DOXEPIN HCL
DESCRIPTION:
DOXIN (doxepin hydrochloride) is one of a class of psychotherapeutic
agents known as dibenzoxepin tricyclic compounds. The molecular formula of the
compound is C19H21NO.HCl having a molecular weight of 316. It is a white
crystalline solid readily soluble in water, lower alcohols and chloroform.
Inert ingredients for the capsule formulations are: hard gelatin capsules (which
may contain Blue 1, Red 3, Red 40, Yellow 10, and other inert ingredients);
magnesium stearate; sodium lauryl sulfate; starch.
Inert ingredients for the oral concentrate formulation are: glycerin;
methylparaben; peppermint oil; propylparaben; water.
CHEMISTRY
DOXIN (doxepin HCl) is a dibenzoxepin derivative and is the first of a family
of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture
of: 1-Propanamine, 3-dibenz(b,e)oxepin-11(6H)ylidene-N,N-dimethyl-,
hydrochloride.
ACTIONS/CLINICAL PHARMACOLOGY:
The mechanism of action of DOXIN (doxepin HCl) is not definitely known. It is
not a central nervous system stimulant nor a monoamine oxidase inhibitor. The
current hypothesis is that the clinical effects are due, at least in part, to
influences on the adrenergic activity at the synapses so that deactivation of
norepinephrine by reuptake into the nerve terminals is prevented. Animal studies
suggest that doxepin HCl does not appreciably antagonize the antihypertensive
action of guanethidine. In animal studies anticholinergic, antiserotonin and
antihistamine effects on smooth muscle have been demonstrated. At higher than
usual clinical doses, norepinephrine response was potentiated in animals. This
effect was not demonstrated in humans.
At clinical dosages up to 150 mg per day, DOXIN can be given to man
concomitantly with guanethidine and related compounds without blocking the
antihypertensive effect. At dosages above 150 mg per day blocking of the
antihypertensive effect of these compounds has been reported.
DOXIN is virtually devoid of euphoria as a side effect. Characteristic of
this type of compound, DOXIN has not been demonstrated to produce the
physical tolerance or psychological dependence associated with addictive
compounds.
INDICATIONS AND USAGE:
DOXIN is recommended for the treatment of:
1. Psychoneurotic patients with depression and/or anxiety.
2. Depression and/or anxiety associated with alcoholism (not to be taken
concomitantly with alcohol).
3. Depression and/or anxiety associated with organic disease (the possibility
of drug interaction should be considered if the patient is receiving other
drugs concomitantly).
4. Psychotic depressive disorders with associated anxiety including
involutional depression and manic-depressive disorders.
The target symptoms of psychoneurosis that respond particularly well to DOXIN
include anxiety, tension, depression, somatic symptoms and concerns, sleep
disturbances, guilt, lack of energy, fear, apprehension and worry.
Clinical experience has shown that DOXIN is safe and well tolerated even in
the elderly patient. Owing to lack of clinical experience in the pediatric
population, DOXIN is not recommended for use in children under 12 years of
age.
CONTRAINDICATIONS:
DOXIN is contraindicated in individuals who have shown hypersensitivity to
the drug. Possibility of cross sensitivity with other dibenzoxepines should be
kept in mind.
DOXIN is contraindicated in patients with glaucoma or a tendency to urinary
retention. These disorders should be ruled out, particularly in older patients.
WARNINGS:
The once-a-day dosage regimen of DOXIN in patients with intercurrent illness
or patients taking other medications should be carefully adjusted. This is
especially important in patients receiving other medications with
anticholinergic effects.
USAGE IN GERIATRICS: The use of DOXIN on a once-a-day dosage regimen in
geriatric patients should be adjusted carefully based on the patient's
condition.
USAGE IN PREGNANCY: Reproduction studies have been performed in rats, rabbits,
monkeys and dogs and there was no evidence of harm to the animal fetus. The
relevance to humans is not known. Since there is no experience in pregnant women
who have received this drug, safety in pregnancy has not been established. There
has been a report of apnea and drowsiness occurring in a nursing infant whose
mother was taking DOXIN.
USAGE IN CHILDREN: The use of DOXIN in children under 12 years of age is not
recommended because safe conditions for its use have not been established.
PRECAUTIONS:
DRUG INTERACTIONS: 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 resemble poor 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 antiarrythmics 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 coadministered with another drug known to be an
inhibitor of P450 2D6.
MAO Inhibitors: Serious side effects and even death have been reported
following the concomitant use of certain drugs with MAO inhibitors. Therefore,
MAO inhibitors should be discontinued at least two weeks prior to the cautious
initiation of therapy with DOXIN. The exact length of time may vary and is
dependent upon the particular MAO inhibitor being used, the length of time it
has been administered, and the dosage involved.
