jueves, 28 de enero de 2016

Clinical Pharmacology Corner: FDA Approves BRIDION (Sugammadex)

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FDA Approves BRIDION (Sugammadex) for the Reversal of Neuromuscular Blockade Induced by Rocuronium Bromide and Vecuronium Bromide in Adults Undergoing Surgery
On December 15, 2015, the United States Food and Drug Administration (FDA) approved BRIDION® (Sugammadex) injection for the reversal of neuromuscular blockade induced by rocuronium bromide and vecuronium bromide in adults undergoing surgery. Doses and timing of BRIDION administration should be based on monitoring for twitch responses and the extent of spontaneous recovery that has occurred. Administer BRIDION intravenously as a single bolus injection. The bolus injection may be given over 10 seconds, into an existing intravenous line. BRIDION can be used to reverse different levels of rocuronium- or vecuronium-induced neuromuscular blockade. The approved recommended BRIDION dosages are listed below. The use of lower than recommended doses of BRIDION may lead to an increased risk of recurrence of neuromuscular blockade after initial reversal and is not recommended.
For rocuronium and vecuronium reversal:
  • 4 mg/kg is recommended if spontaneous recovery of the twitch response has reached 1-2 post-tetanic counts (PTC) and there are no twitch responses to train-of-four (TOF) stimulation.
  • 2 mg/kg is recommended if spontaneous recovery has reached the reappearance of the second twitch (T2) in response to TOF stimulation.
For rocuronium only:
  • 16 mg/kg is recommended if there is a clinical need to reverse neuromuscular blockade soon (approximately 3 minutes) after administration of a single dose of 1.2 mg/kg of rocuronium.
Mechanism of Action (MOA), General Pharmacokinetics (PK) and Pharmacodynamics (PD) of Sugammadex
Sugammadex pharmacokinetic parameters were calculated from the total sum of non-complex-bound and complex-bound concentrations of sugammadex which are assumed to be the same in anesthetized patients. 
  • MOA: Sugammadex forms a complex with the neuromuscular blocking agents rocuronium and vecuronium that reduces the amount of neuromuscular blocking agent available to bind to nicotinic cholinergic receptors in the neuromuscular junction. 
  • Impurities: BRIDION may contain up to 7% of the mono OH-derivative of sugammadex. The mono OH-derivative was demonstrated to have approximately 50% of the affinity as sugammadex for rocuronium and vecuronium and that product, with up to 7% of the mono OH-derivative, has nearly similar efficacy in reversing rocuronium- or vecuronium-induced blockade in preclinical pharmacology studies.
  • Dose Proportionality: Sugammadex exhibits linear kinetics in the dosage range of 1 (50% of the lowest approved recommended dosage) to 16 mg/kg.
  • Plasma Protein Binding: Neither sugammadex nor the complex of sugammadex and rocuronium binds to plasma proteins or erythrocytes in vitro.
  • Half-life: The elimination half-life of sugammadex is about 2 hours in adult anesthetized patients with normal renal function.
  • Metabolism: No sugammadex metabolites were observed in clinical studies.
  • Excretion: More than 90% of a radio-labeled sugammadex dose was excreted within 24 hours in a clinical study. Ninety-six percent of this dose was excreted in urine (at least 95% unchanged) and less than 0.02% was excreted via feces or expired air.
  • Dose-response: A dose-response relationship for rocuronium and vecuronium reversal was observed at BRIDION dosages ranging from 0.5 mg/kg (25% of the lowest approved recommended dosage) to 16 mg/kg in clinical trials.
Drug Interaction Potential: 
Drug interaction potential was determined using binding affinity between sugammadex and other drugs, preclinical experiments, clinical studies, and simulations using a pharmacokinetic-pharmacodynamic (PK-PD) model. With the exception of toremifene and hormonal contraceptives, no clinically significant pharmacodynamic interactions with other drugs are expected.  
  • The recovery to TOF ratio to 0.9 could be delayed in patients who have received toremifene on the same day of surgery. Toremifene has a relatively high binding affinity for sugammadex and some displacement of vecuronium or rocuronium from the complex with sugammadex could occur.
  • Administration of a bolus dose of BRIDION is considered to be equivalent to missing dose(s) of oral contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day that BRIDION is administered, the patient must use an additional, non-hormonal, contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days. In vitro binding studies indicate that sugammadex may bind to progestogen, thereby decreasing progestogen exposure.
  • In the case of non-oral hormonal contraceptives, the patient must use an additional, non-hormonal contraceptive method or back-up method of contraception (such as condoms and spermicides) for the next 7 days.
