Cleviprex

• The Medicines Company

Serious side effects have been reported with Cleviprex. See the “Cleviprex Precautions” section.

Common side effects of Cleviprex include:

• headache
• nausea
• vomiting

This is not a complete list of Cleviprex side effects. Ask your doctor or pharmacist for more information.

Tell your doctor if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X - are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Cleviprex falls into category C. In animal studies, pregnant animals were given this medication and had some babies born with problems. No well-controlled studies have been done in humans. Therefore, this medication may be used if the potential benefits to the mother outweigh the potential risks to the unborn child.

Take Cleviprex exactly as prescribed.

This medication comes in an injectable form to be given directly into a vein (IV) by a healthcare professional.

If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take 2 doses of Cleviprex at the same time.

Your doctor or pharmacist can provide more information about clevidipine.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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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

• Importance of advising patients with underlying hypertension that they require continued monitoring of their condition and importance of taking oral antihypertensive drugs as directed.1

• Importance of contacting a clinician immediately if symptoms of a new hypertensive emergency occur (e.g., neurologic symptoms, visual changes, evidence of CHF).1

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.1

• Importance of informing patients of other important precautionary information.1 (See Cautions.)

Clevidipine is used to treat high blood pressure (hypertension). High blood pressure adds to the workload of the heart and arteries. If it continues for a long time, the heart and arteries may not function properly. This can damage the blood vessels of the brain, heart, and kidneys, resulting in a stroke, heart failure, or kidney failure. High blood pressure may also increase the risk of heart attacks. These problems may be less likely to occur if blood pressure is controlled.

Clevidipine is a calcium channel blocker. It works by affecting the movement of calcium into the cells of the heart and blood vessels. As a result, clevidipine relaxes blood vessels and increases the supply of blood and oxygen to the heart while reducing its workload.

This medicine is available only with your doctor's prescription.

The following risk is discussed elsewhere in the labeling:

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

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.

Perioperative Hypertension

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).

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.

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.

No clinical drug interaction studies were conducted. Clevidipine and its major dihydropyridine metabolite do not have the potential for blocking or inducing any CYP enzyme.

You should not receive Cleviprex if you are allergic to clevidipine, eggs, or soy products. You also should not receive Cleviprex if you have high cholesterol or triglyceride levels in your blood, pancreatitis with high cholesterol or triglycerides, a kidney disorder called lipoid nephrosis, or severe narrowing of the aortic valve in your heart (aortic stenosis).

Before you receive Cleviprex, tell your doctor if you have food allergies, pancreatitis, pheochromocytoma (an adrenal gland tumor), heart disease, or a history of high cholesterol.

In an emergency situation it may not be possible before you are treated to tell your caregivers about your health conditions or if you are pregnant or breast feeding. Make sure any doctor caring for you afterward knows that you have received this medication.

Tell your doctor about all other heart or blood pressure medications you are using.

If you are also taking a beta-blocker (such as Betapace, Coreg, Corgard, Dutoprol, Inderal, InnoPran, Lopressor, Normodyne, Tenormin, Tenoretic, Toprol, Trandate, and others), do not suddenly stop using the beta blocker without first talking to your doctor. You may need to use less and less before you stop the medication completely. Stopping a beta blocker too quickly can cause serious heart problems that will not be prevented by Cleviprex.