ADVERSE REACTIONS
Associated with Discontinuation of Treatment
Approximately 16% of the 3496 patients who received SERZONE (nefazodone hydrochloride) in worldwide premarketing clinical trials discontinued treatment due to an adverse experience. The more common (≥1%) events in clinical trials associated with discontinuation and considered to be drug related (ie, those events associated with dropout at a rate approximately twice or greater for SERZONE compared to placebo) included: nausea (3.5%), dizziness (1.9%), insomnia (1.5%), asthenia (1.3%), and agitation (1.2%).
Incidence in Controlled Trials
Commonly Observed Adverse Events in Controlled Clinical Trials
The most commonly observed adverse events associated with the use of SERZONE (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (ie, significantly higher incidence for SERZONE compared to placebo, p≤0.05), derived from the table below, were: somnolence, dry mouth, nausea, dizziness, constipation, asthenia, lightheadedness, blurred vision, confusion, and abnormal vision.
Adverse Events Occurring at an Incidence of 1% or More Among SERZONE-Treated Patients
The table that follows enumerates adverse events that occurred at an incidence of 1% or more, and were more frequent than in the placebo group, among SERZONE-treated patients who participated in short-term (6- to 8-week) placebo-controlled trials in which patients were dosed with SERZONE (nefazodone hydrochloride) to ranges of 300 to 600 mg/day. This table shows the percentage of patients in each group who had at least one episode of an event at some time during their treatment. Reported adverse events were classified using standard COSTART-based Dictionary terminology.
The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the side-effect incidence rate in the population studied.
Treatment-Emergent Adverse Experience Incidence in 6- to 8-Week Placebo-Controlled Clinical Trials1, SERZONE 300 to 600 mg/day Dose Range | Percent of Patients |
|---|
| Body System | Preferred Term | SERZONE
(n=393) | Placebo
(n=394) |
|---|
| 1 Events reported by at least 1% of patients treated with SERZONE and more frequent than the placebo group are included; incidence is rounded to the nearest 1% (<1% indicates an incidence less than 0.5%). Events for which the SERZONE incidence was equal to or less than placebo are not listed in the table, but included the following: abdominal pain, pain, back pain, accidental injury, chest pain, neck pain, palpitation, migraine, sweating, flatulence, vomiting, anorexia, tooth disorder, weight gain, edema, myalgia, cramp, agitation, anxiety, depression, hypesthesia, CNS stimulation, dysphoria, emotional lability, sinusitis, rhinitis, dysmenorrhea4, dysuria. |
| 2 Vasodilatation—flushing, feeling warm. |
| 3 Abnormal vision—scotoma, visual trails. |
| 4 Incidence adjusted for gender. |
| Body as a Whole | Headache | 36 | 33 |
| Asthenia | 11 | 5 |
| Infection | 8 | 6 |
| Flu syndrome | 3 | 2 |
| Chills | 2 | 1 |
| Fever | 2 | 1 |
| Neck rigidity | 1 | 0 |
| Cardiovascular | Postural hypotension | 4 | 1 |
| Hypotension | 2 | 1 |
| Dermatological | Pruritus | 2 | 1 |
| Rash | 2 | 1 |
| Gastrointestinal | Dry mouth | 25 | 13 |
| Nausea | 22 | 12 |
| Constipation | 14 | 8 |
| Dyspepsia | 9 | 7 |
| Diarrhea | 8 | 7 |
| Increased appetite | 5 | 3 |
| Nausea & vomiting | 2 | 1 |
| Metabolic | Peripheral edema | 3 | 2 |
| Thirst | 1 | <1 |
| Musculoskeletal | Arthralgia | 1 | <1 |
| Nervous | Somnolence | 25 | 14 |
| Dizziness | 17 | 5 |
| Insomnia | 11 | 9 |
| Lightheadedness | 10 | 3 |
| Confusion | 7 | 2 |
| Memory impairment | 4 | 2 |
| Paresthesia | 4 | 2 |
| Vasodilatation2 | 4 | 2 |
| Abnormal dreams | 3 | 2 |
| Concentration decreased | 3 | 1 |
| Ataxia | 2 | 0 |
| Incoordination | 2 | 1 |
| Psychomotor retardation | 2 | 1 |
| Tremor | 2 | 1 |
| Hypertonia | 1 | 0 |
| Libido decreased | 1 | <1 |
| Respiratory | Pharyngitis | 6 | 5 |
| Cough increased | 3 | 1 |
| Special Senses | Blurred vision | 9 | 3 |
| Abnormal vision3 | 7 | 1 |
| Tinnitus | 2 | 1 |
| Taste perversion | 2 | 1 |
| Visual field defect | 2 | 0 |
| Urogenital | Urinary frequency | 2 | 1 |
| Urinary tract infection | 2 | 1 |
| Urinary retention | 2 | 1 |
| Vaginitis4 | 2 | 1 |
| Breast pain4 | 1 | <1 |
Dose Dependency of Adverse Events
The table that follows enumerates adverse events that were more frequent in the SERZONE (nefazodone hydrochloride) dose range of 300 to 600 mg/day than in the SERZONE dose range of up to 300 mg/day. This table shows only those adverse events for which there was a statistically significant difference (p≤0.05) in incidence between the SERZONE dose ranges as well as a difference between the high dose range and placebo.
