[Federal Register Volume 62, Number 9 (Tuesday, January 14, 1997)]
[Notices]
[Pages 1889-1892]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-714]


=======================================================================
-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration
[Docket No. 96N-0512]


Hoechst Marion Roussel, Inc., and Baker Norton Pharmaceuticals, 
Inc.; Terfenadine; Proposal To Withdraw Approval of Two New Drug 
Applications and One Abbreviated New Drug Application; Opportunity for 
a Hearing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

-----------------------------------------------------------------------

SUMMARY: The Food and Drug Administration (FDA) is proposing to 
withdraw approval of two new drug applications (NDA's) and one 
abbreviated new drug application (ANDA) for drug products containing 
terfenadine. NDA 18-949 (Seldane) and NDA 19-664 (Seldane-D) are held 
by Hoechst Marion Roussel (HMR), Inc., P.O. Box 9627, Kansas City, MO 
64134-0627. ANDA 74-475 is held by Baker Norton Pharmaceuticals, Inc., 
4400 Biscayne Blvd., Miami, FL 33137. On July 25, 1996, FDA approved 
HMR's NDA 20-625 for fexofenadine hydrochloride (Allegra). Fexofenadine 
is the active metabolite of terfenadine that is responsible for the 
desired beneficial properties of terfenadine. When patients take 
terfenadine, parent terfenadine is ordinarily present in their blood at 
very low concentrations, because the terfenadine molecule is 
metabolized to form fexofenadine. Fexofenadine is responsible for 
providing patients with essentially all the clinical benefits of taking 
terfenadine. If terfenadine's metabolism is inhibited, either by 
another drug or by intrinsic liver disease, the level of parent 
terfenadine can rise to levels that can cause serious side effects in 
people as a result of the effect of parent terfenadine on cardiac 
potassium channels. Inhibition of these channels causes delayed cardiac 
repolarization (prolonged electrocardiographic QT interval) and 
increases the risk of a characteristic kind of ventricular tachycardia 
called torsades de pointes and possibly the risk of other rhythm 
abnormalities. Fexofenadine hydrochloride, however, has not been shown 
to affect cardiac potassium channels and has been shown not to cause 
prolongation of the electrocardiographic QT interval, even at larger-
than-recommended doses. Based on all data to date, fexofenadine 
hydrochloride appears to lack parent terfenadine's risk of serious 
cardiovascular adverse events. The basis for the proposed withdrawal of 
the applications is a finding that the availability of fexofenadine 
hydrochloride provides patients with an alternative that can provide 
essentially all the benefits of terfenadine, because it is identical in 
molecular structure to the metabolized (active) form of terfenadine, 
without the serious and potentially fatal risks associated with 
terfenadine when terfenadine's metabolism is inhibited either by 
another drug or by intrinsic liver disease. Because of the availability 
of fexofenadine hydrochloride, terfenadine is not shown to be safe for 
use under the conditions of use that formed the basis upon which the 
applications were approved.

DATES: A hearing request is due on February 13, 1997; data and 
information in support of the hearing request are due on March 17, 
1997.

ADDRESSES: A request for hearing, supporting data, and other comments 
are to be identified with docket no. 96N-0512 and submitted to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, 
12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: 
    For information on medical/scientific issues: John K. Jenkins, 
Center for Drug Evaluation and Research (HFD-570), Food and Drug 
Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-827-

[[Page 1890]]

      1050.
    For general information concerning this notice: David T. Read, 
Center for Drug Evaluation and Research (HFD-7), Food and Drug 
Administration, 7520 Standish Pl., Rockville, MD 20855, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

