Doxepin Hydrochloride

Doxepin is recommended for the treatment of:

1. Psychoneurotic patients with depression and/or anxiety.

2. Depression and/or anxiety associated with alcoholism (not to be taken concomitantly with alcohol).

3. Depression and/or anxiety associated with organic disease (the possibility of drug interaction should be considered if the patient is receiving other drugs concomitantly).

4. 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 pediatric patients 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 to 50 mg/day.

The total daily dosage of doxepin 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. Anti-anxiety effect is apparent before the antidepressant effect. Optimal antidepressant effect may not be evident for two to three weeks.

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.

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, 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: Drugs Metabolized by P450 2D6: The biochemical activity of the drug metabolizing isozyme cytochrome P450 2D6 (debrisoquin hydroxylase) is reduced in a subset of the Caucasian population (about 7-10% 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 a 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 a patient being withdrawn from fluoxetine, given the long half-life of the parent and active metabolite (at least 5 weeks may be necessary).

Concomitant use of tricyclic antidepressants with drugs that can inhibit cytochrome P450 2D6 may require lower doses than usually prescribed for either the tricyclic antidepressant or the other drug. Furthermore, whenever one of these other drugs is withdrawn from co-therapy, an increased dose of tricyclic antidepressant may be required. It is desirable to monitor TCA plasma levels whenever a TCA is going to be coadministered with another drug known to be an inhibitor of P450 2D6.

Doxepin is primarily metabolized by CYP2D6 (withCYP1A2 & CYP3A4 as minor pathways) inhibitors or substrates ofCYP2D6 (i.e., quinidine, selective serotonin reuptake inhibitors[SSRIs]) may increase the plasma concentration of doxepin whenadministered concomitantly. The extent of interaction depends on thevariability of effect on CYP2D6. The clinical significance of thisinteraction with doxepin has not been systematically evaluated.

MAOInhibitors: Serious side effects and even death have been reportedfollowing the concomitant use of certain drugs with MAO inhibitors.Therefore, MAO inhibitors should be discontinued at least two weeksprior to the cautious initiation of therapy with doxepin. The exactlength of time may vary and is dependent upon the particular MAOinhibitor being used, the length of time it has been administered, andthe dosage involved.

Cimetidine:Cimetidine has been reported to produce clinically significantfluctuations in steady-state serum concentrations of various tricyclicantidepressants. Serious anticholinergic symptoms (i.e., severe drymouth, urinary retention and blurred vision) have been associated withelevations in the serum levels of tricyclic antidepressant whencimetidine therapy is initiated. Additionally, higher than expectedtricyclic antidepressant levels have been observed when they are begunin patients already taking cimetidine. In patients who have beenreported to be well controlled on tricyclic antidepressants receivingconcurrent cimetidine therapy, discontinuation of cimetidine has beenreported to decrease established steady-state serum tricyclicantidepressant levels and compromise their therapeutic effects.

Alcohol:It should be borne in mind that alcohol ingestion may increase thedanger inherent in any intentional or unintentional doxepin overdosage.This is especially important in patients who may use alcoholexcessively.

Tolazamide:A case of severe hypoglycemia has been reported in a type II diabeticpatient maintained on tolazamide (1 gm/day) 11 days after the additionof doxepin (75 mg/day).

Drowsiness:Since drowsiness may occur with the use of this drug, patients shouldbe warned of the possibility and cautioned against driving a car oroperating dangerous machinery while taking the drug. Patients shouldalso be cautioned that their response to alcohol may be potentiated.

Sedatingdrugs may cause confusion and over sedation in the elderly; elderlypatients generally should be started on low doses of doxepin andobserved closely (see PRECAUTIONS - Geriatric Use).

Suicide: Since suicide is an inherent risk in any depressed patient and mayremain so until significant improvement has occurred, patients shouldbe closely supervised during the early course of therapy. Prescriptionsshould be written for the smallest feasible amount.

Psychosis:Should increased symptoms of psychosis or shift to manic symptomatologyoccur, it may be necessary to reduce dosage or add a major tranquilizerto the dosage regimen.

Doxepin hydrochloride 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 315.84. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform.

Doxepin hydrochloride oral solution is available as a concentrate for oral administration containing doxepin hydrochloride equivalent to 10 mg of doxepin per mL. It also contains the following inactive ingredients: glycerin; methylparaben; peppermint flavor; propylparaben; water. May contain hydrochloric acid and/or sodium hydroxide.

Doxepin hydrochloride 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-dimethyl-, hydrochloride.

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.

Doxepin Hydrochloride Oral Solution USP (Concentrate) is available in 120 mL bottles (NDC 54838-512-40) with an accompanying dropper calibrated at 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg. Each mL contains doxepin hydrochloride equivalent to 10 mg doxepin. Immediately prior to taking thismedication, dilute each dose with approximately 120 mL (4 ounces) of water, whole or skimmed milk, or orange, grapefruit, tomato, prune or pineapple juice. Doxepin Hydrochloride Oral Solution USP (Concentrate) is not physically compatible with a number of carbonated beverages. For those patients requiring antidepressant therapy who are on methadone maintenance, Doxepin Hydrochloride Oral Solution USP (Concentrate) and methadone syrup can be mixed together with Gatorade®, lemonade, orange juice, sugar water, Tang® or water, but not with grape juice. Preparation and storage of bulk dilutions is not recommended.

Recommended Storage

Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature].

Distributed by:

Lannett Company, Inc.

Philadelphia, PA 19136

10-1104

Rev. 03/20

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 4400 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 1000 patients treated) are provided in Table 1.

Table 1

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 Oral Solution should be written for the smallest quantity 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 Oral Solution 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 Oral Solution 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 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.

Usage in Pediatric Patients: The use of doxepin hydrochloride oral solution in children under 12 years of age is not recommended because safe conditions for its use have not been established.