Sandoz Pharmaceuticals Corp.; Bromocriptine Mesylate (Parlodel) for the Prevention of Physiological Lactation; Opportunity for a Hearing on a Proposal To Withdraw Approval of the Indication

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 94N-0304]

Sandoz Pharmaceuticals Corp.; Bromocriptine Mesylate (Parlodel)

for the Prevention of Physiological Lactation; Opportunity for a

Hearing on a Proposal To Withdraw Approval of the Indication

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to

withdraw approval of those parts of the new drug application (NDA) for

Parlodel (bromocriptine mesylate) that pertain to the prevention of

physiological lactation. NDA 17-962 is held by Sandoz Pharmaceuticals

Corp., 59 Route 10, East Hanover, NJ 07936 (Sandoz). The basis for the

action is a reevaluation finding that this drug product is not shown to

be safe for use under the conditions of use upon the basis of which the

application was approved.

DATES: A hearing request is due on or before September 22, 1994; data

and information in support of the hearing request are due on or before

October 24, 1994.

ADDRESSES: A request for hearing, supporting data, and other comments

are to be identified with Docket No. 94N-0304 and submitted to the

Dockets Management Branch (HFA-305), Food and Drug Administration, rm.

1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT:

For information on medical/scientific issues: Solomon Sobel, Center

for Drug Evaluation and Research (HFD-510), Food and Drug

Administration, 5600 Fishers Lane, Rockville, MD 20857, 301-443-3490.

For general information concerning this notice: Harry T. Schiller,

or David T. Read, Center for Drug Evaluation and Research (HFD-366),

Food and Drug Administration, 7500 Standish Pl., Rockville, MD 20855,

301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

Estrogens were used in the treatment of postpartum breast

engorgement beginning in the 1940's. In the 1970's, FDA and what is now

the Fertility and Maternal Health Drugs Advisory Committee (the

Committee) became concerned about mounting evidence, presented in

diverse studies, scientific publications, and adverse drug experience

(ADE) reports received by FDA's Spontaneous Reporting System (SRS),

suggesting that these estrogen-containing drug products were of

questionable effectiveness for this indication because of rebound

lactation, and possibly unsafe because of an increased risk of

thromboembolism.

In January 1978, the Committee considered whether bromocriptine, a

nonestrogen, should be labeled for the prevention of physiological

lactation. It recommended against approval of the indication at that

time because insufficient studies had been done to show safety and

effectiveness.

Subsequently, FDA reviewed Sandoz's supplemental new drug

application for Parlodel, in which Sandoz sought approval for a new

indication for use of the drug for the prevention of physiological

lactation. NDA 17-962 for Parlodel (bromocriptine) was originally

approved on June 28, 1978, for the temporary relief of amenorrhea-

galactorrhea due to nonpituitary tumor etiology. Sandoz submitted

studies on bromocriptine that showed evidence of effectiveness in the

prevention of physiological lactation without any reports of serious

adverse experiences in the study population. FDA approved the

supplement for the new indication in 1980 to provide the medical

community with what was then believed to be a safer therapeutic

alternative to existing estrogen-containing drug products labeled for

similar indications; e.g., to prevent painful swelling of the breasts

after pregnancy, and to prevent postpartum breast engorgement.

By 1983, after bromocriptine had been used for the prevention of

physiological lactation in the general population, a number of serious

ADE's (see 21 CFR 314.80(a)) were reported in association with this

use. The ADE's at that time included six reports of severe

hypertension, three reports of hypertension and seizures, three reports

of seizures, and three reports of hypertension and strokes. Because of

the seriousness of these ADE's, in May 1983 FDA sought, but was unable

to obtain, Sandoz's agreement to include a warning of these adverse

experiences in Parlodel's labeling.

In April 1984, in its ``Drug Bulletin,'' FDA reported the ADE's for

bromocriptine associated with use of that drug in the prevention of

physiological lactation.

In March 1985, FDA again requested Sandoz to list and update

certain serious adverse experiences in Parlodel's labeling, but Sandoz

did not agree to make the labeling changes.

