2)] . 3) ] . 4) ] . The most common treatment-emergent adverse reactions, reported in ≥ 2% of patients treated with doxepin, and more commonly than in patients treated with placebo, were somnolence/sedation, nausea, and upper respiratory tract infection.
gov/medwatch . 1 Clinical Trials Experience The pre-marketing development program for doxepin tablets 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 doxepin 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 doxepin 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. 7% in the doxepin 1 mg, 3 mg, and 6 mg groups, respectively.
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 doxepin 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 doxepin 3 mg or 6 mg in which the incidence in subjects treated with doxepin 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) Doxepin 3 mg (N=157) Doxepin 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 doxepin-treated group and at a higher rate than placebo.
The most common treatment-emergent adverse reaction in the placebo and each of the doxepin dose groups was somnolence/sedation. 2 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 doxepin.
In a one-night, double-blind study conducted in 565 healthy adult subjects experiencing transient insomnia, doxepin 6 mg showed modest negative changes in SCT and VAS. In a 35-day, double-blind, placebo-controlled, parallel group study of doxepin 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, doxepin 1 mg and 3 mg was comparable to placebo on DSST, SCT, and VAS. 3 Other Reactions Observed During the Pre-marketing Evaluation of Doxepin Doxepin 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 doxepin.
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.