    Terfenadine is an antihistamine, indicated for the relief of 
symptoms associated with seasonal allergic rhinitis such as sneezing, 
rhinorrhea, pruritus, and lacrimation. Terfenadine was the first 
antihistamine approved in the United States that was not associated 
with more somnolence than placebo in clinical trials. The absence of an 
increased risk of somnolence over placebo is an important safety 
advantage to many people who use antihistamines. NDA 18-949 for Seldane 
tablets (terfenadine 60 milligrams (mg)) was approved by FDA on May 8, 
1985. NDA 19-664 for Seldane-D tablets (terfenadine 60 mg and the 
decongestant pseudoephedrine hydrochloride 120 mg) was approved by FDA 
on August 19, 1991.
    Other antihistamines now available in the United States that were 
not associated with more somnolence than placebo in clinical trials are 
astemizole (Hismanal) and loratadine (Claritin), approved on December 
29, 1988, and April 12, 1993, respectively. Most significant to this 
proceeding, on July 25, 1996, FDA approved HMR's NDA 20-625 for 
fexofenadine hydrochloride 60 mg capsules (Allegra). Fexofenadine is 
the metabolite of terfenadine responsible for its desired 
antihistaminic efficacy. Fexofenadine hydrochloride was also not 
associated with more somnolence than placebo in clinical trials.
    After the approval of terfenadine in 1985, there began to be 
reports of certain serious cardiac adverse events associated with 
terfenadine use in patients taking certain antimicrobials or with 
significant liver dysfunction. Very little parent terfenadine normally 
circulates in the plasma because orally administered terfenadine 
undergoes extensive first pass metabolism by a specific cytochrome P-
450 isoenzyme (CYP3A4). This metabolic pathway may be impaired in 
patients with liver dysfunction (e.g., alcoholic cirrhosis) or who are 
taking drugs such as ketoconazole, itraconazole, or macrolide 
antimicrobials (e.g., clarithromycin, erythromycin, or troleandomycin). 
These drugs are all inhibitors of the cytochrome P-450 isoenzyme.
    Interference with the normal metabolism of terfenadine can lead to 
elevated plasma terfenadine levels. At these elevated levels, 
terfenadine can delay cardiac repolarization (prolong the 
electrocardiographic QT interval) because of its effects on cardiac 
potassium channels. The delayed cardiac repolarization increases the 
risk of serious ventricular tachyarrhythmias, most characteristically a 
kind of ventricular tachycardia called torsades de pointes. This 
arrhythmia can cause dizziness and syncope when it is short-lived, but 
it may persist and degenerate into unstable ventricular tachycardia or 
ventricular fibrillation. Ventricular fibrillation is fatal if not 
promptly reversed. These serious and possibly fatal events can occur at 
the recommended dose of terfenadine if it is taken along with other 
medications that interfere with its metabolism or if it is administered 
to someone with significant hepatic dysfunction.
    In an effort to inform the medical and patient communities about 
the serious and potentially fatal cardiac adverse effects associated 
with inappropriate use of terfenadine, the labeling for Seldane and 
Seldane-D have been revised many times. In 1992, terfenadine labeling 
was revised to include a prominent boxed warning cautioning against its 
use in certain settings, particularly with the drugs that inhibit its 
metabolism. In addition, ``Dear Health Care Professional'' letters 
warning health care practitioners of the serious risk of inappropriate 
use of terfenadine were issued by the sponsor in 1990, 1992, and 1996.
    Although the revised labeling and ``Dear Health Care Professional'' 
letters have significantly reduced the inappropriate prescribing of 
terfenadine together with the drugs that block its metabolism, such 
prescribing and dispensing has not been eliminated and almost certainly 
cannot be. Three recently published studies indicate that 
coprescription and codispensing of medications contraindicated with 
terfenadine continues to occur (Refs. 1, 2, and 3). The Cavuto study 
also demonstrates that the computerized drug-interaction screening 
programs used by many pharmacists, who are the last line of defense 
against prescribing errors, do not completely prevent prescribing and 
filling of prescriptions for potentially dangerous combinations of 
terfenadine and contraindicated drugs.
    Terfenadine is an antihistamine that is intended to be used when 
symptoms of seasonal allergic rhinitis occur. Patients often do not 
consume all of the pills they receive in a prescription of terfenadine 
for a single episode of seasonal allergic rhinitis, and may keep the 
remaining pills for later use when needed, as patients often do with 
over-the-counter antihistamines. Because of the nature of seasonal 
allergies, a long period of time (e.g., from early fall to spring) can 
elapse between the time the drug and any associated warning from a 
health care practitioner or pharmacist is received and the time 
terfenadine is used. Such intermittent dosing of terfenadine increases 
the probability that some patients may be taking one of the 
contraindicated medications, such as one of the frequently prescribed 
antimicrobials listed above, at the same time the patient self-
diagnoses his or her seasonal allergy symptoms and takes the remaining 
terfenadine from the pill container in the medicine chest.
    This problem of concomitant use is further compounded by the 
growing list of medications known to inhibit the metabolism of 
terfenadine, many of which are taken for chronic medical conditions and 
may be prescribed by health care practitioners other than the 
practitioner who prescribed the terfenadine. Labeling changes and even 
perfect performance by prescribers and close attention by pharmacists, 
therefore, cannot completely eliminate the risks of serious cardiac 
adverse events associated with the inappropriate use of terfenadine.
    Very low to undetectable blood levels of parent terfenadine are 
found in patients taking the recommended dose of terfenadine. For this 
reason, parent terfenadine appears to have very little, if any, impact 
on the therapeutic efficacy that is associated with terfenadine use.
    The discovery of terfenadine's ability to delay cardiac 
repolarization and its associations with serious and sometimes fatal 
cardiac adverse events when used inappropriately led to evaluation of 
its principal active metabolite as a potentially safer alternative 
antihistamine. It was discovered that the metabolite that is 
responsible for the desired therapeutic effect of terfenadine, 
fexofenadine, does not affect cardiac potassium channels. The agency, 
therefore, encouraged HMR to initiate the development of a drug product 
with only the active metabolite fexofenadine as the active 
antihistamine. Even at doses considerably in excess of those 
recommended for use, fexofenadine hydrochloride has not been shown to 
prolong the QT interval. It therefore should not have, and has not been 
shown to have, the serious cardiovascular adverse events potentially 
associated with unmetabolized terfenadine. No new

