Nefazodone precautions

List of precautions
General Lab tests Carcinogenesis Mutagenesis Impairment of fertility Pregnancy Labor & delivery Nursing mothers Pediatric use Geriatric use
 * Hepatotoxicity
 * Postural hypotension
 * Activation of mania/hypomania
 * Seizures
 * Priapism
 * Patients with concomitant illness

Hepatotoxicity
Cases of life-threatening hepatic failure have been reported in patients treated with Nefazodone hydrochloride tablets. The reported rate in the United States is about 1 case of liver failure resulting in death or transplant per 250,000 to 300,000 patient-years of Nefazodone hydrochloride treatment. The total patient-years is a summation of each patient’s duration of exposure expressed in years. For example, 1 patient-year is equal to 2 patients each treated for 6 months, 3 patients each treated for 4 months, etc. Ordinarily, treatment with Nefazodone hydrochloride tablets should not be initiated in individuals with active liver disease or with elevated baseline serum transaminases. There is no evidence that pre-existing liver disease increases the likelihood of developing liver failure, however, baseline abnormalities can complicate patient monitoring. Patients should be advised to be alert for signs and symptoms of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they occur. Nefazodone hydrochloride tablets should be discontinued if clinical signs or symptoms suggest liver failure. Patients who develop evidence of hepatocellular injury such as increased serum AST or serum ALT levels ≥ 3 times the upper limit of NORMAL, while on Nefazodone hydrochloride tablets should be withdrawn from the drug. These patients should be presumed to be at increased risk for liver injury if Nefazodone hydrochloride is reintroduced. Accordingly, such patients should not be considered for re-treatment. Return to top

Postural hypotension
A pooled analysis of the vital signs monitored during placebo-controlled premarketing studies revealed that 5.1% of Nefazodone patients compared to 2.5% of placebo patients (p ≤ 0.01) met criteria for a potentially important decrease in blood pressure at some time during treatment (systolic blood pressure ≤ 90 mmHg and a change from baseline of ≥ 20 mmHg). While there was no difference in the proportion of Nefazodone and placebo patients having adverse events characterized as ‘syncope’ (Nefazodone, 0.2%; placebo, 0.3%), the rates for adverse events characterized as ‘postural hypotension’ were as follows: Nefazodone (2.8%), tricyclic antidepressants (10.9%), SSRI (1.1%), and placebo (0.8%). Thus, the prescriber should be aware that there is some risk of postural hypotension in association with Nefazodone use. Nefazodone should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication). Return to top

Activation of mania/hypomania
During premarketing testing, hypomania or mania occurred in 0.3% of Nefazodone-treated unipolar patients, compared to 0.3% of tricyclic- and 0.4% of placebo-treated patients. In patients classified as bipolar the rate of manic episodes was 1.6% for Nefazodone, 5.1% for the combined tricyclic-treated groups, and 0% for placebo-treated patients. Activation of mania/hypomania is a known risk in a small proportion of patients with major affective disorder treated with other marketed antidepressants. As with all antidepressants, Nefazodone should be used cautiously in patients with a history of mania. Return to top

Seizures
During premarketing testing, a recurrence of a petit mal seizure was observed in a patient receiving Nefazodone who had a history of such seizures. In addition, one nonstudy participant reportedly experienced a convulsion (type not documented) following a multiple-drug overdose. Rare occurrences of convulsions (including grand mal seizures) following Nefazodone administration have been reported since market introduction. A causal relationship to Nefazodone has not been established. Return to top

Priapism
While priapism did not occur during premarketing experience with Nefazodone, rare reports of priapism have been received since market introduction. A causal relationship to Nefazodone has not been established. If patients present with prolonged or inappropriate erections, they should discontinue therapy immediately and consult their physicians. If the condition persists for more than 24 hours, a urologist should be consulted to determine appropriate management. Return to top

Patients with concomitant illness
Nefazodone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were systematically excluded from clinical studies during the product’s premarketing testing. Evaluation of electrocardiograms of 1153 patients who received Nefazodone in 6 to 8 week, double-blind, placebo-controlled trials did not indicate that Nefazodone is associated with the development of clinically important ECG abnormalities. However, sinus bradycardia, defined as heart rate ≤ 50 bpm and a decrease of at least 15 bpm from baseline, was observed in 1.5% of Nefazodone-treated patients compared to 0.4% of placebo-treated patients (p ≤ 0.05). Because patients with a recent history of myocardial infarction or unstable heart disease were excluded from clinical trials, such patients should be treated with caution. In patients with cirrhosis of the liver, AUC values of Nefazodone and HO-NEF were increased by approximately 25%. Return to top

Lab tests
There are no specific laboratory tests recommended. Return to top

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. Return to top

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. Return to top

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). Return to top

Pregnancy
Teratogenic Effects 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 no-effect 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. Return to top
 * Pregnancy category C

Labor & delivery
The effect of Nefazodone on labor and delivery in humans is unknown. Return to top

Nursing mothers
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. Return to top

Pediatric use
Safety and effectiveness in the pediatric population have not been established (see BOXWARNING and WARNINGS, Clinical Worsening and Suicide Risk). Two placebo-controlled trials in 286 pediatric patients with MDD have been conducted with Nefazodone, and the data were not sufficient to support a claim for use in pediatric patients. Anyone considering the use of Nefazodone hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need. Return to top

Geriatric use
Of the approximately 7000 patients in clinical studies who received Nefazodone for the treatment of depression, 18% were 65 years and older, while 5% were 75 years and older. Based on monitoring of adverse events, vital signs, electrocardiograms, and results of laboratory tests, no overall differences in safety between elderly and younger patients were observed in clinical studies. Efficacy in the elderly has not been demonstrated in placebo-controlled trials. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Due to the increased systemic exposure to Nefazodone seen in single-dose studies in elderly patients, treatment should be initiated at half the usual dose, but titration upward should take place over the same range as in younger patients. The usual precautions should be observed in elderly patients who have concomitant medical illnesses or who are receiving concomitant drugs. Return to top