Clevidipine Butyrate

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]. In case of suspected overdosage, Cleviprex should be discontinued immediately and the patient's blood pressure should be supported.

• Advise patients with underlying hypertension that they require continued follow up for their medical condition, and, if applicable, encourage patients to continue taking their oral antihypertensive medication(s) as directed.
• Advise patients to contact a healthcare professional immediately for any of the following signs of a new hypertensive emergency: neurological symptoms, visual changes, or evidence of congestive heart failure.

Clevidipine is in a group of drugs called calcium channel blockers. It works by relaxing the muscles of your heart and blood vessels.

Clevidipine is used to treat high blood pressure (hypertension) in people who cannot take medicine by mouth.

Clevidipine may also be used for purposes not listed in this medication guide.

The following risk is discussed elsewhere in the labeling:

• Hypotension and Reflex Tachycardia [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

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.

The placebo-controlled experience with Cleviprex in the perioperative setting was both small and brief (about 30 minutes). Table 2 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 2: 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.

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.

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%.

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.

Read the entire FDA prescribing information for Cleviprex (Clevidipine Butyrate)

Calcium-channel blocking agent; dihydropyridine derivative.1 5 6 7 8 9 10

Contraindications

• Defective lipid metabolism (e.g., pathologic hyperlipemia, lipoid nephrosis, acute pancreatitis associated with hyperlipemia).1

• Severe aortic stenosis (because afterload reduction may reduce myocardial oxygen delivery).1

• Known hypersensitivity to soybeans, soy products, eggs, or egg product.1

Warnings/Precautions

Hypotension and Reflex Tachycardia

Possible hypotension and reflex tachycardia.1 10

Reduce dosage if either systemic hypotension or reflex tachycardia occurs.1 Use of β-adrenergic blocking agents for treatment for clevidipine-induced tachycardia is not recommended.1

Lipid Intake

Lipid intake restrictions may be necessary for patients with substantial disorders of lipid metabolism since commercially available clevidipine is an oil-in-water emulsion.1 11

May need to restrict concurrently administered lipids to compensate for the lipid content of the clevidipine formulation (1 mL of clevidipine emulsion contains 0.2 g of fat [2 kcal]).1 Clevidipine is contraindicated in patients with defective lipid metabolism.1 11 (See Contraindications.)

Heart Failure

Potential negative inotropic effects; may precipitate or worsen heart failure.1 Carefully monitor patients with heart failure.1

β-Adrenergic Blocker Withdrawal

Clevidipine is not a β-adrenergic blocking agent and offers no protection against abrupt withdrawal of concomitant β-adrenergic blocking agent therapy; β-adrenergic blocking agents should be withdrawn gradually.1

Rebound Hypertension

Rebound hypertension reported following discontinuance of prolonged clevidipine infusions (up to 72 hours) in patients who were not transferred to other antihypertensive therapy.1 11 Monitor for rebound hypertension for at least 8 hours following discontinuance of infusion.1

Specific Populations

Category C.1

Not known whether clevidipine is distributed into milk.1 Consider possible infant exposure when clevidipine is used in nursing women.1

Safety and efficacy not established in children <18 years of age.1

Safety and efficacy in those ≥65 years of age similar to that in younger adults.1

Common Adverse Effects

Nausea,1 2 3 4 11 vomiting,1 4 11 chest discomfort,4 11 headache,1 4 11 atrial fibrillation,1 2 3 11 fever,2 11 insomnia,3 11 acute renal failure,1 2 11 edema.3 11

Storage

Parenteral

2–8°C; protect form light by storing in carton.1 Do not freeze.1

Vials may be removed from refrigerator and stored at 25°C for ≤2 months; however, may not be returned to refrigerator.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• Inhibits transmembrane influx of calcium ions during depolarization in arterial smooth muscle.1

• Reduces mean arterial BP by decreasing systemic vascular resistance, but does not appear to reduce cardiac filling pressure (i.e., preload), confirming lack of effects on venous capacitance vessels.1 9