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Potential Association With Behavioural And Emotional Changes, Including Self-Harm
Pediatrics: Placebo-Controlled Clinical Trial Data
- Recent analyses of placebo-controlled clinical trial safety databases from SSRIs (Selective Serotonin Reuptake Inhibitors) and other newer anti-depressants suggest that use of these drugs in patients under the age of 18 may be associated with behavioural and emotional changes, including an increased risk of suicidal ideation and behaviour over that of placebo.
- The small denominators in the clinical trial database, as well as the variability in placebo rates, preclude reliable conclusions on the relative safety profiles among these drugs.
Adults and Pediatrics: Additional Data
- There are clinical trial and post-marketing reports with SSRIs and other newer anti-depressants, in both pediatrics and adults, of severe agitation-type adverse events coupled with self-harm or harm to others. The agitation-type events include akathisia, agitation, disinhibition, emotional lability, hostility, aggression and depersonalization. In some cases, the events occurred within several weeks of starting treatment.
Rigorous clinical monitoring for suicidal ideation or other indicators of potential for suicidal behaviour is advised in patients of all ages. This includes monitoring for agitation-type emotional and behavioural changes.
Patients currently taking REMERON® should NOT discontinue treatment abruptly, due to risk of discontinuation symptoms. At the time that a medical decision is made to discontinue an SSRI or other newer anti-depressant drug, a gradual reduction in the dose, rather than an abrupt cessation, is recommended.
Lactose is a non-medicinal ingredient in REMERON® tablets. Therefore, patients with rare hereditary problems of galactose intolerance or glucose-galactose malabsorption should not take REMERON® tablets.
In pre-marketing clinical trials, two (one with Sjögren's Syndrome) out of 2,796 patients treated with REMERON® Tablets and one patient treated with imipramine developed agranulocytosis. In all three cases, the patients recovered after the drug with which they were being treated was stopped. In the post-marketing period with REMERON®, very rare cases of agranulocytosis have been reported, mostly reversible, but in some cases fatal. Fatal cases have mostly concerned patients above 65 years of age, although there has been at least one such fatality in a younger patient. Patients who are to receive REMERON® should be warned about the risk of developing agranulocytosis, and advised to contact their physician if they experience any indication of infection such as fever, chills, sore throat, mucous membrane ulceration. If a patient develops a sore throat, fever, stomatitis or other signs of infection, along with a low WBC count, treatment with REMERON® Tablets should be discontinued and the patient should be closely monitored.
Discontinuation Of Treatment With REMERON®
When discontinuing treatment, patients should be monitored for symptoms which may be associated with discontinuation, e.g., 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 (see ADVERSE REACTIONS). A gradual reduction in the dosage over several weeks, rather than abrupt cessation, is recommended whenever possible. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response (see ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION).
The following additional precautions are listed alphabetically.
Carcinogenesis And Mutagenesis
See Toxicology for animal data.
QT Prolongation / Torsade de Pointes
Cases of QT prolongation, Torsades de Pointes, ventricular tachycardia, ventricular fibrillation, cardiac arrest, and sudden death, have been reported during the post-marketing use of mirtazapine. The majority of reports occurred in association with overdose or in patients with other risk factors for QT prolongation, including concomitant use of QTc prolonging medicines (see DRUG INTERACTIONS, Drug-Drug Interactions and OVERDOSAGE). Caution should be exercised when REMERON® is prescribed in patients with known cardiovascular disease or family history of QT prolongation, and in concomitant use with other medicinal products thought to prolong the QTc interval. Torsade de pointes may be asymptomatic or experienced by the patient as dizziness, palpitations, syncope, or seizures. If sustained, torsade de pointes can progress to ventricular fibrillation and sudden cardiac death.
In U.S. short-term controlled studies, non-fasting cholesterol increases of > 20% above the upper limits of normal were observed in 15% of patients taking REMERON® compared to 7% for placebo. In these same studies, non-fasting triglycerides increased to > 500 mg/dl in 6% of patients taking REMERON® compared to 3% for placebo.
