Summary Basis of Decision for Cleviprex ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
CleviprexTM
Clevidipine, 0.5 mg/mL, Emulsion, Intravenous
The Medicines Company
Submission control no: 125287
Date issued: 2011-07-11
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02366223
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On April 15, 2011, Health Canada issued a Notice of Compliance to The Medicines Company for the drug product, Cleviprex.
Cleviprex contains the medicinal ingredient clevidipine which is an anti-hypertensive agent.
Cleviprex is indicated for the management of acute elevation of blood pressure in perioperative settings. The medicinal ingredient clevidipine, a 1,4-dihydropyridine L-type calcium channel antagonist, lowers arterial blood pressure by decreasing systemic vascular resistance due to an action mainly on resistance (arterial) blood vessels. Clevidipine does not reduce cardiac filling pressure (pre-load), confirming lack of effects on the venous capacitance vessels.
The market authorization was based on quality, non-clinical, and clinical information submitted. The efficacy and safety of Cleviprex were demonstrated in two Phase III double-blind, randomized, parallel, placebo-controlled, multicentre studies (ESCAPE-1 and ESCAPE-2). Both studies used cardiac surgery patients; pre-operative use in ESCAPE-1 [number of patients (n) = 105] and post-operative use in ESCAPE-2 (n = 110).
Cleviprex (0.5 mg/mL, clevidipine) is presented as an emulsion for intravenous infusion and should be administered using aseptic techniques. The initial dose should be at a rate of 1-2 mg/h. The dose may be doubled at short (90 second) intervals until the desired blood pressure level is about to be reached. Continue titration until the desired target range is achieved by increasing the dose in smaller increments and at longer intervals (5-10 minutes). A 1-2 mg/h increase will generally produce an additional 2-4 mm Hg decrease in systolic pressure. The desired therapeutic response for most patients occurs at doses of 4-6 mg/h. Patients may require doses up to 32 mg/h, but there is limited experience at this dose rate. Dosing guidelines are available in the Product Monograph.
Cleviprex is contraindicated for patients that have an allergy to clevidipine, soybeans or soy products, or eggs or egg products; patients that have defective lipid metabolism, or severe aortic stenosis. Cleviprex should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Cleviprex are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Cleviprex is favourable for the management of acute elevation of blood pressure in perioperative settings.
3 Scientific and Regulatory Basis for Decision
A New Drug Submission (NDS) for Cleviprex was filed with Health Canada in October 2008. Upon review, Health Canada concluded that the data and analyses as presented did not support the use of Cleviprex for the submitted indication, and therefore issued a Notice of Non-Compliance (NON) on October 30, 2009. After the response to the NON letter was received, a recommendation was pending because of a manufacturing problem (visible particulate matter in suspension in the vials) that led the sponsor to withdraw several lots from the United States market. Health Canada postponed any decision until this potential safety issue was addressed and the manufacturing process was modified. The sponsor submitted the results of their investigations and a reviewed manufacturing process and process validation on October 21, 2010. With the changes made, the drug product specifications were qualified and were found to support the proposed limits. Questions regarding degradants and impurities in the drug product were resolved satisfactorily, and Health Canada then continued to respond to the clinical issues. In response to the NON, the original indication was revised to be consistent with the efficacy and safety data as reflected in the Phase III clinical studies, and a Notice of Compliance (NOC) was issued for Cleviprex on April 15, 2011. A timeline of these events are reported in section 4 Submission Milestones.
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Clevidipine is the medicinal ingredient of Cleviprex. Clevidipine is classed as an anti-hypertensive agent. It is a calcium channel blocker with the physiologic effect of rapid, selective, arterial vasodilation.
Manufacturing Process and Process Controls
The drug substance is synthetically derived. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance;
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements; and
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of clevidipine has been adequately elucidated. Confirmation of the chemical structure was provided by elemental analysis and spectroscopic analysis.
Clevidipine is a racemic mixture of (+)-S and (-)-R enantiomers. Both enantiomers have been shown to be clinically active.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. These products were found to be within ICH-established limits and/or were qualified from toxicological studies and therefore are considered acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of clevidipine are considered acceptable.
Data from the batch analyses were reviewed and are within the proposed acceptance criteria.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, and accelerated stability data submitted, the proposed retest period and storage conditions for the drug substance were supported and are considered satisfactory.
3.1.2 Drug Product
Description and Composition
Cleviprex is supplied as a sterile, milky-white, oil-in-water emulsion for intravenous injection.
