[Federal Register Volume 59, Number 162 (Tuesday, August 23, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-20562]


[[Page Unknown]]

[Federal Register: August 23, 1994]


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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