has not been established as safe and effective. Other calcium channel blockers suppress uterine contractions in humans. Pregnant rats treated with clevidipine during late gestation had an increased rate of prolonged parturition.
8.3 Nursing Mothers
It is not known whether clevidipine is excreted in human milk. Because many drugs are excreted in human milk, consider possible infant exposure when Cleviprex is administered to a nursing woman.
8.4Pediatric Use
The safety and effectiveness of Cleviprex in children under 18 years of age have not been established.
8.5 Geriatric Use
Of the 1406 subjects (1307 with hypertension) treated with Cleviprex in clinical studies, 620 were ≥65 years of age and 232 were ≥75 years of age. No overall differences in safety or effectiveness were observed between these and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, for an elderly patient doses should be titrated cautiously, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy.
10 OVERDOSAGE
There has been no experience of overdosage in human clinical trials. In clinical trials, doses of Cleviprex up to 106 mg/hour or 1153 mg maximum total dose were administered. The expected major effects of overdose would be hypotension and reflex tachycardia.
Discontinuation of Cleviprex leads to a reduction in antihypertensive effects within 5 to 15 minutes [see Clinical Pharmacology (12.2)]. In case of suspected overdosage, Cleviprex should be discontinued immediately and the patient’s blood pressure should be supported.
11DESCRIPTION
Cleviprex is a sterile, milky-white emulsion containing 0.5 mg/mL of clevidipine suitable for intravenous administration. Clevidipine is a dihydropyridine calcium channel blocker. Chemically, the active substance, clevidipine, is butyroxymethyl methyl 4-(2´,3´-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. It is a racemic mixture with a molecular weight of 456.3 g/mol. Each enantiomer has equipotent antihypertensive activity. The structure and formula are:
Clevidipine is practically insoluble in water and is formulated in an oil-in-water emulsion. In addition to the active ingredient, clevidipine, Cleviprex contains soybean oil (200 mg/mL), glycerin (22.5 mg/mL), purified egg yolk phospholipids (12 mg/mL), oleic acid (0.3 mg/mL), disodium edetate (0.05 mg/mL), and sodium hydroxide to adjust pH. Cleviprex has a pH of 6.0 – 8.0 and is a ready-to-use emulsion.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Clevidipine is a dihydropyridine L-type calcium channel blocker. L-type calcium channels mediate the influx of calcium during depolarization in arterial smooth muscle. Experiments in anesthetized rats and dogs show that clevidipine reduces mean arterial blood pressure by decreasing systemic vascular resistance. clevidipine does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels.
12.2 Pharmacodynamics
Cleviprex is titrated to the desired reduction in blood pressure. The effect of Cleviprex appears to plateau at approximately 25% of baseline systolic pressure. The infusion rate for which half the maximal effect
