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Adverse Drug Reaction Overview
Adverse Events Leading to Discontinuation of Treatment
Sixteen percent of patients treated with REMERON® Tablets in U.S. short-term controlled studies discontinued treatment due to an adverse event, compared to 7% of patients treated with placebo. The adverse event that accounted for more than 5% of discontinuations with REMERON® was somnolence (10%).
Commonly Observed Adverse Events in U.S. Short-Term Controlled Clinical Trials
The most commonly observed adverse events related to the use of REMERON® Tablets (5% or greater drug-related incidence for REMERON® Tablets and at least twice that of placebo) were somnolence (54% vs. 18%), increased appetite (17% vs. 2%), weight gain (12% vs. 2%) and dizziness (7% vs. 3%).
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse drug reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Adverse Events Occurring at an Incidence of 1% or More Among REMERON®-Treated Patients
The table that follows enumerates adverse events that occurred at an incidence of 1% or more among REMERON®-treated patients (and greater than the incidence in placebo-treated patients) who participated in U.S. short-term placebo-controlled trials, in which patients were dosed in a range of 5 to 60 mg/day. The investigators reported adverse clinical experiences using terms of their own choice. Reported adverse events were then classified using the standard COSTART-based dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the side effect incidence rate in the population studied.
TABLE 1: Incidence of adverse clinical experiences ( ≥ 1% for REMERON®) in U.S. short-term placebo controlled studies1,2,3
|Body System Adverse Event||REMERON®
N = 453
N = 361
|Body as a Whole|
|Asthenia||34 (8%)||17 (5%)|
|Flu Syndrome||22 (5%)||9 (3%)|
|Back Pain||9 (2%)||3 (1%)|
|Dry Mouth||112 (25%)||54 (15%)|
|Increased Appetite||76 (17%)||7 (2%)|
|Constipation||57 (13%)||24 (7%)|
|Metabolic and Nutritional Disorders|
|Weight Gain||54 (12%)||6 (2%)|
|Peripheral Edema||11 (2%)||4 (1%)|
|Edema||6 (1%)||1 (0%)|
|Myalgia||9 (2%)||3 (1%)|
|Somnolence||243 (54%)||65 (18%)|
|Dizziness||33 (7%)||12 (3%)|
|Abnormal Dreams||19 (4%)||5 (1%)|
|Thinking Abnormal||15 (3%)||4 (1%)|
|Tremor||7 (2%)||2 (1%)|
|Confusion||9 (2%)||1 (0%)|
|Dyspnea||5 (1%)||1 (0%)|
|Urinary Frequency||8 (2%)||5 (1%)|
|N= Number of Patients
1 % rounded off to the nearest whole integer.
2 Events which had an incidence on placebo > REMERON®: infection, pain, headache, nausea, diarrhea and insomnia.
3 Events which had an incidence of REMERON® comparable to placebo: chest pain, palpitation, tachycardia, postural hypotension, dyspepsia, flatulence, libido decreased, hypertonia, nervousness, rhinitis, pharyngitis, sweating, amblyopia, tinnitus and taste perversion.
There was evidence of adaptation to some adverse events with continued therapy (e.g., increased appetite, dizziness and somnolence).
The electrocardiograms for 338 patients who received REMERON® and 261 patients who received placebo in the U.S. short-term controlled trials were analyzed, in which the QTc calculations using the method of Fridericia was employed. Prolongation in QTc ≥ 500 msec was not observed among mirtazapine-treated patients. Mean change in QTc was +1.6 msec for mirtazapine and -3.1 msec for placebo. Mirtazapine was associated with a mean increase in heart rate of 3.4 bpm, compared to 0.8 bpm for placebo. The clinical significance of these changes is unknown.
Less Common Clinical Trial Adverse Drug Reactions ( < 1%)
During worldwide controlled and uncontrolled clinical trials, REMERON® was administered to 2,796 patients. The listing of events which follows includes those events which were judged by the investigator to be adverse clinical experiences. The investigators used terminology of their own choice to describe the adverse experiences. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized categories. It is important to emphasize that although the events occurred during treatment with REMERON®, they were not necessarily drug-related. Following the adverse experiences tabulations, the incidence of clinically significant laboratory values which occurred at a rate of ≥ 1% of patients is presented.
