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What is FDA announcing?
FDA is announcing that the prescribing information
and Medication Guide for Mifeprex has been updated to include a revised Black Box
warning for Mifeprex and Danco
Laboratories has issued a new Dear Doctor Letter for
Mifeprex.
- Why have the prescribing information and
Medication Guide for Mifeprex been
updated and why has Danco issued a new Dear Doctor
Letter for Mifeprex?
FDA has been informed of additional postmarketing
adverse events in the United States
involving cases of bacterial infection in women
following the use of Mifeprex and
misoprostol for medical abortion. Overwhelming
bacterial infection (septic shock) has
led to death.
Although serious infection and death following
medical abortion is rare health care
professionals and patients should be aware of the
possibility that it may occur.
The label and Medication Guide are the primary
sources of information for physicians
and patients. The revised labeling and Medication
Guide present new information about
bacterial infection and its possible presenting
signs and symptoms. When FDA receives
and reviews new information, the agency provides
appropriate updates to doctors and
their patients so that they have essential
information on how to use a drug safely. A Dear
Health Care Practitioner letter and a Dear Emergency
Room Director letter will assist in
disseminating the updated information as quickly as
possible to those physicians who use
Mifeprex and misoprostol as well as emergency room
physicians who may care for
women seeking medical attention after using the
treatment. Finally, these letters will
enclose a chapter from Obstetric and Gynecologic
Emergencies Diagnosis and
Management (NY: McGraw-Hill, 2004) about
complications of induced surgical and
medical abortions so that emergency rooms will have
a reference available.
- What are the changes to the Prescribing
Information and Medication Guide?
To communicate new safety information about Mifeprex,
Danco Laboratories has
updated the BOXED WARNING and WARNINGS sections of
the Prescribing
Information as well as the Medication Guide and the
Patient Agreement.
Infection and Sepsis
New information on infection and sepsis has been
included in the BOXED WARNING
and WARNINGS sections of the Prescribing
Information:
In postmarketing experience following the use of Mifeprex and misoprostol, FDA
has received reports of cases of serious bacterial
infection, including very rare
cases of fatal septic shock. No causal relationship
between these events and the
use of Mifeprex has been established. Although
infection following medical
abortion is rare, prescribers should be alert to the
possibility of infection in their
patients. In particular, a sustained fever of 100.4
degrees Fahrenheit or higher,
severe abdominal pain, or pelvic tenderness in the
days after taking Mifeprex and
misoprostol may be an indication of infection.
Atypical presentations of serious
infection and sepsis, without fever, severe
abdominal pain, or pelvic tenderness,
but with significant leukocytosis, tachycardia, or
hemoconcentration can occur.
Vaginal Bleeding
Information on vaginal bleeding has been added to
the BOXED WARNING to highlight
the serious nature of this event if not promptly
treated. The WARNINGS section already
stated that vaginal bleeding occurs in almost all
patients during the treatment procedure.
"According to data from the U.S. and French trials,
women should expect to
experience vaginal bleeding or spotting for an
average of nine to 16 days, while
up to 8% of all subjects may experience some type of
bleeding for 30 days or
more." "Prolonged heavy bleeding (soaking through
two thick full-size sanitary
pads per hour for two consecutive hours) may be a
sign of incomplete abortion or
other complications and prompt medical or surgical
intervention may be needed
to prevent the development of hypovolemic shock."
"Excessive vaginal bleeding
usually requires treatment by uterotonics,
vasoconstrictor drugs, curettage, and/or
blood transfusions."
Prescribers should counsel their patients to seek
immediate medical attention if they
experience prolonged heavy vaginal bleeding
following a medical abortion.
Ectopic Pregnancy
Information on ectopic pregnancy has been added to
the WARNINGS section to alert
physicians to the possibility that a patient who is
undergoing a medical abortion could
have an undiagnosed ectopic pregnancy since some of
the expected symptoms of a
medical abortion may be similar to those of a
ruptured ectopic pregnancy.
No causal relationship between these events and
Mifeprex and misoprostol has
been established. Mifeprex is already
contraindicated in patients with a
confirmed or suspected ectopic pregnancy since
Mifeprex is not effective for
terminating these pregnancies. The presence of an
ectopic pregnancy may have
been missed even if the patient underwent
ultrasonography prior to being
prescribed Mifeprex.
The Patient Agreement has been updated to reflect
the new safety information on serious
bacterial infection and vaginal bleeding as well as
the Medication Guide in the section
titled "What is the most important information I
should know about Mifeprex?"