The product is supplied in single-use 50 mL or 100 mL glass vials. Each vial contains 0.5 mg/mL clevidipine. Vials are sealed with a 28 mm black elastomeric stopper and capped with 28 mm flip-off aluminium overseal.
The non-medicinal ingredients are soybean oil, glycerin, and purified egg yolk phospholipids. All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of clevidipine with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Each vial is individually packaged in its own carton and is available in boxes of 10 vials.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
The sponsor informed Health Canada on April 22, 2010, that lots of Cleviprex on the United States market, manufactured at the same facility by the same process as the Canadian proposed Cleviprex, had been recalled due to the presence of visible particulate matter in the drug product. The sponsor submitted the results of their investigations, and a revised manufacturing process and process validation protocol on October 21, 2010. To reduce potential particulate matter in the drug product, the revised manufacturing process includes enhanced equipment maintenance, revised equipment configuration and additional filtration steps for the excipients and final product. The process changes appear sufficient to reduce particulates in the drug product, and the final efficacy of the changes was assessed during process validation of the commercial process. The manufacturing site is rated compliant with the Health Product Food Branch Inspectorate.
Control of Drug Product
The drug product specifications include tests and limits for identity, potency, and purity. Impurity limits were qualified by the sponsor via toxicological evaluation, which was reviewed by Health Canada and found to support the sponsor's proposed limits. The drug product specifications also include tests and limits for key physical characteristics: appearance; particle size distribution; particulate matter; fill volume; bacterial endotoxins; sterility; pH; and identification/assay of key components soybean and phospholipid. The test specifications and analytical methods are considered acceptable; the shelf-life and the release limits for individual and total degradation products are within acceptable limits.
Validation reports submitted for all analytical procedures used for in-process and release testing of the drug product are considered satisfactory.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed shelf-life of 36-months at 2-8°C and for up to 2 months at 15-30°C is considered acceptable when the marketing package is protected from light and freezing.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Cleviprex are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
The only excipient of human or animal origin is the purified egg yolk phospholipids used as an emulsifier in the manufacture of clevidipine. Purified egg yolk phospholipids are made from hens' eggs. There are no reports of the transmission of animal spongiform encephalopathy agents via hens' eggs and there is no use of materials of ruminant origin in the processing of eggs to give egg yolk phospholipids.
Hens' eggs are not a designated risk material according to the Note for Guidance on Minimizing the Risk of transmitting Animal Spongiform Encephalopathy Agents via Human and veterinary medicinal Products (EMEA/410/01 as amended).
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Cleviprex has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
Clevidipine was shown to decrease intracellular calcium in cardiovascular and neuronal cells and to block electrically-stimulated or agonist-induced vascular and cardiac tissue contractions. The pharmacological target of clevidipine was shown to be L-type calcium channels. In spontaneously hypertensive rats (SHR), clevidipine dose-dependently decreased mean arterial blood pressure (MAP) in an extent similar to other drugs in the same class [for example (i.e.) felodipine, isradipine, nicardipine] and demonstrated a short recovery time after the end of the infusion. The two enantiomers of clevidipine similarly reduced MAP whereas its primary metabolite did not itself induce MAP change.
The dose range associated with a decrease in MAP of 20% was evaluated at 2-20 nmol/kg/min in SHR and at 20-30 nmol/kg/min in dogs. In the latter species, a sedative effect, of unknown clinical significance, was observed at a dose of 600 nmol/kg/min. In addition, clevidipine increased the heart rate in conscious but not in anaesthetised rats and dogs. No change on electrocardiogram tracings was observed in SHR following drug administration apart from a decreased PQ-time of unknown clinical significance. The effects of clevidipine on biochemical parameters (i.e., body temperature, blood pH, pCO2, non-esterified fatty acids and triglycerides, plasma potassium and sodium) were also assessed and only a decrease in plasma sodium was observed. In dogs, clevidipine was shown to reduce vascular resistance and vagal nerve stimulation of heart rate but had no effect on parameters assessing cardiac contractility.
Clevidipine dose-dependently reduced urine flow, potassium excretion, glomerular filtration rate, gastric emptying, and small intestinal propulsion in rats. It also decreased bleeding time but did not affect skeletal muscle contraction. The effects of clevidipine on other systems were not assessed.
3.2.2 Pharmacokinetics
Absorption
In the intravenous infusion studies with rats, rabbits, and dogs, the mean steady-state blood concentrations increased linearly as a function of the dose infused. Clevidipine had a short half-life in all three species.
