e 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 coadministration 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 of particular importance, sufficient time must elapse before initiating tca treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).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 furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required.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. 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 2 weeks prior to the cautious initiation of therapy with doxepin. 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 doxepin 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).

drochloride capsules are not recommended for use in children under 12 years of age.

h 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 nine antidepressant drugs in over 4,400 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 1,000 patients treated) are provided in table 1. table 1 age range drug-placebo difference in number of cases of suicidality per 1,000 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 healthcare providers. such monitoring should include daily observation by families and caregivers. prescriptions for doxepin should be written for the smallest number of capsules 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 doxepin is not approved for use in treating bipolar depression. angle-closure glaucoma the pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride capsules may trigger an angle closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. geriatric use the use of doxepin on a once a day dosage regimen in geriatric patients should be adjusted carefully based on the patient's condition (see precautions: geriatric use ). 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 doxepin. pediatric use the use of doxepin in children under 12 years of age is not recommended because safe conditions for its use have not been established.

e therapy only and is not recommended for initiation of treatment . antianxiety effect is apparent before the antidepressant effect. optimal antidepressant effect may not be evident for 2 to 3 weeks.

urred. 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 doxepin administration should be borne in mind. these are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms.

e 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 coadministration 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 cotherapy, 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. 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 2 weeks prior to the cautious initiation of therapy with doxepin. 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 doxepin 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).

compounds has been reported. doxepin is virtually devoid of euphoria as a side effect. characteristic of this type of compound, doxepin has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds.

c 0378-4250-10 bottles of 1000 capsules the 75 mg capsules are hard-shell, gelatin capsules with a brite lite green opaque cap and brite lite green opaque body axially printed with mylan over 5375 in black ink on both the cap and the body. they are available as follows: ndc 0378-5375-01 bottles of 100 capsules ndc 0378-5375-10 bottles of 1000 capsules the 100 mg capsules are hard-shell, gelatin capsules with a brite lite green opaque cap and white opaque body axially printed with mylan over 6410 in black ink on both the cap and the body. they are available as follows: ndc 0378-6410-01 bottles of 100 capsules ndc 0378-6410-10 bottles of 1000 capsules store at 20° to 25°c (68° to 77°f). [see usp controlled room temperature.] protect from light. dispense in a tight, light-resistant container as defined in the usp using a child-resistant closure. pharmacist: dispense a medication guide with each prescription.

ies 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 to day 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 doxepin hydrochloride capsules 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.