[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