[Federal Register Volume 79, Number 63 (Wednesday, April 2, 2014)]
[Notices]
[Pages 18559-18561]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2014-07332]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2011-P-0267]


Determination That NIMOTOP (Nimodipine) Capsules, 30 Milligrams, 
Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) has 
determined that NIMOTOP (Nimodipine) Capsules, 30 milligrams (mg), was 
not withdrawn from sale for reasons of safety or effectiveness. This 
determination means that FDA will not begin procedures to withdraw 
approval of the abbreviated new drug applications (ANDAs) that refer to 
nimodipine capsules, 30 mg, and it will allow FDA to approve ANDAs that 
refer to this drug as long as they meet relevant legal and regulatory 
requirements.

FOR FURTHER INFORMATION CONTACT: Rachel Turow, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave. Bldg. 51, Rm. 6236, Silver Spring, MD 20993-0002, 301-
796-5094.

SUPPLEMENTARY INFORMATION: In 1984, Congress enacted the Drug Price 
Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417) 
(the 1984 amendments), which authorized the approval of duplicate 
versions of drug products under an ANDA procedure. ANDA applicants 
must, with certain exceptions, show that the drug for which they are 
seeking approval contains the same active ingredient in the same 
strength and dosage form as the ``listed drug,'' which is a version of 
the drug that was previously approved. ANDA applicants do not have to 
repeat the extensive clinical testing otherwise necessary to gain 
approval of a new drug application (NDA).
    The 1984 amendments include what is now section 505(j)(7) of the 
Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(j)(7)), which 
requires FDA to publish a list of all approved drugs. FDA publishes 
this list as part of the ``Approved Drug Products With Therapeutic 
Equivalence Evaluations,'' which is known generally as the ``Orange 
Book.'' Under FDA regulations, drugs are removed from the list if the 
Agency withdraws or suspends

[[Page 18560]]

approval of the drug's NDA or ANDA for reasons of safety or 
effectiveness or if FDA determines that the listed drug was withdrawn 
from sale for reasons of safety or effectiveness (21 CFR 314.162).
    Under Sec.  314.161(a) (21 CFR 314.161(a)), the Agency must 
determine whether a listed drug was withdrawn from sale for reasons of 
safety or effectiveness: (1) Before an ANDA that refers to that listed 
drug may be approved; (2) whenever a listed drug is voluntarily 
withdrawn from sale and ANDAs that refer to the listed drug have been 
approved; and (3) when a person petitions for such a determination 
under Sec. Sec.  10.25(a) and 10.30 (21 CFR 10.25(a) and 10.30). 
Section 314.161(d) provides that if FDA determines that a listed drug 
was withdrawn from sale for reasons of safety or effectiveness, the 
Agency will initiate proceedings that could result in the withdrawal of 
approval of the ANDAs that refer to the listed drug. FDA may not 
approve an ANDA that does not refer to a listed drug.
    NIMOTOP (Nimodipine) Capsules, 30 mg, the subject of NDA 18-869, 
held by Bayer HealthCare Pharmaceuticals Inc., was initially approved 
on December 28, 1988. The most recent labeling for NIMOTOP states that 
the product is indicated for the improvement of neurological outcome by 
reducing the incidence and severity of ischemic deficits in patients 
with subarachnoid hemorrhage (ruptured blood vessels in the brain) from 
ruptured intracranial berry aneurysms regardless of their post-ictus 
neurological condition (i.e., Hunt and Hess Grades I-V).
    In a letter dated July 30, 2010, Bayer HealthCare Pharmaceuticals 
Inc. notified FDA that NIMOTOP (Nimodipine) Capsules, 30 mg, was being 
discontinued, and FDA moved the drug product to the ``Discontinued Drug 
Product List'' section of the Orange Book. Currently, there are three 
approved ANDAs for nimodipine capsules, 30 mg. The following table 
lists the approved ANDAs for nimodipine capsules that are listed in the 
``Active Drug Product List'' of the Orange Book and their sponsors.