Distribution
Following intravenous bolus administration or short infusion in rats, clevidipine was found to be widely distributed throughout the body. Radioactive clevidipine or metabolites were still detectable at 28 days post-injection in most tissues and they were shown to penetrate the blood-brain and placental barriers.
The plasma protein binding of clevidipine was high in rats, rabbits, dogs, and pigs (>99.5%).
Metabolism
Clevidipine was rapidly hydrolysed to its primary metabolite (H 152/81) in rat, dog, and human blood with corresponding mean half-lives of 34 sec, 16 min and 6 min, respectively. Its half-life was inversely correlated with blood temperature whereas it was not affected by blood dilution (1:2) although higher dilutions have not been assessed. The half-life was also shown to be increased in blood and plasma of patients heterozygous or homozygous for an atypical plasma cholinesterase.
The effect of clevidipine on different cytochrome P450 (CYP) isoforms was also assessed. In microsomes, clevidipine principally inhibited CYP3A4, CYP2C19 and CYP2C9 isoforms. The metabolite H 152/81 also had an inhibitory effect on the same isoforms but the concentrations required to get 50% inhibition of each isoform activity (IC50) were higher than those of clevidipine. Further assessment would be required to clearly identify possible drug interactions involving these particular CYP isoforms. Common anaesthetic drugs (thiopental sodium, propofol, isoflurane, morphine and diltiazem) had no effect on the hydrolysis rate of clevidipine to its primary metabolite. Nevertheless, this hydrolysis rate was found to be increased by fentanyl and reduced by pancuronium bromide and vecuronium bromide.
Excretion
In rats and dogs, clevidipine was mainly excreted via faeces (45-68% and 42-73%, respectively) and to a lesser extent via urine (22-43% and 12-42%, respectively). A study performed with dogs showed that about 12% of the given dose was recovered as intact drug in the faeces whereas the remainder was excreted as different metabolites.
3.2.3 Toxicology
Single-Dose Toxicity
In mice and male rats, the maximum non-lethal dose levels (140 and 110 mg/kg, respectively) were reported as up to 30 times the daily dose (4.6 mg/kg or approximately 16 mg/hour) that would likely be used therapeutically. Signs of acute toxicity in one or both rodent species (decreased activity, decreased motor activity, ataxia, convulsions, irregular breathing, cyanosis) mainly affected the central nervous system and/or respiratory systems.
Repeat-Dose Toxicity
The no-observed-adverse-effect-levels (NOAELs) were considered to be 23 and 6.8 mg/kg/day in rats and dogs, respectively. Based on a projected human dose of 4.6 mg/kg/day administered intravenous (IV) for a few hours to up to 72 hours, the NOAEL in rats and dogs represent approximately 5-fold and 1.5-fold, respectively, the anticipated daily human dose on a mg/kg/day basis. The steady-state concentrations at the NOAELs in rats and dogs are not greatly different from anticipated concentrations in patients; however, the NOAEL values in animals were derived from studies of 14 or 28 days representing durations exceeding the maximum anticipated in patients.
In the repeat-dose toxicology studies, none of the deaths were attributed to clevidipine, and limited clinical findings occurred only at high dose levels.
Study findings attributed to clevidipine consisted of: subdued behavior at 37 and 198 mg/kg in rats and at 32 and 98 mg/kg in dogs; prolapse of nictitating membrane in dogs at 32 and 98 mg/kg; peripheral vasodilation in dogs at ≥16 mg/kg for 5 days; increased water consumption and urine output in rats at ≥23 mg/kg for 1 month; increased heart weight in rats at ≥6.6 mg/kg for 2 weeks and ≥22 mg/kg for 4 weeks; markedly increased heart rate at ≥16 mg/kg for 5 days and at 6.8 to 66 mg/kg with associated decreases in QT and PR intervals in dogs at 32 and 66 mg/kg for 4 weeks; cardiac lesions in dogs at 16 and 66 mg/kg for 14 days; increased adrenal and ovary weights in rats at ≥39 mg/kg for 4 weeks; and increased spleen weight at 32 and 66 mg/kg in dogs after 4 weeks.
The most significant effects in dogs were markedly increased heart rate and cardiac pathology. These and most treatment-related findings were attributed to exaggerated pharmacology and were considered to reflect compensatory effects in response to purported hypotension. Potential treatment-related effects of clevidipine on heart rate and blood pressure can be monitored and managed in the clinical setting. Increased urine output and compensatory increased water intake are expected findings with a calcium antagonist, as calcium antagonists have a direct inhibitory effect on tubular resorption.
