urinary retention
Mirtazapine (Remeron) Contraindications and Precautions
Mirtazapine is contraindicated for use in any patient hypersensitive or overly sensitive to the effects of the drug.
Although antidepressants are not addictive, the abrupt discontinuation of treatment after long-term administration may result in symptoms such as nausea, headache and malaise.
Mirtazapine should be used with caution in patients with a history of bipolar disorder, mania, or hypomania. In U.S. studies, approximately 0.2% of mirtazapine-treated patients developed mania/hypomania, so the occurrence is relatively rare.
The risk of suicide is inherent in any patient with depression, whether or not they are receiving an antidepressant. The clinician should be vigilant in assessing patients for suicidal ideation prior to use of mirtazapine. The possibility of a suicide attempt is inherent in patients with depressive symptoms, whether these occur in primary depression or in association with another primary disorder such as OCD. Patients at high risk for suicide attempt should be closely supervised during initial drug therapy with mirtazapine. In addition, mirtazapine should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. Caretakers of patients receiving treatment with any antidepressant should talk to their health care provider before stopping the use of these drugs; some antidepressants should not be abruptly discontinued. In October 2004, the FDA directed manufacturers of all antidepressants to include a Black Box warning detailing the risk of suicide in pediatric patients. A causal role has been established for antidepressants in inducing suicidality in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n=4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants (SSRIs and others). The average risk of such events on drug was 4% and 2% for placebo; however, no suicides occurred in these trials. Based on these data, FDA has determined that the following points are appropriate for inclusion in the boxed warning: antidepressants increase the risk of suicidal thinking and behavior (suicidality) in pediatric patients with MDD and other psychiatric disorders (OCD, social anxiety disorder); anyone considering the use of an antidepressant in a pediatric patient for any clinical use must balance the risk of increased suicidality with the clinical need; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior, particularly within the first few months of starting therapy or at the time of dose increase or decrease; such observation would generally include at least weekly face-to-face contact with patients, family members, or caregivers during the first 4 weeks of treatment, then every other week visits for the next 4 weeks, then at 12 weeks, and as clinically indicated beyond 12 weeks; additional contact by telephone may be appropriate between face-to-face visits; adults with MDD or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed similarly for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes; families and caregivers should be advised to closely observe the patient (adult or child) on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or, emergence of suicidality. It is unknown if the suicidality risk in pediatric patients extends to longer-term therapy (i.e., beyond several months) or to adult patients. In patients who exhibit changes in symptoms (see Adverse Events), worsening of depression or emergent suicidality, a decision should be made to change or discontinue treatment. If discontinuing, medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described represent such a conversion is unknown. Patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder prior to initiating treatment. Such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that isocarboxazid is not approved for use in treating bipolar depression.
In October, 2004, the FDA directed manufacturers of all antidepressants to include a Black Box warning detailing the risk of suicide in pediatric patients (see Contraindications, suicidal ideation). Pediatric patients should be monitored closely for the risk of suicide with any antidepressant medication. Among the antidepressants, only fluoxetine is approved for use in treating depression in pediatric patients. Fluoxetine, sertraline, fluvoxamine, and clomipramine are approved for OCD in pediatric patients. None of the drugs is approved for other psychiatric indications in children. Pediatric patients being treated with antidepressants for any indication should be observed daily by caregivers for clinical worsening, as well as agitation, irritability, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. If concerns arise, contact with health care providers should be made immediately. Antidepressants should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A patient medication guide about using antidepressants in children and adolescents is available. Health care providers should instruct patients and caregivers to read the guide and discuss any questions with them.
Mirtazapine should not be used in combination with MAOI therapy or within 14 days of initiating or discontinuing therapy with a MAOI (see Drug Interactions). Concomitant use of MAOIs with other antidepressants have resulted in hypertensive crisis. MAOIs should be discontinued 2 - 4 weeks before initiation of mirtazapine therapy.
Bone marrow suppression, usually presenting as neutropenia or agranulocytosis, has been reported during treatment with most antidepressants, including mirtazapine. This mostly appears after 4 - 6 weeks of treatment and is in general reversible after termination of treatment. The prescriber should be alert for symptoms like fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, mirtazapine treatment should be stopped and CBC should be monitored. During premarketing clinical trials of mirtazapine, agranulocytosis (ANC < 500/mm3) with associated signs and symptoms developed in 2 out of 2,796 patients being treated with mirtazapine. A third patient developed severe neutropenia (ANC < 500/mm3 without symptoms). For these 3 patients, onset of severe neutropenia was detected on days 9, 14 and 61 of treatment, respectively. Following discontinuation of mirtazapine, all patients recovered. Mirtazapine should be used cautiously in patients with pre-existing hematological disease, especially leukopenia, neutropenia, or thrombocytopenia.
