DESCRIPTION:
AMOXAPINE
DEMOLOX amoxapine is an antidepressant of the dibenzoxazepine class tricyclic antidepressant, chemically
distinct from the dibenzazepines, dibenzocycloheptenes, and dibenzoxepines.
is designated chemically as 2-chloro- 11-(1-piperazinyl) dibenz-(b,f)
(1,4)oxazepine. The molecular weight is 313.8. The empirical formula is
C17H16ClN3O.
ACTIONS/CLINICAL PHARMACOLOGY:
DEMOLOX 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.
DEMOLOX 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-hydroxyamoxapine, has a biologic half-life of
30 hours. Metabolites are excreted in the urine in conjugated form as
glucuronides.
Clinical studies have demonstrated that DEMOLOX 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.
INDICATIONS AND USAGE:
DEMOLOX 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.
CONTRAINDICATIONS:
DEMOLOX 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 DEMOLOX, a minimum of 14 days should be allowed to elapse after
the former is discontinued. DEMOLOX 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.
WARNINGS:
TARDIVE DYSKINESIA
Tardive dyskinesia, a syndrome consisting of potentially irreversible,
involuntary, dyskinetic movements may develop in patients treated with
neuroleptic (ie, antipsychotics) 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 appropriate. In patients who do require chronic treatment, the
smallest dose and the shortest duration of treatment producing a satisfactory
clinical response should be sought. The need for continued treatment should be
reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient on neuroleptics,
drug 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 INFORMATION FOR THE PATIENT and ADVERSE
REACTIONS.)
NEUROLEPTIC MALIGNANT SYNDROME (NMS)
A potentially fatal symptom complex sometimes referred to as Neuroleptic
Malignant Syndrome (NMS) 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 (e.g., 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 include 1) immediate discontinuation of
antipsychotic drugs and other drugs not essential to concurrent therapy, 2)
intensive symptomatic treatment and medical monitoring, and 3) 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 drug therapy should be carefully considered. The
patient should be carefully monitored since recurrences of NMS have been
reported.
DEMOLOX 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.
PRECAUTIONS:
GENERAL:
In prescribing the drug it should be borne in mind that the possibility of
suicide is inherent in any severe depression, and persists until a significant
remission occurs; the drug should be dispensed in the smallest suitable amount.
Manic depressive patients may experience a shift to the manic phase.
Schizophrenic patients may develop increased symptoms of psychosis; patients
with paranoid symptomatology may have an exaggeration of such symptoms. This may
require reduction of dosage or the addition of a major tranquilizer to the
therapeutic regimen. Antidepressant drugs can cause skin rashes and/or "drug
fever" in susceptible individuals. These allergic reactions may, in rare cases,
be severe. They are more likely to occur during the first few days of treatment,
but may also occur later. DEMOLOX should be discontinued if rash and/or fever
develop. Amoxapine possesses a degree of dopamine-blocking activity which may
cause extrapyramidal symptoms in <1% of patients. Rarely, symptoms indicative of
tardive dyskinesia have been reported.
INFORMATION FOR THE PATIENT:
Given the likelihood that some patients exposed chronically to neuroleptics will
develop tardive dyskinesia, it is advised that all patients in whom chronic use
is contemplated be given, if possible, full information about this risk. The
decision to inform patients and/or their guardians must obviously take into
account the clinical circumstances and the competency of the patient to
understand the information provided.
possibility of drowsiness that may impair performance of potentially hazardous
tasks such as driving an automobile or operating machinery.
DRUG INTERACTIONS:
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. DEMOLOX 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
DEMOLOX, 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 (debrisoquin hydroxylase) is reduced in a subset of
the caucasian population (about 7-10% of caucasians are so-called "poor
metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of 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. 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 enzyme (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 (SSRIs), 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 pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co- administration of TCAs with any of the SSRIs 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.
CARCINOGENESIS, IMPAIRMENT OF FERTILITY:
In a 21-month toxicity study at three dose levels in rats, pancreatic islet cell
hyperplasia occurred with slightly increased incidence at doses 5-10 times the
human dose. Pancreatic adenocarcinoma was detected in low incidence in the mid-
dose group only, and may possibly have resulted from endocrine-mediated organ
hyperfunction. The significance of these findings to man is not known.
Treatment of male rats with 5 to 10 times the human dose resulted in a slight
decrease in the number of fertile matings. Female rats receiving oral doses
within the therapeutic range displayed a reversible increase in estrous cycle
length.
PREGNANCY: PREGNANCY CATEGORY C:
Studies performed in mice, rats, and rabbits have demonstrated no evidence of
teratogenic effect due to DEMOLOX. Embryotoxicity was seen in rats and rabbits
given oral doses approximating the human dose. Fetotoxic effects (intrauterine
death, stillbirth, decreased birth weight) were seen in animals studied at oral
doses 3-10 times the human dose. Decreased postnatal survival (between days 0-4)
was demonstrated in the offspring of rats at 5 to 10 times the human dose. There
are no adequate and well-controlled studies in pregnant women. DEMOLOX should be
used during pregnancy only if the potential benefit justifies the potential risk
to the fetus.