In February 1987, FDA requested for a third time that Sandoz change

its labeling to include the serious adverse experiences and also

requested that Sandoz send a letter to doctors to alert them to the

potential hazards of using bromocriptine for the prevention of

physiological lactation. In April 1987, Sandoz agreed to and

implemented both requests.

FDA received additional reports of serious ADE's and the agency

presented them to the Committee in June 1988 (Ref. 1). These ADE

reports included 5 reports of isolated hypertension, 26 reports of

seizures, 3 reports of status epilepticus seizures, and 9 reports of

stroke, all of which followed the use of bromocriptine for the

prevention of physiological lactation. Before offering a recommendation

to FDA, the Committee elected to wait for the results of Sandoz's then

ongoing study entitled ``An Epidemiologic Evaluation of the Possible

Relation Between Bromocriptine, Puerperal Seizures and Stroke'' (the

ERI study).

In June 1989, the Committee reconsidered bromocriptine in light of

the final results from Sandoz's ERI study, published at a later date

(Ref. 2). The ERI study failed to allay the concerns of the agency or

the Committee regarding the drug's association with seizures.

Additionally, the ERI study was too small in size to characterize

adequately the risk of stroke.

At the 1989 Committee meeting, FDA reported the ADE's associated

with bromocriptine reported to FDA as of that date, including 28

reports of hypertension, 36 reports of seizures, and 19 reports of

cerebrovascular accidents (CVA's). FDA reported that it had received a

total of 85 serious ADE's, including 10 deaths, since approval of the

indication in 1980. The agency concluded that, although the individual

ADE's did not prove that bromocriptine caused hypertensive crises,

seizures, or CVA's, in the aggregate, the ADE's suggested that

bromocriptine may be the cause of these serious adverse experiences,

therefore warranting further consideration by the Committee.

The Committee recommended that none of the drugs then labeled for

use in lactation suppression, including bromocriptine, should be used

for this indication. The Committee concluded that the possibility that

these drug products may cause serious adverse experiences in some

patients outweighs the limited benefit of their use in a self-resolving

condition that can be managed by more conservative treatment (Ref. 3).

FDA agreed with the Committee's recommendation and asked all

manufacturers of drug products labeled for use in preventing

physiological lactation to remove voluntarily that indication from

their products' labeling. All manufacturers but Sandoz complied with

the request.

In September 1989, FDA again requested Sandoz to withdraw

voluntarily Parlodel's indication for the prevention of physiological

lactation and indicated the agency's intent to initiate proceedings to

withdraw approval of the indication if Sandoz refused. Sandoz declined

to remove the indication and, on April 23, 1990, filed a citizen

petition requesting that FDA reconsider its decision to initiate

withdrawal proceedings.

The Director of the Center for Drug Evaluation and Research (the

Director) has evaluated the evidence suggesting that bromocriptine may

cause hypertension, seizures, and CVA's in some patients using the drug

for prevention of postpartum lactation suppression, and concludes that

these risks outweigh the product's marginal benefit in preventing

postpartum lactation. Accordingly, the Director is proposing to

withdraw approval of the indication recommending bromocriptine for

preventing physiological lactation on the basis that the drug is no

longer shown to be safe for this indication. A full discussion follows.

II. The Effectiveness of Bromocriptine in the Prevention of

Physiological Lactation

On October 27, 1978, Sandoz submitted to FDA a supplement to its

NDA for Parlodel proposing the drug's use in preventing physiological

lactation. This supplement included 24 studies (12 domestic and 12

foreign) using a total of 747 patients. In these studies, 568 patients

received bromocriptine, and 179 received estrogens or placebo. Based on

these studies, FDA concluded that bromocriptine is effective for the

prevention of physiological lactation.

The Director has reevaluated these studies and concludes that the

benefit of using bromocriptine to prevent physiological lactation is

limited by a number of factors.

First, the benefit of using a pharmacologically active systemic

drug for up to 3 weeks to prevent lactation, a self-limiting condition

that generally lasts no longer than a few days, is highly questionable.

Without the stimulation of breast feeding, the ability to lactate

disappears rapidly. The onset of engorgement occurs 48 to 72 hours

after delivery, and engorgement usually disappears in 1 to 2 days.

