Cleviprex (Page 2 of 4)

6.2 Post-Marketing and Other Clinical Experience

Because adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. The following adverse reactions have been identified during post-approval use of Cleviprex: increased blood triglycerides, ileus, hypersensitivity, hypotension, nausea, decreased oxygen saturation (possible pulmonary shunting) and reflex tachycardia.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

The available data based on post-marketing reports with Cleviprex use in pregnant women are not sufficient to inform a drug-associated risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy (see Clinical Considerations). In animal studies, clevidipine was associated with increased incidences of intrauterine deaths, slightly reduced fetal weight, retarded skeletal development, abortion, and embryo lethality at doses higher than the expected human dose. No evidence of embryo-fetal malformation was found with continuous IV infusion of clevidipine administered to pregnant rats and rabbits during the period of organogenesis
at multiples of 2.8 and 7.6 times the expected human dose of 16 mg/hour respectively (see Data).

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

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and postpartum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Data Animal Data

In pregnant rats, clevidipine caused a dose-related increase in mortality, length of gestation, and prolonged parturition at dose levels of 13, 35, and 55 mg/kg/day.

Clevidipine has been shown to cross the placenta in rats. No evidence of embryo-fetal malformation was found with continuous IV infusion of clevidipine during the period of organogenesis at doses up to 13 mg/kg/day in pregnant rats and 35 mg/kg/day in pregnant rabbits (2.8 to 7.6 times the expected human dose of 16 mg/hour). Embryo-fetal toxicity was seen with continuous IV infusion of clevidipine during the period of major embryonic organogenesis at 35 mg/kg/day in pregnant rats and at 55 mg/kg/day in pregnant rabbits (7.6 to 12 times the expected maximum human dose of 16 mg/hour). There was no evidence that clevidipine was teratogenic at the highest dose levels studied in pregnant rats and rabbits.

8.2 Lactation

Risk Summary

There are no data on the presence of clevidipine in human milk, the effects on the breastfed infant, or the effects on milk production.

8.4 Pediatric 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.

11 DESCRIPTION

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 Structure and Formula
(click image for full-size original)

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 is observed is approximately 10 mg/hour.

Onset of Effect: In the perioperative patient population, Cleviprex produces a 4-5% reduction in systolic blood pressure within 2-4 minutes after starting a 0.4 mcg/kg/min infusion (approximately 1-2 mg/hr).

Maintenance of Effect: In studies up to 72 hours of continuous infusion, there was no evidence of tolerance or hysteresis.

Offset of Effect: In most patients, full recovery of blood pressure is achieved in 5-15 minutes after the infusion is stopped.

In studies up to 72 hours of continuous infusion, in patients that were not transitioned to other antihypertensive therapies, there was some evidence of rebound hypertension following Cleviprex discontinuation.

Hemodynamics: Cleviprex causes a dose-dependent decrease in systemic vascular resistance.

Heart Rate: An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced [see Warnings and Precautions (5.2)].

Electrophysiologic Effects: In healthy volunteers, clevidipine or its major carboxylic acid metabolite, at therapeutic and supratherapeutic concentrations (approximately 2.8 times steady-state), did not prolong cardiac repolarization.

12.3 Pharmacokinetics

Clevidipine is rapidly distributed and metabolized resulting in a very short half life. The arterial blood concentration of clevidipine declines in a multi-phasic pattern following termination of the infusion. The initial phase half-life is approximately 1 minute, and accounts for 85-90% of clevidipine elimination. The terminal half-life is approximately 15 minutes.

Distribution: Clevidipine is >99.5% bound to proteins in plasma at 37°C. The steady-state volume of distribution was determined to be 0.17 L/kg in arterial blood.

Metabolism and Elimination: Clevidipine is rapidly metabolized by hydrolysis of the ester linkage, primarily by esterases in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction. The primary metabolites are the carboxylic acid metabolite and formaldehyde formed by hydrolysis of the ester group. The carboxylic acid metabolite is inactive as an antihypertensive. This metabolite is further metabolized by glucuronidation or oxidation to the corresponding pyridine derivative. The clearance of the primary dihydropyridine metabolite is 0.03 L/h/kg and the terminal half-life is approximately 9 hours.

In vitro studies show that clevidipine and its metabolite at the concentrations achieved in clinical practice will not inhibit or induce any CYP enzyme.

In a clinical study with radiolabeled clevidipine, 83% of the drug was excreted in urine and feces. The major fraction, 63-74% is excreted in the urine, 7-22% in the feces. More than 90% of the recovered radioactivity is excreted within the first 72 hours of collection.

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