NURSING MOTHERS:
DEMOLOX, like many other systemic drugs, is excreted in human milk. Because
effects of the drug on infants are unknown, caution should be exercised when
DEMOLOX is administered to nursing women.
PEDIATRIC USE:
Safety and effectiveness in children below the age of 16 have not been
established.
DRUG INTERACTIONS:
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. DEMOLOX 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
DEMOLOX, 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 (debrisoquin hydroxylase) is reduced in a subset of
the caucasian population (about 7%-10% of caucasians are so-called "poor
metabolizers"); reliable estimates of the prevalence of reduced P450 2D6 isozyme
activity among Asian, African and other populations are not yet available. Poor
metabolizers have higher than expected plasma concentrations of 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 (eightfold increase in plasma AUC of the TCA).
In addition, certain drugs inhibit the activity of this isozyme and make normal
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 enzyme (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 (SSRIs), eg, 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 pharmacokinetics of the SSRI involved. Nevertheless, caution is
indicated in the co- administration of TCAs with any of the SSRIs 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.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
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 DEMOLOX.
INCIDENCE GREATER THAN 1%
The most frequent types of adverse reactions occurring with DEMOLOX in
controlled clinical trials were sedative and anticholinergic: these included
drowsiness (14%), dry mouth (14%), constipation (12%), and 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, photosensitization, pruritus, rarely vasculitis,
hepatitis.
CNS And Neuromuscular-tingling, paresthesias of the extremities, tinnitus,
disorientation, seizures, hypomania, numbness, incoordination, disturbed
concentration, hyperthermia, extrapyramidal symptoms, including, rarely, tardive
dyskinesia. Neuroleptic malignant syndrome has been reported. (See WARNINGS.)
Hematologic-leukopenia, agranulocytosis.
Gastrointestinal-epigastric distress, vomiting, flatulence, abdominal pain,
peculiar taste, diarrhea.
Endocrine-increased or decreased libido, impotence, menstrual irregularity,
breast enlargement and galactorrhea in the female, syndrome of inappropriate
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-paralytic 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 DEMOLOX.
Anticholinergic-sublingual adenitis, dilation of the urinary tract.
CNS And Neuromuscular-delusions.
Gastrointestinal-stomatitis, black tongue.
Endocrine-gynecomastia.
OVERDOSAGE:
SIGNS AND SYMPTOMS:
Toxic manifestations of DEMOLOX 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
DEMOLOX overdosage in some cases.
Renal failure may develop two to five days after toxic overdosage in patients
who may appear otherwise recovered. Acute tubular necrosis with rhabdomyolysis
and myoglobinuria 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.
TREATMENT:
Treatment of DEMOLOX overdosage should be symptomatic and supportive, but with
special attention to prevention or control of seizures. If the patient is
conscious, induced emesis followed by gastric lavage with appropriate
precautions to prevent pulmonary aspiration should be accomplished as soon as
possible. Following lavage, activated charcoal may be administered to reduce
absorption, and repeated administrations may facilitate drug elimination.
An adequate airway should be established in comatose patients and assisted
ventilation instituted if necessary. Seizures may respond to standard
anticonvulsant therapy such as intravenous diazepam and/or phenytoin. The value
of physostigmine appears less certain. Status epilepticus, should it develop,
requires vigorous treatment such as that described by Delgado- Escueta et al (N
Engl J Med 1982; 306:1337-1340).
Convulsions, when they occur, typically begin within 12 hours after ingestion.
Because seizures may occur precipitously in some overdosage patients who appear
otherwise relatively asymptomatic, the treating physician may wish to consider
prophylactic administration of anticonvulsant medication during this period.
Treatment of renal impairment, should it occur, is the same as that for nondrug-
induced renal dysfunction.
Serious cardiovascular effects are remarkably rare following DEMOLOX overdosage,
and the ECG typically remains within normal limits except for sinus tachycardia.
Hence, prolongation of the QRS interval beyond 100 milliseconds within the first
24 hours is Not a useful guide to the severity of overdosage with this drug.
Fatalities and, rarely, neurologic sequelae have resulted from prolonged status
epilepticus in DEMOLOX amoxapine overdosage patients. While the lethal dose
appears higher than that of other tricyclic antidepressants (80% of lethal
DEMOLOX overdosages have involved ingestion of 3 grams or more), many factors
other than amount ingested are important in assessing probability of survival.
These include age and physical condition of the patient, concomitant ingestion
of other drugs, and especially the interval between drug ingestion and
initiation of emergency treatment.
DOSAGE AND ADMINISTRATION:
Effective dosage of DEMOLOX 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.
DEMOLOX 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 300mg 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 2 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 DEMOLOX 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, DEMOLOX may conveniently be given in a
single bedtime dose, not to exceed 300 mg.
MAINTENANCE:
Recommended maintenance dosage of DEMOLOX 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.
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