Side Effects of Remeron (mirtazapine)

Remeron (mirtazapine) is a tetracyclic antidepressant used to treat major depression and posttraumatic stress disorder (PTSD). 

Depression is an all-pervasive sense of sadness and gloom. It is believed that in some patients with depression, abnormal levels of neurotransmitters (chemicals that nerves use to communicate with each other) may be the cause of their depression. 

Remeron elevates mood by raising the level of neurotransmitters (norepinephrine and serotonin) in nerves of the brain. Remeron also blocks the effect of histamine. 

Common side effects of Remeron include

• dry mouth,
• weight gain,
• increased appetite,
• increased cholesterol and triglycerides,
• dizziness,
• constipation,
• confusion, and
• abnormal dreams. 

Serious side effects of Remeron include

• seizures,
• abnormal heart beats,
• low blood pressure and dizziness upon standing (orthostatic hypotension),
• manic episodes, and
• decreased blood cells.

Drug interactions of Remeron include alcohol and other drugs that can cause sedation such as benzodiazepines, narcotics, tricyclic antidepressants, certain antihypertensive medications, and some antihistamines, because Remeron adds to their sedating effects. 

• Fluvoxamine, ketoconazole, and cimetidine may increase the levels of Remeron in the blood which may lead to increased side effects from Remeron. 
• Carbamazepine and phenytoin decrease the blood concentration of Remeron by increasing the breakdown of mirtazapine in the liver, possibly reducing the effect of Remeron. 
• Remeron should not be used with monoamine oxidase inhibitors (MAOIs) because high fever, convulsions, and even death can occur from such combinations. 
• Similar reactions may occur if Remeron is combined with other drugs that increase serotonin activity in the brain, such as tryptophan, sumatriptan, linezolid, fluoxetine, venlafaxine, lithium, tramadol, and St. John's wort. 

There are no adequate studies of Remeron in pregnant women. Physicians must balance potential benefits against potential risks when considering Remeron therapy in pregnant women. 

It is unknown if Remeron is secreted in breast milk. Consult your doctor before breastfeeding.

The most common side effects of mirtazapine include drowsiness,

• dry mouth,
• weight gain,
• increased appetite, increased
• cholesterol and
• triglycerides,
• dizziness,
• constipation,
• confusion, and
• abnormal dreams.

Other important side effects that could potentially be serious include

• seizures,
• abnormal heart beats,
• low blood pressure upon standing
• (orthostatic hypotension),
• manic episodes, and
• decreased blood cells.

Associated With Discontinuation Of Treatment

Approximately 16% of the 453 patients who received Remeron (mirtazapine) Tablets in US 6-week controlled clinical trials discontinued treatment due to an adverse experience, compared to 7% of the 361 placebo-treated patients in those studies.

The most common events ( ≥ 1%) associated with discontinuation and considered to be drug related (i.e., those events associated with dropout at a rate at least twice that of placebo) are included in Table 2.

Table 2: Common Adverse Events Associated With Discontinuation of Treatment in 6-Week US Remeron Trials

Commonly Observed Adverse Events In US Controlled Clinical Trials

The most commonly observed adverse events associated with the use of Remeron (mirtazapine) Tablets (incidence of 5% or greater) and not observed at an equivalent incidence among placebo-treated patients (Remeron incidence at least twice that for placebo) are listed in Table 3.

Table 3: Common Treatment-Emergent Adverse Events Associated With the Use of Remeron in 6-Week US Trials

Adverse Events Occurring At An Incidence Of 1% Or More Among Remeron-Treated Patients

Table 4 enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among Remeron (mirtazapine) Tablets-treated patients who participated in short-term US placebo-controlled trials in which patients were dosed in a range of 5 to 60 mg/day.

• This table shows the percentage of patients in each group who had at least 1 episode of an event at some time during their treatment. Reported adverse events were classified using a 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 nondrug factors to the side-effect incidence rate in the population studied.

Table 4: Incidence of Adverse Clinical Experiences* ( ≥ 1%) in Short-Term US Controlled Studies

ECG Changes

The electrocardiograms for 338 patients who received Remeron (mirtazapine) Tablets and 261 patients who received placebo in 6-week, placebo-controlled trials were analyzed.

• 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.
• The effect of Remeron (mirtazapine) on QTc interval was assessed in a clinical randomized trial with placebo and positive (moxifloxacin) controls involving 54 healthy volunteers using exposure response analysis.
• This trial showed a positive relationship between mirtazapine concentrations and prolongation of the QTc interval. However, the degree of QT prolongation observed with both 45 mg (therapeutic) and 75 mg (supratherapeutic) doses of mirtazapine was not at a level generally considered to be clinically meaningful.

Other Adverse Events Observed During The Premarketing Evaluation Of Remeron

During its premarketing assessment, multiple doses of Remeron (mirtazapine) Tablets were administered to 2796 patients in clinical studies.

• The conditions and duration of exposure to mirtazapine varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies.
• Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing.
• 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 event categories.

In the tabulations that follow, reported adverse events were classified using a standard COSTART-based dictionary terminology.

• The frequencies presented, therefore, represent the proportion of the 2796 patients exposed to multiple doses of Remeron who experienced an event of the type cited on at least 1 occasion while receiving Remeron.
• All reported events are included except those already listed in Table 4, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, and those events for which a drug cause was very remote.
• It is important to emphasize that, although the events reported occurred during treatment with Remeron, they were not necessarily caused by it.
• 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 1 or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
• Only those events not already listed in Table 4 appear in this listing. Events of major clinical importance are also described in the prescribing information.

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, chest pain substernal.

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 discoloration, ulcerative stomatitis, salivary gland enlargement, increased salivation, intestinal obstruction, pancreatitis, aphthous stomatitis, cirrhosis of liver, gastritis, gastroenteritis, oral moniliasis, tongue edema.