Secretion usually disappears after approximately 4 days, although it

may last up to 7 days. Maximum discomfort occurs between 2 to 7 days

after delivery, but most patients are uncomfortable for only the first

24 hours of this period.

Conservative treatment entails the use of nonpharmacological aids

such as ice packs and breast binding to suppress lactation, provide

relief from discomfort, and shorten the duration of painful engorgement

or leaking. Patients also can be treated with analgesics to provide

additional relief.

In one study, only 13 percent of placebo patients reported moderate

or severe breast engorgement during the postpartum period, and only 9

percent of placebo patients used analgesics (propoxyphene and codeine)

for pain relief (Ref. 4). A review of a number of studies concluded

that the majority of women can be adequately treated with a tight

brassiere, avoidance of nipple stimulation, and, if needed, minor

analgesics (Ref. 5). These studies also show that up to 30 percent to

40 percent of women may remain in some discomfort and require stronger

analgesics for the first days after parturition, but, ultimately, all

women can achieve a substantial level of comfort through the use of

conservative therapy.

Moreover, bromocriptine is effective for lactation suppression only

if prescribed before lactation begins. Because the small number of

women who will require stronger analgesics for breast symptoms cannot

be identified in advance, the large majority of women who are exposed

to bromocriptine for this use assume the risks of the product without

the potential for meaningful benefit.

Second, the benefit of using bromocriptine is called into question

by the fact that a large number of patients experience rebound

lactation after discontinuing use of the drug. In many cases,

therefore, bromocriptine merely delays lactation.

In its original analysis in 1980 of the studies supporting approval

of bromocriptine for lactation suppression, FDA concluded that 18 to 40

percent of the women taking bromocriptine reported some breast

soreness, leaking, or engorgement after stopping use of the drug. The

actual number of patients experiencing rebound lactation after taking

bromocriptine and the severity of their symptoms are difficult to

assess because Sandoz's studies presented incomplete information on

rebound lactation.

Thus, the evidence shows that the serious risks associated with the

use of bromocriptine to suppress lactation are unacceptable given that

lactation can be suppressed without risk by the use of more

conservative, nonpharmacological treatments occasionally supplemented

with mild analgesics.

III. Safety of Bromocriptine for the Prevention of Physiological

Lactation

The use of bromocriptine has been associated with both minor and

serious adverse experiences. In the domestic clinical trials supporting

the original approval of bromocriptine for preventing physiological

lactation, 22.8 percent of the patients taking bromocriptine reported

at least one adverse experience. The majority of these adverse

experiences were headache (8.5 percent of the patients), nausea (8.1

percent), dizziness (7.4 percent), vomiting (2.9 percent), and rash

(2.6 percent). Four of the 10 bromocriptine patients who dropped out of

the study did so because of drug-related side effects.

In the foreign studies supporting approval, 5 percent of the

patients receiving bromocriptine reported adverse experiences. These

adverse experiences were of the same general nature as the adverse

experiences reported by the American patients.

The most important adverse experience reported by investigators was

hypotension (low blood pressure). A lowering of blood pressure equal to

or greater than 20 conventional millimeters of mercury (mmHg) systolic

and 10 mmHg diastolic was observed in 28.4 percent of all patients

receiving the drug. Analysis showed that the hypotension was both dose-

and time-related, with the most significant hypotension appearing

within 4 hours.

Based on this information, FDA originally concluded that the side

effects associated with bromocriptine were minor or could be controlled

through appropriate labeling. Significantly, at the time of approval

there were no reports of hypertensive crises, seizures, or CVA's in

either the American or the foreign studies. Therefore, FDA approved the

drug as safe for use in preventing physiological lactation.

Since approval, a number of serious adverse drug experiences

associated with the use of bromocriptine in postpartum women have been

reported to FDA and have appeared in the medical literature. These

serious adverse experiences have included hypertension, seizures, and

CVA's.

A. Hypertension

In 1989, the agency reported to the Committee that it had received

28 hypertension ADE's associated with bromocriptine's use in postpartum

women, including 3 reports in 1988 of new-onset hypertension in women

who had not been preeclamptic. Hypertension was accompanied by severe

headaches in two of the three women. Two of the three women had no

history of hypertension, while the third woman had previously presented

only borderline elevations in the diastolic readings. In two of the

three women, there was no evidence of confounding by concomitant

medication.

