Silenor 6 MG Oral Tablet
Generic Name: DOXEPIN HYDROCHLORIDE
Brand Name: Silenor
- Substance Name(s):
- DOXEPIN HYDROCHLORIDE
DRUG INTERACTIONS
7.
MAO inhibitors: Silenor should not be administered in patients on MAOIs within the past two weeks.
(4.2) Cimetidine: Increases exposure to doxepin.
(7.2) Alcohol: Sedative effects may be increased with doxepin.
(7.3, 5.4) CNS Depressants and Sedating Antihistamines: Sedative effects may be increased with doxepin.
(7.4, 5.4) Tolazamide: A case of severe hypoglycemia has been reported.
(7.5) 7.1.
Cytochrome P450 Isozymes Silenor is primarily metabolized by hepatic cytochrome P450 isozymes CYP2C19 and CYP2D6, and to a lesser extent, by CYP1A2 and CYP2C9.
Inhibitors of these isozymes may increase the exposure of doxepin.
Silenor is not an inhibitor of any CYP isozymes at therapeutically relevant concentrations.
The ability of Silenor to induce CYP isozymes is not known.
7.2.
Cimetidine Silenor exposure is doubled with concomitant administration of cimetidine, a nonspecific inhibitor of CYP isozymes.
A maximum dose of 3 mg is recommended in adults and elderly when cimetidine is co-administered with Silenor [see Clinical Pharmacology (12.4)] 7.3.
Alcohol When taken with Silenor, the sedative effects of alcohol may be potentiated [see Warnings and Precautions (5.2, 5.4) ].
7.4.
CNS Depressants and Sedating Antihistamines When taken with Silenor, the sedative effects of sedating antihistamines and CNS depressants may be potentiated [see Warnings and Precautions (5.2, 5.4) ].
7.5.
Tolazamide A case of severe hypoglycemia has been reported in a type II diabetic patient maintained on tolazamide (1 g/day) 11 days after the addition of oral doxepin (75 mg/day).
OVERDOSAGE
10.
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 for the treatment of insomnia are described [see Overdosage (10.1)], as are signs and symptoms associated with higher multiples of the maximum recommended dose (Critical overdose) [see Overdosage (10.2)].
10.1.
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).
10.2.
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.
10.3.
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.
Gastrointestinal Decontamination 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.
Cardiovascular 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.
Central Nervous System 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.
Psychiatric Follow-up Since overdose often is 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 overdoses are similar.
It is strongly recommended that the physician contact the local poison control center for specific pediatric treatment.
DESCRIPTION
11.
Silenor (doxepin) is available in 3 mg and 6 mg strength tablets for oral administration.
Each tablet contains 3.39 mg or 6.78 mg doxepin hydrochloride, equivalent to 3 mg and 6mg of doxepin, respectively.
Chemically, doxepin hydrochloride is an (E) and (Z) geometric, isomeric mixture of 1 propanamine, 3-dibenz[b,e]oxepin-11(6H)ylidene-N,N-dimethyl-hydrochloride.
It has the following structure: Doxepin hydrochloride is a white crystalline powder, with a slight amine-like odor, that is readily soluble in water.
It has a molecular weight of 315.84 and molecular formula of C19 H21 NO•HCl.
Each Silenor tablet includes the following inactive ingredients: microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.
The 3 mg tablet also contains FD&C Blue No.1.
The 6 mg tablet also contains D&C Yellow No.
10 and FD&C Blue No.
1.
Chemical Structure
CLINICAL STUDIES
14.
14.1.
Controlled Clinical Trials The efficacy of Silenor 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 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 Adults A randomized, double-blind, parallel-group study was conducted in adults (N = 221) with chronic insomnia.
Silenor 3 mg and 6 mg was compared to placebo out to 30 days.
Silenor 3 mg and 6 mg were superior to placebo on objective WASO.
Silenor 3 mg was superior to placebo on subjective WASO at night 1 only.
Silenor 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 Elderly subjects with chronic insomnia were assessed in two parallel-group studies.
The first randomized, double-blind study assessed Silenor 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 3 mg was superior to placebo on objective WASO.
The second randomized, double-blind study assessed Silenor 6 mg relative to placebo for 4 weeks in an outpatient setting in elderly subjects (N=254) with chronic insomnia.
On subjective WASO, Silenor 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 6 mg relative to placebo.
Silenor 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 3 mg, or Silenor 6 mg.
