WARNINGS
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Tricyclic
antidepressant drugs, particularly when given in high doses, can
induce sinus tachycardia, changes in conduction time and arrhythmias.
A few instances of unexpected death have been reported in patients
with cardiovascular disorders. Myocardial infarction and stroke
have also been reported with drugs of this class.
Therefore, SINEQUAN should be administered with extreme caution
to patients with a history of cardiovascular disease, those with
circulatory lability and elderly patients. In such cases, treatment
should be initiated with low doses with progressive increases only
if required and tolerated, and the patients should be under close
surveillance at all dosage levels.
Since tricyclic agents are known to reduce the seizure threshold,
SINEQUAN should be used with caution in patients with a history
of convulsive disorders. Concurrent administration of ECT and SINEQUAN
may be hazardous and, therefore, such treatment should be limited
to patients for whom it is essential.
Close supervision is required when SINEQUAN is given to hyperthyroid
patients or those receiving thyroidmedication because of the possibility
of cardiovascular toxicity. At doses above 150 mg/day, it may block
the antihypertensive effect of guanethidine and related compounds.
Pregnancy: The safety of SINEQUAN during pregnancy and lactation
has not been established and therefore, it should not be used in
women of childbearing potential or nursing mothers, unless, in the
opinion of the physician, the potential benefits to the patient
outweigh the possible hazards to the fetus.
Lactation: See Pregnancy.
PRECAUTIONS
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Occupational
Hazards: Since drowsiness may occur with the use of this drug,
patients should be advised against driving or engaging in activities
requiring mental alertness and physical coordination until their
response to the drug has been well established.
Patients should be warned that the effects of other drugs acting
on the central nervous system, such as alcohol, barbiturates and
other CNS depressants, may be potentiated by SINEQUAN.
The possibility of suicide in seriously depressed patients may remain
until significant remission occurs. Such patients should be closely
supervised throughout therapy and consideration should be given
to the possible need for hospitalization. This type of patient should
not have easy access to large quantities of SINEQUAN.
Tricyclic antidepressants may precipitate or aggravate psychotic
manifestations in schizophrenic patients and hypomanic ormanic episodes
inmanic-depressive patients. This may require a reduction of dosage,
discontinuation of the drug, and/or administration of an antipsychotic
agent.
Tricyclic antidepressants may also give rise to paralytic ileus,
particularly in the elderly and in hospitalized patients. Therefore,
appropriate measures should be taken if constipation occurs.
When SINEQUAN is given concomitantly with anticholinergic or sympathomimetic
drugs, close supervision and careful adjustment of dosages are required.
SINEQUAN should be discontinued prior to elective surgery for as
long as the clinical situation will allow.
SINEQUAN should be used with caution in patients with impaired liver
function or with a history of hepatic damage or blood dyscrasias.
Periodic blood counts and liver function tests should be performed
when patients SINEQUAN doxepin in large doses or over prolonged
periods.
Drugs Metabolized by Cytochrome P450 (CYP) 2D6: SINEQUAN, like other
tricyclic antidepressants (TCAs), is metabolized by CYP2D6. Inhibitors
or substrates of CYP2D6 (i.e. quinidine, selective serotonin reuptake
inhibitors [SSRIs]) may increase the plasma concentration of TCAs
when administered concomitantly. The extent of interaction depends
on the variability of effect on CYP2D6 and the therapeutic index
of the TCA. The clinical significance of this interaction with SINEQUAN
has not been systematically evaluated.
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 antidepressants
when cimetidine therapy is initiated. Additionally, higher than
expected tricyclic antidepressant levels have been seen in patients
receiving concurrent cimetidine therapy. Discontinuation of cimetidine
has been reported to decrease established steady-state serum tricyclic
antidepressant levels and compromise their therapeutic effects.
ADVERSE
EFFECTS
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Although
some of the adverse reactions included in the following list have
not been reported with SINEQUAN pharmacological similarities among
the tricyclic antidepressants require that each of the reactions
be considered when prescribing SINEQUAN.
Behavioral: drowsiness, fatigue, excitement, agitation, restlessness,
insomnia, nightmares, hypomania, anxiety, confusion, disorientation,
disturbed concentration, delusions, hallucinations, activation of
latent psychosis.