Use in Patients with Concomitant Illness: Clinical experience with REMERON® in patients with concomitant systemic illness is limited. Accordingly, care is advisable in prescribing REMERON® 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 associated with significant orthostatic hypotension in early clinical pharmacology trials with normal human 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).
Physical and Psychological Dependence: REMERON® 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 behaviour, 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 REMERON® misuse or abuse (e.g., development of tolerance, incrementation of dose, drug-seeking behaviour).
Endocrine And Metabolism
Increased Appetite/Weight Gain: In U.S. short-term controlled studies, the use of REMERON® was associated with increased appetite in 17% and the complaint of weight gain in 12% of patients, compared to 2% for placebo in both cases. In these same trials, weight gain of ≥ 7% occurred in 7.5% of the patients taking REMERON® compared to 0% in patients taking placebo. The average weight gain in the U.S. long-term controlled trials was 8 lb over 28 weeks.
Diabetes: Care should be taken in patients with diabetes mellitus. In patients with diabetes, antidepressants may alter glycaemic control. Insulin and/or oral hypoglycaemic dosage may need to be adjusted and close monitoring is recommended.
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.
Please refer to WARNINGS AND PRECAUTIONS, General, Agranulocytosis.
Hepatic Impairment: Increased plasma concentrations of mirtazapine occur in patients with moderate and severe hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). In such patients, upward dose titration should be carefully monitored (see DOSAGE AND ADMINISTRATION).
Transaminase Elevations: In U.S. short-term controlled studies, clinically significant ALT (SGPT) elevations (3 times the normal range) were noted in 2%, respectively, of patients treated with REMERON® and in 0% of patients treated with placebo. Most patients did not develop signs or symptoms associated with compromised liver function. While some patients were discontinued due to ALT increases, other patients with elevations continued with enzyme levels returning to normal during ongoing treatment. Mirtazapine should be used with caution in patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION).
Jaundice: Treatment should be discontinued if jaundice occurs.
Somnolence: The use of REMERON® Tablets was associated with somnolence in 54% of patients in U.S. short-term controlled studies, compared to 18% with placebo. In these studies, somnolence resulted in discontinuation of 10% of mirtazapine-treated patients compared to 2% of placebo-treated patients. REMERON® may cause mental or motor impairment because of this prominent sedative effect. Thus, patients should be cautioned about engaging in hazardous activities, such as driving a car or operating dangerous machines, until they are reasonably certain that REMERON® therapy does not adversely affect their ability to engage in such activities.
The use of antidepressants have 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.
Dizziness: In U.S. short-term controlled studies, the use of REMERON® was associated with dizziness in 7% of patients, compared to 3% for placebo.
Activation of Mania/Hypomania: Mania/hypomania occurred in approximately 0.2% (3/1,299 patients) of REMERON®-treated patients in all U.S. studies (controlled and non-controlled). Although the incidence of mania/hypomania was very low during treatment with REMERON®, it should be used carefully in patients with a history of mania/hypomania.
Seizures: In pre-marketing clinical trials, only one seizure was reported in 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 REMERON® is used in these patients.
Serotonin Syndrome/Neuroleptic Malignant Syndrome: On rare occasions serotonin syndrome or neuroleptic malignant syndrome-like events have occurred in association with treatment of REMERON®, particularly when given in combination with other serotonergic and/or neuroleptic/antipsychotic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with REMERON® should be discontinued if patients develop a combination of symptoms possibly including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma and supportive symptomatic treatment should be initiated. Due to the risk of serotonergic syndrome or neuroleptic malignant syndrome REMERON® should not be used in combination with MAO inhibitors (including the antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue) which are less well-known examples of MAOIs) or serotonin-precursors (such as L-tryptophan, oxitriptan) and should be used with caution in patients receiving other serotonergic drugs (triptans, lithium, tramadol, St. John's Wort, most tricyclic antidepressants) or neuroleptics/antipsychotics (see CONTRAINDICATIONS and DRUG INTERACTIONS).