In placebo-controlled trials, there were no clinically significant ECG abnormalities reported with mirtazapine use. Mirtazapine may, however, induce orthostatic hypotension. During pharmacology trials, orthostatic hypotension was observed in normal volunteers, however, orthostatic hypotension was infrequently observed in clinical trials of depressed patients. Mirtazapine should be used with caution in patients with known cardiac disease or cerebrovascular disease that could be exacerbated by hypotension, such as a history of angina, cardiac arrhythmias, heart failure, ischemic stroke, or a past myocardial infarction. Conditions that might predispose patients to hypotension include dehydration, hypovolemia, surgery, or pharmacologic antihypertensive therapy. Mirtazapine has not been systematically studied or used in the setting of acute myocardial infarction or other significant heart disease.
Mirtazapine should be used cautiously in patients with renal impairment or renal failure. Compared to those with normal renal function, the oral clearance of mirtazapine is reduced by about 30% and 50% in patients with moderate [CrCl 11 - 39 ml/min] and severe [CrCl <= 10 ml/min] renal dysfunction, respectively.
Mirtazapine should be used cautiously in patients with hepatic disease. The clearance of mirtazapine is reduced roughly 30% in patients with compromised hepatic function compared to normal controls. In addition, during short-term U.S. controlled trials, clinically significant transaminase elevations were observed in 2% of mirtazapine-treated patients compared to 0.3% of placebo-treated patients. Most patients affected did not develop signs or symptoms associated with impaired hepatic function. Mirtazapine was discontinued in some patients while in other cases, the enzyme levels returned to normal even with continued treatment with mirtazapine. If jaundice occurs during treatment, mirtazapine should be discontinued.
Mirtazapine should be used cautiously in elderly patients; the elderly exhibit reduced drug clearance and need lower initial doses and slower dosage titration compared to younger adults.
In pre-marketing studies, mirtazapine was associated with a low incidence of seizures (1 out of 2,796 mirtazapine-treated patients). As with other antidepressants, use with caution in patients with a history of a seizure disorder. If seizures develop during therapy, use of mirtazapine should be terminated.
Mirtazapine should be used cautiously in patients with hypercholesterolemia or hypertriglyceridemia. Nonfasting cholesterol increases to >= 20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine in U.S. controlled studies compared to 7% for placebo and 8% for amitriptyline. In the same studies, nonfasting triglyceride increases to >= 500 mg/dl were observed in 6% of mirtazapine-treated patients compared to 3% for placebo and 3% for amitriptyline. Post-marketing reports of hypertriglyceridemia have also been published, one with resultant pancreatitis and diabetic ketoacidosis (see Adverse Reactions). In general, antidepressants may affect blood glucose concentrations because of their indirect effects on the endocrine system, so they should be used with caution in patients with diabetes mellitus.
Mirtazapine is classified as FDA pregnancy risk category C. Studies in animals have not shown any teratogenic effects, however, data in humans are lacking. Use during pregnancy only if clearly needed.
In animals, mirtazapine is excreted in very small amounts in milk. It is not known if mirtazapine is excreted in human milk. Safe use during breast-feeding has not been established and is not recommended until further data are available.
Mirtazapine exhibits very weak anticholinergic activity. While problems are not expected, it should be used cautiously in patients who might be more susceptible to these effects, such as those with urinary retention, prostatic hypertrophy, those with acute, untreated closed-angle glaucoma or increased intraocular pressure, or those with GI obstruction or ileus. Effects of mirtazapine may be additive to anticholinergic medications.
Mirtazapine may impair concentration and alertness. Patients should avoid the driving or operating machinery or other dangerous tasks requiring concentration, until the effects of the drug are known. Ethanol intoxication should be avoided while taking this medication.
Remeron® SolTab (mirtazapine) tablets should be used cautiously in patients with phenylketonuria. The tablets contain phenylalanine in amounts of 2.6, 5.2, and 7.8 mg per 15, 30, and 45 mg tablet, respectively. The regular mirtazapine tablets do not contain phenylalanine.
[ Last revised: 4/26/2005 3:02:00 PM ]
References
. Chen JL, Spinowitz N, Karwa M. Hypertriglyceridemia, acute pancreatitis and diabetic ketoacidosis possibly associated with mirtazapine: A case report. Pharmacotherapy 2003;23:940 - 4.
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