Mirtazapine (Page 4 of 9)

ECG Changes

The electrocardiograms for 338 patients who received mirtazapine tablets and 261 patients who
received placebo in 6-week, placebo-controlled trials were analyzed. Mirtazapine tablets 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.

Other Adverse Events Observed During the Premarketing Evaluation of Mirtazapine Tablets

The following list does not include reactions: 1) already listed in previous tables or elsewhere in
labeling, 2) for which a drug cause was remote, 3) which were so general or excessively specific so
as to be uninformative, 4) which were not considered to have significant clinical implications, or 5)
which occurred at a rate equal to or less than placebo.
Adverse reactions are categorized by body system according to the following definitions: frequent
adverse reactions are those occurring in at least 1/100 patients; infrequent adverse reactions are
those occurring in 1/100 to 1/1000 patients; rare adverse reactions are those occurring in fewer
than 1/1000 patient.

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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of mirtazapine
tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal relationship to drug
exposure.
Cardiac disorders: ventricular arrhythmia (Torsades de Pointes)
Endocrine disorders: hyperprolactinemia (and related symptoms, e.g., galactorrhea and
gynecomastia)
Musculoskeletal and connective tissue disorders: increased creatine kinase blood levels and
rhabdomyolysis
Psychiatric disorders: somnambulism (ambulation and other complex behaviors out of bed)
Reproductive system and breast disorder: priapism
Skin and subcutaneous tissue disorders: severe skin reactions, including DRESS, Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis

7 DRUG INTERACTIONS

Table 5 includes clinically important drug interactions with Mirtazapine Tablets [see Clinical

Pharmacology (12.3)].

Table 5: Clinically Important Drug Interactions with Mirtazapine Tablets
Monoamine Oxidase Inhibitors (MAOIs)
Clinical Impact The concomitant use of serotonergic drugs, including Mirtazapine Tablets, and MAOIs increases the risk of serotonin syndrome.
Intervention Mirtazapine tablets are contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue [see Dosage and Administration (2.4), Contraindications (4), Warnings and Precautions (5.3)]
Examples selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue
Other Serotonergic Drugs
Clinical Impact The concomitant use of serotonergic drugs with mirtazapine tablets increases the risk of serotonin syndrome.
Intervention Monitor patients for signs and symptoms of serotonin syndrome, particularly during treatment initiation and dosage increases. If serotonin syndrome occurs, consider discontinuation of mirtazapine tablets and/or concomitant serotonergic drugs [see Warnings and Precautions (5.3)]
Examples SSRIs, SNRIs, triptans, tricyclic antidepressants, fentanyl, lithium, amphetamines, St. John’s Wort, tramadol, tryptophan, buspirone
Strong CYP3A Inducers
Clinical Impact The concomitant use of strong CYP3A inducers with mirtazapine tablets decreases the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].
Intervention Increase the dose of mirtazapine tablets if needed with concomitant CYP3A inducer use. Conversely, a decrease in dosage of Mirtazapine Tablets may be needed if the CYP3A inducer is discontinued [see Dosage and Administration (2.5)].
Examples phenytoin, carbamazepine, rifampin
Strong CYP3A Inhibitors
Clinical Impact The concomitant use of strong CYP3A inhibitors with mirtazapine tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)].
Intervention Decrease the dose of mirtazapine tablets if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine tablets may be needed if the CYP3A inhibitor is discontinued [see Dosage and Administration (2.5)].
Examples itraconazole, ritonavir, nefazodone
Cimetidine
Clinical Impact The concomitant use of cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, with mirtazapine tablets may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)]
Intervention Decrease the dose of mirtazapine tablets if needed with concomitant cimetidine use. Conversely, an increase in dosage of mirtazapine tablets may be needed if cimetidine is discontinued [see Dosage and Administration (2.5)].
Benzodiazepines and Alcohol
Clinical Impact The concomitant use of benzodiazepines or alcohol with mirtazapine tablets increases the impairment of cognitive and motor skills produced by mirtazapine tablets alone.
Intervention Avoid concomitant use of benzodiazepines and alcohol with mirtazapine tablets [see Warnings and Precautions (5.7), Clinical Pharmacology (12.3)].
Examples diazepam, alprazolam, alcohol
Drugs that Prolong QTc Interval
Clinical Impact The concomitant use of other drugs which prolong the QTc interval with mirtazapine tablets, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes).
Intervention Use caution when using mirtazapine tablets concomitantly with drugs that prolong the QTc interval [see Warnings and Precautions (5.5), Clinical Pharmacology (12.3)].
Warfarin
Clinical Impact The concomitant use of warfarin with mirtazapine tablets may result in an increase in INR [see Clinical Pharmacology (12.3)].
Intervention Monitor INR during concomitant use of warfarin with mirtazapine tablets

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