Genotoxicity
Clevidipine was genotoxic in vitro in the Ames test, the mouse lymphoma thymidine kinase locus assay, and in the chromosomal aberration assay, but not in the in vivo mouse micronucleus test. Formaldehyde, a metabolite of clevidipine, a known genotoxicant in vitro and a probable human carcinogen, appears to be at least partially responsible for the positive in vitro results. The formaldehyde produced as a result of metabolism of clevidipine is a thousand-fold less than endogenous formation of formaldehyde and therefore is not considered to pose a genotoxic risk to patients at the proposed Cleviprex doses and durations. This conclusion is also supported by the negative in vivo mouse micronucleus conducted with clevidipine.
Carcinogenicity
Carcinogenic studies were not performed due to the intended short-term duration of human use.
Reproductive and Developmental Toxicity
No dose-related effects were observed on male fertility, early embryonic development, male reproductive assessments, organ weights, or testicular histopathology in rats. The clevidipine NOAEL for male reproduction and fertility was 55 mg/kg/day (330 mg/m2/day) in rats. There were also no effects on mating performance, fertility, and early pregnancy in female rats at doses up to 55 mg/kg/day (330 mg/m2/day). All doses (13, 35 and 55 mg/kg; 78, 210 and 330 mg/m2) of clevidipine appeared to affect estrus cycle duration and induced pseudopregnancy in a few rats.
Clevidipine was not teratogenic in rats or rabbits but there was dose-related foetal toxicity and indications of development retardation in rabbits at dose levels of 35 and 55 mg/kg (210 and 330 mg/m2). In the rat, an increased incidence of pre- or post-implantation loss at 35 and 55 mg/kg (210 and 330 mg/m2) may have been related to maternal stress or toxicity but an effect of clevidipine could not be excluded. The developmental NOAEL was 35 mg/kg (420 mg/m2) in the rabbit and 13 mg/kg (78 mg/m2) in the rat.
Administration of clevidipine at 13, 35 and 55 mg/kg from Day 6 of gestation to Day 4 post-partum in rats resulted in dose-dependent increases in mortality, length of gestation and prolonged parturition. These effects have been noted with several calcium antagonists and are believed secondary to effects on calcium signaling on uterine contractions.
3.2.4 Summary and Conclusion
Overall, the non-clinical program performed for clevidipine was appropriate to support the proposed therapeutic route and duration of administration in humans. The non-clinical risk/benefit assessment is considered acceptable and all risks are reflected in the appropriate sections of the Product Monograph.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Cleviprex reduces mean arterial blood pressure by decreasing systemic vascular resistance. The blood pressure lowering effects of the drug are rapid and dose dependent, and are achieved by decreasing systemic vascular resistance without affecting venous capacitance vessels or cardiac filling pressures.
In the perioperative patient population, Cleviprex produced a 4-5% reduction in systolic blood pressure within 2-4 minutes after starting a 0.4 µg/kg/min infusion (approximately 2 mg/h). The time to maximal onset of effect was about 10-15 minutes after the start of the infusion. Most patients returned to pre-treatment baseline values in 5-15 minutes after the infusion was stopped.
Increases in heart rate were reported. An increase in heart rate is a normal response to vasodilation and decrease in blood pressure.
3.3.2 Pharmacokinetics
Absorption
In healthy volunteers, the intravenous infusion administration of gradually increased doses of clevidipine resulted in a linear dose relationship between dose and blood concentration during steady-state.
Distribution
Clevidipine was rapidly distributed and metabolized resulting in a very short half-life. Clevidipine is >99.5% bound to proteins in plasma at 37°C. The steady-state volume of distribution was 0.17 L/kg in arterial blood.
Metabolism
Clevidipine is rapidly metabolized by hydrolysis of the ester linkage, primarily by esterases in the blood and extravascular tissues, making its elimination unlikely to be affected by hepatic or renal dysfunction. The primary metabolites are the carboxylic acid metabolite and formaldehyde formed by hydrolysis of the ester group. The carboxylic acid metabolite is inactive as an anti-hypertensive. This metabolite is further metabolized by glucuronidation or oxidation to the corresponding pyridine derivative.
Elimination
The arterial blood concentration of clevidipine declines in a multi-phasic pattern following termination of the infusion. The initial phase half-life is approximately 1 minute, and accounts for 85-90% of clevidipine elimination. The terminal half-life is approximately 15 minutes.
