indication

For the treatment of psychosis, particular those of schizophrenia, and manic phases of bipolar disorder.

pharmacology

Methotrimeprazine is a phenothiazine with pharmacological activity similar to that of both chlorpromazine and promethazine. It has the histamine-antagonist properties of the antihistamines together with central nervous system effects resembling those of chlorpromazine. (From Martindale, The Extra Pharmacopoeia, 30th ed, p604)

mechanism of action

Methotrimeprazine's antipsychotic effect is largely due to its antagonism of dopamine receptors in the brain. In addition, its binding to 5HT2 receptors may also play a role.

toxicity

Symptoms of overdose include convulsions, spastic movements, and coma.

biotransformation

Hepatic. Methotrimeprazine is metabolized in the liver and degraded to a sulfoxid-, a glucuronid- and a demethyl-moiety.

absorption

Methotrimeprazine has an incomplete oral bioavailability, because it undergoes considerable first-pass-metabolism in the liver. Oral bioavailability is approximately 50 to 60%.

half life

Approximately 20 hours.

drug interactions

Amphetamine: Decreased anorexic effect, may increase psychotic symptoms

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Benzphetamine: Antipsychotics may diminish the stimulatory effect of Amphetamines. Monitor effectiveness of amphetamine therapy when altering concurrent antipsychotic therapy as antipsychotic agents may impair the stimulatory effect of amphetamines.

Brimonidine: Brimonidine may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of brimonidine. Consider therapy modification.

Bromazepam: Concomitant therapy may result in additive CNS depressant effects. The dosage of bromazepam should be decreased by 50% prior to initiating concomitant therapy. Monitor for increased CNS depression.

Bromocriptine: The phenothiazine decreases the effect of bromocriptine

Carisoprodol: Carisoprodol, a CNS depressant, may enhance the CNS depressant effect of methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants like carisoprodol. Reduce the dosage of CNS depressants by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose has been established. Monitor for increased CNS depression with concomitant therapy.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Dantrolene: Concomitant therapy may result in additive CNS depressant effects. The dosage of dantrolene should be decreased by 50% prior to initiating concomitant therapy. Monitor for increased CNS depression.

Dexfenfluramine: Decreased anorexic effect, may increase psychotic symptoms

Dextroamphetamine: Decreased anorexic effect, may increase psychotic symptoms

Diethylpropion: Decreased anorexic effect, may increase psychotic symptoms

Donepezil: Possible antagonism of action

Fenfluramine: Decreased anorexic effect, may increase psychotic symptoms

Galantamine: Possible antagonism of action

Gatifloxacin: Increased risk of cardiotoxicity and arrhythmias

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Guanethidine: Methotrimeprazine may decrease the effect of guanethidine.

Isocarboxazid: Possible severe adverse reaction with this combination

Levofloxacin: Increased risk of cardiotoxicity and arrhythmias

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mazindol: Decreased anorexic effect, may increase psychotic symptoms

Methamphetamine: Decreased anorexic effect, may increase psychotic symptoms

Metrizamide: Increased risk of convulsions

Paliperidone: The CNS depressant agents, paliperidone and methotrimeprazine, may cause additive CNS depressant effects. Monitor for increased CNS depressant effects during concomitant therapy.

Pargyline: Possible severe adverse reaction with this combination

Phendimetrazine: Decreased anorexic effect, may increase psychotic symptoms

Phenelzine: Possible severe adverse reaction with this combination

Phenmetrazine: Decreased anorexic effect, may increase psychotic symptoms

Phentermine: Decreased anorexic effect, may increase psychotic symptoms

Phenylpropanolamine: Decreased anorexic effect, may increase psychotic symptoms

Rivastigmine: Possible antagonism of action

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Tramadol: Additive CNS depressant effects. Decrease dose of tramadol by 50% if initiating methotrimeprazine therapy. Monitor for increased CNS depression and apply further dosage adjustments as required.

Tranylcypromine: Possible severe adverse reaction with this combination

Vigabatrin: Additive CNS depression may occur. Dose adjustments may be required if one agent is added to existing therapy with the other agent. Monitor for increased CNS depression during concomitant therapy.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Zaleplon: Additive CNS depressant effects may occur. A dose reduction of zaleplon may be required. Monitor for increased CNS depression during concomitant therapy.

Ziprasidone: Additive QTc-prolongation may occur increasing the risk of life-threatening ventricular arrhythmias and torsade de pointes. Concomitant therapy should be avoided.

Zolpidem: Additive CNS depressant effects. Reduce zolpidem dose by half upon initiation of methotrimeprazine. Zolpidem dose may be adjusted once methotrimeprazine dose has been established. Monitor for increased CNS depression.

Zonisamide: Additive CNS depressant effects. Reduce zonisamide dose by half upon initiation of methotrimeprazine. Zonisamide dose may be adjusted once methotrimeprazine dose has been established. Monitor for increased CNS depression.

Zopiclone: Additive CNS depressant effects. Reduce zopiclone dose by half upon initiation of methotrimeprazine. Zopiclone dose may be adjusted once methotrimeprazine dose has been established. Monitor for increased CNS depression.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP). Methotrimeprazine, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if methotrimeprazine is initiated, discontinued or dose changed.