[Federal Register Volume 79, Number 16 (Friday, January 24, 2014)]
[Notices]
[Pages 4167-4168]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-01390]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2012-N-0284]


Pediatric Studies of Sodium Nitroprusside Conducted in Accordance 
With the Public Health Service Act; Availability of Summary Report and 
Requested Labeling Changes

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing a summary 
report of the pediatric studies of sodium nitroprusside conducted in 
accordance with the Public Health Service Act (the PHS Act) and is 
making available requested labeling changes for sodium nitroprusside. 
The Agency is making this information available consistent with the PHS 
Act.

FOR FURTHER INFORMATION CONTACT: Lori Gorski, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, rm. 6415, Silver Spring, MD 20993-0002, 301-
796-2200, Fax: 301-796-9855, email: [email protected].

SUPPLEMENTARY INFORMATION:

I. Sodium Nitroprusside Summary Review

    In the Federal Register of January 21, 2003 (68 FR 2789), sodium 
nitroprusside (SNP) was identified as a drug that needed further study 
in pediatrics. The approved labeling lacked adequate information on 
dosing, pharmacokinetics, tolerability, and safety information in 
pediatric patients from birth to 18 years of age who receive SNP for 
controlled reduction of blood pressure.
    A written request (WR) for pediatric studies of sodium 
nitroprusside was issued on July 8, 2002, to Abbott Laboratories, the 
holder of the new drug application for sodium nitroprusside. FDA did 
not receive a response to the written request. Accordingly, the 
National Institutes of Health (NIH) issued a request for proposals to 
conduct the pediatric studies described in the written request in July 
2004 and awarded funds to Duke University and Stanford University in 
September 2004 to complete the studies described in the written 
request.
    The Eunice Kennedy Shriver National Institute of Child Health and 
Human Development (NICHD) submitted clinical study reports for SNP. The 
two studies are:
     NICHD-2003-09-DR-SNP1: A randomized double-blind, parallel 
group, dose-ranging, effect-controlled, multicenter study of 
intravenous infusions of SNP in pediatric patients who require 
deliberate, controlled relative-induced hypotension for at least 2 
hours.
     NICHD-2003-09-LT-SNP2: A multicenter, randomized, double-
blind, placebo-controlled, parallel group study to determine the 
pharmacodynamics of sodium nitroprusside during the prolonged infusion 
in pediatric subjects. This study was a withdrawal to placebo study.
    Upon completion of these pediatric studies, a report of the 
pediatric studies of sodium nitroprusside was submitted to NIH and FDA. 
In the Federal Register of October 3, 2012 (77 FR 60441), FDA announced 
the opening on August 31, 2012, of docket FDA-2012-N-0284 for 
submission of data from pediatric studies of sodium nitroprusside. The 
data submitted to the docket were submitted in accordance with section 
409I of the PHS Act (42 U.S.C. 284m) and were the same data submitted 
to investigational new drug application 71,979, with the exception that 
personal privacy information had been redacted from the data submitted 
to the docket.
    The sodium nitroprusside docket remained opened for public comment 
from October 3, 2012, through November 2, 2012. There were no comments 
submitted to the docket during that time, and a memorandum for the 
record stating such was posted to the docket on November 5, 2012.
    During the review of the submission, the Division of Cardiovascular 
and Renal Products identified inconsistencies in subject numbers 
between the pharmacokinetic/pharmacodynamic (PK/PD) analysis set and 
the ITT-E (intent to treat-efficacy) population in the study report 
NICHD-2003-09-DR-SNP1 and notified NIH. In a meeting with FDA on 
November 29, 2012, NIH indicated that that they identified treatment 
assignment inconsistencies between the two datasets and provided a 
strategy for addressing the concern and performing reanalysis. The need 
for reanalysis resulted in suspension of the review as of November 29, 
2012. The corrected datasets and reanalysis were provided to the Agency 
and submitted to the docket on September 26, 2013.
    The key findings of this submission are:
     The blood pressure lowering effect of SNP was demonstrated 
in both of the trials.

[[Page 4168]]

     A higher proportion of patients in the high-dose group 
achieved target mean arterial pressure (MAP) compared to the lowest 
dose of 0.3 microgram/kilogram/minute ([micro]g/kg/min). The time-to-
target MAP was also significantly shorter for the high-dose groups.
     With a starting dose of 0.3 [micro]g/kg/min, ~25 percent 
of patients achieved target MAP in 5 minutes. Maintaining on a stable 
dose of 0.3 [micro]g/kg/min for 10 minutes resulted in ~50 percent of 
patients reaching target MAP. Hence, a starting dose of 0.3 [micro]g/
kg/min is reasonable. It should also be noted that it may be prudent to 
maintain the infusion rate for an additional 5 to 10 minutes before 
titrating.
     The proportion of patients with MAP reductions of >20 
percent below target increased in a dose-dependent manner.
     The safety profile of SNP in both the trials was largely 
consistent with the expected events as a result of the underlying 
disease and preoperative setting. Only blood pressure reduction events 
were clearly drug- and dose-related.
     Even though only four neonates were studied in the trial, 
there is no expectation that the PK/PD relationship and the safety 
profile would be any different in this age group.
     The FDA Adverse Event Reporting System (FAERS) search (up 
to October 25, 2012) retrieved only 26 pediatric cases with SNP use. Of 
these, four cases of elevated carboxyhemoglobin associated with SNP 
treatment were reported. The Office of Surveillance and Epidemiology 
review outlines several reasons why these data cannot be used to 
calculate incidence of adverse events in the population.
     For this submission, one large site (N = 36 enrolled in 
Protocol NICHD-2003-09-LT-SNP2; Investigator: Dr. David Rosen) was 
inspected. The Office of Scientific Investigations recommends the data 
be accepted.
     As a part of the WR, long-term safety data and a 1-year 
followup period for patients enrolled in the trial were sought. 
Information from followup was not available in the submission. However, 
the value of such information is limited and is not expected to have an 
impact on the ability to overcome the labeling gap. The complete report 
can be found at docket number FDA-2012-N-0284.

II. Recommendation

    The submission provides a reasonable algorithm for administration 
of sodium nitroprusside to allow its use in perioperative settings to 
achieve controlled hypotension for pediatric patients from birth to 18 
years. FDA's requested labeling changes are available on the FDA Web 
site at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm379088.htm and in the docket (Ref. 1).

III. Reference

    The following reference has been placed on display in the Division 
of Dockets Management (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, rm. 1061, Rockville, MD 20852, and may be seen by 
interested person between 9 a.m. and 4 p.m., Monday through Friday, and 
is available electronically at http://www.regulations.gov.
    1. FDA Requested Labeling Changes.

    Dated: January 10, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-01390 Filed 1-23-14; 8:45 am]
BILLING CODE 4160-01-P