[[Page 1891]]

adverse reaction, not already associated with terfenadine, would be 
expected because the many people who have taken terfenadine have been, 
in fact, exposed primarily to fexofenadine manufactured by their body.
    An NDA for fexofenadine hydrochloride was approved by FDA on July 
25, 1996. Nearly 5 months of marketing of this product in the United 
States have not resulted in any reports of serious cardiac arrhythmias.
    Prior to the approval of fexofenadine hydrochloride, the agency 
considered terfenadine to be safe (i.e., its benefits outweighed its 
risks) despite terfenadine's known serious adverse effects when its 
metabolism was blocked and despite the availability of alternative 
antihistamines that, like terfenadine, were not associated with greater 
somnolence than placebo in clinical trials. This is because the agency 
recognizes that responses to drugs are not uniform among individuals 
and, for reasons that are often unclear and difficult to discover, some 
patients may respond better, with respect to therapeutic effectiveness 
or tolerance, to one drug than to another. Terfenadine certainly 
provided a unique therapeutic benefit when it was the only available 
antihistamine that was not associated with more somnolence than placebo 
in clinical trials, and it continued to provide a benefit and choice to 
patients even after the approval of astemizole and loratadine (e.g., 
some patients may have found that terfenadine provided some advantage 
over either of the other two products or may have been unable to 
tolerate the alternative medications for a variety of medical reasons, 
including drug allergy). So long as terfenadine represented a unique 
molecule, the agency concluded that terfenadine's risks, which had been 
greatly reduced by labeling changes and public awareness, were 
acceptable in light of its benefits. It is only now, when there is an 
alternative that is identical to the molecule that provides the 
therapeutic benefits of terfenadine, that terfenadine's benefits do not 
outweigh its risks. This is because essentially all of its benefits can 
be obtained with fexofenadine hydrochloride without the cardiovascular 
risk caused by QT prolongation.
    Currently, there is no combination of fexofenadine hydrochloride 
and pseudoephedrine approved for marketing in the United States. 
Although the absence of a fexofenadine hydrochloride/pseudoephedrine 
combination product may be inconvenient for patients currently taking 
Seldane-D, there are available over-the-counter extended-release 
pseudoephedrine 120 mg products that could be taken with fexofenadine 
hydrochloride to provide symptomatic relief comparable to that provided 
by Seldane-D for the treatment of seasonal allergic rhinitis. The minor 
inconvenience to patients of having to take separate fexofenadine 
hydrochloride and extended-release pseudoephedrine doses is more than 
offset by the cardiac safety advantage of fexofenadine hydrochloride 
over terfenadine.
    Accordingly, the Director of the Center for Drug Evaluation and 
Research concludes with respect to NDA 18-949 (terfenadine 60 mg) that: 
(1) Prior to the approval of fexofenadine hydrochloride, terfenadine 
provided a unique therapeutic alternative for which the risks 
associated with the use of terfenadine were acceptable; (2) terfenadine 
provides no therapeutic benefit to any patient population that is not 
also provided by fexofenadine hydrochloride, because fexofenadine 
hydrochloride is identical in molecular structure to terfenadine's 
therapeutically active metabolite; (3) current data demonstrate that 
fexofenadine hydrochloride lacks the serious cardiovascular risks 
associated with misuse of terfenadine, and approximately 5 months of 
marketing experience with fexofenadine hydrochloride in the United 
States has not resulted in any reports of serious cardiac arrythmias; 
(4) despite the many interventions undertaken by the agency and by HMR 
(three ``Dear Health Care Professional'' letters, multiple labeling 
changes, and extensive education campaigns), residual coprescribing, 
codispensing, and concomitant use of terfenadine with a growing list of 
medications that inhibit its metabolism continues and cannot be 
expected to be completely eliminated; and (5) terfenadine, therefore, 
is no longer shown to be safe for use under the conditions that formed 
the basis upon which the application was initially approved. The 
Director also finds that ANDA 74-475 refers to NDA 18-949 (Seldane, 60 
mg terfenadine oral tablets) as the listed drug. The Director further 
finds that the conclusions set out above for NDA 18-949 apply with 
respect to NDA 19-664 (terfenadine 60 mg and pseudoephedrine 120 mg), 
and that the inconvenience to patients of taking separate doses of 
fexofenadine hydrochloride and extended-release pseudoephedrine is more 
than offset by the cardiac safety advantage of fexofenadine 
hydrochloride over terfenadine. The Director is proposing to withdraw 
approval of NDA 18-949 and NDA 19-664 in accordance with section 
505(e)(2) of the Federal Food, Drug, and Cosmetic Act (the act) (21 
U.S.C. 355(e)(2)). The Director is proposing to withdraw approval of 
ANDA 74-475 in accordance with section 505(j)(5) of the act.

