two weeks in order to allow sufficient time for evaluation of the therapeutic
response to a given dose.<br/>Administration of REMERONSolTab'
(mirtazapine) Orally Disintegrating Tablets: Patients should be
instructed to open tablet blister pack with dry hands and place the tablet on the
tongue. The tablet should be used immediately after removal from its blister; once
removed, it cannot be stored. REMERONSolTab' (mirtazapine) Orally Disintegrating
Tablets will disintegrate rapidly on the tongue and can be swallowed with saliva.
No water is needed for taking the tablet. Patients should not attempt to split the
tablet.<br/>Elderly and Patients with Renal
or Hepatic Impairment: The clearance of
mirtazapine is reduced in elderly patients and in patients with moderate to severe
renal or hepatic impairment. Consequently, the prescriber should be aware that
plasma mirtazapine levels may be increased in these patient groups, compared to
levels observed in younger adults without renal or hepatic impairment (see
PRECAUTIONS and
CLINICAL
PHARMACOLOGY).<br/>Maintenance/Extended Treatment: 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 REMERON' has demonstrated that its efficacy in major depressive
disorder is maintained for periods of up to 40 weeks following 8���12 weeks of
initial treatment at a dose of 15���45 mg/day (see CLINICAL
PHARMACOLOGY). Based on these limited data, it is unknown whether or
not the dose of REMERON' 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.<br/>Switching Patients To or From a
Monoamine Oxidase Inhibitor: At least 14 days should
elapse between discontinuation of an MAOI and initiation of therapy with
REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets. In addition, at least
14 days should be allowed after stopping REMERONSolTab' before starting an
MAOI.
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REMERONSolTab (mirtazapine)
Orally Disintegrating 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. REMERONSolTab' is available for
oral administration as an orally disintegrating tablet containing 15, 30, or 45 mg of
mirtazapine. It disintegrates in the mouth within seconds after placement on the
tongue allowing its contents to be subsequently swallowed with or without water.
REMERONSolTab' also contains the following inactive ingredients: aspartame, citric
acid, crospovidone, hydroxypropyl methylcellulose, magnesium stearate, mannitol,
microcrystalline cellulose, natural and artificial orange flavor, polymethacrylate,
povidone, sodium bicarbonate, starch, and sucrose.
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Pharmacodynamics: The mechanism of action of
REMERONSolTab' (mirtazapine) Orally Disintegrating 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��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-HTand 5-HTreceptors. Mirtazapine has no
significant affinity for the 5-HTand 5-HTreceptors. Mirtazapine is a potent
antagonist of histamine (H) receptors, a property that may explain its
prominent sedative effects. Mirtazapine is a moderate
peripheral��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.<br/>Pharmacokinetics: REMERONSolTab'
(mirtazapine) Orally Disintegrating Tablets are rapidly and completely absorbed
following oral administration and have a half-life of about 20���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. REMERONSolTab' Orally
Disintegrating Tablets are bioequivalent to REMERON' (mirtazapine) Tablets. 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 unconjugatedmetabolites 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���80 mg. 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). 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���10��g/mL.<br/>Special Populations:<br/>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
REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets to elderly patients
(see PRECAUTIONS and
DOSAGE AND
ADMINISTRATION).<br/>Pediatrics: Safety and
effectiveness of mirtazapine in the pediatric population have not been
established .<br/>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).<br/>Race: There have been no
clinical studies to evaluate the effect of race on the pharmacokinetics of
REMERONSolTab'.<br/>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/1.73 m) and approximately 50% in
patients with severe (Clcr =<10 mL/min/1.73 m) renal
impairment when compared to normal subjects. Caution is indicated in
administering REMERONSolTab' to patients with compromised renal function (see
PRECAUTIONS and
DOSAGE AND
ADMINISTRATION).<br/>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 REMERONSolTab'
to patients with compromised hepatic function (see PRECAUTIONS and
DOSAGE AND
ADMINISTRATION).<br/>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 thesefour studies ranged from 21���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���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 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���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 REMERON' 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.
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REMERONSolTab' (mirtazapine)
Orally Disintegrating Tablets are contraindicated in patients with a known
hypersensitivity to mirtazapine.
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| dailymed-instance:supply |
REMERONSolTab' (mirtazapine)
Orally Disintegrating Tablets are supplied as:<br/>Storage: Store at 25��C (77��F);
excursions permitted to 15���30��C (59���86��F) [see USP Controlled Room Temperature].
Protect from light and moisture. Use immediately upon opening individual tablet
blister. Rx only Manufactured for Organon
USA Inc., Roseland, NJ 07068 by CIMA Labs Inc., Eden
Prairie, MN 55344 ��2007 Organon USA
Inc.
