Source: FDA, National Drug Code (US) Revision Year: 2023
SILENOR is contraindicated in individuals who have shown hypersensitivity to doxepin HCl, any of its inactive ingredients, or other dibenzoxepines.
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.
SILENOR is contraindicated in individuals with untreated narrow angle glaucoma or severe urinary retention.
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.
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.
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.
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)].
The following serious adverse reactions are discussed in greater detail in other sections of labeling:
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.
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.
Infrequent: anemia
Rare: thrombocythemia
Rare: atrioventricular block, palpitations, tachycardia, ventricular extrasystoles
Rare: ear pain, hypoacusis, motion sickness, tinnitus, tympanic membrane perforation
Infrequent: eye redness, vision blurred
Rare: blepharospasm, diplopia, eye pain, lacrimation decreased
Infrequent: abdominal pain, dry mouth, gastroesophageal reflux disease, vomiting
Rare: dyspepsia, constipation, gingival recession, haematochezia, lip blister
Infrequent: asthenia, chest pain, fatigue
Rare: chills, gait abnormal, edema peripheral
Rare: hyperbilirubinemia
Rare: hypersensitivity
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
Infrequent: back injury, fall, joint sprain
Rare: bone fracture, skin laceration
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
Infrequent: anorexia, decreased appetite, hyperkalemia, hypermagnesemia, increased appetite
Rare: hypokalemia
Infrequent: arthralgia, back pain, myalgia, neck pain, pain in extremity
Rare: joint range of motion decreased, muscle cramp, sensation of heaviness
Rare: lung adenocarcinoma stage I, malignant melanoma
Frequent: dizziness
Infrequent: dysgeusia, lethargy, parasthesia, syncope
Rare: ageusia, ataxia, cerebrovascular accident, disturbance in attention, migraine, sleep paralysis, syncope vasovagal, tremor
Infrequent: abnormal dreams, adjustment disorder, anxiety, depression
Rare: confusional state, elevated mood, insomnia, libido decreased, nightmare
Rare: breast cyst, dysmenorrhea
Rare: dysuria, enuresis, hemoglobinuria, nocturia
Infrequent: nasal congestion, pharyngolaryngeal pain, sinus congestion, wheezing
Rare: cough, crackles lung, nasopharyngeal disorder, rhinorrhea, dyspnea
Infrequent: skin irritation
Rare: cold sweat, dermatitis, erythema, hyperhidrosis, pruritis, rash, rosacea
Rare: arthrodesis
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
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 trials of a drug cannot be directly compared to rates in the clinical trials 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.
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%.
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.
Table 1. Incidence (%) of Treatment-Emergent Adverse Reactions in Long-term Placebo-Controlled Clinical Trials:
| System Organ Class Preferred Term* | Placebo (N=278) | SILENOR 3 mg (N=157) | SILENOR 6 mg (N=203) |
|---|---|---|---|
| Nervous System Disorders | |||
| Somnolence/Sedation | 4 | 6 | 9 |
| Infections and Infestations | |||
| Upper Respiratory Tract Infection/Nasopharyngitis | 2 | 4 | 2 |
| Gastroenteritis | 0 | 2 | 0 |
| Gastrointestinal Disorders | |||
| Nausea | 1 | 2 | 2 |
| Vascular Disorders | |||
| Hypertension | 0 | 3 | <1 |
* Includes reactions that occurred at a rate of ≥2% in any SILENOR-treated group and at a higher rate than placebo.
The most common treatment-emergent adverse reaction in the placebo and each of the SILENOR dose groups was somnolence/sedation.
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.
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 (12.3)].
When taken with SILENOR, the sedative effects of alcohol may be potentiated [see Warnings and Precautions (5.2, 5.4)].
When taken with SILENOR, the sedative effects of sedating antihistamines and CNS depressants may be potentiated [see Warnings and Precautions (5.2, 5.4)].
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).
