FDA Group Urges Sux Label Wording Reduced to 'Warning'

Robert C. Morell, M.D.

Adoption of a drug label statement that succinylcholine is contraindicated in pediatric patients provoked a great deal of discussion, including in an extensive debate and editorial in the Spring 1994 APSF Newsletter. Subsequent events have led to a strong recommendation that this contraindication be downgraded to a warning. Outlined here is the chronology of the involved events, revealing to the anesthesiology community for the first time the process by which drug labeling, particularly involving perceived hazards, occurs.

The Issue

The elective use of succinylcholine in children and adolescents has been a topic of intense controversy during the last two years. Corporate, academic, and federal representatives have debated the relative risks and benefits in the anesthesia literature and in the governmental regulatory arena. A great deal of ‘grass roots’ testimony by practicing anesthesiologists from all areas of the country has also been submitted to the U.S. Food and Drug Administration (FDA). The primary issue at the center of the debate is the potential ability of succinylcholine to precipitate an acute hyperkalemic cardiac arrest in children with undiagnosed myopathies (usually Duchenne’s muscular dystrophy). The debate would not exist except for the fact that many anesthesiologists believe that no other drug possesses the same pharmacokinetic and pharmacodynamics characteristics, or allows intramuscular administration.

It is not the purpose of this review to comment on the relative merit of the arguments put forth by any of the participants in this debate. Rather, the intent is to describe the process by which succinylcholine became relatively contraindicated in children and adolescents and the ongoing process which will likely result in the removal of the “contraindication’ label regarding children and, as an alternative, the establishment of a warning for the manufacturer’s package insert.

The Beginning

In 1992, Drs. H. Rosenberg and G. Gronert (1) published a letter in Anesthesiology briefly reviewing four deaths in male children under the age of eight who had received halothane and then succinylcholine. These cases were identified through the Malignant Hyperthermia (MH) Hotline. Reference was also made to “II similar cases” identified through the German MH Hotline. Their letter concluded with the statement: ‘We have notified the Food and Drug Administration of this potential problem and recommended that anesthesiologists carefully consider the indications for use of succinylcholine in young children.’ This letter was accepted for publication August 24,1992.

Enter the FDA

The Pilot Drug Evaluation Staff of the FDA is responsible for succinylcholine, as it is for all anesthetic drug products.’ Pharmaceutical manufacturers and the FDA share responsibility for the proper labeling of all drug products. The labeling of any drug involves an ongoing process. In the case of succinylcholine, four manufacturers exist. Burroughs Wellcome (one of those four manufacturers) prepared an initial draft of a new label. This draft was revised by the Pilot Drug review team.

Enter the Anesthetic and Life Support Drugs Advisory Committee (ALSAC)

This committee serves in an advisory capacity to the Pilot Drug Evaluation Staff of the FDA. The ALSAC committee met on November 23, 1992, and considered the revised labeling of succinylcholine. Representatives from all manufacturers, the committee members, consultants and members of the public were in attendance. Dr. Ed Miller was chairman of the ALSAC committee and led the discussion. Transcripts from that meeting demonstrate that the committee was opposed to the contraindication of succinylcholine in the pediatric population. Rather than recommend even a relative contraindication, the ALSAC members recommended that a warning be added to the labeling of succinylcholine. Subsequent direct communication with the Not Drug Evaluation Staff has confirmed that this recommendation was made. Several months later, however, Burroughs Wellcome renewed dialogue with the FDA and voiced the position that a warning was not acceptable and a contraindication was still being sought. Representatives of Burroughs Wellcome subsequently met with selected members of the ALSAC committee and members of the Pilot Drug Evaluation Staff. As a result of this dialogue a relative contraindication was negotiated rather than the warning initially recommended by the full ALSAC committee. The label change was put into effect by Burroughs Wellcome in November, 1993, and revised package inserts were mailed to practicing anesthesiologists across the country. This relative contraindication reads as follows:

“Except when used for emergency tracheal intubation or in instances where immediate securing of the airway is necessary, succinylcholine is contraindicated in children and adolescent patients…”

Enter Practicing Anesthesiologists

The FDA was clearly surprised at the response that followed the issuing of this contraindication. Thousands of letters and calls were received voicing numerous concerns. The anesthesia literature has been a forum for debating the risk/benefit ratio of succinylcholine relative to the potential for inducing life threatening hyperkalemia in children with undiagnosed myopathies. Badgwell et all (3) and Morell et al (4) published letters of concern in the January, 1994 issue of Anesthesiology, and letters of reply from the Pilot Drug Evaluation Staff (2) and Burroughs Wellcome (5) appeared in that same issue. Lerman et al voiced similar concern in the Canadian Journal of Anaesthesia. (6) The Spring issue of the Anesthesia Patient Safety Foundation Newsletter contained a lengthy debate and editorial on the controversy. (7,8) Committees of the American Society of Anesthesiologists (ASA), the Society for Pediatric Anesthesia (SPA) and the American Academy of Pediatrics (AAP) met to either write opinion letters or statements or form consensus opinions. The FDA responded to all this input.

