Doxepin Hydrochloride

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 hydrochloride.

CONTRAINDICATIONS Doxepin is contraindicated in individuals who have shown hypersensitivity to the drug. Possibility of cross sensitivity with other dibenzoxepines should be kept in mind. Doxepin is contraindicated in patients with glaucoma or a tendency to urinary retention. These disorders should be ruled out, particularly in older patients.

DESCRIPTION Doxepin hydrochloride, USP is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C 19 H 21 NO ∙ HCl having a molecular weight of 316. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform. It may be represented by the following structural formula: Doxepin HCl Chemically, doxepin hydrochloride, USP is a dibenzoxepin derivative and is the first of a family of tricyclic psychotherapeutic agents. Specifically, it is an isomeric mixture of 1-Propanamine, 3-dibenz[ b,e ]oxepin-11 (6 H )ylidene- N,N -dimethyl-,hydrochloride. Each 10 mg, 25 mg, 50 mg, 75 mg and 100 mg doxepin capsule for oral administration contains doxepin hydrochloride, USP equivalent to 10 mg, 25 mg, 50 mg, 75 mg and 100 mg of doxepin, respectively and the following inactive ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose, pregelatinized starch and sodium lauryl sulfate. The empty gelatin capsule shells contain gelatin and titanium dioxide. In addition, the 10 mg empty gelatin capsule shells contain yellow iron oxide, 25 mg and 50 mg empty gelatin capsule shells contain D&C Yellow No. 10 and FD&C Yellow No. 6 and the 75 mg and 100 mg empty gelatin capsule shells contain yellow iron oxide and FD&C Blue No. 1. Black ink contains shellac glaze, isopropyl alcohol, black iron oxide, n-butyl alcohol, propylene glycol, and ammonium hydroxide. image description

DOSAGE AND ADMINISTRATION For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day. In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day. In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25 to 50 mg/day. The total daily dosage of doxepin (as hydrochloride) may be given on a divided or once-a-day dosage schedule. If the once-a-day schedule is employed, the maximum recommended dose is 150 mg/day. This dose may be given at bedtime. The 150 mg capsule strength is intended for maintenance therapy only and is not recommended for initiation of treatment. Anti-anxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for two to three weeks.

INDICATIONS AND USAGE Doxepin hydrochloride capsules are recommended for the treatment of: Psychoneurotic patients with depression and/or anxiety. Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol). Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly). Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders. The target symptoms of psychoneurosis that respond particularly well to doxepin include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry. Clinical experience has shown that doxepin is safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, doxepin is not recommended for use in children under 12 years of age.

WARNINGS

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 a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after tricyclic antidepressant overdose; therefore, hospital monitoring is required as soon as possible.

CLINICAL PHARMACOLOGY The mechanism of action of doxepin hydrochloride is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin hydrochloride does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses, norepinephrine response was potentiated in animals. This effect was not demonstrated in humans. At clinical dosages up to 150 mg per day, doxepin can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect. At dosages above 150 mg per day blocking of the antihypertensive effect of these 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.

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Doxepin Hydrochloride Doxepin Hydrochloride SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE STARCH, CORN SODIUM LAURYL SULFATE GELATIN, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE YELLOW SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA DOXEPIN HYDROCHLORIDE DOXEPIN yellow cap and body CE;68 Doxepin Hydrochloride Doxepin Hydrochloride SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE STARCH, CORN SODIUM LAURYL SULFATE GELATIN, UNSPECIFIED TITANIUM DIOXIDE D&C YELLOW NO. 10 FD&C YELLOW NO. 6 SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA DOXEPIN HYDROCHLORIDE DOXEPIN light yellow cap white body CE;69 Doxepin Hydrochloride Doxepin Hydrochloride SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE STARCH, CORN SODIUM LAURYL SULFATE GELATIN, UNSPECIFIED TITANIUM DIOXIDE D&C YELLOW NO. 10 FD&C YELLOW NO. 6 SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA DOXEPIN HYDROCHLORIDE DOXEPIN light yellow cap and body CE;70 Doxepin Hydrochloride Doxepin Hydrochloride SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE STARCH, CORN SODIUM LAURYL SULFATE GELATIN, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE YELLOW FD&C BLUE NO. 1 SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA DOXEPIN HYDROCHLORIDE DOXEPIN light green cap and body CE;71 Doxepin Hydrochloride Doxepin Hydrochloride SILICON DIOXIDE MAGNESIUM STEARATE MICROCRYSTALLINE CELLULOSE STARCH, CORN SODIUM LAURYL SULFATE GELATIN, UNSPECIFIED TITANIUM DIOXIDE FERRIC OXIDE YELLOW FD&C BLUE NO. 1 SHELLAC ISOPROPYL ALCOHOL FERROSOFERRIC OXIDE BUTYL ALCOHOL PROPYLENE GLYCOL AMMONIA DOXEPIN HYDROCHLORIDE DOXEPIN light green cap and white body CE;72

ANDA210268

Doxepin Hydrochloride

Doxepin Hydrochloride

62135-563

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Doxepin Hydrochloride Capsules, USP 10mg - NDC 62135-560-90 - 90's - Bottle-Label Doxepin Hydrochloride Capsules, USP 25mg - NDC 62135-561-90 - 90's - Bottle-Label Doxepin Hydrochloride Capsules, USP 50mg - NDC 62135-562-90 - 90's - Bottle-Label Doxepin Hydrochloride Capsules, USP 75mg - NDC 62135-563-90 - 90's - Bottle-Label Doxepin Hydrochloride Capsules, USP 100mg - NDC 62135-564-90 - 90's - Bottle-Label image description image description image description image description image description

Clinical Worsening and Suicide Risk Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 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 a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 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 quantity of capsules consistent with good patient management, in order to reduce the risk of overdose.

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 capsule is a hard-shell, gelatin capsule with a yellow opaque cap and yellow opaque body. The capsules are imprinted with “CE” in black ink on the cap and “68” on the body. They are available as follows: Bottles of 90 capsules (NDC 62135-560-90) The 25 mg capsule is a hard-shell, gelatin capsule with a light yellow opaque cap and white opaque body. The capsules are imprinted with "CE” in black ink on the cap and "69” on the body. They are available as follows: Bottles of 90 capsules (NDC 62135-561-90) The 50 mg capsule is a hard-shell, gelatin capsule with a light yellow opaque cap and light yellow opaque body. The capsules are imprinted with “CE” in black ink on the cap and “70” on the body. They are available as follows: Bottles of 90 capsules (NDC 62135-562-90) The 75 mg capsule is a hard-shell, gelatin capsule with a light green opaque cap and light green opaque body. The capsules are imprinted with “CE” in black ink on the cap and "71” on the body. They are available as follows: Bottles of 90 capsules (NDC 62135-563-90) The 100 mg capsule is a hard-shell, gelatin capsule with a light green opaque cap and a white opaque body. The capsules are imprinted with “CE” in black ink on the cap and “72” on the body. They are available as follows: Bottles of 90 capsules (NDC 62135-564-90) 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. Manufactured for Chartwell RX, LLC Congers, NY 10920 L70893 Revised 11/2022 Print Medication Guide at: www.chartwellpharma.com/medguides

Suicidality and Antidepressant Drugs Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of doxepin or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. 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 in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Doxepin is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk , PRECAUTIONS: Information for Patients and PRECAUTIONS: Pediatric Use .)

PRECAUTIONS