Nefazodone

Teratogenic Effects — Pregnancy Category C

Reproduction studies have been performed in pregnant rabbits and rats at daily doses up to 200 and 300 mg/kg, respectively (approximately 6 and 5 times, respectively, the maximum human daily dose on a mg/m² basis). No malformations were observed in the offspring as a result of nefazodone treatment. However, increased early pup mortality was seen in rats at a dose approximately five times the maximum human dose, and decreased pup weights were seen at this and lower doses, when dosing began during pregnancy and continued until weaning. The cause of these deaths is not known. The noeffect dose for rat pup mortality was 1.3 times the human dose on a mg/m² basis. There are no adequate and well-controlled studies in pregnant women. Nefazodone should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is not known whether nefazodone or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when nefazodone is administered to a nursing woman.

Carcinogenesis

There is no evidence of carcinogenicity with nefazodone. The dietary administration of nefazodone to rats and mice for 2 years at daily doses of up to 200 mg/kg and 800 mg/kg, respectively, which are approximately 3 and 6 times, respectively, the maximum human daily dose on a mg/m² basis, produced no increase in tumors.

Mutagenesis

Nefazodone has been shown to have no genotoxic effects based on the following assays: bacterial mutation assays, a DNA repair assay in cultured rat hepatocytes, a mammalian mutation assay in Chinese hamster ovary cells, an in vivo cytogenetics assay in rat bone marrow cells, and a rat dominant lethal study.

Impairment of Fertility

A fertility study in rats showed a slight decrease in fertility at 200 mg/kg/day (approximately three times the maximum human daily dose on a mg/m² basis) but not at 100 mg/kg/day (approximately 1.5 times the maximum human daily dose on a mg/m² basis).

Associated with Discontinuation of Treatment

A pproximately 16% of the 3496 patients who received nefazodone (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 (i.e., those events associated with dropout at a rate approximately twice or greater for nefazodone 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 nefazodone (incidence of 5% or greater) and not seen at an equivalent incidence among placebo-treated patients (i.e., significantly higher incidence for nefazodone 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 Nefazodone-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 nefazodone-treated patients who participated in short-term (6- to 8-week) placebo-controlled trials in which patients were dosed with nefazodone 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, nefazodone 300 to 600 mg/day Dose Range:

¹ Events reported by at least 1% of patients treated with nefazodone 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 nefazodone hydrochloride 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.

Dose Dependency of Adverse Events

The table that follows enumerates adverse events that were more frequent in the nefazodone dose range of 300 to 600 mg/day than in the nefazodone 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 nefazodone dose ranges as well as a difference between the high dose range and placebo.

Dose Dependency of Adverse Events in Placebo-Controlled Trials¹:

¹ Events for which there was a statistically significant difference (p≤0.05) between the nefazodone dose groups.

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-dependendency 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 nefazodone.

Vital Sign Changes

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, i.e., 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, i.e., 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 nefazodone

During its premarketing assessment, multiple doses of nefazodone 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 nefazodone 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 nefazodone who experienced an event of the type cited on at least one occasion while receiving nefazodone. 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 nefazodone (nefazodone hydrochloride), 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 1/1,000 patients; rare events are those occurring in fewer than 1/1,000 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: impotencea.

Infrequent: cystitis, urinary urgency, metrorrhagia^a, amenorrhea^a, polyuria, vaginal hemorrhage^a, breast enlargement^a, menorrhagia^a, urinary incontinence, abnormal ejaculation^a, hematuria, nocturia, and kidney calculus.

Rare: uterine fibroids enlargeda, uterine hemorrhage^a, anorgasmia, and oliguria.

^a Adjusted for gender.

Postintroduction Clinical Experience

Postmarketing experience with nefazodone has shown an adverse experience profile similar to that seen during the premarketing evaluation of nefazodone. Voluntary reports of adverse events temporally associated with nefazodone 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; priapism; prolactin increased; rhabdomyolysis involving patients receiving the combination of nefazodone and lovastatin or simvastatin; serotonin syndrome; and Stevens-Johnson syndrome; and thrombocytopenia.