A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Remeron Warnings, Precautions, Pregnancy, Nursing, Abuse - Mirtazapine
Remeron Warnings, Precautions, Pregnancy, Nursing, Abuse - Mirtazapine
WARNINGS
Agranulocytosis
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/mm3
with associated signs and symptoms, e.g., fever, infection, etc.] and
a third patient developed severe neu-tropenia (ANC < 500/mm3 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 bediscontinued and
the patient should be closely monitored.
MAO Inhibitors
In patients receiving other drugs for major depressive disorder
in combination with a monoamine oxidase inhibitor (MAOI) and in patients who
have recently discontinued a drug for major depressive disorder and then are
started on an MAOI, there have been reports of serious, and sometimes fatal,
reactions, e.g., including nausea, vomiting, flushing, dizziness, tremor, myo-clonus,
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.
Clinical Worsening and Suicide Risk
Patients with major depressive disorder, both adult and pediatric,
may experience worsening of their depression and/or the emergence of suicidal
ideation and behavior (suicidality), whether or not they are taking antidepressant
medications, and this risk may persist until significant remission occurs. Although
there has been a long-standing concern that antidepressants may have a role
in inducing worsening of depression and the emergence of suicidality in certain
patients, a causal role for antidepressants in inducing such behaviors has not
been established. Nevertheless, patients being treated with antidepressants
should be observed closely for clinical worsening and suicidality, especially
at the beginning of a course of drug therapy, or at the time of dose changes,
either increases or decreases. Consideration should be given to changing
the therapeutic regimen, including possibly discontinuing the medication, in
patients whose depression is persistently worse or whose emergent suicidality
is severe, abrupt in onset, or was not part of the patient’s presenting symptoms.
Because of the possibility of co-morbidity between major depressive
disorder and other psychiatric and nonpsychiatric disorders, the same precautions
observed when treating patients with major depressive disorder should be observed
when treating patients with other psychiatric and nonpsychiatric disorders.
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,
consideration should be given to changing the therapeutic regimen, including
possibly discontinuing the medication, in patients for whom such 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, and the other symptoms described above, as well as the emergence
of suicidality, and to report such symptoms immediately to health care providers.
Prescriptions for REMERON® (mirtazapine) Tablets should be
written for the smallest quantity of tablets consistent with good patient management,
in order to reduce the risk of overdose.
It should be noted that REMERON® is not approved
for use in treating any indications in the pediatric population.
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 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 REMERON® is not approved for use in treating
bipolar depression.
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 ³ 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.
Cholesterol/Triglycerides
In US controlled studies, nonfasting cholesterol increases
to ³ 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 ³ 500 mg/dL were observed in 6% of patients
treated with mirtazapine, compared to 3% for placebo and 3% for amitriptyline.
Transaminase Elevations
Clinically significant ALT (SGPT) elevations (³
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. REMERON®
should be used with caution in patients with impaired hepatic function
(see CLINICAL PHARMACOLOGY
and DOSAGE AND
ADMINISTRATION).
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.
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.
Use in Patients with Concomitant Illness
Clinical experience with REMERON® 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.
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 m2] and severe
[GFR < 10 mL/min/1.73 m2] 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
Physicians are advised to discuss the following issues with
patients for whom they prescribe REMERON® (mirtazapine) Tablets:
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.
Clinical Worsening and Suicide Risk Patients and their families
should be encouraged to be alert to the emergence of anxiety, agitation, panic
attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania,
mania, worsening of depression, and suicidal ideation, especially early during
antidepressant treatment. Such symptoms should be reported to the patient’s
physician, especially if they are severe, abrupt in onset, or were not part
of the patient’s presenting symptoms.
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.
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 REMERON® to interact with other drugs.
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 mirtazapine.
Pregnancy
Patients should be advised to notify their physician if they
become pregnant or intend to become pregnant during REMERON® therapy.
Nursing
Patients should be advised to notify their physician if they
are breast-feeding an infant.
Laboratory Tests
There are no routine laboratory tests recommended.
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/m2 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/m2
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 100mg/kg and 40 mg/kg, respectively [20and 17 times the maximum recommended
human dose (MRHD) on a mg/m2 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 3days 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/m2 basis.
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.
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
REMERON® (mirtazapine) Tablets are administered to nursing women.
Pediatric Use
Safety and effectiveness in children have not been established
(see WARNINGS-Clinical Worsening and Suicide
Risk).
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 REMERON®
to elderly patients (see CLINICAL PHARMACOLOGY
and DOSAGE AND
ADMINISTRATION).
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