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 of particular importance, sufficient time must elapse before initiating tca treatment in a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).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 furthermore, whenever one of these other drugs is withdrawn from cotherapy, an increased dose of tricyclic antidepressant may be required.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 hydrochloride 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 hydrochloride when administered concomitantly. the extent of interaction depends on the variability of effect on cyp2d6. the clinical significance of this interaction with doxepin hydrochloride 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 doxepin hydrochloride. 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 hydrochloride 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 hydrochloride (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. sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride 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.

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 hydrochloride should be written for the smallest quantity 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 hydrochloride 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 hydrochloride 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 hydrochloride. pediatric use the use of doxepin hydrochloride 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 two to three weeks.

uritus 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 doxepin hydrochloride administration should be borne in mind. these are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms. to report suspected adverse reactions, contact novadoz pharmaceuticals llc at 1-855-668-2369 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

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 hydrochloride 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 hydrochloride when administered concomitantly. the extent of interaction depends on the variability of effect on cyp2d6. the clinical significance of this interaction with doxepin hydrochloride 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 doxepin hydrochloride. 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 hydrochloride 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 hydrochloride (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. sedating drugs may cause confusion and over sedation in the elderly; elderly patients generally should be started on low doses of doxepin hydrochloride 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.

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

: ndc 72205-090-91 bottles of 100 capsules ndc 72205-090-99 bottles of 1000 capsules the 75 mg capsule is a green opaque body imprinted with “75 mg” in black ink and green opaque cap imprinted with “md15” in black ink filled with white to off white powder. they are available as follows: ndc 72205-091-91 bottles of 100 capsules ndc 72205-091-99 bottles of 1000 capsules the 100 mg capsule is a white opaque body imprinted with “100 mg” in black ink and green opaque cap imprinted with “md16” in black ink filled with white to off white powder. they are available as follows: ndc 72205-092-91 bottles of 100 capsules ndc 72205-092-99 bottles of 1000 capsules store at 20º to 25ºc (68º to 77ºf); excursions permitted to 15° to 30°c (59° to 86°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 the accompanying medication guide to each patient.