Description: Mirtazapine is an antidepressant that is not chemically related to any other class of antidepressants. It belongs to a unique class known as piperazinoazepines and is a tetracyclic compound. Mirtazapine possesses an anxiolytic effect that may be useful in depressed patients who have a coexisting anxiety disorder. The drug may also improve sleep patterns associated with depression. Mirtazapine is associated with fewer ADRs than tricyclic antidepressants and is better tolerated.[1344] [1345] Compared to the tricyclics and some SSRIs, mirtazapine may have a faster onset of antidepressant efficacy, with maximal effects within 2—4 weeks of adequate dosage selection. Selective blockade of specific serotonin receptors by mirtazapine is thought to help to minimize certain side effects (e.g., sexual dysfunction and weight gain) typical of other antidepressants. Off label uses of mirtazapine are still being explored, including efficacy for various neurologic-induced tremors. Initial FDA approval of mirtazapine was granted June 14, 1996. An orally disintegrating tablet was approved in January 2001. Mechanism of Action: The primary mechanism of action of mirtazapine is antagonism at central pre-synaptic alpha2-receptors. Normally, these receptors are involved in a negative feedback loop and activation causes inhibition of further norepinephrine (NE) release. By blocking pre-synaptic alpha2-receptors, mirtazapine defeats negative feedback to the presynaptic nerve and causes an increase in NE release. Antagonism at central alpha2-receptors is 10-fold higher than at peripheral alpha2-receptors which results in a reduced incidence of peripheral adverse effects. Mirtazapine also antagonizes several subtypes of serotonin (5-HT) receptors. The drug is a weak antagonist at 5-HT1 receptors and a potent antagonist at 5-HT2 (particularly subtypes 2A and 2C) and 5-HT3 receptors. Blockade of these receptors may result in a lower incidence of certain adverse effects such as anxiety, insomnia, and nausea that occur with other agents like the selective serotonin reuptake inhibitors (SSRIs). Serotonergic neurons also contain alpha2-receptors, called heteroreceptors and blockade of heteroreceptors results in enhanced release of 5-HT. The increased amount of 5-HT released interacts with 5-HT1 receptors which may be relevant to the antidepressant and anxiolytic effects of mirtazapine. Mirtazapine has no effects on the reuptake of either NE or 5-HT. In addition, mirtazapine exhibits significant antagonism at H1-receptors. Histamine H1-receptor blockade is generally associated with sedation, however, the enhancement of NE release may offset the sedative potential of the drug at higher doses. Mirtazapine has minimal activity at dopaminergic and muscarinic receptors. Pharmacokinetics: Mirtazapine is administered orally. Following oral administration, mirtazapine is rapidly and completely absorbed. Peak plasma concentrations are reached within about 2 hours after an oral dose. Food has minimal effects on both the rate and extent of absorption and does not require adjustments in the dose. Absolute bioavailability is about 50%. Plasma protein binding is approximately 85% over a concentration range of 0.01 to 10 µg/ml. Mirtazapine steady-state plasma levels are reached within 5 days. Antidepressant actions can onset within 1—2 weeks, with maximal therapeutic efficacy within 2—4 weeks following the selection of an effective dose. Metabolism is extensive after oral administration and occurs via demethylation and hydroxylation followed by glucuronide conjugation. In vitro data indicate that cytochrome P450 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite, whereas the cytochrome P4503A isoenzyme group is responsible for the formation of the N-desmethyl and N-oxide metabolite. Several unconjugated metabolites have pharmacologic activity but are present at very low plasma levels. Elimination occurs via the urine (75%) and the feces (15%). The (—) enantiomer has an elimination half-life that is about twice that of the (+) enantiomer. The elimination half-life of mirtazapine is long and ranges 20—40 hours across age and gender subgroups, so dosage increases should take place no sooner than every 7—14 days. •Special Populations: Gender, age, and organ dysfunctions may affect the pharmacokinetics of mirtazapine. Females of all ages exhibit significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). The oral clearance of mirtazapine is reduced in elderly patients. Following administration of mirtazapine 20 mg/day for 7 days clearance was reduced in the elderly compared to younger adults. Elderly males exhibited a 40% lower clearance while elderly females had a 10% lower clearance when compared to younger adults. In patients with renal impairment, oral clearance may be reduced by 30—50% compared to normal subjects. Following a single 15 mg oral dose, patients with moderate hepatic impairment had roughly 30% reduction in clearance, compared to normal subjects.

