Doxepin Tablets

Dosage Forms And Strengths

Silenor (doxepin tablets) is an immediate-release, oval-shaped, tablet for oral administration available in strengths of 3 mg and 6 mg. The tablets are blue (3 mg) or green (6 mg) and are debossed with 3 or 6, respectively, on one side and SP on the other. Silenor (doxepin tablets) tablets are not scored.

Silenor (doxepin tablets) 3 mg tablets are oval shaped, blue, identified with debossed markings of “3” on one side and “SP” on the other, and are supplied as:

NDC 42847-103-30..................Bottle of 30
NDC 42847-103-10..................Bottle of 100
NDC 42847-103-50..................Bottle of 500
NDC 42847-103-03..................Blister trade pack of 30

Silenor (doxepin tablets) 6 mg tablets are oval shaped, green, identified with debossed markings of “6” on one side and “SP” on the other, and are supplied as:

NDC 42847-106-30..................Bottle of 30
NDC 42847-106-10..................Bottle of 100
NDC 42847-106-50..................Bottle of 500
NDC 42847-106-03..................Blister trade pack of 30

Storage and Handling

Store at controlled room temperature 20° - 25°C (68° - 77°F), protected from light.

Manufactured for: Somaxon Pharmaceuticals, Inc. San Diego, CA 92130 USA.

Doxepin is routinely administered for indications other than insomnia at doses 10- to 50-fold higher than the highest recommended dose of Silenor.

The signs and symptoms associated with doxepin use at doses several-fold higher than the maximum recommended dose (Excessive dose) of Silenor (doxepin tablets) for the treatment of insomnia are described, as are signs and symptoms associated with higher multiples of the maximum recommended dose (Critical overdose).

Signs and Symptoms of Excessive Doses

The following adverse effects have been associated with use of doxepin at doses higher than 6 mg.

Anticholinergic Effects: constipation and urinary retention.

Central Nervous System: disorientation, hallucinations, numbness, paresthesias, extrapyramidal symptoms, seizures, tardive dyskinesia.

Cardiovascular: hypotension.

Gastrointestinal: aphthous stomatitis, indigestion.

Endocrine: raised 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.

Other: tinnitus, weight gain, sweating, flushing, jaundice, alopecia, exacerbation of asthma, and hyperpyrexia (in association with chlorpromazine).

Signs and Symptoms of Critical Overdose

Manifestations of doxepin critical overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression including coma. Electrocardiogram changes, particularly in QRS axis or width, are clinically significant indicators of tricyclic compound toxicity. Other signs of overdose may include, but are not limited to: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia.

Recommended Management

As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. In addition, the possibility of a multiple drug ingestion should be considered.

If an overdose is suspected, an ECG should be obtained and cardiac monitoring should be initiated immediately. The patient's airway should be protected, an intravenous line should be established, and gastric decontamination should be initiated. 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.

All patients suspected of overdose should receive gastrointestinal decontamination. This should include large volume gastric lavage followed by administration of activated charcoal. If consciousness is impaired, the airway should be secured prior to lavage. Emesis is contraindicated.

A maximal limb-lead QRS duration of ≥ 0.10 seconds may be the best indication of the severity of an overdose. Serum alkalinization, using intravenous sodium bicarbonate should be used to maintain the serum pH in the range of 7.45 to 7.55 for patients with dysrhythmias and/or QRS widening. 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 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 treatment of tricyclic compound poisoning.

In patients with central nervous system 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 or 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.

Since overdose often is deliberate, patients may attempt suicide by other means during the recovery phase. Psychiatric referral may be appropriate.

The principles of management of child and adult overdoses are similar. It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.

Mechanism of Action

Doxepin binds with high affinity to the histamine H1 receptor (Ki < 1 nM) where it functions as an antagonist. The exact mechanism by which doxepin exerts its sleep maintenance effect is unknown but is believed due to its antagonism of the H1 receptor.

Pharmacodynamics

In a thorough QTc prolongation clinical study in healthy subjects, doxepin had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 50 mg.

Pharmacokinetics

The median time to peak concentrations (Tmax) of doxepin occurred at 3.5 hours postdose after oral administration of a 6 mg dose to fasted healthy subjects. Peak plasma concentrations (Cmax) of Silenor (doxepin tablets) increased in approximately a dose-proportional manner for 3 mg and 6 mg doses. The AUC was increased by 41% and Cmax by15% when 6 mg Silenor (doxepin tablets) was administered with a high fat meal. Additionally, compared to the fasted state, Tmax was delayed by approximately 3 hours. Therefore, for faster onset and to minimize the potential for next day effects, it is recommended that Silenor (doxepin tablets) not be taken within 3 hours of a meal [see DOSAGE AND ADMINISTRATION].

