Adverse reactions reported in controlled studies in the United States are categorized with respect to incidence below. Following this is a listing of reactions known to occur with other antidepressant drugs of this class but not reported to date with Amoxapine Tablets.

Incidence Greater Than 1%

The most frequent types of adverse reactions occurring with Amoxapine Tablets in controlled clinical trials were sedative and anticholinergic. These included:

• drowsiness (14 %)
• dry mouth ( 14 %)
• constpation (12 %)
• blurred vision ( 7 % )

Less frequently reported reactions are:

• CNS and Neuromuscular, anxiety, insomnia, restlessness, nervousness, palpitations, tremors, confusion, excitement, nightmares, ataxia, alterations in EEG patterns.
• Allergic edema, skin rash.
• Endocrine elevation of prolactin levels.
• Gastrointestinal nausea.
• Other - dizziness, headache, fatigue, weakness, excessive appetite, increased perspiration.

Incidence Less Than 1%

• Anticholinergic - disturbances of accommodation, mydriasis, delayed micturition. urinary retention. nasal stuffiness.
• Cardiovascular - hypotension. hypertension,, syncope, tachycardia.
• Allergic - drug fever,urticaria, photosensitizatlon, pruritus, rarely vasulitis, hepatitis.
• CNS and Neuromuscular - tingling, paresthesias of the extremities tinnitus., disorientation seizures, hypomania, numbness, incoordinatlon, disturbed concentration, hyperthermia, extrapyramidal symptoms, including rarely, tardive dykinesia. Neuroleptic malignant syndrome has been reported (See WARNINGS)
• Hematologic - leukopenia, agranulocytosis.
• Gastrointestinal - epigastric distress, vomiting, flatulence, abdominal pain, peculiar taste, diarrhea.
• Endocrine - increase or decreased libido, impotence, menstrual irregularity, breast enlargement, and alactorrhea in the female, syndrome of inapproriate antidiuretic hormone secretion.
• Other - lacrimation, weight gain or loss, altered liver function, painful ejaculation.

Drug Relationship Unknown

The following reactions have been reported very rarely and occurred under uncontrolled circumstances where a drug relationship was difficult to assess. These observations are listed to serve as alerting information to physicians.

• Anticholinergic - paralitic ileus
• Cardiovascular - atrial arrhythmias (including atrial fibrillation), myocardial infarction. stroke, heart block.
• CNS and Neuromuscular - hallucinations.
• Hematologic - thrombocytopenia eosinophilia, purpura, petechiae.
• Gastrointestinal - parotid swelling.
• Endocrine - change in blood glucose levels.
• Other - pancreatitis, hepatitis, jaundice, urinary frequency, testicular swelling anorexia. alopecia.

Additional Adverse REACTIONS

The following reactions have been reported with other antidepressant drugs but not with Amoxapine Tablets

• Anticholinergic - sublingual adenitis, dilation of the urinary tract.
• CNS and Neuromuscular - delusions.
• Gastrointestinal - stomatitis, black tongue.
• Endocrine - gynecomastia.

See CONTRAINDICATIONS about concurrent usage of tricyclic antidepressants and monoamine oxidase inhibitors. 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 b 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.

Therapeutic Interactions

Concurrent administration with electroshock therapy may increase the hazards associated with such therapy.

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