Doxepin

SINEQUAN® (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 316. It is a white crystalline solid readily soluble in water, lower alcohols and chloroform.

Inert ingredients for the capsule formulations are: hard gelatin capsules (which may contain Blue 1, Red 3, Red 40, Yellow 10, and other inert ingredients); magnesium stearate; sodium lauryl sulfate; starch.

Inert ingredients for the oral concentrate formulation are: glycerin; methylparaben; peppermint oil; propylparaben; water.

Chemistry

SINEQUAN (doxepin HCl) 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.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

Doxepin Capsule and Doxepin Oral Solution:

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 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 hydrochloride is not approved for use in pediatric patients.

Controlled Clinical Trials

Systemic Adverse Effects: In controlled clinical trials of patients treated with Doxepin HCl Cream 5%, the most common systemic adverse effect reported was drowsiness. Drowsiness occurred in 22% of patients treated with Doxepin HCl Cream 5% (and 2% of patients treated with placebo cream) and resulted in the premature discontinuation of the drug in approximately 5% of patients treated.

Other systemic adverse effects reported in approximately 1 to 10% of these patients included: Dry mouth, dry lips, thirst, headache, fatigue, dizziness, emotional changes, and taste changes.

Other systemic adverse effects reported in less than 1% of these patients included: Nausea, anxiety and fever.

Local Site Adverse Effects: In controlled clinical trials of patients treated with Doxepin HCl Cream 5%, the most common local site adverse effect reported was burning and/or stinging at the site of application. These occurred in approximately 21% of these patients. Most of these reactions were categorized as "mild"; however, approximately 25% of patients who reported burning and/or stinging reported the reaction as "severe". Four patients treated with Doxepin HCl Cream 5% withdrew from the study because of the burning and/or stinging.

Other local site adverse effects reported in approximately 1 to 10% of these patients included: Pruritus exacerbation, eczema exacerbation, dryness and tightness to skin, paresthesias, and edema.

Other local site adverse effects reported in less than 1% of these patients included: Irritation, tingling, scaling, and cracking.

Post Marketing Experience

Some cases of allergic contact dermatitis have been reported in patients using Doxepin HCl 5% cream.

Read the entire FDA prescribing information for Prudoxin (Doxepin)

Doxepin is a tricyclic antidepressants. Doxepin affects chemicals in the brain that may become unbalanced.

Doxepin (Sinequan or other generic name) is used to treat symptoms of depression and/or anxiety associated with alcoholism, psychiatric conditions, or manic-depressive conditions.

Doxepin may also be used for purposes not listed in this medication guide.

You should not take doxepin if you have glaucoma or problems with urination. Do not use if you are allergic to doxepin or to similar medications such as amitriptyline, amoxapine, clomipramine, desipramine, imipramine, nortriptyline, protriptyline, or trimipramine.

Do not use doxepin if you have taken an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include furazolidone, isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Abdominal or stomach pain
• agitation
• black, tarry stools
• bleeding gums
• blood in the urine or stools
• blurred vision
• burning, crawling, itching, numbness, prickling, "pins and needles", or tingling feelings
• canker sores
• chest pain
• chills
• clay-colored stools
• cold sweats
• confusion about identity, place, and time
• convulsions
• cool, pale skin
• cough or hoarseness
• dark urine
• decrease in the frequency of urination
• decrease in urine volume
• decreased urine output
• depression
• difficulty in passing urine (dribbling)
• difficulty with breathing
• difficulty with speaking
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• drooling
• dry mouth
• fast, pounding, or irregular heartbeat or pulse
• feeling of warmth
• fever
• flushed, dry skin
• fruit-like breath odor
• general feeling of tiredness or weakness
• headache
• hearing loss
• hostility
• increased hunger
• increased thirst
• increased urination
• irritability
• itching or rash
• lethargy
• lip smacking or puckering
• loss of appetite
• loss of balance control
• loss of bladder control
• lower back or side pain
• mood or mental changes
• muscle spasm or jerking of all extremities
• muscle trembling, jerking, or stiffness
• muscle twitching
• nausea
• nervousness
• nightmares
• noisy breathing
• painful or difficult urination
• pinpoint red spots on the skin
• pounding in the ears
• puffing of the cheeks
• rapid or worm-like movements of the tongue
• rapid weight gain
• redness of the face, neck, arms, and occasionally, upper chest
• restlessness
• ringing or buzzing or other unexplained noise in the ears that continues
• seeing, hearing, or feeling things that are not there
• seizures
• shakiness and unsteady walk
• shakiness in the legs, arms, hands, or feet
• shuffling walk
• sore throat
• sores, ulcers, or white spots on the lips, tongue, or in the mouth
• slurred speech
• stiffness of the limbs
• stupor
• sudden loss of consciousness
• sweating
• swelling of the face, ankles, or hands
• swollen glands
• tightness in the chest
• troubled breathing
• twisting movements of the body
• uncontrolled chewing movements
• uncontrolled movements, especially of the arms, face, legs, neck, and back
• unexplained weight loss
• unpleasant breath odor
• unsteadiness, trembling, or other problems with muscle control or coordination
• unusual bleeding or bruising
• unusual tiredness or weakness
• vomiting of blood
• yellow eyes or skin

Get emergency help immediately if any of the following symptoms of overdose occur:

• Clumsiness
• disturbed concentration
• drowsiness
• enlarged pupils
• increased or excessive unconscious or jerking movements
• low body temperature
• muscle aches
• muscle weakness
• shivering
• sleepiness
• weak or feeble pulse
• weight gain

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Change in taste or bad, unusual or unpleasant (after) taste
• decreased interest in sexual intercourse
• diarrhea
• difficulty having a bowel movement (stool)
• enlargement of the breasts
• gas in the stomach
• hair loss or thinning of the hair
• heartburn
• inability to have or keep an erection
• increased in sexual ability, desire, drive, or performance
• increased interest in sexual intercourse
• increased sensitivity of the skin to sunlight
• loss in sexual ability, desire, drive, or performance
• redness or other discoloration of the skin
• severe sunburn
• swelling of the breasts or breast soreness in both females and males
• swelling of the testicles
• unexpected or excess milk flow from breasts
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

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.

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 GlaucomaThe 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.

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.

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.

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 overdose of Doxepin.

General Recommendations:
General: Obtain an ECG and immediately initiate cardiac monitoring. Protect the patient's airway, establish an intravenous line and initiate gastric decontamination. A minimum of six 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: A 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. A pH > 7.60 or a pCO2 <20 mm Hg is undesirable. Dysrhythmias unresponsive to sodium bicarbonate therapy/hyperventilation may respond to lidocaine, bretylium or phenytoin. Type lA 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 a 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.

Consult your pharmacist.

In the US -

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088 or at www.fda.gov/medwatch.

In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345.

If someone has overdosed and has serious symptoms such as passing out or trouble breathing, call 911. Otherwise, call a poison control center right away. US residents can call their local poison control center at 1-800-222-1222. Canada residents can call a provincial poison control center.

Notes

Missed Dose

Consult your pharmacist.

Storage

Consult your pharmacist.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2016. Copyright(c) 2016 First Databank, Inc.