In a clinical study with radiolabelled clevidipine, 83% of the drug was excreted in urine and faeces. The main route of elimination was found to be renal (urine 63-74%), 7-22% was excreted in the faeces. More than 90% of the recovered radioactivity was excreted within the first 72 hours of collection.
3.3.3 Clinical Efficacy
As part of the clinical program, six Phase III studies were submitted to support the initial indication, "for the reduction of blood pressure when rapid and predictable control is desired". The Phase III studies were ESCAPE-1 and ESCAPE-2; ECLIPSE-NTG, ECLIPSE-SNP, ECLIPSE-NIC; and VELOCITY. The clinical program attempted to study two distinctly different patient populations; the perioperative mild-moderate essential hypertensive cardiac surgery patients (ESCAPE, ECLIPSE), and the severe hypertensive patient (VELOCITY). The ESCAPE I and ESCAPE II studies were randomized and placebo-controlled, and are described in more detail in the following paragraphs. The ECLIPSE studies were open-label, comparative studies, using one of the following active comparators: nitroglycerin (NTG), nitroprusside sodium (SNP), and nicardipine (NIC). The main objective of the ECLIPSE studies was to establish the safety of Cleviprex in the treatment of peripoperative hypertension. In contrast, the main objective of the open-label, uncontrolled, VELOCITY study was to confirm the efficacy and safety of Cleviprex for the treatment of severe hypertension. The VELOCITY study demonstrated that 89% of the patients reached target systolic blood pressure range within 30 minutes. However; the study did not provide adequate data to qualify or quantify the use of Cleviprex in severe hypertensive patients. The sponsor was therefore asked to restrict the use of the drug to patients in whom its use had been acceptably documented in Phase III clinical studies. The sponsor agreed with this request and modified the indication. The efficacy of Cleviprex for perioperative settings was primarily based on studies ESCAPE-1 and ESCAPE-2.
ESCAPE-1 and ESCAPE-2 were two double-blind, randomized, parallel, placebo-controlled, multicentre studies of cardiac surgery patients; pre-operative use in ESCAPE-1 (n=105) and post-operative use in ESCAPE-2 (n=110). The study population included patients that were undergoing coronary artery bypass grafting, with or without valve replacement. Inclusion in ESCAPE-1 required a systolic pressure ≥160 mm Hg. In ESCAPE-2, the entry criterion was systolic pressure of ≥140 mm Hg within 4 hours of the completed surgery. The mean baseline blood pressure was 178/77 mm Hg in ESCAPE-1 and 150/71 mm Hg in ESCAPE-2. The population of both studies included 27% females and 47% patients older than age 65.
Cleviprex was infused in ESCAPE-1 preoperatively for 30 minutes, until treatment failure, or until induction of anesthesia, whichever came first. Cleviprex was infused in ESCAPE-2 postoperatively for a minimum of 30 minutes unless alternative therapy was required. The maximum infusion time allowed in the ESCAPE studies was 60 minutes.
In both studies infusion of Cleviprex was started at a dose of 1-2 mg/hour and was titrated upwards, as tolerated, in doubling increments every 90 seconds up to an infusion rate of 16 mg/hour in order to achieve the desired blood pressure-lowering effect. At doses above 16 mg/hour increments were 7 mg/hour. The average Cleviprex infusion rate in ESCAPE-1 was 15.3 mg/hour and in ESCAPE-2 it was 5.1 mg/hour. The mean duration of exposure in the ESCAPE studies was 30 minutes for the Cleviprex-treated patients. Approximately 4% of Cleviprex-treated patients in ESCAPE-1 and 41% in ESCAPE-2 were on concomitant vasodilators during the first 30 minutes of Cleviprex administration.
The primary efficacy measure in the ESCAPE studies was the need to bailout patients, defined as a premature discontinuation of study drug during the first 30 minutes of the infusion. Results demonstrated that Cleviprex was more effective than placebo in treating preoperative and postoperative hypertension when titrated to effect in this high-risk cardiac surgical population. Efficacy was demonstrated by a statistically significantly higher rate of treatment success (absence of bailout) in the Cleviprex groups when compared with the placebo groups. Combined data from both ESCAPE studies resulted in less bailout in the Cleviprex group compared to placebo, 7.9% versus 81.9%, respectively.
The blood pressure lowering effects of Cleviprex were rapid. The median time to achieve a 15% reduction in systolic blood pressure from baseline was 5-6 minutes in patients treated with Cleviprex. The majority of patients treated with Cleviprex achieved treatment success at a dose of 3.2 µg/kg/min (16 mg/hr) or less. Patients in both studies received Cleviprex for 30 minutes on average, with a maximum duration of 1 hour.