Reconsideration

On June 9, 1994, the ALSAC committee convened on the FDA campus in Rockville, MD. The initial item on the committee’s agenda was a reconsideration of the recent label changes regarding succinylcholine’s use in children and adolescents. Dr. James Eisenach directed the discussion which opened with a public forum. During this forum more than a dozen distinguished anesthesiologists voiced their objections to the contraindication. These speakers included Drs. Frederic Berry (UVA), Dr. Charles Cote’ (Children’s Memorial Chicago), Dr. William Greeley (SPA, Duke), Dr. Steven Hall (SPA, Northwestern), Dr. Richard Kaplan (Children’s National Medical Center), Dr. Robert Morell (Bowman Gray), Dr. William Ross (UVA), Dr. Theodore Striker (AAP, Children’s Hospital Cincinnati), Dr. Thomas Wolfe (Riley Children’s Hospital Indianapolis), Dr. Myron Yaster (ASA Committee on Pediatric Anesthesia, Johns Hopkins) and Dr. Marilyn Larach (Penn State Children’s Hospital and North American Malignant Hyperthermia Association). AU of these speakers rejected the concept of a contraindication of succinylcholine in children and adolescents. Dr. Uwe Schulte-Sasse (Heidelberg, Germany) presented his data from the German MH Hotline regarding reported cases of hyperkalemic arrest and/or rhabdomyolysis. Following the open public hearing Dr. Ryan Cook (Children’s Hospital, Pittsburgh) presented a review of the use of succinylcholine in children. Subsequent to these presentations the members of ALSAC unanimously voted to stand behind their prior recommendation that succinylcholine NOT be contraindicated in children and adolescents. A recommendation was issued to the Pilot Drug Evaluation Staff that, instead, a warning be placed on the front of the package insert. The warning will inform physicians that succinylcholine has been associated with hyperkalemic cardiac arrest in children with undiagnosed myopathies, usually Duchenne’s muscular dystrophy. It will also emphasize that male children under the age of eight may be at the greatest risk for developing this rare, yet potentially lethal response. Educational information regarding the appropriate role of intravenous calcium administration will most likely be included.

Interestingly, both the Health Protection Branch of the Canadian government and the Canadian pediatric anaesthetists rejected the ‘Dear Doctor’ letter sent to all Canadian anaesthetists by Burroughs Wellcome. This letter bore the same contraindication issued in the United States. In late 1993, a revision of that letter was sent to the Health Protection Branch which did not contain the contraindication. Rather, a statement of warning was included which read: ‘In infants and children, especially in boys under eight years of age, the rare possibility of inducing life-threatening hyperkalemia in undiagnosed myopathies by the use of succinylcholine must be balanced against the risk of alternative means of securing the airway.’ This warning has subsequently been adopted in Canada.

We have come full circle, and that is good, because the process that occurred has served to educate our physicians and our residents. This issue has received a tremendous amount of attention and has heightened our awareness of a rare, but potentially lethal side effect of a commonly used drug. Further, the discussion surrounding this controversy will educate anesthesiologists on the need for prompt and appropriate treatment should hyperkalemic arrest occur. This treatment involves the intravenous administration of calcium. With proper treatment, approximately 50% of patients have survived this catastrophic hyperkalernia. The regulatory process has also educated the public as to the roles played by the FDA, the Pilot Drug Evaluation Staff, the ALSAC Committee, and pharmaceutical manufacturers regarding the labeling of anesthetic drugs. The current ALSAC recommendation is based on the available data and recognizes the risks as well as the unique beneficial characteristics of succinylcholine.

Dr. Morell is from the Department of Anesthesia, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.

References

1. Rosenberg H, Gronert GA: Intractable cardiac arrest in children given succinylcholine. [letter] Anesthesiology 1992;77:1054.

2. Katz L, Wright C, Harter J, Zung M, Scally D, Spyker D: Revised label regarding use of succinylcholine in children and adolescents: 11. [reply] Anesthesiology 1994; 80:24344.

3. Badgwell JM, Hall SC, Lockhart C: Revised label regarding use of succinylcholine in children and adolescents: H. [letter] Anesthesiology 1994; 80: 243.

4. Morell RC, Berman JM, Royster RL, Petrozza PH, Kelly JS, Colonna DM: Revised label regarding use of succinylcholine in children and adolescents: 1. [letter] Anesthesiology 1994; 80: 242.

5. Kent RS: Revised label regarding use of succinylcholine in children and adolescents: 11. [reply] Anesthesiology 1994; SO: 244-45.

6. Lennan J, Berdock SE, Bissonnette B, et al: Succinylcholine warning. Can j Anaesth 1994,41:165.

7. Morell RC, Berman JM (pro); Woelfel SK (Con): In my opinion: a debate: is succinylcholine safe for children? Anesthesia Patient Safety Foundation Newsletter 1994; 9(l):1,3-5.

8. Eichhom JH: Editorial: are we becoming too afraid of complications? Anesthesia Patient Safety Foundation Newsletter 1994; 9(l):2-3.