Neurological: seizures, alteration in EEG patterns, dizziness,
tremors, extrapyramidal symptoms, numbness, tingling, paresthesias
of the extremities, peripheral neuropathy, tinnitus, syndrome of
inappropriate ADH (antidiuretic hormone) secretion, ataxia, tardive
dyskinesia.
Cardiovascular: hypotension, hypertension, tachycardia, palpitations.
A quinidine-like effect and other reversible ECG changes such as
flattening or inversion of T-waves, bundle branch block, depressed
S-T segments, prolonged conduction time and asystole, arrhythmias,
heart block, fibrillation, myocardial infarction, stroke and unexpected
death in patients with cardiovascular disorders have been reported
with other tricyclic antidepressants.
Autonomic: dry mouth, blurred vision, disturbances of accommodation,
mydriasis, constipation, nasal stuffiness, delayed micturition,
sublingual adenitis, paralytic ileus, urinary retention, dilation
of the urinary tract, precipitation of latent and aggravation of
existing glaucoma, vertigo.
Endocrine: increased or decreased libido, impotence, menstrual
irregularity, testicular swelling, breast enlargement and galactorrhea
in the female, gynecomastia in the male, elevation and lowering
of blood sugar levels.
Allergic or Toxic: pruritus, skin rash, photosensitization,
edema, drug fever, leukopenia, urticaria, petechiae, obstructive
jaundice and bone marrow depression, including agranulocytosis,
eosinophilia, purpura and thrombocytopenia.
Gastrointestinal: nausea, epigastric distress, vomiting,
flatulence, abdominal pain, diarrhea, peculiar taste, stomatitis.
Miscellaneous: weakness, chills, flushing, headache, weight
gain or loss, excessive appetite, anorexia, increased perspiration,
urinary frequency, lacrimation, alopecia, parotid swelling, black
tongue, hepatitis, exacerbation of asthma, and hyperpyrexia (in
association with chlorpromazine).
Withdrawal Symptoms: Abrupt cessation of treatment with tricyclic
antidepressants after prolonged administration may produce nausea,
headache and malaise. These symptoms are not indicative of addiction.
OVERDOSAGE
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For
management of a suspected drug overdose, CPhA recommends that you
contact your regional Poison Control Centre. See the CPS Directory
section for a list of Poison Control Centres.
Symptoms: Excessive drowsiness leading tominor alterations
of consciousness and even unresponsiveness could be an early indication
of excessive dosage. However, overdosage with SINEQUAN is more likely
to be manifested by increased psychomotor agitation and convulsions
leading to apnea and coma. The ECG changes (broadening of QRS and
T-wave abnormalities) tend to be a late finding and are not always
accompanied by cardiovascular hemodynamic changes.
Treatment: In general, treatment of overdosage should be
symptomatic and supportive. Cardiac arrhythmias and CNS involvement
pose the greatest threat with tricyclic antidepressant overdosage
and may occur suddenly even when initial symptoms appear to be mild.
Therefore, patients who may have ingested an overdosage of SINEQUAN,
particularly children, should be hospitalized and kept under close
surveillance.
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. An adequate airway
should be established in comatose patients and assisted ventilation
instituted, if necessary. The possibility of occurrence of seizures
should be kept in mind. External stimulation should be minimized
to reduce the tendency to convulsions. Convulsions, should they
occur, may respond to standard anticonvulsant therapy; however,
barbiturates should be avoided since they may potentiate respiratory
depression, particularly in children, and aggravate hypotension
and coma.
ECG monitoring in an intensive care unit is recommended in all patients,
particularly in the presence of ECG abnormalities, and should be
maintained for several days after the cardiac rhythm has returned
to normal. A patient who has ingested a toxic overdose of a tricyclic
antidepressant may remain medically and psychiatrically unstable
for several days due to sustained excessive drug levels. Unexpected
cardiac deaths have occurred up to 6 days after overdosage with
other antidepressants. The QRS interval of the electrocardiogram
appears to be a reliable correlate of the severity of overdosage.
If the QRS interval exceeds 100 milliseconds any time during the
first 24 hours after overdosage, cardiac function should be continuously
monitored for 5 or 6 days. Because of its effect on cardiac conduction,
digitalis should be used only with caution. If rapid digitalization
is required for the treatment of congestive heart failure, special
care should be exercised in using the drug.
