ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS NOTE: Some of the adverse reactions noted below have not been specifically reported with doxepin use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing doxepin.. 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 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.

DRUG INTERACTIONS SECTION.

Drug Interactions Drugs Metabolized by P450 2D6. The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in subset of the Caucasian population (about 7% to 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 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 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 patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 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 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 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. case of severe hypoglycemia has been reported in type II diabetic patient maintained on tolazamide (1 gm/day) 11 days after the addition of doxepin (75 mg/day).

HOW SUPPLIED SECTION.

HOW SUPPLIED Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg or 100 mg of doxepin.The 10 mg capsules are hard-shell, gelatin capsules with buff opaque cap and buff opaque body axially printed with MYLAN over 1049 in black ink on both the cap and the body. They are available as follows:NDC 0378-1049-01bottles of 100 capsulesNDC 0378-1049-10bottles of 1000 capsulesThe 25 mg capsules are hard-shell, gelatin capsules with an ivory opaque cap and white opaque body axially printed with MYLAN over 3125 in black ink on both the cap and the body. They are available as follows:NDC 0378-3125-01bottles of 100 capsulesNDC 0378-3125-10bottles of 1000 capsulesThe 50 mg capsules are hard-shell, gelatin capsules with an ivory opaque cap and ivory opaque body axially printed with MYLAN over 4250 in black ink on both the cap and the body. They are available as follows:NDC 0378-4250-01bottles of 100 capsulesNDC 0378-4250-10bottles of 1000 capsulesThe 75 mg capsules are hard-shell, gelatin capsules with 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 0378-5375-01bottles of 100 capsulesNDC 0378-5375-10bottles of 1000 capsulesThe 100 mg capsules are hard-shell, gelatin capsules with 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 0378-6410-01bottles of 100 capsulesNDC 0378-6410-10bottles of 1000 capsulesStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect from light.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.PHARMACIST: Dispense Medication Guide with each prescription.

INFORMATION FOR PATIENTS SECTION.

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 doxepin and should counsel them in its appropriate use. patient Medication Guide about Antidepressant Medicines, Depression and Other Serious Mental Illnesses and Suicidal Thoughts or Actions is available for doxepin. 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 doxepin.. 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 day to day basis, since changes may be abrupt. Such symptoms should be reported to the patients prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patients presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate 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 risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible.

OVERDOSAGE SECTION.

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 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 patients airway, establish an intravenous line and initiate gastric decontamination. minimum of 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. 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. pH 7.60 or 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 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.

PRECAUTIONS SECTION.

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 doxepin and should counsel them in its appropriate use. patient Medication Guide about Antidepressant Medicines, Depression and Other Serious Mental Illnesses and Suicidal Thoughts or Actions is available for doxepin. 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 doxepin.. 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 day to day basis, since changes may be abrupt. Such symptoms should be reported to the patients prescriber or health professional, especially if they are severe, abrupt in onset, or were not part of the patients presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate 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 risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible.. Drug Interactions Drugs Metabolized by P450 2D6. The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in subset of the Caucasian population (about 7% to 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 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 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 patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 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 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 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. case of severe hypoglycemia has been reported in 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 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 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 major tranquilizer to the dosage regimen.. 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 doxepin in child or adolescent must balance the potential risks with the clinical need.. Geriatric Use A determination has not been made whether controlled clinical studies of doxepin included sufficient numbers of subjects aged 65 and over to define 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 doxepin 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 over sedation in the elderly; elderly patients generally should be started on low doses of doxepin and observed closely. (See WARNINGS.).

SPL MEDGUIDE SECTION.

