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

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