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             Applicant                   Application No.       Dosage form; route              Strength
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Banner Pharmacaps..................  ANDA 076740...........  Capsule; Oral.........  30 mg.
Barr Labs, Inc.....................  ANDA 077811...........  Capsule; Oral.........  30 mg.
Sun Pharmaceuticals Inds., Inc.      ANDA 077067...........  Capsule; Oral.........  30 mg.
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    Lachman Consultant Services, Inc., submitted a citizen petition 
dated April 11, 2011 (Docket No. FDA-2011-P-0267) (Petition), under 
Sec.  10.30, requesting that the Agency determine whether NIMOTOP 
(Nimodipine) Capsules, 30 mg, was withdrawn from sale for reasons of 
safety or effectiveness. In the Petition, the petitioner identified no 
data or other information suggesting that NIMOTOP (Nimodipine) 
Capsules, 30 mg, was withdrawn for reasons of safety or effectiveness.
    In responding to the Petition, we have carefully reviewed our files 
for records concerning the withdrawal of NIMOTOP (Nimodipine) Capsules, 
30 mg. We have also independently evaluated relevant literature and 
data for possible postmarketing adverse events. The adverse event 
reports included 36 reports of medication errors associated with the 
administration or prescribing of nimodipine capsules, 30 mg, which were 
received between 1989 (the initial marketing of NIMOTOP) and November 
2013.\1\ Of these 36 reports, 27 involved the erroneous intravenous 
administration of nimodipine.\2\ The intravenous injection of 
nimodipine can result in cardiac arrest, severe drop in blood pressure, 
other cardiac-related complications, and death. In almost all of the 
cases involving erroneous intravenous administration, there were 
serious or potentially serious outcomes, with 5 of the 27 cases 
resulting in the death of the patient. FDA has attributed these 
medication errors to the use of an intravenous needle and syringe at 
bedside to extract the capsule contents for administration to patients 
that are unconscious or cannot swallow the capsules. In such cases, the 
professional labeling instructions call for using an 18-gauge needle to 
make a hole on both ends of the capsule to extract the capsule's liquid 
contents into a syringe, and then administering the extracted liquid to 
the patient orally or via a nasogastric tube (feeding tube). Because a 
needle will not fit on an oral syringe, the health care provider must 
use a parenteral syringe to extract the liquid from the capsule. Once 
the drug is prepared in a parenteral syringe, rather than administering 
it orally or through a nasogastric tube as further directed in the 
drug's labeling, a conditioned response can occur where the drug is 
erroneously administered intravenously. Most patients receiving 
nimodipine capsules require complex care, are hospitalized in critical 
care units, and are receiving other intravenous medications, which may 
further contribute to the occurrence of such errors.
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    \1\ FDA became aware of these reports through a search of the 
FDA Adverse Event Reporting System (FAERS), the Pennsylvania Patient 
Safety Reporting System (PA-PSRS), the Institute for Safe Medication 
Practices' (ISMP) Quantros MEDMARX database, the Council for 
International Organizations of Medical Sciences (CIOMS) II database, 
or through their publication in the medical literature. Thirty-one 
of the 36 cases occurred between 1989 and 2009. (See FDA Drug Safety 
Communication: Serious medication errors from intravenous 
administration of nimodipine oral capsules, available at http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm220386.htm.) FDA identified five additional cases through 
searches of the Agency's FAERS database conducted in 2012 and 2013.
    \2\ The remaining reports of medication errors involved 
prescribing errors (i.e., physician erroneously prescribed that the 
drug be administered intravenously), sublingual administration, or 
drug name confusion.
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    Each year, between 20,000 and 30,000 patients in the United States 
\3\ are administered nimodipine for the emergency treatment of 
subarachnoid hemorrhage. Since NIMOTOP was approved in 1988, FDA has 
taken several actions to reduce these medication errors. These include 
labeling changes, a Dear Healthcare Professional Letter, two FDA 
Patient Safety News Webcasts, and a Drug Safety Communication.\4\ As 
recently as August 2010, FDA issued a safety alert, again emphasizing 
to health care professionals that nimodipine capsules should be given 
only by mouth or through a nasogastric tube and that they should never 
be given by intravenous administration.\5\ In addition, in

[[Page 18561]]

