Overdose
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.
Deaths have been reported involving overdoses of doxepin.
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.
Contraindications
SINEQUAN is contraindicated in individuals who have shown
hypersensitivity to the drug. Possibility of cross sensitivity with other
dibenzoxepines should be kept in mind.
SINEQUAN is contraindicated in patients with glaucoma or
a tendency to urinary retention. These disorders should be ruled out,
particularly in older patients.
Undesirable effects
NOTE: Some of the adverse reactions noted below
have not been specifically reported with SINEQUAN use. However, due to the
close pharmacological similarities among the tricyclics, the reactions should
be considered when prescribing SINEQUAN (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, angle closure glaucoma, mydriasis 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 SINEQUAN administration
should be borne in mind. These are not indicative of addiction and gradual
withdrawal of medication should not cause these symptoms.
Therapeutic indications
SINEQUAN is recommended for the treatment of:
- Psychoneurotic patients with depression and/or anxiety.
- Depression and/or anxiety associated with alcoholism (not
to be taken concomitantly with alcohol).
- Depression and/or anxiety associated with organic disease
(the possibility of drug interaction should be considered if the patient is
receiving other drugs concomitantly).
- Psychotic depressive disorders with associated anxiety
including involutional depression and manic-depressive disorders.
The target symptoms of psychoneurosis that respond
particularly well to SINEQUAN include anxiety, tension, depression, somatic
symptoms and concerns, sleep disturbances, guilt, lack of energy, fear,
apprehension and worry.
Clinical experience has shown that SINEQUAN is safe and
well tolerated even in the elderly patient. Owing to lack of clinical
experience in the pediatric population, SINEQUAN is not recommended for use in
children under 12 years of age.
Name of the medicinal product
Sinequan
Qualitative and quantitative composition
SINEQUAN is available as capsules containing doxepin HCl
equivalent to:
10 mg – 100's (NDC 0049-5340-66)
25 mg – 100's (NDC 0049-5350-66)
50 mg – 100's (NDC 0049-5360-66)
75 mg – 100's (NDC 0049-5390-66)
100 mg – 100's (NDC 0049-5380-66)
150 mg – 50's (NDC 0049-5370-50)
SINEQUAN Oral Concentrate is available in 120 mL bottles
(NDC 0049-5100-47) with an accompanying dropper calibrated at 5 mg, 10 mg, 15
mg, 20 mg, and 25 mg. Each mL contains doxepin HCl equivalent to 10 mg doxepin.
Just prior to administration, SINEQUAN Oral Concentrate should be diluted with
approximately 120 mL of water, whole or skimmed milk, or orange, grapefruit,
tomato, prune or pineapple juice. SINEQUAN Oral Concentrate is not physically
compatible with a number of carbonated beverages. For those patients requiring
antidepressant therapy who are on methadone maintenance, SINEQUAN Oral
Concentrate and methadone syrup can be mixed together with Gatorade®, lemonade,
orange juice, sugar water, Tang®, or water; but not with grape juice.
Preparation and storage of bulk dilutions is not recommended.
Distributed by: Roerig, Division of Pfizer Inc, NY, NY
10017. June 2014
Special warnings and precautions for use
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 18-24) 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 |
| 18-24 |
5 additional cases |
| |
Decreases Compared to Placebo |
| 25-64 |
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 Sinequan 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
Sinequan is not approved for use in treating bipolar depression.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many
antidepressant drugs including Sinequan may trigger an angle closure attack in
a patient with anatomically narrow angles who does not have a patent
iridectomy.
Usage in Geriatrics: The use of SINEQUAN on a
once-a-day dosage regimen in geriatric patients should be adjusted carefully
based on the patient's condition (see PRECAUTIONS-Geriatric Use).
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 SINEQUAN.
Usage in Children: The use of SINEQUAN in children
under 12 years of age is not recommended because safe conditions for its use
have not been established.
