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warnings and cautions
5 WARNINGS AND PRECAUTIONS Maintain aseptic technique. Discard unused portion 12 hours after stopper puncture. (5.1) Hypotension and reflex tachycardia are potential consequences of rapid upward titration of Cleviprex. (5.2) Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. (5.4) Cleviprex gives no protection against the effects of abrupt beta-blocker withdrawal. (5.5) Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. (5.6) 5.1 Need for Aseptic Technique Use aseptic technique and discard any unused product within 12 hours of stopper puncture [see Dosage and Administration (2.3)] . 5.2 Hypotension and Reflex Tachycardia Cleviprex may produce systemic hypotension and reflex tachycardia. If either occurs, decrease the dose of Cleviprex. There is limited experience with short-duration therapy with beta-blockers as a treatment for Cleviprex-induced tachycardia. Beta-blocker use for this purpose is not recommended. 5.3 Lipid Intake Cleviprex contains approximately 0.2 g of lipid per mL (2.0 kcal). Lipid intake restrictions may be necessary for patients with significant disorders of lipid metabolism. For these patients, a reduction in the quantity of concurrently administered lipids may be necessary to compensate for the amount of lipid infused as part of the Cleviprex formulation. 5.4 Negative Inotropy Dihydropyridine calcium channel blockers can produce negative inotropic effects and exacerbate heart failure. Monitor heart failure patients carefully. 5.5 Beta-Blocker Withdrawal Cleviprex is not a beta-blocker, does not reduce heart rate, and gives no protection against the effects of abrupt beta-blocker withdrawal. Withdraw beta-blockers only after a gradual reduction in dose. 5.6 Rebound Hypertension Patients who receive prolonged Cleviprex infusions and are not transitioned to other antihypertensive therapies should be monitored for the possibility of rebound hypertension for at least 8 hours after the infusion is stopped. 5.7 Pheochromocytoma There is no information to guide use of Cleviprex in treating hypertension associated with pheochromocytoma.
6 ADVERSE REACTIONS The following risk is discussed elsewhere in the labeling: Hypotension and Reflex Tachycardia [see Warnings and Precautions (5.2)] Most common adverse reactions (>2%) are headache, nausea, and vomiting. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Chiesi USA, Inc. at 1-888-661-9260 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 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. Use in Perioperative Hypertension The placebo-controlled experience with Cleviprex in the perioperative setting was both small and brief (about 30 minutes). Table 1 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 1. Common adverse reactions in placebo-controlled perioperative studies. ESCAPE-1 ESCAPE-2 CLV N=53(%) PBO N=51(%) CLV N=61(%) PBO N=49(%) Any common adverse event 27 (51%) 21 (41%) 32 (53%) 24 (49%) Acute renal failure 5 (9%) 1 (2%) -- -- Atrial fibrillation -- -- 13 (21%) 6 (12%) Nausea -- -- 13 (21%) 6 (12%) 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. Use in 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 6.2 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.