Clevidipine

Registered South African indications:

• Reduction of blood pressure when oral therapy is not feasible or not desirable

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Hypersensitivity to soybeans, refined soya-bean oil; soy products; peanuts; eggs or egg products
• Defective lipid metabolism, such as pathologic hyperlipemia, lipoid nephrosis, or acute pancreatitis accompanied by hyperlipidemia
• Severe aortic stenosis due to the risk of reduced myocardial oxygen delivery caused by excessive afterload reduction

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment

Aseptic technique

• Strict aseptic technique must be used when handling the product
• Discard any unused product within 12 hours of stopper puncture to avoid contamination and potential systemic infection

Hypotension and reflex tachycardia

• Rapid reductions in blood pressure may lead to systemic hypotension and reflex tachycardia
• If hypotension or reflex tachycardia occurs, consider reducing the dose by half or stopping the infusion

Use in specific cardiovascular conditions

• Patients with aortic stenosis, hypertrophic obstructive cardiomyopathy, mitral stenosis, aortic dissection, or pheochromocytoma have not been studied in clinical trials with clevidipine

Hypoxia

• Clevidipine should not be used in patients with uncorrected critical aortic stenosis, as excessive afterload reduction may reduce myocardial oxygen delivery
• For patients who have undergone valve replacement surgery, clevidipine may be used post-operatively if compensatory mechanisms for decreased blood pressure are restored
• Patients with hypertrophic obstructive cardiomyopathy or mitral stenosis may also be at risk of reduced oxygen delivery
• Use with caution in patients unable to increase their heart rate adequately  for reduced blood pressure, such as those with left bundle-branch block or primary ventricular pacing

Limited data for certain conditions

• Limited data exists for the use of clevidipine in acute myocardial infarction or acute coronary syndrome

Sodium content

• Clevidipine contains less than 1 mmol sodium (23mg) per vial, which is considered essentially 'sodium-free

Effects on ability to drive and use machines

• Clevidipine has a moderate influence on the ability to drive and use machines
• It may cause dizziness, potentially interfering with activities such as driving or operating machinery
• However, patients receiving clevidipine will remain hospitalised for the duration of treatment

Forms avail. in SA and covered in this monograph: inj

South African registered indications and dosages

Reduction of blood pressure when oral therapy is not feasible or not desirable

• IV: Initial: 2mg/hr (4ml/hr); Double dose every 90secs if needed; Continue titration until desired target range is achieved; Maintenance: Desired therapeutic response for most patients occurs at doses of 4-6mg/hr (8-12ml/hr); Max: 32mg/hr (64ml/hr)

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Clevidipine is intended for intravenous use

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Titrate medicine to achieve the desired blood pressure reduction. Individualise dosage depending on the blood pressure to be obtained and the response of the patient. Blood pressure and heart rate must be monitored continually during the infusion, and then until vital signs are stable. See Monitoring for other parameters to check

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Maximum dose
Most patients in clinical studies were treated with doses of 16mg/hr (32ml/hr) or less
The maximum recommended dose is 32mg/hr (64ml/hr). Patients with severe hypertension may require doses up to 32mg/hr (64ml/hr), but there is limited experience with this dose rate. No more than 1000ml of clevidipine infusion is recommended per 24hr period due to the associated lipid load. There is limited experience with clevidipine infusion durations beyond 72hr at any dose

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Patients on other lipid-based therapies
Clevidipine contains approximately 0.2g of lipid per ml (8.4 kJ/2.0kcal). In patients with lipid load restrictions the quantity of concurrently administered lipids may need to be adjusted to compensate for the amount of lipid infused as part of the clevidipine formulation

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See Additional Prescribing Points for details for transition to an oral antihypertensive medicine and instructions of use