February 2012, Barr Pharmaceuticals added the following statement to 
the labeling directing health care professionals to transfer the 
capsule contents to a syringe that cannot accept a needle: ``A 
parenteral syringe can be used to extract the liquid inside the 
capsule, but the liquid should always be transferred to a syringe that 
cannot accept a needle and that is designed for administration orally 
or via a nasogastric tube or PEG.'' \6\
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    \3\ American Heart Association Guidelines for the Management of 
Aneurysmal Subarachnoid Hemorrhage, 2009, Stroke, 40:994-1025; see 
also, National Institute of Neurological Disorders and Stroke--
Cerebral Aneurysms Fact Sheet, available at 
http:[sol][sol]www.ninds.nih.gov/disorders/cerebral_aneurysm/
detail_cerebral_aneurysms.htm#228933098.
    \4\ Nimodipine (marketed as Nimotop)--Healthcare Professional 
Sheet, text version, available at http:[sol][sol]www.fda.gov/Drugs/
DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/
ucm129297.htm; NIMOTOP Safety alert, available at 
http:[sol][sol]www.fda.gov/Safety/MedWatch/SafetyInformation/
SafetyAlertsforHumanMedicalProducts/ucm150728.htm.
    \5\ FDA Drug Safety Communication: Serious Medication Errors 
from Intravenous Administration of Nimodipine oral Capsules (August 
2010), available at http:[sol][sol]www.fda.gov/Drugs/DrugSafety/
PostmarketDrugSafetyInformationforPatientsandProviders/
ucm220386.htm.
    \6\ As used here, PEG refers to a percutaneous endoscopic 
gastrostomy tube.
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    Despite these efforts by FDA and the drug's sponsor, a small number 
of adverse events due to erroneous intravenous administration continue 
to be reported to the Agency. Nevertheless, FDA believes that it is in 
the best interest of the public health for patients to continue to have 
access to this lifesaving drug for a number of reasons. First, only a 
portion of the patients treated with nimodipine capsules are 
unconscious and unable to swallow--these are the patients who are most 
vulnerable to the medication errors identified. Of those patients that 
begin their course of treatment (two capsules every 4 hours for 21 
days) while unable to swallow, many improve to the point where they are 
awake and able to swallow a capsule soon after treatment begins. Hence, 
for many patients, the risk of erroneous intravenous administration is 
only present during a small percentage of their overall duration of 
treatment.
    Second, we believe the approval of a nimodipine oral solution \7\ 
that is administered via an oral syringe only will further prevent 
erroneous intravenous administration because it can be used for those 
patients who are unconscious or unable to swallow and eliminates the 
need for use of a parenteral syringe, which is the source of the 
medication errors. And third, we believe the capsules play an important 
role in treating patients with subarachnoid hemorrhage because many are 
discharged from the hospital while taking capsules, and capsules 
provide a more convenient route of administration that increases 
patient compliance.
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    \7\ Nymalize was approved on May 10, 2013. See FDA's News 
Release, ``FDA Approves Nymalize--First Nimodipine Oral Solution for 
Use in Certain Brain Hemorrhage Patients,'' available at 
http:[sol][sol]www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/
ucm352280.htm.
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    As a result, we believe that the benefits of having nimodipine 
capsules on the market to treat these extremely sick patients, who 
could die or have serious permanent injury without treatment, outweigh 
the risks of medication errors.
    Therefore, after considering the Petition and reviewing Agency 
records, and based on the information we have at this time, FDA has 
determined under Sec.  314.161 that NIMOTOP (nimodipine) Capsules, 30 
mg, was not withdrawn for reasons of safety or effectiveness.
    Accordingly, the Agency will continue to list NIMOTOP (Nimodipine) 
Capsules, 30 mg, in the ``Discontinued Drug Product List'' section of 
the Orange Book. The ``Discontinued Drug Product List'' delineates, 
among other items, drug products that have been discontinued from 
marketing for reasons other than safety or effectiveness. FDA will not 
begin procedures to withdraw approval of the approved ANDAs that refer 
to NIMOTOP (Nimodipine) Capsules, 30 mg. Additional ANDAs that refer to 
NIMOTOP (Nimodipine) Capsules, 30 mg, may also be approved by the 
Agency as long as they meet all other legal and regulatory requirements 
for the approval of ANDAs. If FDA determines that labeling for this 
drug product should be revised to meet current standards, the Agency 
will advise ANDA applicants to submit such labeling.

    Dated: March 27, 2014.
Leslie Kux,
Assistant Commissioner for Policy.
[FR Doc. 2014-07332 Filed 4-1-14; 8:45 am]
BILLING CODE 4160-01-P