Medication Guide Antidepressant Medicines, Depression and Other Serious Mental Illnesses,and Suicidal Thoughts or Actions Read the Medication Guide that comes with your or your family members antidepressant medicine. This Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your, or your family members, healthcare provider about: oall risks and benefits of treatment with antidepressant medicines oall treatment choices for depression or other serious mental illness What is the most important information should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions 1.Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2.Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have particularly high risk of having suicidal thoughts or actions. These include people who have (or have family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3.How can watch for and try to prevent suicidal thoughts and actions in myself or family member oPay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. oCall the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. oKeep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. Call healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you: othoughts about suicide or dying oattempts to commit suicide onew or worse depression onew or worse anxiety ofeeling very agitated or restless opanic attacks otrouble sleeping (insomnia) onew or worse irritabilityoacting aggressive, being angry, or violentoacting on dangerous impulses oan extreme increase in activity and talking (mania) oother unusual changes in behavior or mood oVisual problems: eye pain, changes in vision, swelling or redness in or around the eyeWhat else do need to know about antidepressant medicines oNever stop an antidepressant medicine without first talking to healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. oVisual problems: Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. oAntidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.oAntidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. oAntidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. oNot all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your childs healthcare provider for more information. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.This Medication Guide has been approved by the U.S. Food and Drug Administration for all antidepressants.Manufactured for: Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Revised: 6/2023VPL:DXPN:R1mmh. oall risks and benefits of treatment with antidepressant medicines oall treatment choices for depression or other serious mental illness 1.Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment. 2.Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have particularly high risk of having suicidal thoughts or actions. These include people who have (or have family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. 3.How can watch for and try to prevent suicidal thoughts and actions in myself or family member oPay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. oCall the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. oKeep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. oPay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed. oCall the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings. oKeep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms. othoughts about suicide or dying oattempts to commit suicide onew or worse depression onew or worse anxiety ofeeling very agitated or restless opanic attacks otrouble sleeping (insomnia) onew or worse irritability. oacting aggressive, being angry, or violent. oacting on dangerous impulses oan extreme increase in activity and talking (mania) oother unusual changes in behavior or mood oVisual problems: eye pain, changes in vision, swelling or redness in or around the eye. oNever stop an antidepressant medicine without first talking to healthcare provider. Stopping an antidepressant medicine suddenly can cause other symptoms. oVisual problems: Only some people are at risk for these problems. You may want to undergo an eye examination to see if you are at risk and receive preventative treatment if you are. oAntidepressants are medicines used to treat depression and other illnesses. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.. oAntidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member. oAntidepressant medicines can interact with other medicines. Know all of the medicines that you or your family member takes. Keep list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider. oNot all antidepressant medicines prescribed for children are FDA approved for use in children. Talk to your childs healthcare provider for more information.

SPL UNCLASSIFIED SECTION.

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 known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been long-standing concern, however, that antidepressants may have 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 to 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 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 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 total of 295 short-term trials (median duration of months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but 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 1Age RangeDrug-Placebo Difference inNumber of Cases of SuicidalityPer 1,000 Patients TreatedIncreases Compared to Placebo< 1814 additional cases18 to 245 additional casesDecreases Compared to Placebo25 to 641 fewer case>= 656 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 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 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 patients 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.

WARNINGS SECTION.