As of September 1993, FDA had received 77 domestic spontaneous

reports of hypertension in postpartum women 15 through 45 years of age

who used bromocriptine for lactation suppression.

In 1989, Watson and associates reported on a study of the

relationship between hypertension and the use of bromocriptine in

postpartum women (Ref. 6; data from this study were presented to the

Committee in 1988 prior to publication). This was a retrospective study

based on data obtained after hospital discharge from 1,813 patients,

1,320 of whom were taking bromocriptine for lactation suppression. Data

were obtained 3 to 21 days after delivery.

Hypertension was defined, for study purposes, as systolic pressure

of 140 mmHg or more, or diastolic pressure of 90 mmHg or more. The use

of bromocriptine was the independent variable and postpartum

hypertension was the dependent variable. Covariates were age, race,

parity, weight, chronic hypertension, pregnancy-induced hypertension,

and antihypertensive medication. Data were analyzed by discriminant

analysis.

Although bromocriptine use alone was not found to be a significant

factor, the investigators concluded that the use of bromocriptine by

women who had previously exhibited pregnancy-induced hypertension

contributed significantly (p < 0.01) to a higher risk for the

development of postpartum hypertension.

Also in 1989, Ruch and Duhring reported on a 27-year-old woman with

pregnancy-induced hypertension who had taken bromocriptine for

lactation suppression (Ref. 7). Eight days after starting

bromocriptine, she presented with severe hypertension followed by

cardiac arrest and death. An autopsy revealed no evidence of coronary

atherosclerosis. However, the autopsy did show a 60 to 70 percent

stenotic plaque in the left anterior descending artery, which the

authors described as likely to have been secondary to a coronary artery

spasm induced, at least partially, by bromocriptine.

Kulig and associates reported on two women who developed severe

headaches after taking bromocriptine for lactation suppression in 1991

(Ref. 8). The use in addition to bromocriptine of a therapeutic

sympathomimetic agent resulted in ventricular tachycardia and cardiac

dysfunction in one case and seizures and cerebral vasospasm in the

other.

B. Seizures

FDA presented an analysis of 29 seizure ADE reports from the SRS to

the Committee in 1988: 16 reports were of grand mal seizures, 3 reports

were of status epilepticus, 1 report was of a focal seizure, and 9

reports were of seizures not otherwise specified.

Fourteen of the 29 postpartum patients had no prior history of

seizures. One patient previously had a single isolated seizure

associated with pericarditis. Information on hypertension was available

on 18 patients: 17 had no history of hypertension, and 1 previously had

a blood pressure reading of 160/90 immediately postpartum.

Information on concomitant medication was available for 25 of the

29 patients. Six were not taking any medication at the time of their

seizures. Nineteen were taking a variety of medications, including

antibiotics for caesarean section infection prophylaxis or treatment of

endometritis, narcotic and over-the-counter analgesics for postpartum

pain or headache, and diet pills. One patient was reportedly using

cocaine just prior to her seizure.

Status epilepticus was examined separately because it is a

potentially life-threatening condition. Three seizure cases were

diagnosed as status epilepticus by the reporting physicians. Three

other cases, initially reported as grand mal seizures, also met the

clinical profile of status epilepticus (Ref. 9). All six women had

unremarkable pregnancies and deliveries. Five of the six had a negative

seizure history. The status of the remaining patient is unknown. None

of the six was reported to have had blood pressure problems prior to

using bromocriptine.

In its summary to the Committee of seizure reports through 1988,

FDA noted that the onset of seizures tended to occur around 5 to 6 days

after bromocriptine use began.

In 1989, FDA updated the Committee on seven new ADE's received in

the preceding year involving women 18 to 36 years old. Six of the seven

began taking bromocriptine for the prevention of physiological

lactation 3 to 8 days prior to their seizures. In the seventh case,

there was no information on how long the patient had taken

bromocriptine before seizure. Six of the seven had no history of

preeclampsia. Five of the seven had no underlying medical conditions.