Indications...Dosage For the treatment of major depression: NOTE: It is generally agreed that pharmacological treatment for acute episodes of depression should continue for 4—6 months or longer. Whether the dose needed to induce remission is the same as the needed maintenance dose is unknown. Oral dosage: Adults: Initially, 15 mg PO at bedtime. The effective dose range is 15—45 mg/day. Dosage adjustments should not be made more often than every 1—2 weeks. Treatment with an adequate dose should result in a positive response within 2—4 weeks. Elderly: See adult dosage, slower titration may be indicated, based on patient response and tolerance. Initially, 7.5 mg PO at bedtime is recommended. Make dosage adjustments no more frequently than every 1—2 weeks, due to a long half-life and reduced clearance in the elderly. Adolescents and children: Safe and effective use has not been established. For the treatment of resting tremor†, benign familial tremor† (essential tremor†) or for the treatment of levodopa-induced dyskinesias†: Oral dosage: Adults: In limited reports the effective dose, after titration, was 30 mg PO at bedtime. Elderly: See adult dosage, slower titration may be indicated, based on patient response and tolerance. Maximum Dosage Limits: •Adults: 45 mg/day PO. •Elderly: 45 mg/day PO. •Adolescents: Safe and effective use has not been established. •Children: Safe and effective use has not been established. Patients with hepatic impairment: Modify dosage depending on clinical response and degree of hepatic impairment; no quantitative recommendations are available. Discontinue if jaundice is present. Patients with renal impairment: CrCl >= 40 ml/min: No adjustment appears needed. CrCl 11—39 ml/min: Initiate with lowest dosage and titrate slowly due to a rough 30% reduction in normal drug clearance. CrCl <= 10 ml/min: Initiate with lowest dosage and titrate slowly due to a rough 50% reduction in normal drug clearance.

Oral Administration •Mirtazapine may be administered without regard to meals. •Mirtazapine is suitable for once-a-day administration. It should be taken preferably as a single bedtime dose. Daily dose may also be given in equally divided doses (once in the morning and once at bedtime). •Orally disintegrating tablets (Remeron® SolTab™): Place tablet in mouth on tongue, allow to dissolve, then swallow. SolTabs™ do not need to be administered with water or other liquids, nor do they need to be chewed.

Contraindications Mirtazapine is contraindicated for use in any patient hypersensitive or overly sensitive to the effects of the drug. Although antidepressants are not addictive, the abrupt discontinuation of treatment after long-term administration may result in symptoms such as nausea, headache and malaise. Suicidal ideation is inherent in depression and may persist until significant remission occurs. Used with caution because of the possibility of suicide. Close monitoring of the patient is essential during the initial stages of therapy and mirtazapine should be prescribed in the smallest quantity consistent with good management, in order to reduce the risk of overdose. Mirtazapine should not be used in combination with a monoamine oxidase inhibitor (MAOI) or within 14 days of initiating or discontinuing therapy with a MAOI. Concomitant use of MAOIs with other antidepressants have resulted in hypertensive crisis. MAOIs should be discontinued 2—4 weeks before initiation of mirtazapine therapy. Bone marrow suppression, usually presenting as neutropenia or agranulocytosis, has been reported during treatment with most antidepressants, including mirtazapine. This mostly appears after 4—6 weeks of treatment and is in general reversible after termination of treatment. The prescriber should be alert for symptoms like fever, sore throat, stomatitis or other signs of infection; when such symptoms occur, mirtazapine treatment should be stopped and CBC should be monitored. During premarketing clinical trials of mirtazapine, agranulocytosis (ANC < 500/mm3) with associated signs and symptoms developed in 2 out of 2,796 patients being treated with mirtazapine. A third patient developed severe neutropenia (ANC < 500/mm3 without symptoms). For these 3 patients, onset of severe neutropenia was detected on days 9, 14 and 61 of treatment, respectively. Following discontinuation of mirtazapine, all patients recovered. Mirtazapine should be used cautiously in patients with pre-existing hematological disease, especially leukopenia, neutropenia, or thrombocytopenia. Mirtazapine