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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 REMERONSolTab' (mirtazapine)
Orally Disintegrating 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. REMERONSolTab' is not
approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and
Suicide Risk, PRECAUTIONS: Information for
Patients, and PRECAUTIONS: Pediatric
Use)
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dailymed-ingredient:Aspartame,
dailymed-ingredient:Citric_Acid,_Anhydrous_Fine_Granular,
dailymed-ingredient:Crospovidone,
dailymed-ingredient:Granular_Mannitol_2080,
dailymed-ingredient:Magnesium_Stearate,
dailymed-ingredient:Mannitol,
dailymed-ingredient:Microcystalline_Cellulose,
dailymed-ingredient:Natural&Artificial_Orange_Flavor,
dailymed-ingredient:Sodium_Bicarbonate,_No._1
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General:<br/>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).<br/>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'.<br/>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���45 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).<br/>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 were observed in 6% of patients treated
with mirtazapine, compared to 3% for placebo and 3% for
amitriptyline.<br/>Transaminase Elevations: Clinically significant
ALT (SGPT) elevations (���3 times the upper limit of the normal range) were
observed in 2.0% (8/424) of patients exposed to REMERON' in a pool of
short-term US controlled trials, compared to 0.3% (1/328) of placebo patients
and 2.0% (3/181) of amitriptyline patients. Most of these patients with ALT
increases did not develop signs or symptoms associated with compromised liver
function. While some patients were discontinued for the ALT increases, in
other cases, the enzyme levels returned to normal despite continued REMERON'
treatment. REMERONSolTab' should be used with caution in patients with
impaired hepatic function (see CLINICAL
PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).<br/>Activation of Mania/Hypomania: Mania/hypomania
occurred in approximately 0.2% (3/1299 patients) of REMERON'-treated patients
in US studies. Although the incidence of mania/hypomania was very low during
treatment with mirtazapine, it should be used carefully in patients with a
history of mania/hypomania.<br/>Seizure: In premarketing
clinical trials only one seizure was reported among the 2796 US and non-US
patients treated with REMERON'. However, no controlled studies have been
carried out in patients with a history of seizures. Therefore, care should be
exercised when mirtazapine is used in these patients.<br/>Use in Patients with
Concomitant Illness: Clinical experience
with REMERONSolTab' in patients with concomitant systemic illness is limited.
Accordingly, care is advisable in prescribing mirtazapine for patients with
diseases or conditions that affect metabolism or hemodynamic responses. REMERONSolTab' 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. REMERONSolTab' 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] and severe [GFR<10 mL/min/1.73
m] renal impairment, and also in patients with hepatic
impairment. Caution is indicated in administering REMERONSolTab' to such
patients (see CLINICAL
PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).<br/>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 REMERONSolTab' (mirtazapine)
Orally Disintegrating 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
REMERONSolTab'. 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 REMERONSolTab'.<br/>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 werenot 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.<br/>Agranulocytosis: Patients who are to
receive REMERONSolTab' 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.<br/>Interference with Cognitive
and Motor Performance: REMERONSolTab' 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 REMERONSolTab'
therapy does not adversely affect their ability to engage in such
activities.<br/>Completing Course of Therapy: While patients may
notice improvement with REMERONSolTab' therapy in 1���4 weeks, they should be
advised to continue therapy as directed.<br/>Concomitant Medication: Patients should be
advised to inform their physician if they are taking, or intend to take, any
prescription or over-the-counter drugs since there is a potential for
REMERONSolTab' to interact with other drugs.<br/>Alcohol: The impairment of
cognitive and motor skills produced by REMERON' has been shown to be additive
with those produced by alcohol. Accordingly, patients should be advised to
avoid alcohol while taking any dosage form of mirtazapine.<br/>Phenylketonurics: Phenylketonuric
patients should be informed that REMERONSolTab' contains phenylalanine 2.6 mg
per 15 mg tablet, 5.2 mg per 30 mg tablet, and 7.8 mg per 45 mg
tablet.<br/>Pregnancy: Patients should be
advised to notify their physician if they become pregnant or intend to become
pregnant during REMERONSolTab' therapy.<br/>Nursing: Patients should be
advised to notify their physician if they are breast-feeding an
infant.<br/>Laboratory Tests: There are no routine
laboratory tests recommended.<br/>Drug Interactions: 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).<br/>Drugs Affecting Hepatic
Metabolism: The metabolism and
pharmacokinetics of REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets
may be affected by the induction or inhibition of drug-metabolizing
enzymes.<br/>Drugs that are Metabolized by
and/or Inhibit Cytochrome P450 Enzymes: 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,
anindication 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 REMERONSolTab' 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 REMERONSolTab' with such drugs.<br/>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 REMERONSolTab'.<br/>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 REMERONSolTab'.<br/>Carcinogenesis and Mutagenesis
and Impairment of Fertility:<br/>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/mbasis 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.<br/>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.<br/>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/mbasis]. 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.<br/>Pregnancy:<br/>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/mbasis, 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 the MRHD, on
a mg/mbasis. There are no adequate and well controlled studies in
pregnant women. Because animal reproduction studies are not always predictive
of human response, this drug should be used during pregnancy only if clearly
needed.<br/>Nursing Mothers: It is not known whether
mirtazapine is excreted in human milk. Because many drugs are excreted in human
milk, caution should be exercised when REMERONSolTab' (mirtazapine) Orally
Disintegrating Tablets are administered to nursing women.<br/>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 REMERON' (mirtazapine) Tablets, and the
data were not sufficient to support a claim for use in pediatric patients. Anyone
considering the use of REMERONSolTab' (mirtazapine) Orally Disintegrating 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���45 mg/day, 49% of REMERON'-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 REMERON'-treated patients versus 1
kg (2 kg SD) for placebo-treated patients .<br/>Geriatric Use: Approximately 190 elderly
individuals (���65 years of age) participated in clinical studies with REMERON'
(mirtazapine) Tablets. This drug is known to be substantially excreted by the
kidney (75%), and the risk of decreased clearance of this drug is greater in
patients with impaired renal function. Because elderly patients are more likely to
have decreased renal function, care should be taken in dose selection. Sedating
drugs may cause confusion and over-sedation in the elderly. No unusual adverse
age-related phenomena were identified in this group. Pharmacokinetic studies
revealed a decreased clearance in the elderly. Caution is indicated in
administering REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets to
elderly patients (see CLINICAL
PHARMACOLOGY and DOSAGE AND
ADMINISTRATION).
