Remeron, Page 3

Remeron® (mirtazapine) Tablets are indicated for the treatment of major depressive disorder. Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity.

Risperidone

In an in vivo, nonrandomized, interaction study, subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg b.i.d.).

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 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 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 an 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 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.

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 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 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).

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).

ADVERSE REACTIONS

Associated with Discontinuation of Treatment

Approximately 16% 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% 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
Adverse Event Percentage of Patients 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
Adverse Event Percentage of Patients 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 1 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 nondrug factors to the side-effect incidence rate in the population studied.

INCIDENCE OF ADVERSE CLINICAL EXPERIENCES* (≥1%) IN SHORT-TERM US CONTROLLED STUDIES
Body System
Adverse Clinical Experience
REMERON
(n=453)
Placebo
(n=361)
*
Events reported by at least 1% of patients treated with REMERON are included, except the following events which had an incidence on placebo greater than or equal to REMERON: headache, infection, pain, chest pain, palpitation, tachycardia, postural hypotension, nausea, dyspepsia, diarrhea, flatulence, insomnia, nervousness, libido decreased, hypertonia, pharyngitis, rhinitis, sweating, amblyopia, tinnitus, taste perversion.
Body as a Whole
Asthenia 8% 5%
Flu Syndrome 5% 3%
Back Pain 2% 1%
Digestive System
Dry Mouth 25% 15%
Increased Appetite 17% 2%
Constipation 13% 7%
Metabolic and Nutritional Disorders
Weight Gain 12% 2%
Peripheral Edema 2% 1%
Edema 1% 0%
Musculoskeletal System
Myalgia 2% 1%
Nervous System
Somnolence 54% 18%
Dizziness 7% 3%
Abnormal Dreams 4% 1%
Thinking Abnormal 3% 1%
Tremor 2% 1%
Confusion 2% 0%
Respiratory System
Dyspnea 1% 0%
Urogenital System
Urinary Frequency 2% 1%

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.

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 1 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 1 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, hyponatremia.

Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, 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 (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin 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.

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