Silenor (doxepin tablets) is widely distributed throughout the body tissues. The mean apparent volume of distribution following a single 6 mg oral dose of Silenor (doxepin tablets) to healthy subjects was 11,930 liters. Silenor (doxepin tablets) is approximately 80% bound to plasma proteins.

Following oral administration, Silenor (doxepin tablets) is extensively metabolized by oxidation and demethylation. The primary metabolite is N-desmethyldoxepin (nordoxepin).

The primary metabolite undergoes further biotransformation to glucuronide conjugates.

In vitro studies have shown that CYP2C19 and CYP2D6 are the major enzymes involved in doxepin metabolism, and that CYP1A2 and CYP2C9 are involved to a lesser extent.

Doxepin appears not to have inhibitory effects on human CYP enzymes at therapeutic concentrations. The potential of doxepin to induce metabolizing enzymes is not known. Doxepin is not a Pgp substrate.

Doxepin is excreted in the urine mainly in the form of glucuronide conjugates.

Less than 3% of a doxepin dose is excreted in the urine as parent compound or nordoxepin. The apparent terminal half-life (t ½) of doxepin was 15.3 hours and for nordoxepin was 31 hours.

Drug Interactions

Since doxepin is metabolized by CYP2C19 and CYP2D6, inhibitors of these CYP isozymes may increase the exposure of doxepin.

The effect of cimetidine, a non-specific inhibitor of CYP1A2, 2C19, 2D6, and 3A4, on Silenor (doxepin tablets) plasma concentrations was evaluated in healthy subjects. When cimetidine 300 mg BID was co-administered with a single dose of Silenor (doxepin tablets) 6 mg, there was approximately a 2fold increase in Silenor (doxepin tablets) Cmax and AUC compared to Silenor given alone. A maximum dose of doxepin in adults and elderly should be 3 mg, when doxepin is co-administered with cimetidine.

The effect of sertraline HCl, a selective serotonin reuptake inhibitor, on doxepin plasma concentrations was evaluated in a daytime study conducted with 24 healthy subjects. Following co-administration of doxepin 6 mg with sertraline 50 mg (at steady-state), the doxepin mean AUC and Cmax estimates were approximately 21% and 32% higher, respectively, than those obtained following administration of doxepin alone. Psychomotor function as measured by the digit symbol substitution test and symbol copy test performance was decreased more at 2-4 hours post dosing for the combination of sertraline and doxepin as compared to doxepin alone, but subjective measures of alertness were comparable for the two treatments.

Special Population:

The effects of renal impairment on doxepin pharmacokinetics have not been studied. Because only small amounts of doxepin and nordoxepin are eliminated in the urine, renal impairment would not be expected to result in significantly altered doxepin concentrations.

The effects of Silenor (doxepin tablets) in patients with hepatic impairment have not been studied. Because doxepin is extensively metabolized by hepatic enzymes, patients with hepatic impairment may display higher doxepin concentrations than healthy individuals.

Poor metabolizers of CYP2C19 and CYP2D6 may have higher doxepin plasma levels than normal subjects.

Clinical Studies

Controlled Clinical Trials

The efficacy of Silenor (doxepin tablets) for improving sleep maintenance was supported by six randomized, double-blind studies up to 3 months in duration that included 1,423 subjects, 18 to 93 years of age, with chronic (N=858) or transient (N=565) insomnia. Silenor (doxepin tablets) was evaluated at doses of 1 mg, 3 mg, and 6 mg relative to placebo in inpatient (sleep laboratory) and outpatient settings.

The primary efficacy measures for assessment of sleep maintenance were the objective and subjective time spent awake after sleep onset (respectively, objective Wake After Sleep Onset [WASO] and subjective WASO).

Subjects in studies of chronic insomnia were required to have at least a 3-month history of insomnia.

Chronic Insomnia

A randomized, double-blind, parallel-group study was conducted in adults (N = 221) with chronic insomnia. Silenor (doxepin tablets) 3 mg and 6 mg was compared to placebo out to 30 days.

Silenor (doxepin tablets) 3 mg and 6 mg were superior to placebo on objective WASO. Silenor (doxepin tablets) 3 mg was superior to placebo on subjective WASO at night 1 only. Silenor (doxepin tablets) 6 mg was superior to placebo on subjective WASO at night 1, and nominally superior at some later time points out to Day 30.

Elderly subjects with chronic insomnia were assessed in two parallel-group studies.

