Brands, Medical Use, Clinical Data
- Adrenergic Uptake Inhibitors
- Antidepressive Agents, Second-Generation
- Dopamine Antagonists
- Neurotransmitter Uptake Inhibitors
- Serotonin Uptake Inhibitors
- Tablet (25 mg, 50 mg, 100 mg or 150 mg)
Brands / Synonyms
Amoxapine; Amoxepine; Ascendin; Asendin; Asendis; Defanyl; Demolox; Moxadil
For the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. Also for depression accompanied by anxiety or agitation.
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).
Absorbed rapidly and reaches peak blood levels approximately 90 minutes after ingestion
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.
Biotrnasformation / Drug Metabolism
Amoxapine is almost completely metabolized, producing the major metabolite 8-hydroxyamoxapine.
Amoxapine tablets are contraindicated in patients who have shown prior hypersensitivity to dibenzoxazepine
compounds. It should not be given concomitantly with monoamine oxidase inhibitors. Hyperpyretic crises, severe
convulsions, and deaths have occurred in patients receiving tricyclic antidepressants and monoamine oxidase
inhibitors simultaneous. When it is desired to replace monoamine oxidase inhibitor with amoxapine, a minimum of 14
days should be allowed to elapse after the former is discontinued. Amoxapine should then be initiated cautiously with
gradual increase in dosage until optimum response is achieved. The drug is not recommended for use during the acute
recovery phase following myocardial infarction.
The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptic drugs, discontinuation should be
considered. However, some patients may require treatment despite the presence of the syndrome.
(For further information about the description of tardive dyskinesia and its clinical detection, please refer to
the sections on PATIENT INFORMATON and ADVERSE
Neuroleptic Malignant Syndrome (NMS):
A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been has
been reported in association with antipsychotic drugs and with amoxapine. Clinical manifestations of NMS are
hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability ( irregular pulse or blood
pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is
important to identify cases where the clinical presentation includes both serious medical illness (eg.,pneumonia,
systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS).Other
important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug
fever and primary central nervous System (CNS) pathology.
The management of NMS should and primary central nervous System (CNS) include;
- Immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy.
- Intensive symptomatic treatment and medical monitoring.
- Treatment of any concomitant serious medical problems for which specific treatments are available.
There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS.
If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of the
drug thereafter should be carefully considered. The patient should be carefully monitored, since recurrences of NMS
have been reported.
Amoxapine should be used with caution in patients with a history of urinary retention, angle-closure glaucoma or
increased intraocular pressure. Patients with cardiovascular disorders should be watched closely. Tricyclic
antidepressant drugs, particularly when given in high doses, can induce sinus tachycardia, changes in conduction
time, and arrhythmias. Myocardial infarction and stroke have been reported with drugs of this class.
Extreme caution should be used in treating patients with a history of convulsive disorder or those with overt or
latent seizure disorders
Paralytic ileus may occur in patients taking tricyclic antidepressants in combination with anticholinergic drugs. Amoxapine may enhance the response to alcohol and the effects of barbiturates and other CNS depressants. Serum levels of several tricyclic antidepressants have been reported to be significantly increased when cimetidine is administered concurrently Although such an interaction has not been reported to date with amoxapine, specific interaction studies have not been done, and the possibility should be considered.
Drugs Metabolized by P450 2D6
The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (dehrisoquin hydroxylase) is reduced in a subset of the caucasian population (about 7 to 10% of caucasians are so called of reduced P450 2D6 isozyme activity among p.o. metabolizers); reliable estimates of the prevalence Asian, African and other populatlons are not yet available when given usual doses. Poor metabolizers have higher than expected plasma concentrations tricyclic antidepressants (TCAs) when given usual doses. Depending on the fraction of drug metabolized by P450 2D6, the increase in plasma concentration may be small, or quite large (8 fold increase in plasma AUC of the TCA).
In addition certain drugs inhibit the activity of this isozyme and make normal metabolizers resemble p.o. metabolizers. An individual who is stable on a given dose of TCA may become abruptly toxic when given one of these inhibiting drugs as concomitant therapy. The drugs that inhibit cytochrome P450 2D6 include some that are not metabolized by the enzymes quinidine, cimetidine, and many that are substrates for P450 2D6 (many other antidepressants, phenothiazines, and the Type 1C antiarrhythmics propafenone and flecainide). While all the selective serotonin reuptake inhibitors (SSRls), e.g. fluoxetine, sertraline, and paroxetine inhibit P450 2D6, they may vary in the extent of inhibition. The extent to which SSRI-TCA interactions may pose clinical problems will depend on the degree of inhibition and the pharmacokmetics of the SSRI involved. Nevertheless, caution is indicated in the co-administration of TCA's with any of the SSRI's and also in switching from one class to the other of particular importance. Sufficient time must elapse before initiating TCA treatment in a patient being withdrawn from fluoxetine given. The long half-life of the parent and active metabolite (at least 5 weeks may be necessary).
Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be co-administered with another drug known to be an inhibitor of P450 2D6.
Concurrent administration with electroshock therapy may increase the hazards associated with such therapy.