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 known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been long-standing concern, however, that antidepressants may have 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 to 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 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 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 total of 295 short-term trials (median duration of months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but 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 1Age RangeDrug-Placebo Difference inNumber of Cases of SuicidalityPer 1,000 Patients TreatedIncreases Compared to Placebo< 1814 additional cases18 to 245 additional casesDecreases Compared to Placebo25 to 641 fewer case>= 656 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 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 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 patients 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 mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such 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 detailed psychiatric history, including 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 patient with anatomically narrow angles who does not have patent iridectomy.. Geriatric Use The use of doxepin on once day dosage regimen in geriatric patients should be adjusted carefully based on the patients 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 report of apnea and drowsiness occurring in 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Doxepin Hydrochloride Capsules, USP are available containing doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg or 100 mg of doxepin.oThe 10 mg capsules are hard-shell, gelatin capsules with buff opaque cap and buff opaque body axially printed with MYLAN over 1049 in black ink on both the cap and the body.oThe 25 mg capsules are hard-shell, gelatin capsules with an ivory opaque cap and white opaque body axially printed with MYLAN over 3125 in black ink on both the cap and the body.oThe 50 mg capsules are hard-shell, gelatin capsules with an ivory opaque cap and ivory opaque body axially printed with MYLAN over 4250 in black ink on both the cap and the body.oThe 75 mg capsules are hard-shell, gelatin capsules with 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. oThe 100 mg capsules are hard-shell, gelatin capsules with 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. oThe 10 mg capsules are hard-shell, gelatin capsules with buff opaque cap and buff opaque body axially printed with MYLAN over 1049 in black ink on both the cap and the body.. oThe 25 mg capsules are hard-shell, gelatin capsules with an ivory opaque cap and white opaque body axially printed with MYLAN over 3125 in black ink on both the cap and the body.. oThe 50 mg capsules are hard-shell, gelatin capsules with an ivory opaque cap and ivory opaque body axially printed with MYLAN over 4250 in black ink on both the cap and the body.. oThe 75 mg capsules are hard-shell, gelatin capsules with 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. oThe 100 mg capsules are hard-shell, gelatin capsules with 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. oCapsules: 10 mg, 25 mg, 50 mg, 75 mg and 100 mg (3) oCapsules: 10 mg, 25 mg, 50 mg, 75 mg and 100 mg (3).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Absorption. In healthy volunteers, single oral doxepin hydrochloride capsule dose of 75 mg resulted in peak plasma doxepin concentrations that ranged from 8.8 ng/mL to 45.8 ng/mL (mean 26.1 ng/mL). Peak levels were reached between and hours (mean 2.9 hours) after doxepin hydrochloride capsules administration. Peak levels for the primary active metabolite N-desmethyldoxepin (nordoxepin) ranged from 4.8 ng/mL to 14.5 ng/mL (mean 9.7 ng/mL) and were achieved between and 10 hours after doxepin hydrochloride capsules administration. Distribution. The mean apparent volume of distribution for doxepin was approximately 20 L/kg. The protein binding for doxepin was approximately 76%. Elimination. In healthy volunteers, the plasma elimination half-life of doxepin ranged from to 24 hours (mean 17 hours). The half-life of nordoxepin ranged from 33 to 80 hours (mean 51 hours). The mean plasma clearance for doxepin was approximately 0.84 L/hour/kg. Metabolism After oral doxepin administration, approximately 55% to 87% of doxepin undergoes first-pass metabolism in the liver, forming the primary active metabolite nordoxepin. Metabolic pathways of doxepin include demethylation, N-oxidation, hydroxylation and glucuronide formation. Excretion Doxepin is excreted primarily in the urine, mainly as its metabolites, either free or in conjugate form. Specific Populations. Patients with Hepatic Impairment Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with hepatic impairment. Patients with hepatic impairment may have greater systemic doxepin exposure than those with normal liver function [see Use in Specific Populations (8.6)]. Patients with Renal Impairment The extent of renal excretion of doxepin is unknown. Specific clinical