Two had also taken Percocet, two had received a nonsteroidal anti-

inflammatory drug for pain, and one woman had received pseudoephedrine.

Five of the seven recovered completely. The long-term outcome for the

other two is unknown. In these cases, seizures occurred 5 to 10 days

after postpartum bromocriptine use.

A similar clustering effect with a mean time of 6 days was also

noted in an agency followup investigation of seizure ADE's from the

start of marketing in 1980 through September 1993. To date, the agency

has received 63 domestic reports of seizures in women taking

bromocriptine for the prevention of physiological lactation, plus one

report of a seizure in a nursing 2-year-old whose mother had taken

bromocriptine. In 27 of these 64 reports, there was no mention of any

confounding factors such as a history of seizures or eclampsia.

Although many of these patients received anticonvulsant medication, and

the outcome was not reported for many patients, withdrawal of the drug

resulted in no further seizures in all but three patients. Seizures

were often preceded by a headache or accompanied by hypertension,

blurred vision, or loss of vision. Clinicians described these seizures

as grand mal or tonic-clonic. When performed, electroencephalograms and

computed tomography scans were normal.

Sandoz's ERI study noted an association between late occurring

seizures and bromocriptine. The results from this study were reported

to the Committee in 1989. This retrospective study reviewed hospital

records showing medical diagnostic codes indicative of seizure and

stroke.

The rarity of seizures, the small number of cases examined, and the

study's resultant lack of statistical power severely reduce its

usefulness in providing epidemiologic information. At only one of three

sites were patient identifiers used that allow investigators to track

the histories of individual patients for complete case ascertainment,

including, most importantly, readmissions. If the use of bromocriptine

for the prevention of physiological lactation causes late-occurring

seizures, seizures attributable to bromocriptine use would be most

likely to occur after hospital discharge. The lack of readmission data

suggests a possible bias towards cases under-ascertainment in the ERI

study's raw data and conclusions.

During the first 3 days of bromocriptine therapy, the ERI study

reported 22 percent fewer seizures among women taking bromocriptine

than in postpartum nonbromocriptine users. The authors of the study

conclude that this reduction in seizure risk is due to a protective

effect from bromocriptine. However, because this was a retrospective

study rather than a clinical trial, the study's patients were not

randomly assigned to bromocriptine and placebo groups. Therefore,

another explanation for the reduced number of early seizure reports may

be patient selection; doctors may well be less likely to prescribe

bromocriptine for ill patients.

The ERI study also reported that, after 3 days, women on

bromocriptine therapy for the prevention of physiological lactation

faced a 1.6 times greater than normal risk of seizures, even when

controlled for seizure history. The suggestion by the authors of the

study that bromocriptine may delay seizures, thereby shifting some

early-onset seizures so that they became late-onset seizures, is

unsubstantiated. Moreover, even if bromocriptine delays seizures, such

an effect is potentially dangerous if it delays seizures from a time

when patients are monitored in a hospital to a time when patients are

ordinarily at home without constant medical supervision or readily

available medical support.

C. CVA's

In 1988, FDA reviewed six cases of stroke associated with

bromocriptine for the Committee. The agency also reported the results

of a separate search of the scientific literature, which contained

accounts of 44 women suffering postpartum CVA's with onset in the first

30 days after delivery.

In 1989, FDA updated the Committee on 10 additional ADE's regarding

CVA's received since 1988. Three of the 10 women died while 2 others

survived but remained severely disabled. Nine of the 10 cases occurred

between 4 and 26 days postpartum.

These patients were between 22 and 38 years old. Information on the

duration of bromocriptine use is known for all but one case. Eight

patients had taken bromocriptine for lactation suppression 3 to 13 days

prior to their CVA. All CVA's occurred while the patient was receiving

the drug. Information on concomitant medications is known for seven

patients. Five of the 10 patients took no medication other than

bromocriptine, 1 also took acetaminophen, and one also took Aldomet

because of a 6-year history of hypertension. The last patient also had

sickle cell trait. Seven of the 10 patients had no history of

preeclampsia. One of the 10 patients had a transient ischemic attack

and her physician described her as having mild toxemia on the basis of

moderately elevated blood pressure and trace proteinuria. Eight

patients had no significant underlying illnesses that would predispose

them to a CVA.

