CLEVIPREX Emulsion for infusion Ref.[27458] Active ingredients: Clevidipine

5.1 Need for Aseptic Technique

Use aseptic technique and discard any unused product within 12 hours of stopper puncture [see Dosage and Administration (2.3)].

5.2 Hypotension and Reflex Tachycardia

Cleviprex may produce systemic hypotension and reflex tachycardia. If either occurs, decrease the dose of Cleviprex. There is limited experience with short-duration therapy with beta-blockers as a treatment for Cleviprex-induced tachycardia. Beta-blocker use for this purpose is not recommended.

5.3 Lipid Intake

Cleviprex contains approximately 0.2 g of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, a reduction in the quantity of concurrently administered lipids may be necessary to compensate for the amount of lipid infused as part of the Cleviprex formulation.

5.4 Negative Inotropy

Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully.

5.5 Beta-Blocker Withdrawal

Cleviprex is not a beta-blocker, does not reduce heart rate, and gives no protection against the effects of abrupt beta-blocker withdrawal. Withdraw beta-blockers only after a gradual reduction in dose.

5.6 Rebound Hypertension

Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped.

5.7 Pheochromocytoma

There is no information to guide use of Cleviprex in treating hypertension associated with pheochromocytoma.

The following risk is discussed elsewhere in the labeling:

• Hypotension and Reflex Tachycardia [see Warnings and Precautions (5.2)]

Cleviprex clinical development included 19 studies, with 99 healthy subjects and 1307 hypertensive patients who received at least one dose of clevidipine (1406 total exposures). Clevidipine was evaluated in 15 studies in hypertensive patients: 1099 patients with perioperative hypertension, 126 with severe hypertension and 82 patients with essential hypertension.

The desired therapeutic response was achieved at doses of 4-6 mg/hour. Cleviprex was infused for <24 hours in the majority of patients (n=1199); it was infused as a continuous infusion in an additional 93 patients for durations between 24 and 72 hours.

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.

Use in Perioperative Hypertension

The placebo-controlled experience with Cleviprex in the perioperative setting was both small and brief (about 30 minutes). Table 1 shows treatment-emergent adverse reactions and the category of “any common adverse event” in ESCAPE-1 and ESCAPE-2 where the rate on Cleviprex exceeded the rate on placebo by at least 5% (common adverse reactions).

Table 1. Common adverse reactions in placebo-controlled perioperative studies:

Three randomized, parallel, open-label studies called ECLIPSE, with longer exposure in cardiac surgery patients define the adverse reactions for patients with perioperative hypertension. Each ECLIPSE study compared Cleviprex (n=752) to an active comparator: nitroglycerin (NTG, n=278), sodium nitroprusside (SNP, n=283), or nicardipine (NIC, n=193). The pooled mean maximum dose in these studies was 10 mg/hour and the mean duration of treatment was 8 hours.

There were many adverse events associated with the operative procedure in the clinical studies of Cleviprex and relatively few plausibly related to the drugs used to lower blood pressure. Thus, the ability to differentiate the adverse event profile between treatments is limited. The adverse events observed within one hour of the end of the infusion were similar in patients who received Cleviprex and in those who received comparator agents. There was no adverse reaction that was more than 2% more common on Cleviprex than on the average of all comparators.

Serious Adverse Events and Discontinuation – Perioperative Hypertension Studies

The incidence of adverse events leading to study drug discontinuation in patients with perioperative hypertension receiving Cleviprex was 5.9% versus 3.2% for all active comparators. For patients receiving Cleviprex and all active comparators the incidence of serious adverse events within one hour of drug infusion discontinuation was similar.

Use in Severe Hypertension

The adverse events for patients with severe hypertension are based on an uncontrolled study in patients with severe hypertension (VELOCITY, n=126).

The common adverse reactions for Cleviprex in severe hypertension included headache (6.3%), nausea (4.8%), and vomiting (3.2%). The incidence of adverse events leading to study drug discontinuation for Cleviprex in severe hypertension was 4.8%.

Less Common Adverse Reactions in Patients with Severe or Essential Hypertension

Adverse reactions that were reported in <1% of patients with severe or essential hypertension included:

Cardiac: myocardial infarction, cardiac arrest

Nervous system: syncope

Respiratory: dyspnea

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.

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.

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.

The safety and effectiveness of Cleviprex in children under 18 years of age have not been established.

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.