II. Notice of Opportunity for a Hearing

    The Director has evaluated the information discussed above and, on 
the grounds stated, is proposing to withdraw approval of NDA 18-949, 
NDA 19-664, and ANDA 74-475. Therefore, notice is given to HMR and 
Baker Norton Pharmaceuticals, Inc. that the Director proposes to issue 
an order under section 505(e)(2) of the act, withdrawing approval of 
NDA 18-949 and NDA 19-664, and all amendments and supplements thereto, 
and under section 505(j)(5) of the act, withdrawing approval of ANDA 
74-475, and all amendments and supplements thereto. The Director finds 
that new evidence of clinical experience, not contained in NDA 18-949 
and NDA 19-664 or not available to the Director until after the 
applications were approved, evaluated together with the evidence 
available to the Director when the applications were approved, shows 
that terfenadine is not shown to be safe for use under the conditions 
which formed the basis upon which the applications were approved. The 
Director also finds that ANDA 74-475 refers to the drug that is the 
subject of NDA 18-949.
    In accordance with section 505 of the act and part 314 (21 CFR part 
314), HMR and Baker Norton Pharmaceuticals, Inc. are hereby given an 
opportunity for a hearing to show why approval of the NDA's should not 
be withdrawn.
    An applicant who decides to seek a hearing shall file: (1) On or 
before February 13, 1997, a written notice of appearance and request 
for hearing, and (2) on or before March 17, 1997, the data, 
information, and analyses relied on to demonstrate that there is a 
genuine issue of material fact to justify a hearing, as specified in 
Sec. 314.200. Any other interested person may also submit comments on 
this notice. The procedures and requirements governing this notice of 
opportunity for a hearing, a notice of appearance and request for a 
hearing, information and analyses to justify a hearing, other comments, 
and a grant or denial of a hearing are contained in Secs. 314.151 and 
314.200, and in 21 CFR part 12.
    The failure of an applicant to file a timely written notice of 
appearance and request for hearing, as required by Sec. 314.200, 
constitutes an election by that person not to use the opportunity for a

[[Page 1892]]

hearing concerning the action proposed and a waiver of any contentions 
concerning the legal status of that person's drug products. Any new 
drug product marketed without an approved new drug application is 
subject to regulatory action at any time.

III. References

    The following references have been placed on display in the Dockets 
Management Branch (address above) and may be seen by interested persons 
between 9 a.m. and 4 p.m., Monday through Friday.
    1. Thompson, D., and G. Oster, ``Use of Terfenadine and 
Contraindicated Drugs,'' Journal of the American Medical 
Association, 275(17):1339-1341, 1996.
    2. Cavuto, N. J., R. L. Woosley, and M. Sale, ``Pharmacies and 
Prevention of Potentially Fatal Drug Interactions'' (letter), 
Journal of the American Medical Association, 275(14):1086-1087, 
1996.
    3. Carlson, A. M., and L. S. Morris, ``Coprescription of 
Terfenadine and Erythromycin and Ketoconazole: An Assessment of 
Potential Harm,'' Journal of the American Pharmaceutical 
Association, NS36(4):263-269, 1996.
    A request for a hearing may not rest upon mere allegations or 
denials, but must present specific facts showing that there is a 
genuine and substantial issue of fact that requires a hearing. If it 
conclusively appears from the face of the data, information, and 
factual analyses in the request for a hearing that there is no genuine 
and substantial issue of fact that precludes the withdrawal of approval 
of the applications, or when a request for hearing is not made in the 
required format or with the required analyses, the Commissioner of Food 
and Drugs will enter summary judgment against the person who requests 
the hearing, making findings and conclusions, and denying a hearing.
    All submissions pursuant to this notice of opportunity for a 
hearing are to be filed in four copies. Except for data and information 
prohibited from public disclosure under 21 U.S.C. 331(j) or 18 U.S.C. 
1905, the submissions may be seen in the Dockets Management Branch 
(address above) between 9 a.m. and 4 p.m., Monday through Friday.
    This notice is issued under the Federal Food, Drug, and Cosmetic 
Act (sec. 505 (21 U.S.C. 355)) and under authority delegated to the 
Director of the Center for Drug Evaluation and Research (21 CFR 5.82).

    Dated: January 7, 1997.
Janet Woodcock,
Director, Center for Drug Evaluation and Research.
[FR Doc. 97-714 Filed 1-10-97; 8:45 am]
BILLING CODE 4160-01-F