Not established for use in children below 18 years

Pregnancy 

South African recommendations

• Caution; not recommended
• There is no adequate data from the use of clevidipine in pregnant women. Rats dosed with clevidipine during late gestation and lactation showed a dose-related increase in mortality, length of gestation, and prolonged parturition at dose levels of 13.35, and 55mg/kg/day
• Clevidipine has been shown to cross the placenta in rats. No evidence of embryo-foetal malformation was found with continuous IV infusion of clevidipine during the period of organogenesis at doses up to 13mg/kg/day in pregnant rats and 35mg/kg/day in pregnant rabbits (2.8 to 7.6 times the expected human dose of 16mg/hour)
• Embryo-foetal toxicity (intrauterine deaths, slightly reduced foetal weight, retarded skeletal development, abortion, and embryo lethality) was seen with continuous IV infusion of clevidipine during the period of organogenesis at 35mg/kg/day in pregnant rats and at 55mg/kg/day in pregnant rabbits (7.6 to 12 times the expected maximum human dose of 16mg/hour)
• In rats, a reduction in ossification of paws was observed that included partially ossified metacarpals, metatarsals and phalanges suggesting developmental retardation
• Renal pelvic cavitation was also observed. In addition, malrotations of a hind limb were observed that were not considered related to skeletal alterations
• Rabbits exhibited a reduction in ossification of supraoccipital bones and sternebrae and unossified heads of longlimb bones
• In addition, an increase in fused and/or misaligned sternebrae were observed. There was no evidence that clevidipine was teratogenic at the highest dose levels studied in pregnant rats and rabbits
• Clevidipine should not be used during pregnancy unless clearly necessary

Breastfeeding

South African recommendations

• Caution; not recommended
• It is unknown whether clevidipine is excreted in human breast milk. The excretion of clevidipine in milk has not been studied in animals
• Clevidipine should not be used during breastfeeding

Fertility

South African recommendations

• There were no adverse effects on fertility or mating behaviour of male rats at celvidipine doses of up to 55mg/kg/day, approximately equivalent to the maximum recommended human dose (MRHD) of 504mg/day (21mg/hour x 24 hours) on a body surface area basis
• Female rats demonstrated pseudopregnancy and changes in estrus cycle at doses as low as 13mg/kg/day (about 1/4th the MRHD); however, doses of up to 55mg/kg/day did not affect mating performance or fertility

South African recommendations

• Caution; no dose adjustment recommended
  Data regarding the dosage regimen in patients with renal impairment is limited and has not been specifically studied
  The recommended titration of clevidipine does not need to be adjusted in patients with renal impairment

South African recommendations

• Caution; no dose adjustment recommended
  Data regarding the dosage regimen in patients with hepatic impairment is limited and has not been specifically studied. No dose adjustment is required in patients with hepatic impairment

South African recommendations

• No dose adjustment recommended

Cardiac Disorders

Common

• Atrial fibrillation
• Sinus tachycardia

Uncommon

• Atrial flutter
• Tachycardia
• Cardiac failure congestive
• Bradycardia
• Complete atrioventricular block
• Bundle branch block

Gastrointestinal Disorders

Uncommon

• Constipation
• Nausea
• Vomiting

Rare

• Ileus

General Disorders and Administration Site Conditions

Common

• Oedema
• Chest pain

Investigations

Very rare

• Increased blood triglycerides

Nervous System Disorders

Uncommon

• Dizziness
• Headache

Renal and Urinary Disorders

Common

• Acute kidney injury

Respiratory, Thoracic and Mediastinal Disorders

Common

• Hypoxia

Uncommon

• Pulmonary congestion

Vascular Disorder

Common

• Hypotension

Additional adverse reactions (as seen in clinical studies in patients in non-perioperative settings)

Common

• Flushing
• Feeling hot
• Polyuria

Uncommon

• Hypersensitivity
• Myocardial infarction
• Cardiac arrest
• Syncope
• Dyspnoea

• Oral or IV antihypertensive medicines, including beta-blockers (see Additional Prescribing Points)

• Blood pressure
• Heart rate

Specific cases may require

• Triglycerides (with concurrent administration with propofol (or other sources of lipids))

Additional observations

• Patients who receive prolonged infusions of clevidipine and are not transitioned to other antihypertensive therapy should be monitored for the possibility of rebound hypertension for at least 8 hours after discontinuation

Clevidipine is a dihydropyridine L-type calcium channel blocker. L-type calcium channels mediate the influx of calcium during depolarisation in arterial smooth muscle. Experiments in anaesthetised 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.