  • Special attention should be paid to the possibility of recurrence of neuromuscular blockade when drugs that potentiate neuromuscular blockade are used in the post-operative phase.
Laboratory Test Interference
BRIDION may interfere with the serum progesterone assay. Interference with this test was observed at sugammadex plasma concentrations of 100 mcg/mL, which may be observed for up to 30 minutes after a 16 mg/kg dose.
Use in Specific Populations
  • The risk of adverse reactions to BRIDION may be greater in patients with impaired renal function because sugammadex is substantially excreted by the kidney. BRIDION is not recommended for use in patients with severe renal impairment (estimated creatinine clearance (CLcr) by Cockcroft-Gault (C-G) method: less than 30 mL/minute) due to insufficient safety information combined with the prolonged and increased overall exposure in these patients. A 17-fold and 5-fold higher sugammadex exposure was observed in patients with severe renal impairment in two clinical studies.
  • No significant difference in the ability of sugammadex to reverse the pharmacodynamic effect of rocuronium was observed in elderly patients with mild to moderate renal impairment. Despite this, it may be useful to monitor renal function in the elderly receiving BRIDION and carefully consider dose selection because of the likelihood of decreased renal function in this population.
  • Exercise caution when administering BRIDION to patients with hepatic impairment accompanied by coagulopathy or severe edema. Dedicated trials in patients with hepatic impairment have not been conducted.
  • Sex or race did not result in a clinically significant effect on sugammadex exposure.                
Safety and Efficacy
  • Return of the T4/T1 ratio to 0.9 after the reappearance of T2 (moderate blockade) was found to be overall faster with BRIDION 2 mg/kg as compared to neostigmine 50 mcg/kg in the setting of rocuronium- or vecuronium-induced neuromuscular blockade in a multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded trial. Generally, a T4/T1 ratio ≥0.9 correlates with recovery from neuromuscular blockade.  The median time to recovery after administration of BRIDION was 1.4 minutes for rocuronium (with 25th and 75th percentiles of 1.2 and 1.7 minutes), and 2.1 minutes for vecuronium (with 25th and 75th percentiles of 1.8 and 3.4 minutes) as compared to neostigmine (21.5 minutes with 25th and 75th percentiles of 9.8 and 42 minutes for rocuronium, and 29 minutes with 25th and 75th percentiles of 12.2 and 76.2 minutes for vecuronium).
  • Return of the T4/T1 ratio to 0.9 in patients with 1 to 2 PTCs (deep blockade) with BRIDION 4 mg/kg had a wider range of recovery times as compared to neostigmine 70 mcg/kg but the median time to recovery was comparable to the study of reversal at T2 (2.7 minutes with 25th and 75th percentiles of 2.1 and 4.3 minutes for rocuronium, and 3.3 minutes with 25th and 75th percentiles of 2.3 and 6.6 minutes for vecuronium) in a multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded trial. 
  • Recovery to T1 of 10% of baseline (relative to the time of administration of rocuronium or succinylcholine) was overall faster in the rocuronium/BRIDION group compared with succinylcholine alone in a multicenter, randomized, parallel-group, active-controlled, safety-assessor blinded comparative trial of time to recovery from neuromuscular blockade induced by succinylcholine 1 mg/kg compared with recovery from neuromuscular blockade induced by rocuronium 1.2 mg/kg followed 3 minutes later with BRIDION 16 mg/kg.    
  • Most common adverse reactions reported in clinical trials were vomiting, pain, nausea, hypotension, and headache. 
  • Clinicians should be prepared for the possibility of drug hypersensitivity reactions (including anaphylactic reactions) and take the necessary precautions. 
  • Cases of marked bradycardia, some of which have resulted in cardiac arrest, have been observed within minutes after the administration of BRIDION. Patients should be closely monitored for hemodynamic changes during and after reversal of neuromuscular blockade. Treatment with anticholinergic agents, such as atropine, should be administered if clinically significant bradycardia is observed. 

Full prescribing information is available at http://go.usa.gov/cQfdj
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).
The Office of Clinical Pharmacology (OCP) regulatory reviews for new drugs or biologics are often available for viewing shortly following approval at the Agency's Drugs@FDA website (http://go.usa.gov/cQfGY). 
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This burst was prepared by the OCP review team including Srikanth C. Nallani, Ph.D., Atul V. Bhattaram, Ph.D., Kevin Krudys, Ph.D., and Yun Xu, Ph.D., Division of Clinical Pharmacology II and Division of Pharmacometrics, Office of Clinical Pharmacology, Office of Translational Sciences, CDER, FDA.

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