Through September 1993, the agency had received reports of 31 cases

of CVA in association with bromocriptine used for the prevention of

physiological lactation. Nine patients died; 20 were hospitalized and

discharged with various degrees of permanent impairment. No confounding

factor was reported for 13 of the 31 patients.

The ERI study found one relatively unconfounded case of stroke

involving a woman taking bromocriptine for the prevention of

physiological lactation.

In 1986, Nedd and associates reported on two patients who suffered

subarachnoid hemorrhages after using bromocriptine postpartum (Ref.

10). One woman had an aneurysm, while the other woman was diagnosed

with a superior sagittal sinus thrombosis. She also had a history of

hypertension and sickle cell trait.

In 1990, Maurel and associates reported on a case of an obese, 30-

year-old woman smoker who suffered a cerebral infarction 2 weeks after

beginning bromocriptine (Ref. 11). Her pregnancy and delivery were

unremarkable, and the investigators could not explain the infarction by

any other cause.

D. Summary of Safety Information

Since approval of bromocriptine for use in preventing physiological

lactation, FDA has received a number of reports of serious and life-

threatening adverse experiences (hypertension, seizures, and CVA's)

associated with the use of bromocriptine for this indication. FDA

believes that the number of women experiencing such adverse experiences

may well be greater than those reported to FDA.

The above evidence, in aggregate, calls into question

bromocriptine's safety for use in postpartum women given that

bromocriptine may be responsible for hypertension, seizures, and CVA's

in a small but significant number of patients. Moreover, bromocriptine

may be an additional risk factor in patients who are already at risk

for seizures and stroke.

In addition, a possible mode of action exists for these adverse

events. In the general population, a risk factor for hypertensive

crises and spasms is exposure to ergot alkaloids. Bromocriptine is a

semi-synthetic ergot alkaloid. Bakht and associates have suggested that

a subpopulation may exist in which bromocriptine exerts vasospastic

effects similar to other ergot alkaloids (Ref. 12).

Pregnancy-induced hypertension is also known to be a catecholamine-

sensitive disorder. Bromocriptine is a dopaminergic agonist and is

structurally similar to dopamine, a catecholamine nucleus. It is

therefore possible that bromocriptine may act as an adrenergic

stimulant, like other ergot alkaloids, and precipitate pregnancy-

induced hypertension or other related adverse events.

Moreover, the clustering of late-onset seizure reports suggests an

association between seizures and bromocriptine use in some postpartum

women. In the general population, the majority of seizures in the

postpartum period occur within the first 48 hours, and are generally

diagnosed as eclamptic. After 3 or 4 days, seizures are viewed as

unusual, suggesting a possible relationship between bromocriptine use

and this adverse experience.

IV. Benefit/Risk Analysis and Conclusions

FDA approved bromocriptine in 1980 for the prevention of

physiologic lactation, despite its limited benefits, to provide what

appeared to be a safe, nonestrogenic therapy for this indication. At

the time of approval, FDA had no knowledge of the association of

serious adverse experiences with bromocriptine therapy, and believed

that a drug with roughly the same therapeutic effectiveness was better

than existing estrogenic therapies, which were associated with the

serious adverse experience of thrombosis.

FDA now has new information suggesting that therapeutic use of

bromocriptine for the prevention of physiological lactation may lead to

serious adverse experiences, including death and paralysis, in a small

but significant number of patients. Patients at high risk of

experiencing these serious adverse experiences cannot be adequately

predetermined. In light of the limited benefit of using bromocriptine

for the prevention of lactation, and the effectiveness and lack of

serious adverse effects of conservative treatments such as breast

binding with or without mild analgesics, the risk that bromocriptine

may cause a serious adverse effect in a postpartum woman is

unacceptable.

Accordingly, the Director concludes that the potential risks

associated with the use of bromocriptine for the prevention of

physiological lactation outweigh its limited benefits and bromocriptine

is no longer shown to be safe for use in preventing physiological

lactation. The Director is proposing to withdraw approval of the

indication recommending bromocriptine for use in the prevention of

physiological lactation in accordance with section 505(e)(2) of the

Federal Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 355(e)(2)).