should be used with caution in patients with a history of bipolar disorder, mania, or hypomania. In U.S. studies, approximately 0.2% of mirtazapine-treated patients developed mania/hypomania, so the occurrence is relatively rare. In placebo-controlled trials, there were no clinically significant ECG abnormalities reported with mirtazapine use. Mirtazapine may, however, induce orthostatic hypotension. During pharmacology trials, orthostatic hypotension was observed in normal volunteers, however, orthostatic hypotension was infrequently observed in clinical trials of depressed patients. Mirtazapine should be used with caution in patients with known cardiac disease or cerebrovascular disease that could be exacerbated by hypotension, such as a history of angina, cardiac arrhythmias, heart failure, ischemic stroke, or a past myocardial infarction. Conditions that might predispose patients to hypotension include dehydration, hypovolemia, surgery, or pharmacologic antihypertensive therapy. Mirtazapine has not been systematically studied or used in the setting of acute myocardial infarction or other significant heart disease. Mirtazapine should be used cautiously in patients with renal impairment or renal failure. Compared to those with normal renal function, the oral clearance of mirtazapine is reduced by about 30% and 50% in patients with moderate [CrCl 11—39 ml/min] and severe [CrCl <= 10 ml/min] renal dysfunction, respectively. Mirtazapine should be used cautiously in patients with hepatic disease. The clearance of mirtazapine is reduced roughly 30% in patients with compromised hepatic function compared to normal controls. In addition, during short-term U.S. controlled trials, clinically significant transaminase elevations were observed in 2% of mirtazapine-treated patients compared to 0.3% of placebo-treated patients. Most patients affected did not develop signs or symptoms associated with impaired hepatic function. Mirtazapine was discontinued in some patients while in other cases, the enzyme levels returned to normal even with continued treatment with mirtazapine. If jaundice occurs during treatment, mirtazapine should be discontinued. Mirtazapine should be used cautiously in elderly patients; the elderly exhibit reduced drug clearance and need lower initial doses and slower dosage titration compared to younger adults. In premarketing studies, mirtazapine was associated with a low incidence of seizures (1 out of 2,796 mirtazapine-treated patients). As with other antidepressants, use with caution in patients with a history of a seizure disorder. If seizures develop during therapy, use of mirtazapine should be terminated. Mirtazapine should be used cautiously in patients with hypercholesterolemia or hypertriglyceridemia. Nonfasting cholesterol increases to >= 20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine in U.S. controlled studies compared to 7% for placebo and 8% for amitriptyline. In the same studies, nonfasting triglyceride increases to >= 500 mg/dl were observed in 6% of mirtazapine-treated patients compared to 3% for placebo and 3% for amitriptyline. Safe and effective use of mirtazapine in children has not been established. Mirtazapine is classified as FDA pregnancy risk category C. Studies in animals have not shown any teratogenic effects, however, data in humans are lacking. Use during pregnancy only if clearly needed. In animals, mirtazapine is excreted in very small amounts in milk. It is not known if mirtazapine is excreted in human milk. Safe use during breast-feeding has not been established and is not recommended until further data are available. Mirtazapine exhibits very weak anticholinergic activity. While problems are not expected, it should be used cautiously in patients who might be more susceptible to these effects, such as those with urinary retention, prostatic hypertrophy, those with acute, untreated closed-angle glaucoma or increased intraocular pressure, or those with GI obstruction or ileus. Effects of mirtazapine may be additive to anticholinergic medications. Mirtazapine may impair concentration and alertness. Patients should avoid the driving or operating machinery or other dangerous tasks requiring concentration, until the effects of the drug are known. Ethanol intoxication should be avoided while taking this medication. In general, antidepressants may affect blood glucose concentrations because of their indirect effects on the endocrine system, so they should be used with caution in patients with diabetes mellitus.