There was no indication of a withdrawal syndrome after discontinuation of Silenor 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, 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 3 mg and 6 mg showed no evidence of rebound insomnia.
HOW SUPPLIED
16.
/STORAGE AND HANDLING 16.1.
How Supplied Silenor 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 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 16.2.
Storage and Handling Store at controlled room temperature 20° – 25°C (68° – 77°F), protected from light.
GERIATRIC USE
8.5.
Geriatric Use A total of 362 subjects who were ≥ 65 years and 86 subjects who were ≥ 75 years received Silenor in controlled clinical studies.
No overall differences in safety or effectiveness were observed between these subjects and younger adult subjects.
Greater sensitivity of some older individuals cannot be ruled out.
Sleep-promoting drugs may cause confusion and over-sedation in the elderly.
A starting dose of 3 mg is recommended in this population and evaluation prior to considering dose escalation is recommended [see Dosage and Administration (2.2)].
DOSAGE FORMS AND STRENGTHS
3.
Silenor 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 tablets are not scored.
3 mg and 6 mg tablets.
Tablets not scored.
(3)
MECHANISM OF ACTION
12.1.
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.
INDICATIONS AND USAGE
1.
Silenor is indicated for the treatment of insomnia characterized by difficulty with sleep maintenance.
The clinical trials performed in support of efficacy were up to 3 months in duration [see Clinical Studies (14) ].
Silenor (doxepin) tablets are indicated for the treatment of insomnia characterized by difficulties with sleep maintenance.
(1, 14)
PEDIATRIC USE
8.4.
Pediatric Use The safety and effectiveness of Silenor in pediatric patients have not been evaluated.
PREGNANCY
8.1.
Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Silenor in pregnant women.
Silenor should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of doxepin to pregnant animals resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 6 mg/day.
When doxepin (30, 100 and 150 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, developmental toxicity (increased incidences of fetal structural abnormalities and decreased fetal body weights) was noted at ≥100 mg/kg/day.
The plasma exposures (AUC) at the no-effect dose for embryo-fetal developmental toxicity in rats (30 mg/kg/day) are approximately 6 and 3 times the plasma AUCs for doxepin and nordoxepin (the primary metabolite in humans), respectively, at the MRHD.
When administered orally to pregnant rabbits (10, 30 and 60 mg/kg/day) during the period of organogenesis, fetal body weights were reduced at the highest dose in the absence of maternal toxicity.
The plasma exposures (AUC) at the no-effect dose for developmental effects (30 mg/kg/day) are approximately 6 and 18 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD.
Oral administration of doxepin (10, 30 and 100 mg/kg/day) to rats throughout the pregnancy and lactation periods resulted in decreased pup survival and transient growth delay at the highest dose.
The plasma exposures (AUC) at the no-effect dose for adverse effects on pre- and postnatal development in rats (30 mg/kg/day) are approximately 3 and 2 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD.
NUSRING MOTHERS
8.3.
Nursing Mothers Doxepin is excreted in human milk after oral administration.
There has been a report of apnea and drowsiness occurring in a nursing infant whose mother was taking the higher dose of doxepin used to treat depression.
Caution should be exercised when Silenor is administered to nursing women.
WARNING AND CAUTIONS
5.
WARNINGS AND PRECAUTIONS Need to Evaluate for Co-morbid Diagnoses: Reevaluate if insomnia persists after 7 to 10 days of use.
(5.1) Abnormal thinking, behavioral changes, complex behaviors: May include “Sleep-driving” and hallucinations.
Immediately evaluate any new onset behavioral changes.
(5.2) Depression: Worsening of depression or suicidal thinking may occur.
Prescribe the least amount feasible to avoid intentional overdose.
(5.3) CNS-depressant effects: Use can impair alertness and motor coordination.
Avoid engaging in hazardous activities such as operating a motor vehicle or heavy machinery after taking drug.
(5.4) Do not use with alcohol.
(5.4, 7.3) Potential additive effects when used in combination with CNS depressants or sedating antihistamines.
Dose reduction may be needed.
(5.4, 7.4) Patients with severe sleep apnea: Silenor is ordinarily not recommended for use in this population.
(8.7) 5.1.
Need to Evaluate for Comorbid Diagnoses Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient.
The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated.
Exacerbation of insomnia or the emergence of new cognitive or behavioral abnormalities may be the consequence of an unrecognized psychiatric or physical disorder.
