Prescription Drug Information: Mirtazapine (Page 3 of 8)

PRECAUTIONS

General

Discontinuation Symptoms

There have been reports of adverse reactions upon the discontinuation of mirtazapine tablets, USP (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 underlying disease.

Patients currently taking mirtazapine tablets should NOT discontinue treatment abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue treatment with mirtazapine tablets, a gradual reduction in the dose, rather than an abrupt cessation, is recommended.

Akathisia/Psychomotor Restlessness

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 detrimental.

Hyponatremia

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 hyponatremia.

Somnolence

In US controlled studies, somnolence was reported in 54% of patients treated with mirtazapine tablets, compared to 18% for placebo and 60% for amitriptyline. In these studies, somnolence resulted in discontinuation for 10.4% of mirtazapine tablets-treated patients, compared to 2.2% for placebo. It is unclear whether or not tolerance develops to the somnolent effects of mirtazapine tablets. Because of the potentially significant effects of mirtazapine tablets 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 PRECAUTIONS: Information for Patients).

Dizziness

In US controlled studies, dizziness was reported in 7% of patients treated with mirtazapine tablets, 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 tablets.

Increased Appetite/Weight Gain

In US controlled studies, appetite increase was reported in 17% of patients treated with mirtazapine tablets, 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, open-label treatment, 8% of patients receiving mirtazapine tablets discontinued for weight gain. In an 8-week-long pediatric clinical trial of doses between 15 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 (see PRECAUTIONS: Pediatric Use).

Cholesterol/Triglycerides

In US controlled studies, nonfasting cholesterol increases to ≥20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine tablets, 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 (≥3 times the upper limit of the normal range) were observed in 2.0% (8/424) of patients exposed to mirtazapine tablets 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 mirtazapine treatment. Mirtazapine tablets 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 mirtazapine tablet-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 mirtazapine tablets. 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 mirtazapine tablets 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 tablets have 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 tablets were 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 tablets 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 to 39 mL/min/1.73 m 2 ] and severe [GFR <10 mL/min/1.73 m 2 ] renal impairment, and also in patients with hepatic impairment. Caution is indicated in administering mirtazapine tablets to such patients (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

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 mirtazapine tablets and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and other Serious Mental Illnesses, and Suicidal Thoughts or Actions” is available for mirtazapine tablets. The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide 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 mirtazapine tablets.

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.

Agranulocytosis

Patients who are to receive mirtazapine tablets 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

Mirtazapine tablets 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 tablet therapy does not adversely affect their ability to engage in such activities.

Completing Course of Therapy

While patients may notice improvement with mirtazapine tablet 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 mirtazapine tablets to interact with other drugs.

Patients should be made aware of a potential increased risk for serotonin syndrome if concomitant use of mirtazapine tablets 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.

Alcohol

The impairment of cognitive and motor skills produced by mirtazapine tablets has been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking mirtazapine.

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