Interactions According to the manufacturer, in vitro studies identify mirtazapine as a substrate for several hepatic cytochrome CYP450 isoenzymes including 2D6, 1A2, and 3A4. Mirtazapine is not a potent inhibitor of any of these enzymes; clinically significant pharmacokinetic interactions are not likely with drugs metabolized by CYP enzymes. Use of mirtazapine concurrently with the MAOIs is contraindicated. If combined, there is a possibility of developing serious reactions such as hyperpyrexia, hypertension, or seizures. Mirtazapine should also not be used with other drugs that exhibit MAO-inhibition, such as furazolidone, linezolid, and procarbazine. An interval of 14 days is recommended between cessation of MAOI therapy and initiation of mirtazapine therapy and vice versa. Mirtazapine should also not be administered with anxiolytics, sedatives, and hypnotics because the CNS effects on cognitive performance and motor skills can be additive; the manufacturer specifically warns against coadministration of ethanol or diazepam. Additive sedative effects could also potentially occur with barbiturates, benzodiazepines, general anesthetics, sedating H1-blockers, opiate agonists, phenothiazines, skeletal muscle relaxants, tramadol, or tricyclic antidepressants. Some medicines used for treatment of Parkinson's disease, like entacapone, tolcapone, ropinirole, or pramipexole, could potentially cause additive drowsiness when coadministered with mirtazapine. Antidepressants may interact with herbal products such as kava kava, Piper methysticum or valerian, Valeriana officinalis. Potential interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action. Although unlikely to occur with use of mirtazapine alone, the coadministration of other medications that potentiate the actions of serotonin (like the SSRIs) could theoretically result in serotonin syndrome. A case report of serotonin syndrome from an interaction of mirtazapine with fluoxetine has been described; other interactions are considered theoretical. Examples of other medications that may interact (and mechanisms involved) include: increased serotonin synthesis (L-tryptophan); decreased serotonin metabolism (MAOIs); increased serotonin release (amphetamines, cocaine, dexfenfluramine); inhibition of serotonin uptake (amphetamine, cocaine, dextroamphetamine, dextromethorphan, meperidine, nefazodone, St. John's wort, Hypericum perforatum, trazodone, tricyclic antidepressants); direct action at serotonin receptors (buspirone, serotonin-receptor agonists); or increased serotonin neurotransmission (lithium). Mirtazapine exhibits weak anticholinergic activity that is not expected to be clinically significant. However, the anticholinergic effects may be additive to the antimuscarinics. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function, the CNS, the eye, and temperature regulation. Mirtazapine has been noted in a case report to counteract dopamine-induced dyskinesias resulting from levodopa in a patient with Parkinson's disease. Data are limited to this one patient, but a beneficial interaction from the pharmacodynamic effects of mirtazapine appeared to occur. Clonidine stimulates central alpha-2 adrenergic receptors. Mirtazapine is known to have inhibitory effects on these same receptors. Mirtazapine may antagonize the antihypertensive and other pharmacologic effects of clonidine. Use of another antidepressant would be preferable in patients taking clonidine.

Adverse Reactions In US controlled clinical trials, about 16% of mirtazapine-treated patients discontinued mirtazapine therapy because of drowsiness (10.4% vs. 2.2% for placebo vs. 60% for amitriptyline) or nausea/vomiting (1.5%/0% vs. 0% for placebo vs. 14%/0% for amitriptyline). The most commonly reported adverse reactions occurring at an incidence of >= 5% for mirtazapine and at least twice the incidence for placebo were drowsiness/sedation (54% vs. 18% for placebo), appetite stimulation (17% vs. 2%), weight gain (12% vs. 2%), and dizziness (7% vs. 3%). Weight gain of greater than 7% of body weight was reported in 7.5% of mirtazapine-treated patients compared to 0% for placebo. Other adverse reactions occurring in >= 1% of mirtazapine-treated patients and at a greater incidence than in placebo in controlled trials include asthenia (8% vs. 5% for placebo), flu syndrome (5% vs. 3%), back pain (2% vs. 1%), xerostomia (25% vs. 15%), constipation (13% vs. 7%), peripheral edema (2% vs. 1%), edema (1% vs. 0%), myalgia (2% vs. 1%), abnormal dreams (4% vs. 1%), abnormal thinking (3% vs. 1%), tremor (2% vs. 1%), confusion or impaired