PRECAUTIONS
Information For Patients
Prescribers or other health professionals should inform
patients, their families, and their caregivers about the benefits and risks
associated with treatment with Sinequan and should counsel them in its
appropriate use. A patient Medication Guide about “Antidepressant Medicines,
Depression and other Serious Mental Illness, and Suicidal Thoughts or Actions”
is available for Sinequan. The prescriber or health professional should
instruct patients, their families, and their caregivers to read the Medication
Guide and should assist them in understanding its contents. Patients should be
given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions
they may have. The complete text of the Medication Guide is reprinted at the
end of this document.
Patients should be advised of the following issues and
asked to alert their prescriber if these occur while taking Sinequan.
Clinical Worsening and Suicide Risk
Patients, their families, and their caregivers should be
encouraged to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia
(psychomotor restlessness), hypomania, mania, other unusual changes in
behavior, worsening of depression, and suicidal ideation, especially early
during antidepressant treatment and when the dose is adjusted up or down.
Families and caregivers of patients should be advised to look for the emergence
of such symptoms on a day-today basis, since changes may be abrupt. Such
symptoms should be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of the
patient's presenting symptoms. Symptoms such as these may be associated with an
increased risk for suicidal thinking and behavior and indicate a need for very
close monitoring and possibly changes in the medication.
Patients should be advised that taking Sinequan can cause
mild pupillary dilation, which in susceptible individuals, can lead to an
episode of angle closure glaucoma. Pre-existing glaucoma is almost always
open-angle glaucoma because angle closure glaucoma, when diagnosed, can be
treated definitively with iridectomy. Open-angle glaucoma is not a risk factor
for angle closure glaucoma. Patients may wish to be examined to determine
whether they are susceptible to angle closure, and have a prophylactic
procedure (e.g., iridectomy), if they are susceptible.
Pediatric Use
Safety and effectiveness in the pediatric population have
not been established (see BOX WARNING and WARNINGS - Clinical
Worsening and Suicide Risk).
Anyone considering the use of SINEQUAN in a child or
adolescent must balance the potential risks with the clinical need.
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.
Sedating drugs may cause confusion and oversedation in
the elderly; elderly patients generally should be started on low doses of
SINEQUAN and observed closely. (See PRECAUTIONS - Geriatric Use.)
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.
Geriatric Use
A determination has not been made whether controlled
clinical studies of SINEQUAN included sufficient numbers of subjects aged 65
and over to define a difference in response from younger subjects. Other
reported clinical experience has not identified differences in responses
between the elderly and younger patients. In general, dose selection for an
elderly patient should be cautious, usually starting at the low end of the
dosing range, reflecting the greater frequency of decreased hepatic, renal or
cardiac function, and of concomitant disease or other drug therapy.
The extent of renal excretion of SINEQUAN has not been
determined. Because elderly patients are more likely to have decreased renal
function, care should be taken in dose selections.
Sedating drugs may cause confusion and oversedation in
the elderly; elderly patients generally should be started on low doses of
SINEQUAN and observed closely. (See WARNINGS.)
Dosage (Posology) and method of 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 SINEQUAN 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.
Interaction with other medicinal products and other forms of interaction
SIDE EFFECTS
NOTE: Some of the adverse reactions noted below
have not been specifically reported with SINEQUAN use. However, due to the
close pharmacological similarities among the tricyclics, the reactions should
be considered when prescribing SINEQUAN (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, angle closure glaucoma, mydriasis 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 SINEQUAN administration
should be borne in mind. These are not indicative of addiction and gradual
withdrawal of medication should not cause these symptoms.
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 antiarrhythmics propafenone and flecainide). While
all the selective serotonin reuptake inhibitors (SSRIs), e.g., citalopram,
escitalopram, 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.
Doxepin is primarily metabolized by CYP2D6 (with CYP1A2
& CYP3A4 as minor pathways). Inhibitors or substrates of CYP2D6 (i.e.,
quinidine, selective serotonin reuptake inhibitors [SSRIs]) may increase the
plasma concentration of doxepin when administered concomitantly. The extent of
interaction depends on the variability of effect on CYP2D6. The clinical
significance of this interaction with doxepin has not been systematically
evaluated.
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 SINEQUAN. 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
SINEQUAN 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).