V. References

The following references have been placed on display at 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. Transcript of the June 1988 meeting of the Fertility and

Maternal Health Drugs Advisory Committee.

2. Rothman, K. J., D. P. Funch, and N. A. Dreyer,

``Bromocriptine and Puerperal Seizures,'' Epidemiology, 1(3):232-

238, 1990.

3. Transcript of the June 1989 meeting of the Fertility and

Maternal Health Drugs Advisory Committee.

4. Niebyl, J. R. et al., ``The Effect of Chlorotrianisene as

Postpartum Lactation Suppression on Blood Coagulation Factors,''

American Journal of Obstetrics and Gynecology, 134(5):518-522, 1979.

5. Kochenour, N. K., ``Lactation Suppression,'' Clinical

Obstetrics and Gynecology, 23(4):1045-1059, 1980.

6. Watson, D. L. et al., ``Bromocriptine Mesylate for Lactation

Suppression: A Risk for Postpartum Hypertension?'' Obstetrics and

Gynecology, 74(4):573-576, 1989.

7. Ruch, A., and J. L. Duhring, ``Postpartum Myocardial

Infarction in a Patient Receiving Bromocriptine,l,'' Obstetrics and

Gynecology, 74(3 Pt.2):448-451, 1989.

8. Kulig, K. et al., ``Bromocriptine-Associated Headache:

Possible Life-Threatening Sympathomimetic Interaction,'' Obstetrics

and Gynecology, 78(5 pt.2):941-943, 1991.

9. Delgato-Escueta, A. V. et al., ``Management of Status

Epilepticus,'' New England Journal of Medicine, 306:1337-1340, 1983.

10. Nedd, K. J., M. Kent, and V. Powell, Jr., ``Subarachnoid

Hemorrhage During Pregnancy and the Puerperium: Report of 3 Cases

and Review of the Literature,'' Journal of the American Osteopathic

Association, 86(3):183-188, 1986.

11. Maurel, C. et al., ``Acute Thrombotic Accident in the

Postpartum Period in a Patient Receiving Bromocriptine,'' Critical

Care Medicine, 18(10):1180-1181, 1990.

12. Bakht, F. R. et al., ``Postpartum Cardiovascular

Complications After Bromocriptine and Cocaine Use,'' American

Journal of Obstetrics and Gynecology, 162:1065-1066, 1990.

VI. 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 17-962

insofar as it pertains to the indication recommending the use of

bromocriptine for the prevention of physiological lactation.

Therefore, notice is given to Sandoz and to all other interested

persons that the Director proposes to issue an order under section

505(e)(2) of the act, withdrawing approval of NDA 17-962, and all

amendments and supplements thereto, insofar as they pertain to the

indication recommending the use of bromocriptine for the prevention of

physiological lactation. The Director finds that new evidence of

clinical experience, not contained in the application and not available

to the Director until after the application was approved, evaluated

together with the evidence available to the Director when the

application was approved, shows that the drug is not shown to be safe

for use in the prevention of physiological lactation.

In accordance with section 505 of the act and 21 CFR part 314, the

applicant is hereby given an opportunity for a hearing to show why

approval of pertinent parts of the NDA should not be withdrawn.

An applicant who decides to seek a hearing shall file: (1) On or

before September 22, 1994, a written notice of appearance and request

for hearing, and (2) on or before October 24, 1994, 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 21

CFR 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 21 CFR 314.200 and

21 CFR part 12.

The failure of the applicant to file a timely written notice of

appearance and request for a hearing, as required by 21 CFR 314.200,

constitutes an election by that person not to use the opportunity for a

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, or in any way that is not consistent

with, an approved new drug application is subject to regulatory action

at any time.

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 pertinent parts of the application, 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: August 15, 1994.

Janet Woodcock,

Director, Center for Drug Evaluation and Research.

[FR Doc. 94-20562 Filed 8-17-94; 3:39 pm]

BILLING CODE 4160-01-P