Cleviprex

Generic Name: Clevidipine Butyrate
Class: Dihydropyridines
VA Class: CV200
Chemical Name: 4-(2,3-Dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid methyl (1-oxobutoxy)methyl ester
Molecular Formula: C₂₁H₂₃Cl₂NO₆
CAS Number: 167221-71-8

Introduction

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

Uses for Cleviprex

Hypertension

Used to reduce BP when oral antihypertensive therapy is not feasible or desirable.¹

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Use for treatment of hypertension associated with pheochromocytoma not established.¹

Cleviprex Dosage and Administration

General

• Individualize dosage according to the patient’s response to achieve the desired BP reduction.¹

• Monitor BP and heart rate continuously during IV infusion and until vital signs are stable.¹ In patients being transferred to an oral antihypertensive agent, continue BP monitoring until the desired effect is achieved.¹

• Patients who receive prolonged infusions and are not transferred to other antihypertensives should be monitored for rebound hypertension for ≥8 hours following discontinuance of infusion.¹ (See Rebound Hypertension under Cautions.)

Administration

IV Administration

Administer by IV infusion into a central or peripheral vein using an infusion device allowing calibrated infusion rates.¹

Commercially available standard plastic cannulae may be used to administer the infusion.¹

Vials are for single use only.¹

Use strict aseptic technique since emulsion can support microbial growth.^{1 11}

Invert vials gently several times before use to ensure uniformity of the emulsion prior to administration.¹

Administration must be completed within 4 hours after initial puncture of the vial stopper; discard any unused portions after 4 hours.¹

Do not administer in the same IV line as other drugs.¹

Clevidipine emulsion should not be diluted; however, it may be administered with sterile water for injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.9% sodium chloride injection, lactated Ringer’s and 5% dextrose injection, lactated Ringer’s injection, or 10% amino acid injection.¹

Dosage

Available as clevidipine butyrate; dosage expressed in terms of the salt.¹

Adults

Hypertension

IV

Initially, 1–2 mg/hour.¹ Initially, dosage may be doubled at short (90-second) intervals; as BP approaches the desired value, increase dosage in smaller increments (less than doubling) at 5- to 10-minute intervals.¹

An increase in dosage of approximately 1–2 mg/hour generally produces an additional 2- to 4-mm Hg decrease in SBP.¹ Desired therapeutic responses usually occur at dosages of 4–6 mg/hour.¹

Patients with severe hypertension: Most patients have received maximum dosages of ≤16 mg/hour; however, dosages up to 32 mg/hour may be required.¹

Patients being transferred to an oral antihypertensive agent: Discontinue clevidipine or decrease dosage while appropriate oral therapy is established; consider lag time to onset of the oral antihypertensive agent’s effects.¹

Prescribing Limits

Adults

Hypertension

IV

Usually, maximum 16 mg/hour; limited, short-term experience with dosages up to 32 mg/hour and limited experience with infusion durations >72 hours at any dosage.¹

Administer a maximum 1 L of clevidipine emulsion in a 24-hour period (average dosage of 21 mg/hour) because each mL of emulsion contains 200 mg of lipids.¹ (See Lipid Intake under Cautions.)

Special Populations

Hepatic Impairment

Hypertension

IV

Initially, 1–2 mg/hour.¹

Renal Impairment

Hypertension

IV

Patients with moderate to severe renal impairment: Initially, 1–2 mg/hour.¹

Geriatric Patients

Careful dosage selection, usually starting at the low end of the dosing range, recommended due to possible age-related decrease in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.¹

Cautions for Cleviprex

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

Pregnancy

Category C.¹

Lactation

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

Pediatric Use

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

Geriatric Use

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}

No clinical drug interaction studies performed to date.^{1 11}

Does not appear to inhibit or induce CYP isoenzymes at clinically relevant concentrations in vitro.¹

Cleviprex Pharmacokinetics

Absorption

Onset

Reduces SBP by 4–5% within 2–4 minutes after initiation of an IV infusion of 0.4 mcg/kg per minute.¹

Duration

Full recovery of BP generally occurs within 5–15 minutes following discontinuance of infusion.^{1 2 3 4 5 6 7 8 9 10}

Distribution

Extent

Rapidly distributed.^{1 2 3 4 7 8}

Plasma Protein Binding

>99.5%.¹

Elimination

Metabolism

Rapidly metabolized via hydrolysis, principally by esterases in the blood and extravascular tissues, to form an inactive carboxylic acid metabolite and formaldehyde.^{1 2 3 4 5 6 8 9 10}

Elimination Route

Excreted in urine (63–74%) and in feces (7–22%).^{1 6 7 10}

Half-life

Multiphasic; initial half-life is about 1 minute (accounts for 85–90% of elimination) and terminal half-life is about 15 minutes.^{1 2 3 4 7 8 9 10}

Special Populations

Elimination unlikely to be affected by hepatic or renal dysfunction.^{1 2 3 4 5 6 8 9 10}

Stability

Storage

Parenteral

Injectable Emulsion

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

Solution Compatibility

Actions

• 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}

Advice to Patients

• 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.