Mirtazapine (Page 4 of 7)
6.2 Postmarketing Experience
The following adverse reactions have been identified during post-approval use of mirtazapine. 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 disorders: 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 [see Clinical Pharmacology (12.3)].
Monoamine Oxidase Inhibitors (MAOIs) | |
Clinical Impact | The concomitant use of serotonergic drugs, including mirtazapine, and MAOIs increases the risk of serotonin syndrome. |
Intervention | Mirtazapine is 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 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 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 decreases the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)]. |
Intervention | Increase the dose of mirtazapine if needed with concomitant CYP3A inducer use. Conversely, a decrease in dosage of mirtazapine 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 may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)]. |
Intervention | Decrease the dose of mirtazapine if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of mirtazapine 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 may increase the plasma concentration of mirtazapine [see Clinical Pharmacology (12.3)]. |
Intervention | Decrease the dose of mirtazapine if needed with concomitant cimetidine use. Conversely, an increase in dosage of mirtazapine 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 increases the impairment of cognitive and motor skills produced by mirtazapine alone. |
Intervention | Avoid concomitant use of benzodiazepines and alcohol with mirtazapine [see Warnings and Precautions (5.8), 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, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes). |
Intervention | Use caution when using mirtazapine 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 may result in an increase in INR [see Clinical Pharmacology (12.3)]. |
Intervention | Monitor INR during concomitant use of warfarin with mirtazapine. |
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Exposure Registry
There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants/.
Risk Summary
Prolonged experience with mirtazapine in pregnant women, based on published observational studies and postmarketing reports, has not reliably identified a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks associated with untreated depression in pregnancy (see Clinical Considerations).
In animal reproduction studies, oral administration of mirtazpine to pregnant rats and rabbits during the period of organogenesis revealed no evidence of teratogenic effects up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg, respectively, based on mg/m2 body surface area. However, in rats, there was an increase in postimplantation loss at 20 times the MRHD based on mg/m2 body surface area. Oral administration of mirtazapine to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths and a decrease in pup birth weights at doses 20 times the MRHD based on mg/m2 body surface area (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations
Disease-Associated Maternal and/or Embryo/Fetal Risk
Women who discontinue antidepressants during pregnancy are more likely to experience a relapse of major depression than women who continue antidepressants. This finding is from a prospective, longitudinal study that followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated depression when discontinuing or changing treatment with antidepressant medication during pregnancy and postpartum.
Data
Animal Data
Mirtazapine was administered orally to pregnant rats and rabbits during the period of organogenesis at doses of 2.5, 15, and 100 mg/kg/day and 2.5, 10, and 40 mg/kg/day, respectively, which are up to 20 and 17 times the maximum recommended human dose (MRHD) of 45 mg based on mg/m2 body surface area, respectively. No evidence of teratogenic effects was observed. However, in rats, there was an increase in postimplantation loss in dams treated with mirtazapine at 100 mg/kg/day which is 20 times the MRHD based on mg/m2 body surface area. Oral administration of mirtazapine at doses of 2.5, 15, and 100 mg/kg/day to pregnant rats during pregnancy and lactation resulted in an increase in pup deaths during the first 3 days of lactation and a decrease in pup birth weights at 20 times the MRHD based on mg/m2 body surface area. The cause of these deaths is not known. The no effect dose level is 3 times the MRHD based on mg/m2 body surface area.
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