Endocrine System: rare: goiter, hypothyroidism.

Hemic and Lymphatic System: rare: lymphadenopathy, leukopenia, petechia, anemia, thrombocytopenia, lymphocytosis, pancytopenia.

Metabolic and Nutritional Disorders: frequent: thirst; infrequent: dehydration, weight loss; rare: gout, SGOT increased, healing abnormal, acid phosphatase increased, SGPT increased, diabetes mellitus, hyponatremia.

Musculoskeletal System: frequent: myasthenia, arthralgia; infrequent: arthritis, tenosynovitis; rare: pathologic fracture, osteoporosis fracture, bone pain, myositis, tendon rupture, arthrosis, bursitis.

Nervous System: frequent: hypesthesia, apathy, depression, hypokinesia, vertigo, twitching, agitation, anxiety, amnesia, hyperkinesia, paresthesia; infrequent: ataxia, delirium, delusions, depersonalization, dyskinesia, extrapyramidal syndrome, libido increased, coordination abnormal, dysarthria, hallucinations, manic reaction, neurosis, dystonia, hostility, reflexes increased, emotional lability, euphoria, paranoid reaction; rare: aphasia, nystagmus, akathisia (psychomotor restlessness), stupor, dementia, diplopia, drug dependence, paralysis, grand mal convulsion, hypotonia, myoclonus, psychotic depression, withdrawal syndrome, serotonin syndrome.

Respiratory System: frequent: cough increased, sinusitis; infrequent: epistaxis, bronchitis, asthma, pneumonia; rare: asphyxia, laryngitis, pneumothorax, hiccup.

Skin and Appendages: frequent: pruritus, rash; infrequent: acne, exfoliative dermatitis, dry skin, herpes simplex, alopecia; rare: urticaria, herpes zoster, skin hypertrophy, seborrhea, skin ulcer.

Special Senses: infrequent: eye pain, abnormality of accommodation, conjunctivitis, deafness, keratoconjunctivitis, lacrimation disorder, angle-closure 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.

Other Adverse Events Observed During Postmarketing Evaluation Of Remeron

• Adverse events reported since market introduction, which were temporally (but not necessarily causally) related to mirtazapine therapy, include cases of the ventricular arrhythmia Torsades de Pointes.
• In the majority of these cases, however, concomitant drugs were implicated.
• Cases of severe skin reactions, including Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have also been reported. Increased creatine kinase blood levels and rhabdomyolysis have also been reported.

Drug Abuse And Dependence

Controlled Substance Class

• Remeron (mirtazapine) Tablets are not a controlled substance.

Physical And Psychologic Dependence

• Remeron (mirtazapine) Tablets have 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 Remeron misuse or abuse (e.g., development of tolerance, incrementations of dose, drug-seeking behavior).

As with other drugs, the potential for interaction by a variety of mechanisms (e.g., pharmacodynamic, pharmacokinetic inhibition or enhancement, etc.) is a possibility.

Monoamine Oxidase Inhibitors

See prescribing information.

Serotonergic Drugs

See prescribing information.

Drugs Affecting Hepatic Metabolism

The metabolism and pharmacokinetics of Remeron (mirtazapine) Tablets may be affected by the induction or inhibition of drug-metabolizing enzymes.

Drugs that are Metabolized by and/or Inhibit Cytochrome P450 Enzymes

CYP Enzyme 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 about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 45%. Mirtazapine did not significantly affect the pharmacokinetics of phenytoin.

Carbamazepine

In healthy male patients (n=24), carbamazepine (400 mg b.i.d.) increased mirtazapine (15 mg b.i.d.) clearance about 2-fold, resulting in a decrease in average plasma mirtazapine concentrations of 60%.

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, a weak inhibitor of CYP1A2, CYP2D6, and CYP3A4, given at 800 mg b.i.d. at steady state was coadministered with mirtazapine (30 mg daily) at steady state, the Area Under the Curve (AUC) of mirtazapine increased more than 50%. Mirtazapine did not cause relevant changes in the pharmacokinetics of cimetidine. 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), coadministration 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 of mirtazapine by approximately 40% and 50%, respectively.

Caution should be exercised when coadministering 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 cause relevant changes in the pharmacokinetics of steady state paroxetine (40 mg/day), a CYP2D6 inhibitor.

Other Drug-Drug Interactions

Amitriptyline

In healthy, CYP2D6 extensive metabolizer patients (n=32), amitriptyline (75 mg daily), at steady state, did not cause relevant changes in the pharmacokinetics of steady state mirtazapine (30 mg daily); mirtazapine also did not cause relevant changes to the pharmacokinetics of amitriptyline.

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 Normalized Ratio (INR) in subjects treated with warfarin. 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 effects of higher doses of lithium on the pharmacokinetics of mirtazapine are unknown.

Risperidone

In an in vivo, nonrandomized, interaction study, subjects (n=6) in need of treatment with an antipsychotic and antidepressant drug, showed that mirtazapine (30 mg daily) at steady state did not influence the pharmacokinetics of risperidone (up to 3 mg b.i.d.).

Alcohol

Concomitant administration of alcohol (equivalent to 60 g) had a minimal effect on plasma levels of mirtazapine (15 mg) in 6 healthy male subjects. However, the impairment of cognitive and motor skills produced by Remeron were shown to be additive with those produced by alcohol. Accordingly, patients should be advised to avoid alcohol while taking Remeron.

Diazepam

Concomitant administration of diazepam (15 mg) had a minimal effect on plasma levels of mirtazapine (15 mg) in 12 healthy subjects. However, 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.

QTc-Prolonging Drugs

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.