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Human Experience: There is very limited
experience with REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets
overdose. In premarketing clinical studies, there were eight reports of REMERON'
overdose alone or in combination with other pharmacological agents. The only drug
overdose death reported while taking REMERON' was in combination with
amitriptyline and chlorprothixene in a non-US clinical study. Based on plasma
levels, the REMERON' dose taken was 30���45 mg, while plasma levels of amitriptyline
and chlorprothixene were found to be at toxic levels. All other premarketing
overdose cases resulted in full recovery. Signs and symptoms reported in
association with overdose included disorientation, drowsiness, impaired memory,
and tachycardia. There were no reports of ECG abnormalities, coma or convulsions
following overdose with REMERON' alone.<br/>Overdose Management: Treatment should consist of
those general measures employed in the management of overdose with any drug
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. Because of the rapid disintegration of
REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets, pill fragments may not
appear in gastric contents obtained with lavage. 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 centers
are listed in the Physicians' Desk
Reference (PDR).
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| dailymed-instance:genericMe... |
mirtazapine
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| dailymed-instance:fullName |
Remeron (Tablet, Orally Disintegrating)
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| dailymed-instance:adverseRe... |
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:<br/>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:<br/>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���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.<br/>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.<br/>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 one occasion while receiving
REMERON'. 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
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 one
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 the previous table
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. 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.<br/>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 four cases of the ventricular arrhythmia
torsades de pointes. In three of the four cases, however, concomitant drugs were
implicated. All patients recovered.
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| dailymed-instance:warning |
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 along-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. 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. 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 healthcare providers. Such monitoring should
include daily observation by families and caregivers. Prescriptions
for REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets 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: A major depressive episode
may be the initial presentation of bipolar disorder. It is generally believed
(though not established in controlled trials) that treating such an episode with
an antidepressant alone may increase the likelihood of precipitation of a
mixed/manic episode in patients at risk for bipolar disorder. Whether any of the
symptoms described above represent such a conversion is unknown. However, prior to
initiating treatment with an antidepressant, patients with depressive symptoms
should be adequately screened to determine if they are at risk for bipolar
disorder; such screening should include a detailed psychiatric history, including
a family history of suicide, bipolar disorder, and depression. It should be noted
that REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets are not approved
for use in treating bipolar depression.<br/>Agranulocytosis: In premarketing clinical trials, two (one with Sj��gren's
Syndrome) out of 2796 patients treated with REMERON' (mirtazapine) Tablets
developed agranulocytosis [absolute neutrophil count (ANC)<500/mmwith associated signs and symptoms, e.g., fever, infection,
etc.] and a third patient developed severe neutropenia (ANC<500/mmwithout 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 REMERONSolTab'
(mirtazapine) Orally Disintegrating Tablets should be discontinued and the
patient should be closely monitored.<br/>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 REMERONSolTab' (mirtazapine) Orally Disintegrating Tablets, it
is recommended that REMERONSolTab' not be used in combination with an MAOI, or
within 14 days of initiating or discontinuing therapy with an MAOI.
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| dailymed-instance:indicatio... |
REMERONSolTab' (mirtazapine)
Orally Disintegrating Tablets are indicated for the treatment of major depressive
disorder. The efficacy of REMERON'
(mirtazapine) Tablets 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 . 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
REMERONSolTab' in hospitalized depressed patients has not been adequately studied. The
efficacy of REMERON' in maintaining a response in patients with major depressive
disorder for up to 40 weeks following 8���12 weeks of initial open-label treatment was
demonstrated in a placebo-controlled trial. Nevertheless, the physician who elects
to use REMERON' for extended periods should
periodically re-evaluate the long-term usefulness of the drug for the individual
patient (see CLINICAL
PHARMACOLOGY).
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
Remeron
|