Mirtazapine precautions

List of precautions
General Clinical worsening and suicide risk Lab tests Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Nursing mothers Pediatric use Geriatric use Drug abuse/dependence
 * Somnolence
 * Dizziness
 * Increased appetite/weight gain
 * Cholesterol/triglycerides
 * Transaminase elevations
 * Activation of mania/hypomania
 * Seizure
 * Use in patients with concomitant illness
 * Agranulocytosis
 * Interference with cognitive/motor performance
 * Completing course of therapy
 * Concomitant medication
 * Alcohol
 * Pregnancy (risk)
 * Nursing
 * Controlled substance class
 * Physical/psychological dependence

Somnolence
In U.S. controlled studies, somnolence was reported in 54% of patients treated with Mirtazapine, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of Mirtazapine treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of Mirtazapine. Because of Mirtazapine'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. Return to top

Dizziness
In U.S. controlled studies, dizziness was reported in 7% of patients treated with Mirtazapine, 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 Mirtazapine. Return to top

Increased appetite/weight gain
In U.S. controlled studies, appetite increase was reported in 17% of patients treated with Mirtazapine, 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 U.S. studies, including many patients for long-term, open label treatment, 8% of patients receiving Mirtazapine discontinued for weight gain. In an 8-week long pediatric clinical trial of doses between 15 mg/day to 45 mg/day, 49% of Mirtazapine-treated patients had a weight gain of at least 7%, compared to 5.7% of placebo-treated patients. Return to top

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 Mirtazapine 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. Return to top

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 Mirtazapine in a pool 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 Mirtazapine treatment. Mirtazapine should be used with caution in patients with impaired hepatic function. Return to top

Activation of mania/hypomania
Mania/hypomania occurred in approximately 0.2% (3/1,299 patients) of Mirtazapine 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. Return to top

Seizure
In premarketing clinical trials only one seizure was reported among the 2,796 U.S. and non-U.S. patients treated with Mirtazapine. 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. Return to top

Use in patients with concomitant illness
Clinical experience with Mirtazapine 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. Mirtazapine 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. Mirtazapine 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. Mirtazapine 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 mL/min/1.73 m2 to 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 Mirtazapine to such patients. Return to top

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. Return to top

Agranulocytosis
Patients who are to receive Mirtazapine 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. Return to top

Interference with cognitive/motor performance
Mirtazapine 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 Mirtazapine therapy does not adversely affect their ability to engage in such activities. Return to top

Completing course of therapy
While patients may notice improvement with Mirtazapine therapy in 1 to 4 weeks, they should be advised to continue therapy as directed. Return to top

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 Mirtazapine to interact with other drugs. Return to top

Alcohol
The impairment of cognitive and motor skills produced by Mirtazapine has been shown to be additive with those produced by alcohol. Accordingly patients should be advised to avoid alcohol while taking Mirtazapine. Return to top

Pregnancy (risk)
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during Mirtazapine therapy. Return to top

Nursing
Patients should be advised to notify their physician if they are breast-feeding an infant. Return to top

Lab tests
There are no routine laboratory tests recommended. Return to top

Carcinogenesis
Carcinogenicity studies were conducted with Mirtazapine given in the diet at doses of 2 mg/kg/day, 20 mg/kg/day and 200 mg/kg/day to mice and 2 mg/kg/day, 20 mg/kg/day 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 Mirtazapine. Return to top

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 Iymphocytes, in vivo bone marrow micronucleus test in rats, and unscheduled DNA synthesis assay in HeLa cells. Return to top

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. Return to top

Pregnancy
Pregnancy category C Teratogenic Effects Return to top
 * 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. 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 Mirtazapine tablets USP are administered to nursing women. Return to top

Pediatric use
Safety and effectiveness in the pediatric population have not been established. Two placebo-controlled trials in 258 pediatric patients with MDD have been conducted with Mirtazapine tablets USP, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Mirtazapine 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 mg/day to 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 Mirtazapine-treated patients versus 1 kg (2 kg SD) for placebo-treated patients. Return to top

Geriatric use
Approximately 190 elderly individuals (≥ 65 years of age) participated in clinical studies with Mirtazapine. 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 Mirtazapine to elderly patients. Return to top

Controlled substance class
Mirtazapine tablets USP are not a controlled substance. Return to top

Physical/psychological dependence
Mirtazapine has not been systematically studied in animals or humans for its potential for abuse, tolerance or physical dependence. While the clinical trials did not reveal any tendency for any drug-seeking behavior, these observations were not systematic and it is not possible to predict on the basis of this limited experience the extent to which a CNS-active drug will be misused, diverted and/or abused once marketed. Consequently, patients should be evaluated carefully for history of drug abuse, and such patients should be observed closely for signs of Mirtazapine misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior). Return to top