[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Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness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not withdrawn from sale for reasons of safety or effectiveness.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