Silenor

Silenor is a prescription medication used to treat adults who are having difficulty staying asleep.

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

• Pernix Therapeutics, LLC

After taking Silenor, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with Silenor. Reported activities include:

• driving a car ("sleep-driving")
• making and eating food
• talking on the phone
• having sex
• sleep-walking

Call your healthcare provider right away if you find out that you have done any of the above activities after taking Silenor.

1. Take Silenor exactly as prescribed
2. Do not take Silenor:

• with alcohol
• if you take other medicines that can make you sleepy. Talk to your healthcare provider about all of your medicines. Your healthcare provider will tell you if you can take Silenor with your other medicines

Do not take Silenor if you:

• take a monoamine oxidase inhibitor (MAOI) medicine or have taken an MAOI in the last 14 days (2 weeks). Ask your healthcare provider if you are not sure if your medicine is an MAOI.
• have an eye problem called narrow angle glaucoma that is not being treated
• have trouble urinating
• are allergic to any of the ingredients in Silenor

While taking Silenor, avoid the following:

• You should not drink alcohol while taking Silenor. Alcohol can increase your chances of getting serious side effects with Silenor.
• You should not drive, operate heavy machinery, or do other dangerous activities after taking Silenor.

What is the most important information I should know about this medication, depression, and other serious mental illnesses, and suicidal thoughts or actions?

1. This medication may increase suicidal thoughts or actions in some children, teenagers, and young adults within the first few months of treatment.
2. Depression and other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions. These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions.
3. How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?

• Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an this medication is started or when the dose is changed.
• Call the healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.
• Keep all follow-up visits with the healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

This medication falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The recommended starting dose is 6 mg, once daily for adults.

The recommended starting dose is 3 mg once daily for the elderly.

• It is used to treat sleep problems.
• It may be given to you for other reasons. Talk with the doctor.

. Hypersensitivity

Silenor is contraindicated in individuals who have shown hypersensitivity to doxepin HCl, any of its inactive ingredients, or other dibenzoxepines.

. Co-administration with Monoamine Oxidase Inhibitors (MAOIs)

Serious side effects and even death have been reported following the concomitant use of certain drugs with MAO inhibitors. Do not administer Silenor if patient is currently on MAOIs or has used MAOIs within the past two weeks. The exact length of time may vary depending on the particular MAOI dosage and duration of treatment.

. Glaucoma and Urinary Retention

Silenor is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention.

The following serious adverse reactions are discussed in greater detail in other sections of labeling:

• Abnormal thinking and behavioral changes [see Warnings and Precautions (5.2)].
• Suicide risk and worsening of depression [see Warnings and Precautions (5.3)].
• CNS Depressant effects [see Warnings and Precautions (5.4)].

. Clinical Trials Experience

The pre-marketing development program for Silenor included doxepin HCl exposures in 1017 subjects (580 insomnia patients and 437 healthy subjects) from 12 studies conducted in the United States. 863 of these subjects (580 insomnia patients and 283 healthy subjects) participated in six randomized, placebo-controlled efficacy studies with Silenor doses of 1 mg, 3 mg, and 6 mg for up to 3-months in duration.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. However, data from the Silenor studies provide the physician with a basis for estimating the relative contributions of drug and non-drug factors to adverse reaction incidence rates in the populations studied.

Associated with Discontinuation of Treatment

The percentage of subjects discontinuing Phase 1, 2, and 3 trials for an adverse reaction was 0.6% in the placebo group compared to 0.4%, 1.0%, and 0.7% in the Silenor 1 mg, 3 mg, and 6 mg groups, respectively. No reaction that resulted in discontinuation occurred at a rate greater than 0.5%.

Adverse Reactions Observed at an Incidence of ≥ 2% in Controlled Trials

Table 1 shows the incidence of treatment-emergent adverse reactions from three long-term (28 to 85 days) placebo-controlled studies of Silenor in adult (N=221) and elderly (N=494) subjects with chronic insomnia.

Reactions reported by Investigators were classified using a modified MedDRA dictionary of preferred terms for purposes of establishing incidence. The table includes only reactions that occurred in 2% or more of subjects who received Silenor 3 mg or 6 mg in which the incidence in subjects treated with Silenor was greater than the incidence in placebo-treated subjects.

The most common treatment-emergent adverse reaction in the placebo and each of the Silenor dose groups was somnolence/sedation.

. Studies Pertinent to Safety Concerns for Sleep-promoting Drugs

Residual Pharmacological Effect in Insomnia Trials

Five randomized, placebo-controlled studies in adults and the elderly assessed next-day psychomotor function within 1 hour of awakening utilizing the digit-symbol substitution test (DSST), symbol copying test (SCT), and visual analog scale (VAS) for sleepiness, following night time administration of Silenor.

In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, Silenor 6 mg showed modest negative changes in SCT and VAS.

In a 35-day, double-blind, placebo-controlled, parallel group study of Silenor 3 and 6 mg in 221 adults with chronic insomnia, small decreases in the DSST and SCT occurred in the 6 mg group.

In a 3-month, double-blind, placebo-controlled, parallel group study in 240 elderly subjects with chronic insomnia, Silenor 1 mg and 3 mg was comparable to placebo on DSST, SCT, and VAS.