Cimetidine: Cimetidine has been reported to produce clinically significant
fluctuations in steady-state serum concentrations of various tricyclic
antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth,
urinary retention and blurred vision) have been associated with elevations in
the serum levels of tricyclic antidepressant when cimetidine therapy is
initiated. Additionally, higher than expected tricyclic antidepressant levels
have been observed when they are begun in patients already taking cimetidine. In
patients who have been reported to be well controlled on tricyclic
antidepressants receiving concurrent cimetidine therapy, discontinuation of
cimetidine has been reported to decrease established steady-state serum
tricyclic antidepressant levels and compromise their therapeutic effects.
Alcohol: It should be borne in mind that alcohol ingestion may increase the
danger inherent in any intentional or unintentional DOXIN overdosage. This is
especially important in patients who may use alcohol excessively.
Tolazamide: A case of severe hypoglycemia has been reported in a type II
diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition
of doxepin (75 mg/day).
DROWSINESS: Since drowsiness may occur with the use of this drug, patients
should be warned of the possibility and cautioned against driving a car or
operating dangerous machinery while taking the drug. Patients should also be
cautioned that their response to alcohol may be potentiated.
SUICIDE: Since suicide is an inherent risk in any depressed patient and may
remain so until significant improvement has occurred, patients should be closely
supervised during the early course of therapy. Prescriptions should be written
for the smallest feasible amount.
PSYCHOSIS: Should increased symptoms of psychosis or shift to manic
symptomatology occur, it may be necessary to reduce dosage or add a major
tranquilizer to the dosage regimen.
DRUG INTERACTIONS:
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 resemble poor 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 antiarrythmics 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 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 coadministered with another drug known to be an
inhibitor of P450 2D6.
MAO Inhibitors: Serious side effects and even death have been reported
following the concomitant use of certain drugs with MAO inhibitors. Therefore,
MAO inhibitors should be discontinued at least two weeks prior to the cautious
initiation of therapy with DOXIN. The exact length of time may vary and is
dependent upon the particular MAO inhibitor being used, the length of time it
has been administered, and the dosage involved.
Cimetidine: Cimetidine has been reported to produce clinically significant
fluctuations in steady-state serum concentrations of various tricyclic
antidepressants. Serious anticholinergic symptoms (i.e., severe dry mouth,
urinary retention and blurred vision) have been associated with elevations in
the serum levels of tricyclic antidepressant when cimetidine therapy is
initiated. Additionally, higher than expected tricyclic antidepressant levels
have been observed when they are begun in patients already taking cimetidine. In
patients who have been reported to be well controlled on tricyclic
antidepressants receiving concurrent cimetidine therapy, discontinuation of
cimetidine has been reported to decrease established steady-state serum
tricyclic antidepressant levels and compromise their therapeutic effects.
Alcohol: It should be borne in mind that alcohol ingestion may increase the
danger inherent in any intentional or unintentional DOXIN overdosage. This is
especially important in patients who may use alcohol excessively.
Tolazamide: A case of severe hypoglycemia has been reported in a type II
diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition
of doxepin (75 mg/day).
DROWSINESS: Since drowsiness may occur with the use of this drug, patients
should be warned of the possibility and cautioned against driving a car or
operating dangerous machinery while taking the drug. Patients should also be
cautioned that their response to alcohol may be potentiated.
SUICIDE: Since suicide is an inherent risk in any depressed patient and may
remain so until significant improvement has occurred, patients should be closely
supervised during the early course of therapy. Prescriptions should be written
for the smallest feasible amount.
PSYCHOSIS: Should increased symptoms of psychosis or shift to manic
symptomatology occur, it may be necessary to reduce dosage or add a major
tranquilizer to the dosage regimen.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
NOTE: Some of the adverse reactions noted below have not been specifically
reported with DOXIN use. However, due to the close pharmacological
similarities among the tricyclics, the reactions should be considered when
prescribing DOXIN (doxepin HCl).
Anticholinergic Effects: Dry mouth, blurred vision, constipation, and urinary
retention have been reported. If they do not subside with continued therapy, or
become severe, it may be necessary to reduce the dosage.
Central Nervous System Effects: Drowsiness is the most commonly noticed side
effect. This tends to disappear as therapy is continued. Other infrequently
reported CNS side effects are confusion, disorientation, hallucinations,
numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive
dyskinesia, and tremor.
Cardiovascular: Cardiovascular effects including hypotension, hypertension, and
tachycardia have been reported occasionally.
Allergic: Skin rash, edema, photosensitization, and pruritus have occasionally
occurred.
Hematologic: Eosinophilia has been reported in a few patients. There have been
occasional reports of bone marrow depression manifesting as agranulocytosis,
leukopenia, thrombocytopenia, and purpura.
Gastrointestinal: Nausea, vomiting, indigestion, taste disturbances, diarrhea,
anorexia, and aphthous stomatitis have been reported. (See Anticholinergic
Effects.)
Endocrine: Raised or lowered libido, testicular swelling, gynecomastia in
males, enlargement of breasts and galactorrhea in the female, raising or
lowering of blood sugar levels, and syndrome of inappropriate antidiuretic
hormone secretion have been reported with tricyclic administration.
Other: Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness,
flushing, jaundice, alopecia, headache, exacerbation of asthma, and
hyperpyrexia(in association with chlorpromazine) have been occasionally observed
as adverse effects.
