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Mirtazapine (Remeron) Interactions

NOTE: 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 monoamine oxidase inhibitors (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 has been noted to counteract levodopa-induced dyskinesias in patients with Parkinson’s disease; a beneficial interaction from the pharmacodynamic effects of mirtazapine appeared to occur. 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, there have been rare case reports of serotonin syndrome with the drug. The coadministration of other medications that potentiate the actions of serotonin (e.g., SSRIs) could result in serotonin syndrome. Case reports of serotonin syndrome from an interaction of mirtazapine with fluoxetine or with fluvoxamine have been described. In vitro studies identify mirtazapine as a substrate for several hepatic cytochrome CYP450 isoenzymes including 2D6, 1A2, and 3A4. Increased mirtazapine serum concentrations (3 - 4 fold) have been reported following the addition of fluvoxamine to stable mirtazapine regimens. It may be necessary to reduce the dosage of either mirtazapine and/or the SSRI when they are administered concurrently.

Evidence suggests that mirtazapine enhances central noradrenergic and serotonergic activity. This action may be duplicative to the tricyclic antidepressants (TCAs) and the two drugs should be used together with caution, due to a theoretical potential for additive pharmacology and/or side effects (e.g., drowsiness, serotonin syndrome). While one small study in healthy subjects (n=24) reported that the combination of mirtazapine with a tricyclic antidepressant (e.g., amitriptyline) may be tolerable and result in only minor alterations in the pharmacokinetics of either agent, the authors still recommended caution and the need for further human data, including safety data and evidence of combined treatment efficacy.

Although unlikely to occur with use of mirtazapine alone, there have been rare case reports of serotonin syndrome with the drug. It is likely that the activation of 5-HT(1A) receptors by mirtazapine, combined with coadministration of other medications that potentiate the actions of serotonin (e.g., SSRIs), could result in serotonin syndrome. Examples of medications that may exhibit additive effects on serotonin (and mechanisms involved) include: increased serotonin synthesis (L-tryptophan); decreased serotonin metabolism (MAOIs); increased serotonin release (amphetamines, cocaine, dexfenfluramine, tramadol); inhibition of serotonin uptake (amphetamine, cocaine, dextroamphetamine, dextromethorphan, meperidine, nefazodone, St. John’s wort, Hypericum perforatum, tramadol, trazodone, tricyclic antidepressants); direct action at serotonin receptors (buspirone, serotonin-receptor agonists); or increased serotonin neurotransmission (lithium). Consistent with the pharmacology of mirtazapine and the drug’s side effect profile, additive effects (e.g., drowsiness) may occur with some of these CNS-active agents.

Consistent with the pharmacology of mirtazapine and the drug’s side effect profile, additive effects may occur with other CNS-active agents. Mirtazapine should be administered with caution with such agents because the CNS effects on cognitive performance and motor skills can be additive; the manufacturer specifically warns against coadministration of ethanol; patients should avoid combination of mirtazapine with alcoholic beverages. Use particular caution with anxiolytics, sedatives, and hypnotics; in studies, there has been an additive impairment of motor skills and impaired learning acquisition (pharmacodynamic effect) when mirtazapine is coadministered with a benzodiazepine (i.e., diazepam); mirtazapine and diazepam concentrations were not significantly affected. Additive sedative effects could also potentially occur with barbiturates, general anesthetics, sedating H1-blockers, opiate agonists, buprenorphine, butorphanol, nalbuphine, pentazocine, dronabinol, THC, phenothiazines, skeletal muscle relaxants, tramadol, or tricyclic antidepressants. Use together with caution.

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.

Clonidine stimulates central alpha-2 adrenergic receptors. Mirtazapine is known to have inhibitory effects on these same receptors. Mirtazapine has been shown to antagonize the antihypertensive and other pharmacologic effects of clonidine. Use of another antidepressant would be preferable in patients taking clonidine.

Mirtazapine plasma concentrations and pharmacologic action may be decreased in patients taking hydantoins. The mechanism appears to be induction of cytochrome P450 enzymes CYP3A3 and CYP3A4 by the hydantoin, leading to increased metabolism of mirtazapine. In an in-vivo pharmacokinetic study, phenytoin addition to an existing regimen of mirtazapine resulted in a 47% reduction in the AUC of mirtazapine; Cmax decreased from 69.7 to 46.9 ng/ml. Mirtazapine did not appear to affect the pharmacokinetics of phenytoin. Closely monitor mirtazapine response if hydantoin therapy is started, stopped or if the dose is adjusted; alter mirtazapine doses as needed.

[ Last revised: 3/20/2006 3:25:00 PM ]