Shock should be treated with supportivemeasures such as i.v. fluids,
oxygen and corticosteroids. Pressor agents, such as norepinephrine
(but not epinephrine), are rarely indicated and should be given
only after careful consideration and under continuous monitoring.
The slow i.v. administration of physostigmine salicylate has been
reported to reverse most of the cardiovascular and CNS anticholinergic
manifestations of tricyclic overdosage. The recommended dosage in
adults has been 1 to 2 mg in very slow i.v. injection. In children,
the initial dosage should not exceed 0.5 mg and should be adjusted
to age and response. Since physostigmine has a short duration of
action, administration may have to be repeated at 30 to 60 minute
intervals.
Deaths by deliberate or accidental overdosage have occurred with
this class of drugs. Since the propensity for suicide is high in
depressed patients, a suicide attempt by other means may occur during
the recovery phase. The possibility of simultaneous ingestion of
other drugs should also be considered.
DOSAGE
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The
optimum daily dosage of SINEQUAN
depends on the condition which is being treated and the response
of the individual. Some patients respond promptly: others may not
respond for 2 weeks or longer. An initial dosage of 25 mg 3 times
daily may be used in most patients. This dosage should be increased
as required by 25 mg increments at appropriate intervals until a
therapeutic response is obtained. The usual optimum dosage range
is 100 to 150mg/day. In some patients, up to 300mg/daymay be required,
but there is rarely any benefit to be obtained by increasing this
dosage. In elderly patients it is advisable to proceed more cautiously
with dosage increments and to initiate treatment with a lower dosage.
Once
a satisfactory therapeutic response has been obtained, it is generally
possible to reduce the dosage and still maintain this effect.
For maintenance therapy in depressed patients, the total daily dosage,
up to 150 mg, may be given on a once-aday schedule. This dosage
should be established as described above and should preferably be
given at bedtime.
The 150 mg dosage is intended for maintenance therapy only and is
not recommended for initiation of treatment.
SUPPLIED
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10 mg: Each pink/scarlet capsule
contains: doxepin HCl equivalent to 10 mg of doxepin. Nonmedicinal
ingredients: cornstarch, pregelatinized starch, magnesium stearate
and sodium lauryl sulfate; capsule shell: D&C Yellow No. 10,
FD&C Blue No. 1, Acid Red 27, FD&C Red No. 3, FD&C Yellow
No. 6, gelatin, silicon dioxide, sodium lauryl sulfate and titanium
dioxide. Tartrazine-free. Bottles of 100.
25 mg: Each pink/blue capsule contains: doxepin HCl equivalent
to 25 mg of doxepin. Nonmedicinal ingredients: cornstarch, pregelatinized
starch, magnesium stearate and sodium lauryl sulfate; capsule shell
contains FD&C Blue No. 1, FD&C Red No. 3, gelatin, silicon
dioxide, sodium lauryl sulfate and titanium dioxide. Tartrazine-free.
Bottles of 100.
50 mg: Each flesh/pink capsule contains: doxepin HCl equivalent
to 50 mg of doxepin. Nonmedicinal ingredients: cornstarch, pregelatinized
starch, magnesium stearate and sodium lauryl sulfate; capsule shell
contains D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red
No. 3, gelatin, silicon dioxide, sodium lauryl sulfate and titanium
dioxide.
Tartrazine-free. Bottles of 100.
75 mg: Each flesh/flesh capsule contains: doxepin HCl equivalent
to 75 mg of doxepin. Nonmedicinal ingredients: cornstarch, pregelatinized
starch, magnesium stearate and sodium lauryl sulfate; capsule shell
contains D&C Yellow No. 10, FD&C Red No. 3, gelatin, silicon
dioxide, sodium lauryl sulfate and titanium dioxide. Tartrazine-free.
Bottles of 100.
100mg: Each flesh/blue capsule contains: doxepin HCl equivalent
to 100 mg of doxepin. Nonmedicinal ingredients: cornstarch, pregelatinized
starch, magnesium stearate and sodium lauryl sulfate; capsule shell
contains D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red
No. 3, gelatin, silicon dioxide, sodium lauryl sulfate and titanium
dioxide.
Tartrazine-free. Bottles of 100.
Store between 15 and 30°C.
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