studies have not been performed to evaluate the pharmacokinetics of doxepin in patients with renal impairment compared to those with normal renal function. Drug Interaction Studies. Carbamazepine After concomitant use of doxepin and carbamazepine, the combined exposure of doxepin and nordoxepin (12 hours after the last dose) was decreased by 55% compared to that after the use of doxepin alone [see Drug Interactions (7)]. Strong CYP2D6 Inhibitors CYP2D6 contributes to the metabolism of doxepin and concomitant use of doxepin with strong CYP2D6 inhibitors may increase doxepin exposure [see Drug Interactions (7)]. Cimetidine Cimetidine is non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4. When cimetidine 300 mg twice daily was administered concomitantly with single mg dose of another oral doxepin product, there was approximately 2-fold increase in doxepin Cmax and AUC compared to doxepin without cimetidine [see Drug Interactions (7)]. CYP2D6 Substrates: Concomitant use of doxepin and other CYP2D6 substrates may have impact on the plasma doxepin concentrations. The clinical significance of this possible impact is unknown.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: Neonates exposed to TCAs, including doxepin hydrochloride capsules, late in the third trimester have developed poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability). Monitor neonates who were exposed to doxepin hydrochloride capsules in the third trimester of pregnancy for poor neonatal adaptation syndrome. (8.1) oLactation: Breastfeeding not recommended. (8.2) oGeriatric Use: May cause confusion and oversedation. (8.5) oCYP2C19 and CYP2D6 Poor Metabolizers: Increased risk of doxepin hydrochloride capsule-associated adverse reactions. (8.7) oPregnancy: Neonates exposed to TCAs, including doxepin hydrochloride capsules, late in the third trimester have developed poor adaptation (respiratory distress, temperature instability, feeding difficulty, hypotonia, irritability). Monitor neonates who were exposed to doxepin hydrochloride capsules in the third trimester of pregnancy for poor neonatal adaptation syndrome. (8.1) oLactation: Breastfeeding not recommended. (8.2) oGeriatric Use: May cause confusion and oversedation. (8.5) oCYP2C19 and CYP2D6 Poor Metabolizers: Increased risk of doxepin hydrochloride capsule-associated adverse reactions. (8.7) 8.1 Pregnancy Pregnancy Exposure Registry. There is pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antidepressants, including doxepin hydrochloride capsules, during pregnancy. Health care providers are encouraged to advise patients to register by calling the National Pregnancy Registry for Antidepressants 1-866-961-2388 or visiting online at https://womensmentalhealth.org/clinical-and-researchprograms/pregnancyregistry/antidepressants.. Risk Summary. Available data from published epidemiological studies and postmarketing reports have not established an increased risk for major birth defects or miscarriage with doxepin hydrochloride capsules use (see Data). There are risks (see Clinical Considerations):oTo the mother associated with untreated depression in pregnancy. oPoor neonate adaptation from exposure to tricyclic antidepressants (TCAs), including doxepin hydrochloride capsules, during the third trimester of pregnancy. Animal reproduction toxicity of doxepin has not been fully characterized.The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. oTo the mother associated with untreated depression in pregnancy. oPoor neonate adaptation from exposure to tricyclic antidepressants (TCAs), including doxepin hydrochloride capsules, during the third trimester of pregnancy. Clinical Considerations. Disease-associated Maternal and/or Embryofetal Risk Women who discontinue antidepressants during pregnancy are more likely to experience relapse of MDD than women who continue antidepressants. This finding is from prospective longitudinal study of 201 pregnant women with history of MDD who were euthymic and taking antidepressants at the beginning of pregnancy. Consider the risk of untreated MDD when considering discontinuation of doxepin drugs during pregnancy and the postpartum period. Fetal/Neonatal Adverse Reactions Neonates previously exposed to TCAs, including doxepin hydrochloride capsules, late in the third trimester during pregnancy have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These findings are consistent with either direct toxic effects of TCAs or possibly drug discontinuation syndrome. Monitor neonates who were exposed to doxepin hydrochloride capsules in the third trimester of pregnancy for poor neonatal adaptation syndrome. Data. Human Data Published epidemiological studies of pregnant women exposed to TCAs, including doxepin hydrochloride capsules, have not established an association with major birth defects, miscarriage, or adverse maternal outcomes. Methodological limitations of these observational studies include small sample size and lack of adequate controls.. 