In the tabulations that follow, adverse events as reported by the investigator were classified using a standard COSTART-based dictionary terminology. Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients, infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, and rare events are those occurring in fewer than 1/1,000 patients. Only those events not already listed in Table 1 appear in this listing. Events of major clinical importance are also described in the WARNINGS AND PRECAUTIONS section.
Body as a Whole: frequent: malaise, abdominal pain, abdominal syndrome acute; infrequent: chills, fever, face edema, ulcer, photosensitivity reaction, neck rigidity, neck pain, abdomen enlarged; rare: cellulitis, substernal chest pain.
Cardiovascular System: frequent: hypertension, vasodilatation; infrequent: angina pectoris, myocardial infarction, bradycardia, ventricular extrasystoles, syncope, migraine, hypotension; rare: atrial arrhythmia, bigeminy, vascular headache, pulmonary embolus, cerebral ischemia, cardiomegaly, phlebitis, left heart failure.
Digestive System: frequent: vomiting, anorexia; infrequent: eructation, glossitis, cholecystitis, nausea and vomiting, gum hemorrhage, stomatitis, colitis, liver function tests abnormal; rare: tongue discolouration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema.
Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss, rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus.
Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthosis, bursitis.
Nervous System: frequent: hypoesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: aggression, ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidial syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia, stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome.
Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, glaucoma, hyperacusis, ear pain; rare: blepharitis, partial transitory deafness, otitis media, taste loss, parosmia.
Urogenital System: frequent: urinary tract infection; infrequent: kidney calculus, cystitis, dysuria, urinary incontinence, urinary retention, vaginitis, hematuria, breast pain, amenorrhea, dysmenorrhea, leukorrhea, impotence, rare: polyuria, urethritis, metrorrhagia, menorrhagia, abnormal ejaculation, breast engorgement, breast enlargement, urinary urgency.
The following adverse events were observed commonly in clinical trials in children: significant weight gain ( ≥ 7 %) was observed in 48.8 % of the REMERON® treated subjects compared to 5.7 % in the placebo arm; urticaria (11.8 % vs. 6.8 %) and hypertriglyceridaemia (2.9 % vs. 0 %) were also commonly observed. (See also ACTION AND CLINICAL PHARMACOLOGY Special Populations and Conditions/Pediatrics).
Abnormal Hematologic And Clinical Chemistry Findings
Abnormal Laboratory Values
The plasma samples were drawn from non-fasting patients, and these parameters are affected by diet. Patients taking REMERON® had increased appetite and weight gain, and are likely to have had increased food intake. Increased food intake may account for the increased triglyceride and cholesterol values. Moreover, LDL:HDL ratio data from a limited number of patients suggest that fat metabolism does not change with REMERON® treatment, further suggesting that the increase in triglyceride and cholesterol values reflected increased dietary intake.
Mild changes in liver function are shown by increases in liver enzymes. However, changes are temporary, mild, and are not expected to negatively influence liver function. Premature terminations due to liver enzyme abnormalities were, respectively, REMERON®, 1.7% and placebo, 1.1%.
Post-Market Adverse Drug Reactions
Adverse Events Observed During Post-Marketing Evaluation of REMERON®
Note: Adverse events reported during clinical trials, which were also reported during post-marketing, are not included in this section.
Adverse events reported since market introduction, which were temporally (but not necessary causally) related to mirtazapine therapy, include four cases of the ventricular arrhythmia torsades de pointes. In three of the four cases, however, concomitant drugs were implicated. All patients recovered.
Adverse events are listed under the appropriate System Organ Class
Metabolism and nutrition disorders: hyponatremia.
Psychiatric disorders: insomnia, nightmares, psychomotor restlessness, suicidal ideation, suicidal behaviours.
Investigations: electrocardiogram QT prolonged, increased creatine kinase.
Vascular disorders: orthostatic hypotension
Gastrointestinal disorders: diarrhea, mouth edema, oral hypoaesthesia.