cognition (2% vs. 0%), dyspnea (1% vs. 0%), and increased urinary frequency (2% vs. 1%). The following adverse events have also been reported to occur in 1% of mirtazapine-treated patients, except those already listed for controlled trials. These events come from data in all trials, including open-label and uncontrolled studies. It is important to emphasize that although the events reported occurred during treatment with mirtazapine, they were not necessarily caused by it. Some events occurred at rates similar to placebo in controlled clinical trials. The following events are listed by body system. Body as a whole: abdominal pain, malaise. Cardiovascular: hypertension, vasodilation (flushing). Digestive/GI: anorexia, vomiting. Metabolic: polydipsia (increased thirst). Musculoskeletal: arthralgia, myasthenia. Nervous system/Psychiatric: agitation, anxiety, amnesia, apathy, depression, dyskinesia ( reported as either hypokinesia or hyperkinesia), hypoesthesia, paresthesias, twitching, and vertigo. In U.S. studies, approximately 0.2% of mirtazapine-treated patients developed mania/hypomania, so the occurrence is relatively rare. Respiratory: increased cough, sinusitis. Skin and Appendages: pruritus, rash (unspecified). Urogenital system: urinary tract infection. NOTE; additional reported infrequent side effects (0.1—1% of patients) and rare events (<= 0.1% of patients) in which a causal relationship to mirtazapine has not been established are listed in the manufacturer's prescribing information. The following events were reported in at least 1% of mirtazapine-treated patients, but occurred in placebo-treated groups at an equal or greater incidence: amblyopia, chest pain (unspecified), diaphoresis (sweating), dysgeusia, dyspepsia, diarrhea, flatulence, infection, insomnia, hypertonia, nervousness, libido decrease, orthostatic hypotension, palpitation, pharyngitis, rhinitis, sinus tachycardia, and tinnitus. During pharmacology trials, orthostatic hypotension due to mirtazapine was observed in normal volunteers, however, orthostatic hypotension was infrequently observed in controlled clinical trials of depressed patients. In ECG studies, changes from baseline occurred in equal rates in placebo- and mirtazapine-treated groups and were generally non-clinically significant. During short-term U.S. controlled trials, clinically significant elevated hepatic enzymes were observed in 2% of mirtazapine-treated patients compared to 0.3% of placebo-treated patients. Most patients with transaminase elevations did not develop signs or symptoms associated with impaired hepatic function. Mirtazapine was discontinued in some patients, while in other cases, the enzyme levels returned to normal even with continued treatment with mirtazapine. If jaundice occurs during mirtazapine treatment, discontinue the drug. Three cases of agranulocytosis were reported during premarketing clinical trials of mirtazapine. Agranulocytosis (ANC < 500/mm3 with associated signs and symptoms) developed in 2 (one with Sjogren's syndrome) out of 2,796 patients being treated with mirtazapine. A third patient developed severe neutropenia (ANC < 500/mm3 without any associated symptoms). For these three patients, onset of severe neutropenia was detected on days 61, 9, and 14 of treatment, respectively. Following discontinuation of mirtazapine, all three patients recovered. If a patient develops sore throat, fever, stomatitis, or other signs of infection, along with neutropenia, mirtazapine therapy should be discontinued. Mirtazapine may increase hypercholesterolemia or hypertriglyceridemia. Nonfasting cholesterol increases to >= 20% above the upper limits of normal were observed in 15% of patients treated with mirtazapine in U.S. controlled studies compared to 7% for placebo and 8% for amitriptyline. In the same studies, nonfasting triglyceride increases to >= 500 mg/dl were observed in 6% of mirtazapine-treated patients compared to 3% for placebo and 3% for amitriptyline. In clinical trials with mirtazapine, apart from excessive sedation no clinically relevant effects have been observed following overdose. Toxicity studies demonstrate that clinically relevant cardiotoxic effects will not occur after overdosing with mirtazapine.

Mirtazapine Remeron® | Remeron®, Remeron® SolTab™

1344. Bremner JD. A double-blind comparison of Org 3770, amitriptyline, and placebo in major depression. J Clin Psychiatry 1995;56:519—25.

1345. Smith WT, Glaudin V, Panagides J, et al. Mirtazapine vs. amitriptyline vs. placebo in the treatment of major depressive disorder. Psychopharmacol Bull 1990;26:191—6.