8.2 Lactation Risk Summary. Data from published literature report the presence of doxepin and nordoxepin in human milk. There are reports of excessive sedation, respiratory depression, poor suckling and swallowing and hypotonia in breastfed infants exposed to doxepin at doses used to treat MDD. There are no data on the effects of doxepin on milk production.Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in breastfed infant, advise patients that breastfeeding is not recommended during doxepin hydrochloride capsules treatment.. 8.4 Pediatric Use The safety and effectiveness of doxepin hydrochloride capsules in pediatric patients have not been established. Antidepressants increase the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings and Precautions (5.1)].. 8.5 Geriatric Use Clinical studies of doxepin did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients.Sedating drugs, including doxepin hydrochloride capsules, may cause confusion and oversedation in geriatric patients. The recommended starting doxepin hydrochloride capsules dosage in geriatric patients is generally lower than those of younger adult patients. 8.6 Hepatic Impairment The effect of hepatic impairment (HI) on the pharmacokinetics of doxepin has not been studied. Doxepin is primarily metabolized in the liver. Doxepin hydrochloride capsules-treated patients with HI may have greater systemic doxepin exposure than those with normal liver function. Consider obtaining doxepin concentrations in patients with HI and modifying the dosage as appropriate.. 8.7 Use in Genomic Subgroups The recommended doxepin hydrochloride capsules dosage in CYP2C19 and CYP2D6 poor metabolizers is lower than the recommended dosage in CYP2C19 and CYP2D6 normal metabolizers [see Dosage and Administration (2.6)]. According to the literature, doxepin is primarily metabolized by CYP2D6 and/or CYP2C19; thus, the use of doxepin hydrochloride capsules in CYP2D6 and/or CYP2C19 poor metabolizers will likely result in higher doxepin exposures and an increased risk of doxepin hydrochloride capsule-associated adverse reactions.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oSuicidal Thoughts and Behaviors: Monitor for clinical worsening and suicide thoughts and behaviors. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride capsules, in patients who are experiencing emergent suicidal thoughts or behaviors. (5.1) oSerotonin Syndrome: Risk increases with concomitant use of other serotonergic drugs. Monitor all patients taking doxepin hydrochloride capsules for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride capsules and any concomitant serotonergic agents immediately and initiate supportive treatment if serotonin syndrome occurs. (5.2, 7) oAngle-Closure Glaucoma: Avoid use of doxepin hydrochloride capsules in patients with untreated anatomically narrow angles. (5.3) oSedation and Driving Risks: Because doxepin hydrochloride capsules can cause sedation, warn patients against driving car or operating dangerous machinery while taking doxepin hydrochloride capsules. (5.4) oActivation of Mania or Hypomania: Prior to initiating antidepressant therapy, screen for bipolar disorder. Doxepin hydrochloride capsules are not approved for use in treating bipolar depression. (5.5). oSuicidal Thoughts and Behaviors: Monitor for clinical worsening and suicide thoughts and behaviors. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride capsules, in patients who are experiencing emergent suicidal thoughts or behaviors. (5.1) oSerotonin Syndrome: Risk increases with concomitant use of other serotonergic drugs. Monitor all patients taking doxepin hydrochloride capsules for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride capsules and any concomitant serotonergic agents immediately and initiate supportive treatment if serotonin syndrome occurs. (5.2, 7) oAngle-Closure Glaucoma: Avoid use of doxepin hydrochloride capsules in patients with untreated anatomically narrow angles. (5.3) oSedation and Driving Risks: Because doxepin hydrochloride capsules can cause sedation, warn patients against driving car or operating dangerous machinery while taking doxepin hydrochloride capsules. (5.4) oActivation of Mania or Hypomania: Prior to initiating antidepressant therapy, screen for bipolar disorder. Doxepin hydrochloride capsules are not approved for use in treating bipolar depression. (5.5). 5.1 Suicidal Thoughts and Behaviors in Adolescents and Young Adults In pooled analyses of placebo-controlled trials of antidepressant drugs including tricyclic antidepressants and other antidepressant classes that included approximately 77,000 adult patients and 4,500 pediatric patients (doxepin hydrochloride capsules are not approved for use in pediatric patients), the incidence of suicidal thoughts and behaviors in antidepressant-treated patients age 24 years and younger was greater than in placebo-treated patients. There was considerable variation in risk of suicidal thoughts and behaviors among drugs, but there was an increased risk identified in young patients for most drugs studied. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1,000 patients treated are provided in Table 1. Table 1: Risk Differences of the Number of Patients of Suicidal Thoughts and Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult PatientsAge RangeDrug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1,000 Patients TreatedIncreases Compared to Placebo< 18 years old14 additional patients18-24 years old5 additional patientsDecreases Compared to Placebo25-64 years old1 fewer patient>= 65 years old6 fewer patientsIt is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with MDD that antidepressants delay the recurrence of depression.Monitor all doxepin hydrochloride capsules-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of doxepin hydrochloride capsules therapy, and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the health care provider. Consider changing the therapeutic regimen, including possibly discontinuing doxepin hydrochloride capsules, in patients who are experiencing emergent suicidal thoughts or behaviors.. 5.2 Serotonin Syndrome Tricyclic antidepressants, including doxepin hydrochloride capsules, can precipitate serotonin syndrome, potentially life-threatening condition. This risk is increased with concomitant use of other serotonergic drugs (e.g., other tricyclic antidepressants, SSRIs, serotonin norepinephrine reuptake inhibitors, triptans, tetracyclic antidepressants, opioids), lithium, tryptophan, buspirone, and St. Johns Wort) and with drugs that impair metabolism of serotonin (e.g., MAOIs intended to treat psychiatric disorders and others, such as linezolid or intravenous methylene blue) [see Drug Interactions (7)]. Serotonin syndrome symptoms may include mental status changes (e.g., confusion, agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia, diaphoresis, and flushing), neuromuscular abnormalities (e.g., tremor, rigidity, clonus, and hyperreflexia), seizures and gastrointestinal signs and symptoms (e.g., nausea, vomiting, diarrhea). Patients should be monitored for the emergence of serotonin syndrome. The concomitant use of doxepin hydrochloride capsules with MAOIs is contraindicated. The use of doxepin hydrochloride capsules within 14 days of discontinuing treatment with an MAOI intended to treat psychiatric disorders is contraindicated. Starting doxepin hydrochloride capsules in patient who is being treated with an MAOI such as linezolid or intravenous methylene blue is contraindicated. No reports involved the administration of methylene blue by other routes (such as oral or local tissue injection). If it is necessary to initiate treatment with MAOI such as linezolid or intravenous methylene blue in patient taking doxepin hydrochloride capsules, discontinue doxepin hydrochloride capsules before initiating treatment with the MAOI [see Dosage and Administration (2.4) and Drug Interactions (7)]. Monitor all patients taking doxepin hydrochloride capsules for the emergence of serotonin syndrome. Discontinue doxepin hydrochloride capsules treatment and any concomitant serotonergic agents immediately if the above symptoms occur, and initiate supportive symptomatic treatment. If concomitant use of doxepin hydrochloride capsules with other serotonergic drugs (besides MAOIs which are contraindicated) is clinically warranted, inform patients of the increased risk for serotonin syndrome and monitor for symptoms.. 5.3 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including doxepin hydrochloride capsules may trigger an angle closure glaucoma attack in patient with anatomically narrow angles who does not have patent iridectomy. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have prophylactic procedure (e.g., iridectomy), if they are susceptible.Doxepin hydrochloride capsules are contraindicated in patients with glaucoma. Avoid use of doxepin hydrochloride capsules in patients with untreated anatomically narrow angles.. 5.4 Sedation and Driving Risks Because doxepin hydrochloride capsules can cause sedation, warn patients of the risk of sedation and caution patients against driving car or operating dangerous machinery while taking doxepin hydrochloride capsules. Also caution patients that their response to alcohol may be potentiated.Sedating drugs, including doxepin hydrochloride capsules, may cause oversedation in geriatric patients.. 5.5 Activation of Mania or Hypomania In patients with bipolar disorder, treating MDD with doxepin hydrochloride capsules may precipitate mixed/manic episode. Prior to initiating treatment with doxepin hydrochloride capsules, screen patients for any personal or family history of bipolar disorder, mania, or hypomania. doxepin hydrochloride capsules are not approved for use in treating bipolar depression.. 5.6 Risk of Seizures Caution should be used when doxepin hydrochloride capsules are given to patients with history of seizure disorder, because this drug may lower the seizure threshold. Patients with history of seizures should be monitored during doxepin hydrochloride capsules use to identify recurrence of seizures or increase in frequency of seizures.. 5.7 Psychosis In patients with schizophrenia, treatment with doxepin hydrochloride capsules for MDD may activate psychosis. If this occurs, stop doxepin hydrochloride capsules and consider alternative treatment options.