REMERON and REMERONSolTab contain mirtazapine. Mirtazapine has a tetracyclic chemical structure and belongs to the piperazino-azepine group of compounds. It is designated 1,2,3,4,10,14b-hexahydro-2methylpyrazino [2,1-a] pyrido [2,3-c] benzazepine and has the empirical formula of C17H19N3. Its molecular weight is 265.35.
INDICATIONS AND USAGE
REMERON/REMERON Sol Tab are indicated for the treatment of major depressive disorder (MDD) in adults.
Mechanism of Action
The mechanism of action of mirtazapine for the treatment of major depressive disorder, is unclear. However, its efficacy could be mediated through its activity as an antagonist at central presynaptic α2adrenergic inhibitory autoreceptors and heteroreceptors and enhancing central noradrenergic and serotonergic activity.
DOSAGE AND ADMINISTRATION
The recommended starting dose of REMERON/REMERON Sol Tab is 15 mg once daily, administered orally, preferably in the evening prior to sleep. If patients do not have an adequate response to the initial 15 mg dose, increase the dose up to a maximum of 45 mg per day. Dose changes should not be made in intervals of less than 1 to 2 weeks to allow sufficient time for evaluation of response to a given dose.
Administration of REMERON Sol Tab
- The tablet should remain in the blister pack until the patient is ready to take it.
- The patient or caregiver should use dry hands to open the blister.
- As soon as the blister is opened, the tablet should be removed and placed on the patient’s tongue.
- Use REMERON Sol Tab immediately after removal from its blister; once removed, it cannot be stored.
- The whole tablet should be placed on the tongue and allowed to disintegrate without chewing or crushing. Do not attempt to split the tablet.
- The tablet will disintegrate in saliva so that it can be swallowed.
Screen for Bipolar Disorder Prior to Starting REMERON/REMERON Sol Tab
Prior to initiating treatment with REMERON/REMERON Sol Tab or another antidepressant, screen patients for a personal or family history of bipolar disorder, mania, or hypomania.
Switching Patients to or from a Monoamine Oxidase Inhibitor Antidepressant
At least 14 days must elapse between discontinuation of a monoamine oxidase inhibitor (MAOI) antidepressant and initiation of REMERON/REMERON Sol Tab. In addition, at least 14 days must elapse after stopping REMERON/REMERON Sol Tab before starting an MAOI antidepressant.
Discontinuation of REMERON/REMERON Sol Tab Treatment
Adverse reactions may occur upon discontinuation or dose reduction of REMERON/REMERON Sol Tab. Gradually reduce the dosage of REMERON/REMERON Sol Tab rather than stopping abruptly whenever possible.
REMERON/REMERONSolTab is contraindicated in patients:
- Taking, or within 14 days of stopping, MAOIs (including the MAOIs linezolid and intravenous methylene blue) because of an increased risk of serotonin syndrome.
- With a known hypersensitivity to mirtazapine or to any of the excipients in REMERON/REMERONSolTab. Severe skin reactions, including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome, bullous dermatitis, erythema multiforme and toxic epidermal necrolysis have been reported following the use of REMERON/REMERONSolTab
WARNINGS AND PRECAUTIONS
- SUICIDAL THOUGHTS AND BEHAVIORS: Increased risk of suicidal thoughts and behavior in pediatric andyoung adult patients taking antidepressants. Closely monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors.REMERON/REMERONSolTab is not approved for use in pediatricpatients.
- Agranulocytosis: If sore throat, fever, stomatitis or signs of infection occur, along with a low white blood cell count, treatment with REMERON/REMERONSolTab should be discontinued and the patient should be closely monitored.
- Serotonin Syndrome: Increased risk when co-administered with other serotonergic drugs (e.g., SSRI, SNRI, triptans), but also when taken alone. If it occurs, discontinue REMERON/REMERONSolTab and initiate supportive treatment.
- Angle-Closure Glaucoma: Angle closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants.
- QT Prolongation: Use REMERON/REMERONSolTab with caution in patients with risk factors for QT prolongation.
- Drug Reaction with Eosinophilia and System Symptoms (DRESS): Discontinue REMERON/REMERONSolTab if DRESS is suspected.
- Increased Appetite/Weight Gain: REMERON/REMERONSolTab has been associated with increased appetite and weight gain.
- Somnolence: May impair judgment, thinking and/or motor skills. Use with caution when engaging in activities requiring alertness, such as driving or operating machinery.
- Activation of Mania/Hypomania: Screen patients for bipolar disorder prior to initiating treatment.
- Seizures: Use with caution in patients with a seizure disorder.
- Elevated Cholesterol/Triglycerides: Has been reported with REMERON use.
- Hyponatremia: May occur as a result of treatment with serotonergic antidepressants, including REMERON/REMERONSolTab.
- Transaminase Elevations: Clinically significant elevations have occurred. Use with caution in patients with impaired hepatic function.
