DOXEPIN HYDROCHLORIDE Prescribing Information
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 Hydrochloride 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 antidepressants 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 Hydrochloride is not approved for use in pediatric patients. (See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information for Patients, and PRECAUTIONS: Pediatric Use).
Doxepin Hydrochloride is recommended for the treatment of:
- Psychoneurotic patients with depression and/or anxiety.
- Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol).
- Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly).
- Psychotic depressive disorders with associated anxiety including involutional depression and manic-depressive disorders.
The target symptoms of psychoneurosis that respond particularly well to doxepin hydrochloride include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry.
Clinical experience has shown that doxepin hydrochloride is safe and well tolerated even in the elderly patient. Owing to lack of clinical experience in the pediatric population, doxepin hydrochloride is not recommended for use in children under 12 years of age.
For most patients with illness of mild to moderate severity, a starting daily dose of 75 mg is recommended. Dosage may subsequently be increased or decreased at appropriate intervals and according to individual response. The usual optimum dose range is 75 mg/day to 150 mg/day.
In more severely ill patients higher doses may be required with subsequent gradual increase to 300 mg/day if necessary. Additional therapeutic effect is rarely to be obtained by exceeding a dose of 300 mg/day.
In patients with very mild symptomatology or emotional symptoms accompanying organic disease, lower doses may suffice. Some of these patients have been controlled on doses as low as 25–50 mg/day.
The total daily dosage of doxepin HCl 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.
Doxepin Hydrochloride is contraindicated in individuals who have shown hypersensitivity to the drug. Possibility of cross sensitivity with other dibenzoxepines should be kept in mind.
Doxepin Hydrochloride is contraindicated in patients with glaucoma or a tendency to urinary retention. These disorders should be ruled out, particularly in older patients.
NOTE:
Some of the adverse reactions noted below have not been specifically reported with doxepin HCl use. However, due to the close pharmacological similarities among the tricyclics, the reactions should be considered when prescribing Doxepin Hydrochloride
Anticholinergic Effects
Dry mouth, blurred vision, constipation, and urinary retention have been reported. If they do not subside with continued therapy, or become severe, it may be necessary to reduce the dosage.
Central Nervous System Effects
Drowsiness is the most commonly noticed side effect. This tends to disappear as therapy is continued. Other infrequently reported CNS side effects are confusion, disorientation, hallucinations, numbness, paresthesias, ataxia, extrapyramidal symptoms, seizures, tardive dyskinesia, and tremor.
Cardiovascular
Cardiovascular effects including hypotension, hypertension, and tachycardia have been reported occasionally.
Allergic
Skin rash, edema, photosensitization, and pruritus have occasionally occurred.
Hematologic
Eosinophilia has been reported in a few patients. There have been occasional reports of bone marrow depression manifesting as agranulocytosis, leukopenia, thrombocytopenia, and purpura.
Gastrointestinal
Nausea, vomiting, indigestion, taste disturbances, diarrhea, anorexia, and aphthous stomatitis have been reported. (See Anticholinergic Effects.)
Endocrine
Raised or lowered libido, testicular swelling, gynecomastia in males, enlargement of breasts and galactorrhea in the female, raising or lowering of blood sugar levels, and syndrome of inappropriate antidiuretic hormone secretion have been reported with tricyclic administration.
Other
Dizziness, tinnitus, weight gain, sweating, chills, fatigue, weakness, flushing, jaundice, alopecia, headache, exacerbation of asthma, angle closure glaucoma, mydriasis and hyperpyrexia (in association with chlorpromazine) have been occasionally observed as adverse effects.
Withdrawal Symptoms
The possibility of development of withdrawal symptoms upon abrupt cessation of treatment after prolonged doxepin HCl administration should be borne in mind. These are not indicative of addiction and gradual withdrawal of medication should not cause these symptoms.
Doxepin Hydrochloride, USP is one of a class of psychotherapeutic agents known as dibenzoxepin tricyclic compounds. The molecular formula of the compound is C19H21NO•HCl having a molecular weight of 315.8. It is a white or almost white crystalline powder freely soluble in Water, Ethyl Alcohol (96%) and Dichlormethane.
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 (6H)ylidene-N,N-dimethylhydrochloride.
Each 150 mg Doxepin capsule, USP for oral administration contains Doxepin Hydrochloride, USP equivalent to 150 mg of doxepin, the following inactive ingredients: Corn Starch, Dehydrate Alcohol, Dibasic Calcium Phosphate Dihydrate, Magnesium Stearate, Sodium Lauryl Sulfate.The empty gelatin capsule shells contain FD&C Blue No. 1, gelatin and titanium dioxide.
The imprinting ink contains Black iron oxide, Butyl Alcohol, Dehydrated Alcohol, Isopropyl Alcohol, Potassium Hydroxide, Propylene Glycol, Purified Water, Shellac and Strong Ammonia Solution.
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, anti-serotonin 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 Hydrochloride 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 Hydrochloride is 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.
Doxepin Hydrochloride Capsules, USP is available as capsules containing doxepin Hydrochloride equivalent to:
The 150 mg capsule is a Hard Gelatin Capsule Shell with Opaque Light Blue cap imprinted in black with LP 163 and opaque white body imprinted in black with LP 163. They are available as follows:
NDC 69315-163-50
bottles of 50 capsules
NDC 69315-163-01
bottles of 100 capsules
NDC 69315-163-05
bottles of 500 capsules
Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]
Protect from light.
Dispense in a tight, light-resistant container as defined in the USP using a well-closed closure.
PHARMACIST: Dispense the accompanying Medication Guide to each patient.
Rx only,
Manufactured by:
LIFEPharma FZE
Near Round-About 13,
Plot No MO0502,
Dubai, P.O. Box 17404,
United Arab Emirates (ARE).
Distributed by:
Leading Pharma, LLC
Fairfield, NJ 07004
Rev. 03 12/21
Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short- term trials of 9 antidepressant drugs in over 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 |
18-24 | 5 additional cases |
Decreases Compared to Placebo | |
25-64 | 1 fewer case |
≥65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient's presenting symptoms.
Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about, the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for doxepin hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Screening Patients for Bipolar Disorder: A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that 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.
Usage in Geriatrics
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).
Usage in Pregnancy
Reproduction studies have been performed in rats, rabbits, monkeys and dogs and there was no evidence of harm to the animal fetus. The relevance to humans is not known. Since there is no experience in pregnant women who have received this drug, safety in pregnancy has not been established. There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking doxepin hydrochloride.
Usage in Children
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.