. Other Reactions Observed During the Pre-marketing Evaluation of Silenor

Silenor was administered to 1017 subjects in clinical trials in the United States. Treatment-emergent adverse reactions recorded by clinical investigators were standardized using a modified MedDRA dictionary of preferred terms. The following is a list of MedDRA terms that reflect treatment-emergent adverse reactions reported by subjects treated with Silenor.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions: Frequent adverse reactions are those that occurred on one or more occasions in at least 1/100 subjects; Infrequent adverse reactions are those that occurred in fewer than 1/100 subjects and more than 1/1000 subjects. Rare adverse reactions are those that occurred in fewer than 1/1000 subjects. Adverse reactions that are listed in Table 1 are not included in the following listing of frequent, infrequent, and rare AEs.

Blood and Lymphatic System Disorders: Infrequent: anemia; Rare: thrombocythemia.

Cardiac Disorders: Rare: atrioventricular block, palpitations, tachycardia, ventricular extrasystoles.

Ear and Labyrinth Disorders: Rare: ear pain, hypoacusis, motion sickness, tinnitus, tympanic membrane perforation.

Eye Disorders: Infrequent: eye redness, vision blurred; Rare: blepharospasm, diplopia, eye pain, lacrimation decreased.

Gastrointestinal Disorders: Infrequent: abdominal pain, dry mouth, gastroesophageal reflux disease, vomiting; Rare: dyspepsia, constipation, gingival recession, haematochezia, lip blister.

General Disorders and Administration Site Conditions: Infrequent: asthenia, chest pain, fatigue; Rare: chills, gait abnormal, edema peripheral.

Hepatobiliary Disorders: Rare: hyperbilirubinemia.

Immune System Disorders: Rare: hypersensitivity.

Infections and Infestations: Infrequent: bronchitis, fungal infection, laryngitis, sinusitis, tooth infection, urinary tract infection, viral infection; Rare: cellulitis staphylococcal, eye infection, folliculitis, gastroenteritis viral, herpes zoster, infective tenosynovitis, influenza, lower respiratory tract infection, onychomycosis, pharyngitis, pneumonia.

Injury, Poisoning and Procedural Complications: Infrequent: back injury, fall, joint sprain; Rare: bone fracture, skin laceration.

Investigations: Infrequent: blood glucose increased; Rare: alanine aminotransferase increased, blood pressure decreased, blood pressure increased, electrocardiogram ST-T segment abnormal, electrocardiogram QRS complex abnormal, heart rate decreased, neutrophil count decreased, QRS axis abnormal, transaminases increased.

Metabolism and Nutrition Disorders: Infrequent: anorexia, decreased appetite, hyperkalemia, hypermagnesemia, increased appetite; Rare: hypokalemia.

Musculoskeletal and Connective Tissue Disorders: Infrequent: arthralgia, back pain, myalgia, neck pain, pain in extremity; Rare: joint range of motion decreased, muscle cramp, sensation of heaviness.

Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps): Rare: lung adenocarcinoma stage I, malignant melanoma.

Nervous System Disorders: Frequent: dizziness; Infrequent: dysgeusia, lethargy, parasthesia, syncope; Rare: ageusia, ataxia, cerebrovascular accident, disturbance in attention, migraine, sleep paralysis, syncope vasovagal, tremor.

Psychiatric Disorders: Infrequent: abnormal dreams, adjustment disorder, anxiety, depression; Rare: confusional state, elevated mood, insomnia, libido decreased, nightmare.

Reproductive System and Breast Disorders: Rare: breast cyst, dysmenorrhea.

Renal and Urinary Disorders: Rare: dysuria, enuresis, hemoglobinuria, nocturia.

Respiratory, Thoracic and Mediastinal Disorders: Infrequent: nasal congestion, pharyngolaryngeal pain, sinus congestion, wheezing; Rare: cough, crackles lung, nasopharyngeal disorder, rhinorrhea, dyspnea.

Skin and Subcutaneous Tissue Disorders: Infrequent: skin irritation; Rare: cold sweat, dermatitis, erythema, hyperhidrosis, pruritis, rash, rosacea.

Surgical and Medical Procedures: Rare: arthrodesis.

Vascular Disorders: Infrequent: pallor; Rare: blood pressure inadequately controlled, hematoma, hot flush.

In addition, the reactions below have been reported for other tricyclics and may be idiosyncratic (not related to dose).

Allergic: photosensitization, skin rash.

Hematologic: agranulocytosis, eosinophilia, leukopenia, purpura, thrombocytopenia.

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)].

. 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.

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.

You should not use Silenor if you are allergic to doxepin, or if you have:

• untreated narrow-angle glaucoma;

• severe problems with urination; or

• if you are allergic to antidepressants such as amitriptyline, amoxapine, clomipramine, desipramine, imipramine, nortriptyline, protriptyline, or trimipramine.

Do not use Silenor if you have used an MAO inhibitor in the past 14 days. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, methylene blue injection, phenelzine, rasagiline, selegiline, tranylcypromine, and others.

To make sure Silenor is safe for you, tell your doctor if you have:

• sleep apnea (breathing stops during sleep);

• a history of depression, mental illness, or addiction to drugs or alcohol;

• kidney or liver disease;

• diabetes (doxepin may raise or lower blood sugar); or

• if you have ever had glaucoma, or urination problems.

FDA pregnancy category C. It is not known whether Silenor will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

Doxepin can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.

Do not give this medicine to a child without medical advice.

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

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

To minimize the potential for next day effects, Silenor should not be taken within 3 hours of a meal.

Applies to doxepin: oral capsule, oral solution, oral tablet

Along with its needed effects, doxepin (the active ingredient contained in Silenor) 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 while taking doxepin:

• 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 while taking doxepin:

• 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 of doxepin 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