Such findings have emerged during the course of treatment with hypnotic drugs.
5.2.
Abnormal Thinking and Behavioral Changes Complex behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a hypnotic, with amnesia for the event) have been reported with hypnotics.
These events can occur in hypnotic-naive as well as in hypnotic-experienced persons.
Although behaviors such as “sleep-driving” may occur with hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with hypnotics appears to increase the risk of such behaviors, as does the use of hypnotics at doses exceeding the maximum recommended dose.
Due to the risk to the patient and the community, discontinuation of Silenor should be strongly considered for patients who report a “sleep-driving” episode.
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic.
As with “sleep-driving”, patients usually do not remember these events.
Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.
5.3.
Suicide Risk and Worsening of Depression In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of hypnotics.
Doxepin, the active ingredient in Silenor, is an antidepressant at doses 10- to 100-fold higher than in Silenor.
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.
Risk from the lower dose of doxepin in Silenor can not be excluded.
It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder.
Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.
5.4.
CNS Depressant Effects After taking Silenor, patients should confine their activities to those necessary to prepare for bed.
Patients should avoid engaging in hazardous activities, such as operating a motor vehicle or heavy machinery, at night after taking Silenor, and should be cautioned about potential impairment in the performance of such activities that may occur the day following ingestion.
When taken with Silenor, the sedative effects of alcoholic beverages, sedating antihistamines, and other CNS depressants may be potentiated [see Warnings and Precautions (5.2) and Drug Interactions (7.3, 7.4) ].
Patients should not consume alcohol with Silenor [see Warnings and Precautions (5.2) and Drug Interactions (7.3) ].
Patients should be cautioned about potential additive effects of Silenor used in combination with CNS depressants or sedating antihistamines [see Warnings and Precautions (5.2) and Drug Interactions (7.4) ].
INFORMATION FOR PATIENTS
17.
PATIENT COUNSELING INFORMATION Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with hypnotics, should counsel them in appropriate use, and should instruct them to read the accompanying Medication Guide [see Medication Guide (17.4) ].
17.1.
Sleep-driving and Other Complex Behaviors There have been reports of people getting out of bed after taking a hypnotic and driving their cars while not fully awake, often with no memory of the event.
If a patient experiences such an episode, it should be reported to his or her doctor immediately, since “sleep-driving” can be dangerous.
This behavior is more likely to occur when a hypnotic is taken with alcohol or other central nervous system depressants [see Warnings and Precautions (5.2, 5.4) and Drug Interactions (7.3, 7.4) ].
Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a hypnotic.
As with “sleep-driving”, patients usually do not remember these events.
In addition, patients should be advised to report all concomitant medications to the prescriber.
Patients should be instructed to report events such as “sleep-driving” and other complex behaviors immediately to the prescriber.
17.2.
Suicide risk and Worsening of Depression: Patients, their families, and their caregivers should be encouraged to be alert to worsening of depression, including suicidal thoughts and actions.
Such symptoms should be reported to the patient’s prescriber or health professional.
17.3.
Administration Instructions Patients should be counseled to take Silenor within 30 minutes of bedtime and should confine their activities to those necessary to prepare for bed.
Silenor tablets should not be taken with or immediately after a meal [see Dosage and Administration (2.3) ].
Advise patients NOT to take Silenor when drinking alcohol [see Warnings and Precautions (5.2, 5.4) and Drug Interactions (7.3) ].
17.4.
Medication Guide
DOSAGE AND ADMINISTRATION
2.
The dose of Silenor should be individualized.
Initial dose: 6 mg, once daily for adults (2.1) and 3 mg, once daily for the elderly.
(2.1, 2.2) Take within 30 minutes of bedtime.
Total daily dose should not exceed 6 mg.
(2.3) Should not be taken within 3 hours of a meal.
(2.3, 12.3) 2.1.
Dosing in Adults The recommended dose of Silenor for adults is 6 mg once daily.
A 3 mg once daily dose may be appropriate for some patients, if clinically indicated.
2.2.
Dosing in the Elderly The recommended starting dose of Silenor in elderly patients (≥ 65 years old) is 3 mg once daily.
The daily dose can be increased to 6 mg, if clinically indicated.
2.3.
Administration Silenor should be taken within 30 minutes of bedtime.
To minimize the potential for next day effects, Silenor should not be taken within 3 hours of a meal [see Clinical Pharmacology (12.3) ].
The total Silenor dose should not exceed 6 mg per day.