Dose Dependency of Adverse Events in Placebo-Controlled Trials1 | Percent of Patients | |
|---|
| Body System | Preferred Term | SERZONE
300–600 mg/day
(n=209) | SERZONE
≤300 mg/day
(n=211) | Placebo
(n=212) |
|---|
| 1Events for which there was a statistically significant difference (p≤0.05) between the nefazodone dose groups. |
| Gastrointestinal | Nausea | 23 | 14 | 12 |
| Constipation | 17 | 10 | 9 |
| Nervous | Somnolence | 28 | 16 | 13 |
| Dizziness | 22 | 11 | 4 |
| Confusion | 8 | 2 | 1 |
| Special Senses | Abnormal vision | 10 | 0 | 2 |
| Blurred vision | 9 | 3 | 2 |
| Tinnitus | 3 | 0 | 1 |
Visual Disturbances
In controlled clinical trials, blurred vision occurred in 9% of nefazodone-treated patients compared to 3% of placebo-treated patients. In these same trials, abnormal vision, including scotomata and visual trails, occurred in 7% of nefazodone-treated patients compared to 1% of placebo-treated (see Treatment-Emergent Adverse Experience table, above). Dose-dependency was observed for these events in these trials, with none of the scotomata and visual trails at doses below 300 mg/day. However, scotomata and visual trails observed at doses below 300 mg/day have been reported in postmarketing experience with SERZONE. (See PRECAUTIONS: Information for Patients.)
Vital Sign Changes
(See PRECAUTIONS: Postural Hypotension .)
Weight Changes
In a pooled analysis of placebo-controlled premarketing studies, there were no differences between nefazodone and placebo groups in the proportions of patients meeting criteria for potentially important increases or decreases in body weight (a change of ≥7%).
Laboratory Changes
Of the serum chemistry, serum hematology, and urinalysis parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistical trend between nefazodone and placebo for hematocrit, ie, 2.8% of nefazodone patients met criteria for a potentially important decrease in hematocrit (≤37% male or ≤32% female) compared to 1.5% of placebo patients (0.05<p≤0.10). Decreases in hematocrit, presumably dilutional, have been reported with many other drugs that block alpha1-adrenergic receptors. There was no apparent clinical significance of the observed changes in the few patients meeting these criteria.
ECG Changes
Of the ECG parameters monitored during placebo-controlled premarketing studies with nefazodone, a pooled analysis revealed a statistically significant difference between nefazodone and placebo for sinus bradycardia, ie, 1.5% of nefazodone patients met criteria for a potentially important decrease in heart rate (≤50 bpm and a decrease of ≥15 bpm) compared to 0.4% of placebo patients (p<0.05). There was no obvious clinical significance of the observed changes in the few patients meeting these criteria.
Other Events Observed During the Premarketing Evaluation of SERZONE
During its premarketing assessment, multiple doses of SERZONE (nefazodone hydrochloride) were administered to 3496 patients in clinical studies, including more than 250 patients treated for at least one year. The conditions and duration of exposure to SERZONE varied greatly, and included (in overlapping categories) open and double-blind studies, uncontrolled and controlled studies, inpatient and outpatient studies, fixed-dose and titration studies. Untoward events associated with this exposure were recorded by clinical investigators using terminology of their own choosing. Consequently, it is not possible to provide a meaningful estimate of the proportion of individuals experiencing adverse events without first grouping similar types of untoward events into a smaller number of standardized event categories.
