indication

For the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. May also be used to treat depression accompanied by anxiety or agitation.

pharmacology

Amoxapine is a tricyclic antidepressant of the dibenzoxazepine class, chemically distinct from the dibenzodiazepines, dibenzocycloheptenes, and dibenzoxepines. It has a mild sedative component to its action. The mechanism of its clinical action in man is not well understood. In animals, amoxapine reduced the uptake of nor-epinephirine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine

mechanism of action

Amoxapine acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).

toxicity

Toxic manifestations of amoxapine overdosage differ significantly from those of other tricyclic antidepressants. Serious cardiovascular effects are seldom if ever observed. However, CNS effects, particularly grand mal convulsions, occur frequently, and treatment should be directed primarily toward prevention or control of seizures. Status epilepticus may develop and constitutes a neurologic emergency. Coma and acidosis are other serious complications of substantial amoxapine overdosage in some cases. Renal failure may develop two to five days after toxic overdose in patients who may appear otherwise recovered. Acute tubular necrosis with rhabdomuolysis and myolobinurla is the most common renal complication in such cases. This reaction probably occurs in less than 5% of overdose cases, and typically in those who have experienced multiple seizures.

biotransformation

Amoxapine is almost completely metabolized in the liver to its major metabolite, 8-hydroxyamoxapine, and a minor metabolite, 7-hydroxyamoxapine. Both metabolites are phamacologically inactive and have half-lives of approximately 30 and 6.5 hours, respectively.

absorption

Rapidly and almost completely absorbed from the GI tract. Peak plasma concentrations occur within 1-2 hours of oral administration of a single dose.

half life

8 hours

route of elimination

60-69% of a single orally administered dose of amoxapine is excreted in urine, principally as conjugated metabolites. 7-18% of the dose is excrete feces mainly as unconjugated metabolites. Less than 5% of the dose is excreted as unchanged drug in urine.

drug interactions

Altretamine: Risk of severe hypotension

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

Atazanavir: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if atazanavir if initiated, discontinued or dose changed.

Butabarbital: Barbiturates like butabarbital may increase the metabolism of tricyclic antidepressants like amoxipine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Butalbital: Barbiturates such as butalbital may increase the metabolism of tricyclic antidepressants amoxapine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Cimetidine: Cimetidine may increase the effect of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if cimetidine is initiated, discontinued or dose changed.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clonidine: The tricyclic antidepressant, amoxapine, decreases the effect of clonidine.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dobutamine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of dobutamine.

Donepezil: Possible antagonism of action

Dopamine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of dopamine.

Ephedra: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of ephedra.

Ephedrine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of ephedrine.

Epinephrine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of epinephrine.

Fenoterol: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of fenoterol.

Fluoxetine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of amoxapine if fluoxetine is initiated, discontinued or dose changed.

Fluvoxamine: The SSRI, fluvoxamine, may increase the serum concentration of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of amoxapine if fluvoxamine is initiated, discontinued or dose changed.

Galantamine: Possible antagonism of action

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Guanethidine: The tricyclic antidepressant, amoxapine, decreases the effect of guanethidine.

Isocarboxazid: Possibility of severe adverse effects

Isoproterenol: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of isoproterenol.

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

Mephentermine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of mephentermine.

Metaraminol: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of metaraminol.

Methoxamine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of methoxamine.

Moclobemide: Possible severe adverse reaction with this combination

Norepinephrine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of norepinephrine.

Orciprenaline: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of orciprenaline.

Phenelzine: Possibility of severe adverse effects

Phenylephrine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of phenylephrine.

Phenylpropanolamine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of phenylpropanolamine.

Pirbuterol: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of pirbuterol.

Procaterol: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of procaterol.

Pseudoephedrine: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of pseudoephedrine.

Rasagiline: Possibility of severe adverse effects

Rifabutin: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, amoxapine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if rifabutin is initiated, discontinued or dose changed.

Rifampin: The rifamycin, rifampin, may decrease the effect of the tricyclic antidepressant, amoxapine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if rifampin is initiated, discontinued or dose changed.

Ritonavir: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, amoxapine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of amoxapine if ritonavir if initiated, discontinued or dose changed.

Rivastigmine: Possible antagonism of action

Salbutamol: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of salbutamol.

Sibutramine: Increased risk of CNS adverse effects

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Amoxapine, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Terbinafine: Terbinafine may reduce the metabolism and clearance of Amoxapine. Consider alternate therapy or monitor for therapeutic/adverse effects of Amoxapine if Terbinafine is initiated, discontinued or dose changed.

Terbutaline: The tricyclic antidepressant, amoxapine, increases the sympathomimetic effect of terbutaline.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Tramadol increases the risk of serotonin syndrome and seizures.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimethobenzamide: Trimethobenzamide and Amoxapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. Additive QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Amoxapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Amoxapine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

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).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and amoxapine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

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).