There have been reports of adverse reactions upon the
discontinuation of REMERON (mirtazapine) Tablets (particularly when abrupt),
including but not limited to the following: dizziness, abnormal dreams, sensory
disturbances (including paresthesia and electric shock sensations), agitation,
anxiety, fatigue, confusion, headache, tremor, nausea, vomiting, and sweating,
or other symptoms which may be of clinical significance. The majority of the
reported cases are mild and self-limiting. Even though these have been reported
as adverse reactions, it should be realized that these symptoms may be related to
Patients currently taking REMERON should NOT discontinue
treatment abruptly, due to risk of discontinuation symptoms. At the time that a
medical decision is made to discontinue treatment with REMERON, a gradual
reduction in the dose, rather than an abrupt cessation, is recommended.
The use of antidepressants has been associated with the
development of akathisia, characterized by a subjectively unpleasant or
distressing restlessness and need to move, often accompanied by an inability to
sit or stand still. This is most likely to occur within the first few weeks of
treatment. In patients who develop these symptoms, increasing the dose may be
Hyponatremia has been reported very rarely with the
use of mirtazapine. Caution should be exercised in patients at risk, such as
elderly patients or patients concomitantly treated with medications known to cause
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 the potentially significant effects of REMERON 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 PATIENT INFORMATION).
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, openlabel treatment, 8% of patients
receiving REMERON discontinued for weight gain. In an 8-week-long pediatric
clinical trial of doses between 15 to 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).
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.
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. REMERON should be used with
caution in patients with impaired hepatic function (see CLINICAL
PHARMACOLOGY and ).
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.
In premarketing clinical trials, only 1 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
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 ).
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 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 and should assist them in understanding its
contents. Patients should be given the opportunity to discuss the contents of
the and to obtain answers to any questions they may have. The
complete text of the 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.
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 judgment, 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 to 4 weeks, they should be advised to continue therapy as directed.
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.
Patients should be made aware of a potential increased risk
for serotonin syndrome if concomitant use of REMERON with other serotonergic
drugs, including triptans, tricyclic antidepressants, fentanyl, lithium,
tramadol, buspirone, tryptophan, and St. John’s wort, is clinically warranted,
particularly during treatment initiation and dose increases.
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.
Patients should be advised to notify their physician if they
become pregnant or intend to become pregnant during REMERON therapy.
Patients should be advised to notify their physician if they
are breastfeeding an infant.
There are no routine laboratory tests recommended.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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 an 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 nongenotoxic 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 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 an mg/m
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
preimplantation losses occurred at 20 times the MRHD.
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 an mg/m² basis, respectively], have revealed
no evidence of teratogenic effects. However, in rats, there was an increase in postimplantation
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 an 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.
Because some REMERON may be excreted into breast milk,
caution should be exercised when REMERON (mirtazapine) Tablets are administered
to nursing women.
Safety and effectiveness in the pediatric population have
not been established (see BOXED 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 REMERON in a child or adolescent must balance the
potential risks with the clinical need.
In an 8-week-long pediatric clinical trial of doses between
15 to 45 mg/day, 49% of 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 (see PRECAUTIONS: Increased Appetite/Weight Gain).
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
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