Care should be taken in patients with acute narrow-angle glaucoma and increased intra-ocular pressure.
Suicide: Depression is associated with an increased risk of suicidal thoughts, self harm and suicide (suicide-related events). This risk persists until significant remission occurs. As with any patient receiving anti-depressants, high-risk patients should be closely supervised during initial drug therapy. As improvement may not occur during the first few weeks or more of treatment, patients should be closely monitored until such improvement occurs. It is general clinical experience that the risk of suicide may increase in the early stages of recovery. Patients with a history of suicide-related events or those exhibiting a significant degree of suicidal ideation prior to commencement of treatment are known to be at greater risk of suicidal thoughts or suicide attempts, and should receive careful monitoring during treatment.
In addition, a FDA meta-analysis of placebo-controlled clinical trials of antidepressants in adult patients with psychiatric disorders showed an increased risk of suicidal behavior with antidepressants compared to placebo in patients less than 25 years old.
Prescriptions of REMERON® should be written for the smallest amount consistent with good patient management, in order to reduce the risk of overdose (see WARNINGS AND PRECAUTIONS, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm).
Renal and Hepatic Impairment: Increased plasma concentrations of mirtazapine occur in patients with moderate and severe renal impairment and, to a lesser extent, in patients with hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). In such patients, upward dose titration should be carefully monitored (see DOSAGE AND ADMINISTRATION).
Pregnant Women: Safe use of REMERON® during pregnancy has not been established. Therefore, it should not be administered to women of childbearing potential or nursing mothers unless, in the opinion of the treating physician, the expected benefits to the patient outweigh the possible hazards to the child or fetus.
Complications following late third trimester exposure to newer antidepressants: Post-marketing reports indicate that some neonates exposed to SSRIs or other newer anti-depressants, such as REMERON®, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. The frequency of symptoms may vary with each drug. These features are consistent with either a direct toxic effect of SSRIs and other newer anti-depressants, or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome (see WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome). When treating a pregnant woman with REMERON® during the third trimester, the physician should carefully consider the potential risks and benefits of treatment (see DOSAGE AND ADMINISTRATION).
The extent of exposure in pregnancy during clinical trials: None.
Nursing Women: Safe use of REMERON® during lactation has not been established. Animal data and limited human data have detected mirtazapine in breast milk in low concentrations. A decision whether to continue/discontinue therapy with REMERON®, or to continue/discontinue breastfeeding should be made, taking into account the benefits and possible hazards to mother and infant.
Pediatrics ( < 18 years of age): Safety and efficacy in children under 18 years of age have not been established. REMERON® is not indicated for use in patients below the age of 18 years (see WARNINGS AND PRECAUTIONS, General, Potential Association with Behavioural and Emotional Changes, Including Self-Harm; see also ADVERSE REACTIONS, Pediatrics; DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY Special Populations and Conditions/Pediatrics).
Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioral development are lacking.
Geriatrics ( > 65 years of age): Pharmacokinetic studies revealed a decreased clearance in the elderly, with the lowest clearance in elderly females. Elderly patients may be more susceptible to adverse events such as sedation, dizziness or confusion. Care should be exercised in dosage and titration to higher doses (see ACTION AND CLINICAL PHARMACOLOGY; DOSAGE AND ADMINISTRATION; WARNINGS AND PRECAUTIONS, Neurologic, Somnolence).
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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. Based on AUC exposure, the highest doses used were approximately 0.7 and 1.2 times the maximum recommended human dose (MRHD) of 45 mg/day 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 tumours 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 enough to fully characterize the carcinogenic potential of REMERON® Tablets.
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 (1.9 times the MRHD on an AUC basis). Mating and conception were not affected by the drug, but estrous cycling was disrupted at doses that were 1.3 times MRHD based on AUC and pre-implantation losses occurred at 1.9 times MRHD based on AUC.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 12/22/2015
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