The following adverse reactions have been identified during post-approval use of REMERON. 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
|Monoamine Oxidase Inhibitors (MAOIs)|
|Clinical Impact||The concomitant use of serotonergic drugs, including REMERON/REMERONSolTab, and MAOIs increases the risk of serotonin syndrome.|
|Intervention||REMERON/REMERONSolTab is contraindicated in patients taking MAOIs, including MAOIs such as linezolid or intravenous methylene blue|
|Examples||selegiline, tranylcypromine, isocarboxazid, phenelzine, linezolid, methylene blue|
|Other Serotonergic Drugs|
|Clinical Impact||The concomitant use of serotonergic drugs with REMERON/REMERONSolTab 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 REMERON/REMERONSolTab and/or concomitant serotonergic drugs|
|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 REMERON/REMERONSolTab decreases the plasma concentration of mirtazapine|
|Intervention||Increase the dose of REMERON/REMERONSolTab if needed with concomitant CYP3A inducer use. Conversely, a decrease in dosage of REMERON/REMERONSolTab may be needed if the CYP3A inducer is discontinued|
|Examples||phenytoin, carbamazepine, rifampin|
|Strong CYP3A Inhibitors|
|Clinical Impact||The concomitant use of strong CYP3A inhibitors with REMERON/REMERONSolTab may increase the plasma concentration of mirtazapine|
|Intervention||Decrease the dose of REMERON/REMERONSolTab if needed with concomitant strong CYP3A inhibitor use. Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if the CYP3A inhibitor is discontinued|
|Examples||itraconazole, ritonavir, nefazodone|
|Clinical Impact||The concomitant use of cimetidine, a CYP1A2, CYP2D6, and CYP3A inhibitor, with REMERON/REMERONSolTab may increase the plasma concentration of mirtazapine|
|Intervention||Decrease the dose of REMERON/REMERONSolTab if needed with concomitant cimetidine use. Conversely, an increase in dosage of REMERON/REMERONSolTab may be needed if cimetidine is discontinued|
|Benzodiazepines and Alcohol|
|Clinical Impact||The concomitant use of benzodiazepines or alcohol with REMERON/REMERONSolTab increases the impairment of cognitive and motor skills produced by REMERON/REMERONSolTab alone.|
|Intervention||Avoid concomitant use of benzodiazepines and alcohol with REMERON/REMERONSolTab|
|Examples||diazepam, alprazolam, alcohol|
|Drugs that Prolong QTc Interval|
|Clinical Impact||The concomitant use of other drugs which prolong the QTc interval with REMERON/REMERONSolTab, increase the risk of QT prolongation and/or ventricular arrhythmias (e.g., Torsades de Pointes).|
|Intervention||Use caution when using REMERON/REMERONSolTab concomitantly with drugs that prolong the QTc interval|
|Clinical Impact||The concomitant use of warfarin with REMERON/REMERONSolTab may result in an increase in INR|
|Intervention||Monitor INR during concomitant use of warfarin with REMERON/REMERONSolTab.|
USE IN SPECIFIC POPULATIONS
Pregnancy: 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.
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.
Lactation: Data from published literature report the presence of mirtazapine in human milk at low levels with relative infant doses for mirtazapine ranging between 0.6 and 2.8% of the maternal weight-adjusted dose. No adverse effects on the breastfed infant have been reported in most cases of maternal use of mirtazapine. There are no data on the effects of mirtazapine on milk production.
The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for mirtazapine and any potential adverse effects on the breastfed infant from mirtazapine or from the underlying maternal condition.
Pediatric Use: The safety and effectiveness of REMERON/REMERONSolTab have not been established in pediatric patients with MDD.
Renal or Hepatic Impairment: The clearance of mirtazapine is reduced in patients with moderate to severe renal or hepatic impairment. Consequently, plasma mirtazapine levels may be increased in these patient groups, compared to levels observed in patients without renal or hepatic impairment. Dosage decrease may be necessary when administering REMERON/REMERONSolTab to patients with moderate to severe renal or hepatic impairment.
Patients with Phenylketonuria: REMERONSolTab contains phenylalanine, a component of aspartame. REMERONSolTab contains the following amount of phenylalanine: 2.6 mg in 15 mg orally disintegrating tablet, 5.2 mg in 30 mg orally disintegrating tablet, and 7.8 mg in 45 mg orally disintegrating tablet.
In premarketing clinical studies, there were reports of REMERON overdose alone or in combination with other pharmacological agents. Signs and symptoms reported in association with overdose included disorientation, drowsiness, impaired memory, and tachycardia.
Based on post marketing reports, serious outcomes (including fatalities) may occur at dosages higher than the recommended doses, especially with mixed overdoses. In these cases, QT prolongation and Torsades de Pointes have also been reported.
Overdose Management: No specific antidotes for mirtazapine are known. Contact Poison Control (1-800-222-1222) for the latest recommendations.