3.3.4 Clinical Safety
Three open-label, ECLIPSE studies focused on providing safety data for the use of Cleviprex for patients in a perioperative cardiac surgery setting. These studies compared the incidence of death, stroke, myocardial infarction, and renal dysfunction in the Cleviprex group versus the active comparator groups taking nitroglycerin, nitroprusside sodium, or nicardipine; from the initiation of the study drug infusion through to post-operative Day 30. The mean study drug infusion duration in the ECLIPSE studies was 8 hours. No differences were reported in the incidence rates of death, stroke, myocardial infarction, and renal dysfunction at 30 days between the groups. The most common adverse reactions leading to study drug discontinuation in all groups were hypertension and, when combined with a beta-blocker, hypotension. The incidence of serious adverse events and associated discontinuation rates within one hour of the drug infusion were similar among patients receiving Cleviprex and all active comparators. The most common serious adverse event associated with perioperative cardiac surgery patients was atrial fibrillation, although the rate was not different between the groups. No formal statistics were applied in the ECLIPSE studies.
In the placebo-controlled ESCAPE studies (described in section 3.3.3 Clinical Efficacy), there were no clinically significant differences in the incidence rates of treatment emergent adverse events (TEAEs) or of serious TEAEs between the two treatment groups. Adverse event rates in both treatment groups were as expected for this high-risk patient population. In ESCAPE-1, there was a modest, clinically insignificant increase in heart rate in Cleviprex-treated patients during study drug administration. Laboratory values and vital signs did not raise any safety concerns in patients treated with Cleviprex. Tachycardia was increased in Cleviprex patients compared to placebo. This finding is consistent with the non-clinical data. Cleviprex did not appear to prolong QTc interval.
Rebound hypertension appeared to be dose-related. The VELOCITY study demonstrated that nervous disorders were more common in severe hypertension.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The efficacy and safety of Cleviprex for the management of acute elevation of blood pressure in perioperative settings was demonstrated in two Phase III studies (ESCAPE-1 and ESCAPE-2).
The key clinical advantage of intravenously infused Cleviprex for lowering arterial pressure is its rapid onset and offset. A clinically significant reduction can be obtained within a few minutes and a maximal effect attained in 10-15 minutes after the beginning of the infusion. When the infusion is stopped, return to pre-infusion pressure levels are seen in 5 to 15 minutes in most patients. Cleviprex also offers an alternative treatment for patients who need reduction in blood pressure to prevent potential cardiovascular adverse outcomes but are not candidates for other short-acting intravenous therapy or in cases where oral therapy is not appropriate or feasible.
The risk of using Cleviprex is considered acceptable as patients in perioperative settings should be adequately monitored to maintain their blood pressure at desired levels. An advantage of using a calcium channel blocker is that, unlike nitroglycerin or nitroprusside, clevidipine acts selectively on the arterial side to reduce peripheral resistance and thus would not increase significantly vascular capacitance and consequent potential deleterious reduction in venous return and cardiac output.
Overall, the benefit-risk profile is positive taking into account that patients needing therapy with short onset and offset to reduce their blood pressure will be exposed to Cleviprex in perioperative settings and, thus, adequately monitored.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Cleviprex is favourable for the management of acute elevation of blood pressure in perioperative settings.The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: CleviprexTM
| Submission Milestone | Date |
|---|---|
| Submission filed: | 2008-10-07 |
| Screening 1 | |
| Screening Deficiency Notice issued: | 2008-11-14 |
| Response filed: | 2008-11-26 |
| Screening Acceptance Letter issued: | 2009-01-05 |
| Review 1 | |
| Quality Evaluation complete: | 2009-10-27 |
| Clinical Evaluation complete: | 2009-10-28 |
| Notice of Non-Compliance issued by Director General efficacy issues): | 2009-10-30 |
| Response filed: | 2010-01-25 |
| Screening 2 | |
| Screening Acceptance Letter issued: | 2010-03-16 |
| Review 2 | |
| Quality Evaluation complete: | 2011-03-09 |
| Clinical Evaluation complete: | 2010-08-16 |
| Labelling Review complete: | 2011-03-26 |
| Notice of Compliance issued by Director General: | 2011-04-15 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| CLEVIPREX | 02366223 | CHIESI FARMACEUTICI S.P.A. | CLEVIDIPINE 0.5 MG / ML |