The first randomized, double-blind study assessed Silenor (doxepin tablets) 1 mg and 3 mg relative to placebo for 3 months in inpatient and outpatient settings in elderly subjects (N=240) with chronic insomnia. Silenor (doxepin tablets) 3 mg was superior to placebo on objective WASO.

The second randomized, double-blind study assessed Silenor (doxepin tablets) 6 mg relative to placebo for 4 weeks in an outpatient setting in elderly subjects (N=254) with chronic insomnia.

On subjective WASO, Silenor (doxepin tablets) 6 mg was superior to placebo.

Transient Insomnia

Healthy adult subjects (N=565) experiencing transient insomnia during the first night in a sleep laboratory were evaluated in a randomized, double-blind, parallel-group, single-dose study of Silenor (doxepin tablets) 6 mg relative to placebo. Silenor (doxepin tablets) 6 mg was superior to placebo on objective WASO and subjective WASO.

Withdrawal Effects

Potential withdrawal effects were assessed in a 35-day double blind study of adults with chronic insomnia who were randomized to placebo, Silenor (doxepin tablets) 3 mg, or Silenor (doxepin tablets) 6 mg. There was no indication of a withdrawal syndrome after discontinuation of Silenor (doxepin tablets) treatment (3 mg or 6 mg), as measured by the Tyrer's Symptom Checklist. Discontinuation-period emergent nausea and vomiting occurred in 5% of subjects treated with 6 mg Silenor (doxepin tablets) , versus 0% in 3 mg and placebo subjects.

Rebound Insomnia Effects

Rebound insomnia, defined as a worsening in WASO compared with baseline following discontinuation of treatment, was assessed in a double-blind, 35-day study in adults with chronic insomnia. Silenor (doxepin tablets) 3 mg and 6 mg showed no evidence of rebound insomnia.

Do not drink alcohol. Doxepin can increase the effects of alcohol, which could be dangerous.

Doxepin may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be alert.

Avoid taking Silenor within 3 hours after eating a meal.

Your pharmacist can provide more information about doxepin (Silenor).

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

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• If you have an allergy to doxepin or any other part of this medicine (doxepin tablets).
• If you are allergic to any drugs like this one, any other drugs, foods, or other substances. Tell your doctor about the allergy and what signs you had, like rash; hives; itching; shortness of breath; wheezing; cough; swelling of face, lips, tongue, or throat; or any other signs.
• If you have any of these health problems: Trouble passing urine or glaucoma.
• If you are taking any of these drugs: Linezolid or methylene blue.
• If you have taken certain drugs used for low mood (depression) like isocarboxazid, phenelzine, or tranylcypromine or drugs used for Parkinson's disease like selegiline or rasagiline in the last 14 days. Taking this medicine within 14 days of those drugs can cause very bad high blood pressure.
• If you do not have time to get a full night's sleep.
• If you have sleep apnea.

This is not a list of all drugs or health problems that interact with this medicine (doxepin tablets).

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this medicine with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

• Tell all of your health care providers that you take this medicine (doxepin tablets). This includes your doctors, nurses, pharmacists, and dentists.
• Avoid drinking alcohol while taking this medicine.
• Talk with your doctor before you use other drugs and natural products that slow your actions.
• Some people may have a higher chance of eye problems with this medicine (doxepin tablets). Your doctor may want you to have an eye exam to see if you have a higher chance of these eye problems. Call your doctor right away if you have eye pain, change in eyesight, or swelling or redness in or around the eye.
• This medicine may make you sunburn more easily. Use care if you will be in the sun. Tell your doctor if you sunburn easily while taking this drug.
• If you have high blood sugar (diabetes), you will need to watch your blood sugar closely.
• Tell your doctor if you have signs of high or low blood sugar like breath that smells like fruit, dizziness, fast breathing, fast heartbeat, feeling confused, feeling sleepy, feeling weak, flushing, headache, more thirsty or hungry, passing urine more often, shaking, or sweating.
• If you are 65 or older, use this medicine with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine (doxepin tablets) while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.
• Avoid driving and doing other tasks or actions that call for you to be alert after you take this medicine. You may still feel sleepy the day after you take this medicine (doxepin tablets). Avoid these tasks or actions until you feel fully awake.
• Use this medicine for short periods of time. If signs show up again, talk with the doctor.
• If you have been taking this medicine (doxepin tablets) for many weeks, talk with your doctor before stopping. You may want to slowly stop this medicine.
• Some people have done certain tasks or actions while they were not fully awake like driving, making and eating food, and having sex. Most of the time, people do not remember doing these things. Tell your doctor if this happens to you.

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.