General disorders and administration site conditions: Generalized and local edema, fatigue.
Adverse Reactions following Discontinuation of Treatment (or Dose Reduction)
There have been reports of adverse reactions upon the discontinuation of REMERON® (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 (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Patients should be monitored for these or any other symptoms. 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 dose or upon discontinuation of treatment, dose titration should be managed on the basis of the patient's clinical response. These events are generally self-limiting. Symptoms associated with discontinuation have been reported for other anti-depressants with serotonergic effects (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION).
Read the Remeron (mirtazapine) Side Effects Center for a complete guide to possible side effects
Serious Drug Interactions
- Monoamine Oxidase Inhibitors: See CONTRAINDICATIONS
As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility (see CLINICAL PHARMACOLOGY).
The metabolism and pharmacokinetics of mirtazapine may be affected by the induction or inhibition of drug-metabolizing enzymes.
Mirtazapine is extensively metabolized by CYP2D6, CYP3A4, and to a lesser extent by CYP1A2.
Monoamine Oxidase Inhibitors: Combined use of REMERON® and monoamine oxidase inhibitors (including the antibiotic linezolid and the thiazine dye methylthioninium chloride (methylene blue) which are less well-known examples of MAOIs) is contraindicated due to the potential for serious reactions with features resembling serotonin syndrome or neuroleptic malignant syndrome (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).
Drugs Known to Prolong the QT Interval: The risk of QT prolongation and/or ventricular arrhythmias (e.g. Torsades de Pointes) may be increased with concomitant use of medicines which prolong the QTc interval (e.g. some antipsychotics and antibiotics) and in case of mirtazapine overdose.
Diazepam: The impairment of motor skills produced by REMERON® has been shown to be additive with those caused by diazepam. Accordingly, patients should be advised to avoid diazepam and other similar drugs while taking REMERON®.
CYP Enzyme Inducers
CYP3A4 Inducers (these studies used both drugs at steady state):
- Phenytoin: In healthy male patients (n=18), phenytoin (200 mg daily) increased mirtazapine (30 mg daily) clearance, resulting in about a twofold decrease in plasma mirtazapine concentrations. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin. During combined use of mirtazapine and phenytoin, 3 out of 19 patients experienced fatigue and 1 out of 19 patients developed rash (and none had experienced either fatigue or rash with mirtazapine alone or phenytoin alone). The rash was severe enough to necessitate withdrawal from the study.
- Carbamazepine: In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance, resulting in about a twofold decrease in plasma mirtazapine concentrations.
When phenytoin, carbamazepine or another inducer of hepatic metabolism (such as rifampicin) is added to mirtazapine therapy, the mirtazapine dose may have to be increased. If treatment with such a medicinal product is discontinued, it may be necessary to reduce the mirtazapine dose.
CYP Enzyme Inhibitors
Cimetidine: In healthy male patients (n=12), when cimetidine (800 mg b.i.d.) at steady state was co-administered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased by about 60%. Mirtazapine did not significantly change the pharmacokinetics of cimetidine. During combined use, side effects included somnolence [10 of 12 patients (including 1 of moderate severity) vs. 7 of 12 with mirtazapine alone and none with cimetidine alone], arrhythmia (2 of 12 patients vs. none with mirtazapine or cimetidine alone). The mirtazapine dose may have to be decreased when concomitant treatment with cimetidine is started, or increased when cimetidine treatment is discontinued.
Ketoconazole: In healthy, male, Caucasian patients (n=24), co-administration of the potent CYP3A4 inhibitor ketoconazole (200 mg b.i.d. for 6.5 days) increased the peak plasma levels and the AUC of a single 30 mg dose mirtazapine by approximately 40% and 50% respectively. During combined use, 2 severe adverse events have been reported: One patient experienced circulatory collapse and another patient experienced syncope. Both patients have lost consciousness for a brief period. Caution should be exercised when co-administering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin or nefazodone.