In the tabulations that follow, reported adverse events were classified using standard COSTART-based Dictionary terminology. The frequencies presented, therefore, represent the proportion of the 3496 patients exposed to multiple doses of SERZONE who experienced an event of the type cited on at least one occasion while receiving SERZONE. All reported events are included except those already listed in the Treatment-Emergent Adverse Experience Incidence table, those events listed in other safety-related sections of this insert, those adverse experiences subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events for which a drug cause was very remote, and those events which were not serious and occurred in fewer than two patients.
It is important to emphasize that, although the events reported occurred during treatment with SERZONE, they were not necessarily caused by it.
Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients (only those not already listed in the tabulated results from placebo-controlled trials appear in this listing); infrequent adverse events are those occurring in 1/100 to 1/1000 patients; rare events are those occurring in fewer than 1/1000 patients.
Body as a whole—Infrequent: allergic reaction, malaise, photosensitivity reaction, face edema, hangover effect, abdomen enlarged, hernia, pelvic pain, and halitosis. Rare: cellulitis.
Cardiovascular system—Infrequent: tachycardia, hypertension, syncope, ventricular extrasystoles, and angina pectoris. Rare: AV block, congestive heart failure, hemorrhage, pallor, and varicose vein.
Dermatological system—Infrequent: dry skin, acne, alopecia, urticaria, maculopapular rash, vesiculobullous rash, and eczema.
Gastrointestinal system—Frequent: gastroenteritis. Infrequent: eructation, periodontal abscess, abnormal liver function tests, gingivitis, colitis, gastritis, mouth ulceration, stomatitis, esophagitis, peptic ulcer, and rectal hemorrhage. Rare: glossitis, hepatitis, dysphagia, gastrointestinal hemorrhage, oral moniliasis, and ulcerative colitis.
Hemic and lymphatic system—Infrequent: ecchymosis, anemia, leukopenia, and lymphadenopathy.
Metabolic and nutritional system—Infrequent: weight loss, gout, dehydration, lactic dehydrogenase increased, SGOT increased, and SGPT increased. Rare: hypercholesteremia and hypoglycemia.
Musculoskeletal system—Infrequent: arthritis, tenosynovitis, muscle stiffness, and bursitis. Rare: tendinous contracture.
Nervous system—Infrequent: vertigo, twitching, depersonalization, hallucinations, suicide attempt, apathy, euphoria, hostility, suicidal thoughts, abnormal gait, thinking abnormal, attention decreased, derealization, neuralgia, paranoid reaction, dysarthria, increased libido, suicide, and myoclonus. Rare: hyperkinesia, increased salivation, cerebrovascular accident, hyperesthesia, hypotonia, ptosis, and neuroleptic malignant syndrome.
Respiratory system—Frequent: dyspnea and bronchitis. Infrequent: asthma, pneumonia, laryngitis, voice alteration, epistaxis, hiccup. Rare: hyperventilation and yawn.
Special senses—Frequent: eye pain. Infrequent: dry eye, ear pain, abnormality of accommodation, diplopia, conjunctivitis, mydriasis, keratoconjunctivitis, hyperacusis, and photophobia. Rare: deafness, glaucoma, night blindness, and taste loss.
Urogenital system—Frequent: impotence.a Infrequent: cystitis, urinary urgency, metrorrhagiaa, amenorrheaa, polyuria, vaginal hemorrhagea, breast enlargementa, menorrhagiaa, urinary incontinence, abnormal ejaculationa, hematuria, nocturia, and kidney calculus. Rare: uterine fibroids enlargeda, uterine hemorrhagea, anorgasmia, and oliguria.
aAdjusted for gender.
Postintroduction Clinical Experience
Postmarketing experience with SERZONE has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with SERZONE have been received since market introduction that are not listed above and for which a causal relationship has not been established. These include:
Anaphylactic reactions; angioedema; convulsions (including grand mal seizures); galactorrhea; gynecomastia (male); hyponatremia; liver necrosis and liver failure, in some cases leading to liver transplantation and/or death (see WARNINGS); priapism (see PRECAUTIONS); prolactin increased; rhabdomyolysis involving patients receiving the combination of SERZONE and lovastatin or simvastatin (see PRECAUTIONS); serotonin syndrome; Stevens-Johnson syndrome; and thrombocytopenia.
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