Available data from published epidemiologic studies and postmarketing reports have not established an increased risk of major birth defects or miscarriage (see Data). There are risks of poor neonatal adaptation with exposure to tricyclic antidepressants (TCAs), including doxepin, during pregnancy (see Clinical Considerations). In animal reproduction studies, oral administration of doxepin to rats and rabbits during the period of organogenesis caused adverse developmental effects at doses 65 and 23 times the maximum recommended human dose (MRHD) of 6 mg/day based on AUC, respectively. Oral administration of doxepin to pregnant rats during pregnancy and lactation resulted in decreased pup survival and a delay in pup growth at doses 60 times the MRHD based on AUC (see Data).
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of major birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Neonates exposed to TCAs, including doxepin, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hyperreflexia, tremor, jitteriness, irritability and constant crying. These findings are consistent with either direct toxic effects of TCAs or possibly a drug discontinuation syndrome. Monitor neonates who were exposed to SILENOR in the third trimester of pregnancy for poor neonatal adaptation syndrome.
Published epidemiologic studies of pregnant women exposed to TCAs, including doxepin, have not established an association with major birth defects, miscarriage or adverse maternal outcomes. Methodological limitations of these observational studies include small sample size and lack of adequate controls.
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 consisting of non-ossified bones in the skull and sternum and decreased fetal body weights) and maternal toxicity were noted at ≥100 mg/kg/day, which produced plasma exposures (AUCs) of doxepin and nordoxepin (the primary metabolite in humans) approximately 65 and 53 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for embryo-fetal developmental toxicity in rats (30 mg/kg/day) are approximately 6 and 5 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD. When doxepin (10, 30, and 60 mg/kg/day) was administered orally to pregnant rabbits during the period of organogenesis, fetal body weights were reduced at the highest dose in the absence of maternal toxicity, which produced plasma AUCs of doxepin and nordoxepin approximately 23 and 56 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for developmental effects (30 mg/kg/day) are approximately 8 and 25 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 pregnancy and lactation resulted in decreased pup survival and transient growth delay at the highest dose, which produced plasma AUCs of doxepin and nordoxepin approximately 60 and 39 times, respectively, the plasma AUCs at the MRHD. The plasma exposures at the no-effect dose for adverse effects on pre- and postnatal development in rats (30 mg/kg/day) are approximately 2 and 1 times the plasma AUCs for doxepin and nordoxepin, respectively, at the MRHD.
Data from the published literature report the presence of doxepin and nordoxepin in human milk. There are reports of excess sedation, respiratory depression, poor sucking and swallowing, and hypotonia in breastfed infants exposed to doxepin. There are no data on the effects of doxepin on milk production. Because of the potential for serious adverse reactions, including excess sedation and respiratory depression in a breastfed infant, clinicians should advise patients that breastfeeding is not recommended during treatment with SILENOR.
Infants exposed to SILENOR through breast milk should be monitored for excess sedation, respiratory depression and hypotonia.
Based on results from animal fertility studies conducted in rats, doxepin may reduce fertility in females and males of reproductive potential [see Nonclinical Toxicology (13.1)]. It is unknown if the effects are reversible.
The safety and effectiveness of SILENOR in pediatric patients have not been evaluated.
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)].
Patients with hepatic impairment may display higher doxepin concentrations than healthy individuals. Initiate SILENOR treatment with 3 mg in patients with hepatic impairment and monitor closely for adverse daytime effects [see Clinical Pharmacology (12.3)].
SILENOR has not been studied in patients with obstructive sleep apnea. Since hypnotics have the capacity to depress respiratory drive, precautions should be taken if SILENOR is prescribed to patients with compromised respiratory function. In patients with severe sleep apnea, SILENOR is ordinarily not recommended for use.
Doxepin is not a controlled substance.
Doxepin is not associated with abuse potential in animals or in humans. Physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of doxepin (e.g., incrementation of dose, drug-seeking behavior).
In a brief assessment of adverse events observed during discontinuation of doxepin following chronic administration, no symptoms indicative of a withdrawal syndrome were observed. Thus, doxepin does not appear to produce physical dependence.
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