DrugBuyers.Com: Remeron

Remeron - Mirtazapine

REMERON® (mirtazapine) Tablets are an antidepressant for oral administration. Mirtazapine has a tetracyclic chemical structure unrelated to selective serotonin reuptake inhibitors, tricyclics or monoamine oxidase inhibitors (MAOI). Mirtazapine 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 C17H19N3. Its molecular weight is 265.36.

Mirtazapine is a white to creamy white crystalline powder which is slightly soluble in water. REMERON® is supplied for oral administration as scored film-coated tablets containing 15 or 30 mg of mirtazapine, and unscored film-coated tablets containing 45 mg of mirtazapine. Each tablet also contains corn starch, hydroxypropyl cellulose, magnesium stearate, colloidal silicon dioxide, lactose and other inactive ingredients.

REMERON® (mirtazapine) Tablets are indicated for the treatment of depression.

The efficacy of REMERON® in the treatment of depression 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 (see CLINICAL PHARMACOLOGY). 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 antidepressant effectiveness of REMERON® in hospitalized depressed patients has not been adequately studied.
The effectiveness of REMERON® in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use REMERON® for extended periods should periodically evaluate the long-term usefulness of the drug for the individual patient.

WARNINGS

Agranulocytosis

In premarketing clinical trials, two (one with Sjögrens Syndrome) out of 2,796 patients treated with REMERON® (mirtazapine) Tablets developed agranulocytosis (absolute neutrophil count (ANC)
MAO Inhibitors

In patients receiving other antidepressants in combination with a monoamine oxidase inhibitor (MAOI) and in patients who have recently discontinued an antidepressant drug 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, myoclonus, rigidity, diaphoresis, hyperthermia, autonomic instability with rapid fluctuations of vital signs, seizures, and mental status changes ranging from agitation to coma. Although there are no human data pertinent to such an interaction with REMERON® (mirtazapine) Tablets, it is recommended that REMERON® not be used in combination with an MAOI, or within 14 days of initiating or discontinuing therapy with an MAOI.

PRECAUTIONS

General

Somnolence: In U. S. 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 drugs effect on their own psychomotor performance (see PATIENT INFORMATION).

Dizziness: In U.S. 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 U. S. 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 p.o. of premarketing U.S. 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 mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo treated patients (see

PRECAUTIONS
-Pediatric Use).

Cholesterol/Triglycerides: In U.S. 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.

Transaminase Elevations: Clinically significant ALT (SGPT) elevations (³3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to REMERON® in a p.o. of short-term U.S. 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.

Activation of Mania/Hypomania: Mania/hypomania occurred in approximately 0.2% (3/1,299 patients) of REMERON® treated patients in U.S. 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 2,796 U.S. and non- U.S. 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.

Suicide: Suicidal ideation is inherent in depression and may persist until significant remission occurs. As with any patient receiving antidepressants, high-risk patients should be closely supervised during initial drug therapy. Prescriptions of REMERON® should be written for the smallest quantity consistent with good patient management, in order to reduce the risk of overdose.

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 not associated with clinically significant ECG abnormalities in U. S. and non- U.S. placebo controlled trials. 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
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 100 mg/kg and 40 mg/kg, respectively (20 and 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 3 days of lactation and a decrease in pup birth weights. The cause of these deaths is not known. These 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 pediatric patients have not been established. In an 8-week long pediatric clinical trial of doses between 15- 45 mg/day, 49% of mirtazapine-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 (³65 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® (mirtazapine) to elderly 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.

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 patients 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.

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.