amoxapine 25 MG Oral Tablet

INDICATIONS AND USAGE Amoxapine is indicated for the relief of symptoms of depression in patients with neurotic or reactive depressive disorders as well as endogenous and psychotic depressions. It is indicated for depression accompanied by anxiety or agitation.

DOSAGE AND ADMINISTRATION Effective dosage of amoxapine may vary from one patient to another. Usual effective dosage is 200 to 300 mg daily. Three weeks constitutes an adequate period of trial providing dosage has reached 300 mg daily (or lower level of tolerance) for at least two weeks. If no response is seen at 300 mg, dosage may be increased, depending upon tolerance, up to 400 mg daily. Hospitalized patients who have been refractory to antidepressant therapy and who have no history of convulsive seizures may have dosage raised cautiously up to 600 mg daily in divided doses. Amoxapine may be given in a single daily dose, not to exceed 300 mg, preferably at bedtime. If the total daily dosage exceeds 300 mg, it should be given in divided doses. Initial Dosage for Adults Usual starting dosage is 50 mg two or three times daily. Depending upon tolerance, dosage may be increased to 100 mg two or three times daily by the end of the first week. (Initial dosage of 300 mg daily may be given, but notable sedation may occur in some patients during the first few days of therapy at this level.) Increases above 300 mg daily should be made only if 300 mg daily has been ineffective during a trial period of at least two weeks. When effective dosage is established, the drug may be given in a single dose (not to exceed 300 mg) at bedtime. Elderly Patients In general, lower dosages are recommended for these patients. Recommended starting dosage of amoxapine is 25 mg two or three times daily. If no intolerance is observed, dosage may be increased by the end of the first week to 50 mg two or three times daily. Although 100 to 150 mg daily may be adequate for many elderly patients, some may require higher dosage. Careful increases up to 300 mg daily are indicated in such cases. Once an effective dosage is established, amoxapine may conveniently be given in a single bedtime dose, not to exceed 300 mg. Maintenance Recommended maintenance dosage of amoxapine is the lowest dose that will maintain remission. If symptoms reappear, dosage should be increased to the earlier level until they are controlled. For maintenance therapy at dosages of 300 mg or less, a single dose at bedtime is recommended.

WARNINGS Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18 to 24 5 additional cases Decreases Compared to Placebo 25 to 64 1 fewer case ≥65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for amoxapine should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that amoxapine is not approved for use in treating bipolar depression. Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant drugs including amoxapine, may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with neuroleptic (i.e., antipsychotic) drugs. (Amoxapine is not an antipsychotic, but it has substantive neuroleptic activity.) Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of neuroleptic treatment, which patients are likely to develop the syndrome. Whether neuroleptic drug products differ in their potential to cause tardive dyskinesia is unknown. Both the risk of developing the syndrome and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of neuroleptic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if neuroleptic treatment is withdrawn. Neuroleptic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying disease process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, neuroleptics should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic neuroleptic treatment should generally be reserved for patients who suffer from a chronic illness that, 1) is known to respond to neuroleptic drugs, and, 2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appr

CONTRAINDICATIONS Amoxapine is 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 simultaneously. When it is desired to replace a 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.

CLINICAL PHARMACOLOGY Amoxapine is an antidepressant with 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 norepinephrine and serotonin and blocked the response of dopamine receptors to dopamine. Amoxapine is not a monoamine oxidase inhibitor. Amoxapine is absorbed rapidly and reaches peak blood levels approximately 90 minutes after ingestion. It is almost completely metabolized. The main route of excretion is the kidney. In vitro tests show that amoxapine binding to human serum is approximately 90%. In man, amoxapine serum concentration declines with a half-life of eight hours. However, the major metabolite, 8-hydroxy-amoxapine, has a biologic half-life of 30 hours. Metabolites are excreted in the urine in conjugated form as glucuronides. Clinical studies have demonstrated that amoxapine has a more rapid onset of action than either amitriptyline or imipramine. The initial clinical effect may occur within four to seven days and occurs within two weeks in over 80% of responders.