Paroxetine: In an in vivo interaction study in healthy, CYP2D6 extensive metabolizer patients (n=24), mirtazapine (30 mg/day), at steady state, did not significantly change the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor. However, plasma concentrations of mirtazapine and its demethyl metabolite were slightly higher (about 18 and 25%, respectively) during combined administration with paroxetine. This difference is considered to be without clinical relevance. During combined use, side effects included exanthema (1 of 24 patients) that required withdrawal of the patient. Increases in AST and ALT were also reported, with a greater increase in men due to several outliers (including a patient that was withdrawn due to high AST (about 4 fold higher than the upper normal limit) and ALT (about 2 fold higher than the upper normal limit) levels; this patient also showed elevated WBC, neutrophils, decreased lymphocytes and basophils). AST/ALT levels returned to normal following the end of the treatment. Caution is advised for the co-administration of paroxetine with mirtazapine.
Other Drug-Drug Interactions
Amitriptyline: In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not change the pharmacokinetics of steady state mirtazapine (30 mg daily) considerably and mirtazapine also did not change the pharmacokinetics of amitriptyline considerably. During combined use the following adverse reactions have been reported at considerably higher frequencies than with either drug alone: postural hypotension, impaired concentration (about 5 fold higher incidence), nausea (over 4 fold higher incidence) and dizziness (about 2 fold higher incidence). A CYP2D6 slow metabolizer patient experienced a serious adverse event following combined use of amitriptyline and mirtazapine. The subject complained of abdominal discomfort accompanied by dizziness and nausea and then leading to loss of consciousness for about 30 s. Apart from slight tremor (resembling myoclonic contractions) there were no other abnormalities. Caution is advised for the co-administration of amitriptyline with mirtazapine.
Warfarin: In healthy male subjects (n=16) mirtazapine (30 mg daily), at steady state, caused a small (0.2) but statistically significant increase in the International Normalised Ratio (INR) in subjects treated with warfarin to achieve subtherapeutic levels of prothrombin activity (1.5-2.0 INR) at steady state. As at a higher dose of mirtazapine, a more pronounced effect can not be excluded it is advisable to monitor the INR in case of concomitant treatment of warfarin with mirtazapine.
Lithium: No relevant clinical effects or significant changes in pharmacokinetics have been observed in healthy male subjects on concurrent treatment with subtherapeutic levels of lithium (600 mg/day for 10 days) at steady state and a single 30 mg dose of mirtazapine. The serum levels of lithium were approximately 0.3 mmol/L 10 hrs after dosing. The effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown.
Risperidone: In an in vivo non-randomized, interaction study subjects (n=6) in need of treatment with an antipsychiatric and antidepressant drug, the results of the effect of mirtazapine (30 mg daily) at steady state on the pharmacokinetics of risperidone (up to 3 mg b.i.d.) at steady state is inconclusive, due to high inter-patient variability and low number of patients. The study design does not permit conclusions to be made on the safety on the combined use of mirtazapine and risperidone. However, a case report of a male patient receiving combined treatment with mirtazapine (60 mg daily) and risperidone (3 mg daily) documents that, 6 weeks after initiation of this combination therapy, the patient developed pulmonary embolism and rhabdomyolysis. Caution is advised for the co-administration of risperidone with mirtazapine.
Based on the mechanism of action of mirtazapine and the potential for serotonin syndrome, caution is advised when REMERON® is coadministered with other drugs or agents that may affect the serotonergic neurotransmitter systems, such as tryptophan, triptans, serotonin reuptake inhibitors, lithium, tramadol, linezolid, methylene blue or St. John's Wort (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Neurologic, Serotonin Syndrome/Neuroleptic Malignant Syndrome).
Drugs Bound to Plasma Protein: Because mirtazapine is bound to plasma proteins (85%), care should be exercised when REMERON® is co-administered to a patient who may be receiving another drug which is highly protein-bound.
St. John's Wort: Pharmacodynamic interactions between REMERON® and the herbal remedy St. John's Wort may occur and may result in an increase in undesirable effects. Dose adjustment of REMERON® should be considered if clinically indicated.
Alcohol: The impairment of mental and motor skills produced by REMERON® have been shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking REMERON®.
Read the Remeron Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 12/22/2015
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