Withdrawal Symptoms: The possibility of development of withdrawal symptoms upon
abrupt cessation of treatment after prolonged DOXIN administration should be
borne in mind. These are not indicative of addiction and gradual withdrawal of
medication should not cause these symptoms.
DOSAGE AND ADMINISTRATION:
For most patients with illness of mild to moderate severity, a starting daily
dose of 75 mg is recommended. Dosage may subsequently be increased or decreased
at appropriate intervals and according to individual response. The usual optimum
dose range is 75 mg/day to 150 mg/day.
In more severely ill patients higher doses may be required with subsequent
gradual increase to 300 mg/day if necessary. Additional therapeutic effect is
rarely to be obtained by exceeding a dose of 300 mg/day.
In patients with very mild symptomatology or emotional symptoms accompanying
organic disease, lower doses may suffice. Some of these patients have been
controlled on doses as low as 25-50 mg/day.
The total daily dosage of DOXIN may be given on a divided or once-a-day
dosage schedule. If the once-a-day schedule is employed, the maximum recommended
dose is 150 mg/day. This dose may be given at bedtime. THE 150 MG CAPSULE
STRENGTH IS INTENDED FOR MAINTENANCE THERAPY ONLY AND IS NOT RECOMMENDED FOR
INITIATION OF TREATMENT.
Anti-anxiety effect is apparent before the antidepressant effect. Optimal
antidepressant effect may not be evident for two to three weeks.
OVERDOSAGE:
Deaths may occur from overdosage with this class of drugs. Multiple drug
ingestion (including alcohol) is common in deliberate tricyclic antidepressant
overdose. As the management is complex and changing, it is recommended that the
physician contact a poison control center for current information on treatment.
Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant
overdose; therefore, hospital monitoring is required as soon as possible.
MANIFESTATIONS: Critical manifestations of overdose include: cardiac
dysrhythmias, severe hypotension, convulsions, and CNS depression, including
coma. Changes in the electrocardiogram, particularly in QRS axis or width, are
clinically significant indicators of tricyclic antidepressant toxicity.
Other signs of overdose may include: confusion, disturbed concentration,
transient visual hallucinations, dilated pupils, agitation, hyperactive
reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia,
hyperpyrexia, or any of the symptoms listed under ADVERSE REACTIONS.
GENERAL RECOMMENDATIONS:
GENERAL: Obtain an ECG and immediately initiate cardiac monitoring. Protect the
patient's airway, establish an intravenous line and initiate gastric
decontamination. A minimum of six hours of observation with cardiac monitoring
and observation for signs of CNS or respiratory depression, hypotension, cardiac
dysrhythmias and/or conduction blocks, and seizures is strongly advised. If
signs of toxicity occur at any time during this period, extended monitoring is
recommended. There are case reports of patients succumbing to fatal dysrhythmias
late after overdose; these patients had clinical evidence of significant
poisoning prior to death and most received inadequate gastrointestinal
decontamination. Monitoring of plasma drug levels should not guide management of
the patient.
GASTROINTESTINAL DECONTAMINATION: All patients suspected of tricyclic
antidepressant overdose should receive gastrointestinal decontamination. This
should include large volume gastric lavage followed by activated charcoal. If
consciousness is impaired, the airway should be secured prior to lavage. Emesis
is contraindicated.
CARDIOVASCULAR: A maximal limb-lead QRS duration of >/=0.10 seconds may be the
best indication of the severity of the overdose. Intravenous sodium bicarbonate
should be used to maintain the serum pH in the range of 7.45 to 7.55. If the pH
response is inadequate, hyperventilation may also be used. Concomitant use of
hyperventilation and sodium bicarbonate should be done with extreme caution,
with frequent pH monitoring. A pH >7.60 or a pCO2 <20 mm Hg is undesirable.
Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may
respond to lidocaine, bretylium or phenytoin. Type 1A and 1C antiarrhythmics are
generally contraindicated (e.g., quinidine, disopyramide, and procainamide).
In rare instances, hemoperfusion may be beneficial in acute refractory
cardiovascular instability in patients with acute toxicity. However,
hemodialysis, peritoneal dialysis, exchange transfusions, and forced diuresis
generally have been reported as ineffective in tricyclic antidepressant
poisoning.
CNS: In patients with CNS depression, early intubation is advised because of
the potential for abrupt deterioration. Seizures should be controlled with
benzodiazepines, or if these are ineffective, other anticonvulsants (e.g.,
phenobarbital, phenytoin). Physostigmine is not recommended except to treat
life-threatening symptoms that have been unresponsive to other therapies, and
then only in consultation with a poison control center.
PSYCHIATRIC FOLLOW-UP: Since overdosage is often deliberate, patients may
attempt suicide by other means during the recovery phase. Psychiatric referral
may be appropriate.
PEDIATRIC MANAGEMENT: The principles of management of child and adult
overdosages are similar. It is strongly recommended that the physician contact
the local poison control center for specific pediatric treatment.
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