Fenoldopam

Risk Summary

There are insufficient data regarding fenoldopam use in pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes.

In animal studies, there was no evidence of teratogenicity or fetotoxicity when fenoldopam was orally administered to rats and rabbits during organogenesis (see Data). There are adverse effects on maternal and fetal outcomes associated with severe hypertension.

The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in the clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Severe hypertension can result in maternal stroke, pulmonary edema, myocardial ischemia or death of the mother or fetus.

Data

Animal Data

Oral reproduction studies have been performed in rats and rabbits at doses of 12.5 to 200 mg/kg/day and 6.25 to 25 mg/kg/day, respectively, administered during the period of organogenesis. Studies have revealed maternal toxicity at the highest doses tested but no evidence of harm to the fetus due to fenoldopam.

Risk Summary

There are no data on the presence of fenoldopam in human milk, the effects on the breastfed child, or the effects on milk production. Fenoldopam is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

Because of the potential for severe adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with fenoldopam.

In a 24-month study, mice treated orally with fenoldopam at 12.5, 25, or 50 mg/kg/day, reduced to 25 mg/kg/day on day 209 of study, showed no increase above controls in the incidence of neoplasms. Female mice in the highest dose group had an increased incidence and degree of severity of a fibro-osseous lesion of the sternum compared with control or low-dose animals. Compared to controls, female mice in the middle- and upper-dose groups had a higher incidence and degree of severity of chronic nephritis. These pathologic lesions were not seen in male mice treated with fenoldopam.

In a 24-month study, rats treated orally with fenoldopam at 5, 10 or 20 mg/kg/day, with the mid- and high-dose groups increased to 15 or 25 mg/kg/day, respectively, on day 372 of the study, showed no increase above controls in the incidence or type of neoplasms. Compared with the controls, rats in the mid- and high-dose groups had a higher incidence of hyperplasia of collecting duct epithelium at the tip of the renal papilla.

Fenoldopam did not induce bacterial gene mutation in the Ames test or mammalian gene mutation in the Chinese hamster ovary (CHO) cell assay. In the in vitro chromosomal aberration assay with CHO cells, fenoldopam was associated with statistically significant and dose-dependent increases in chromosomal aberrations, and in the proportion of aberrant metaphases. However, no chromosomal damage was seen in the in vivo mice micronucleus or bone marrow assays.

Oral fertility and general reproduction performance studies in male and female rats at 12.5, 37.5 or 75 mg/kg/day revealed no impairment of fertility or reproduction performance due to fenoldopam.

Clinical Trials Experience

Because clinical trials 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.

The most common reactions associated with fenoldopam use are headache, cutaneous dilation (flushing), nausea, and hypotension, each reported in more than 5% of patients.

Adverse reactions occurring more than once in any dosing group (once if potentially important or plausibly drug-related) in the fixed-dose constant-infusion studies are presented in the table below. There was no clear dose relationship, except possibly for headache, nausea, flushing.

Adverse reactions in fixed-dose studies occurring in >5% of subjects on fenoldopam:

The following additional adverse reactions were observed more frequently in patients treated with fenoldopam.

Incidence 0.5% to 5%:

Metabolism and Nutrition Disorders: Hypokalemia

Psychiatric Disorders: Nervousness/Anxiety, insomnia

Nervous System Disorders: Dizziness

Cardiac Disorders: Extrasystoles, palpitations, cardiac failure, ischemic heart disease, myocardial infarction, angina pectoris, tachycardia

Gastrointestinal Disorders: Abdominal pain

Skin and Subcutaneous Tissue Disorders: Hyperhidrosis

Musculoskeletal and Connective Tissue Disorders: Muscle spasms

Renal and Urinary Disorders: Oliguria

General Disorders and Administration Site Conditions: Chest pain, pyrexia

Investigations: Blood urea increased, blood creatinine increased, blood glucose increased, transaminases increased, blood lactate dehydrogenase increased

Postmarketing Experience

The following adverse reactions have been identified during post approval use of fenoldopam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Voluntary reports of adverse reactions temporally associated with fenoldopam that have been received since market introduction include the following:

Cardiac Disorders: Cardiogenic shock

Vascular Disorders: Hypotension

Gastrointestinal Disorders: Abdominal distension

Investigations: Electrocardiogram ST segment depression, oxygen saturation decreased