- What is a serious bacterial infection and how
often does this occur following medical
abortion?
Serious and sometimes fatal infections occur very
rarely following spontaneous, surgical,
and medical abortions, including following Mifeprex
use. A serious bacterial infection is
one that spreads throughout the body, having the
potential to pose a life-threatening
situation. Very rarely, serious bacterial infections
may lead to septic shock and death.
- What is septic shock?
Septic shock is the result of an overwhelming
systemic bacterial infection when there is
both decreased blood pressure and blood flow in the
body. This is a medical emergency
because vital organs, such as the brain, heart,
kidneys, lungs, and liver, may not function
properly or may fail.
- What are the recognizable signs and symptoms of
infection?
In the days after treatment with Mifeprex and
misoprostol, having a fever of 100.4
degrees Fahrenheit or higher that lasts for more
than 4 hours and/or lower abdominal pain
or pelvic tenderness may be signs of an infection.
It is important that the patient contact
her health care provider right away if she develops
any of these signs or symptoms or has
any questions. Patients should have an emergency
contact to call if there are problems,
especially if they experience severe pain, heavy
bleeding or fever.
- Can Mifeprex and misoprostol actually cause
serious bacterial infections?
No. A causal relationship between use of the drugs
and serious bacterial infection has not
been established. There is a risk of infection with
any termination of pregnancy, either
spontaneous or through medical or surgical abortion.
It is important for health care
providers to explain the treatment regimen’s risks
and benefits to patients, answer their
questions and provide them with information about
potentially serious signs and
symptoms that would signal the need to seek medical
attention right away.
- Why is prolonged or heavy bleeding now part of
the Black Box warnings?
In Europe, there was a death from severe prolonged
bleeding in a woman who did not
seek follow-up medical care. Bleeding during medical
abortion is a known side effect
and has been in the WARNINGS section of the labeling
since the drug was approved.
FDA and Danco agree that prolonged or heavy bleeding
severe enough to cause a death
can be avoided if patients and health care providers
monitor bleeding carefully. To
prevent complications of severe blood loss, the
Warning has been elevated to call
everyone’s attention to the need to carefully
monitor bleeding and that prompt medical or
surgical care may be needed.
- What other actions have been taken since Mifeprex
was approved to assure the safety of
the drug?
Mifeprex was approved in 2000 for the termination of
early pregnancy, defined as 49
days or less. In April 2002, a Dear Health Care
Practitioner Letter was sent to prescribers
to warn about the risks of serious infection and
sepsis following abortion as well as to
remind prescribers to rule out ectopic pregnancies
prior to use.
- Has FDA responded to the citizen’s petition on
this product?
No. FDA is still reviewing and considering the
pending citizens petition.
- What information has FDA received pertaining to
adverse events for mifepristone?
Through November 5, 2004, FDA has received
information from United States postmarketing
reports (i.e., not from clinical trials) of 676
adverse events that occurred among
patients who had taken mifepristone for medical
termination of pregnancy. These adverse
events ranged from minor symptoms such as nausea and
dizziness to more serious adverse
events, including hospitalization and death. These
events cannot with certainty be causally
attributed to mifepristone because of information
gaps about patient health status, clinical
management of the patient, concurrent drug use and
other possible medical or surgical
treatments. Because FDA has eliminated duplicate
reports that we have identified and, in
some cases, reclassified the adverse event terms for
individual cases after reviewing the
narrative details, the numbers provided here may
differ from the numbers of the reports that
may be obtained through Freedom of Information Act
requests.
Approximately 350,000 women have been treated with mifepristone in the US, from its
approval in 2000 through the end of October, 2004.
| Post-Marketing Adverse Events in US Women Who Used Mifepristone for
Termination of Pregnancy |
|---|
| Died | 3 |
| Ectopic pregnancies 1 |
17 |
| Experienced blood loss requiring transfusions
2 |
72 |
| Serious bacterial infections, including sepsis |
7 |
1 Administration of mifepristone and misoprostol is
contraindicated in patients with confirmed or suspected ectopic
pregnancy (a pregnancy outside the uterus).
2 As stated in the mifepristone labeling,
bleeding or spotting can be expected for an average of 9-16 days,
and may last for up to 30 days.
- The table in the previous question shows that
there have been three deaths in the
United States. Has FDA investigated the deaths of
the women who had a medical
abortion? What does FDA know about these deaths?
Yes, and the FDA has completed its investigation of
these deaths. One death in September,
2001 was associated with a ruptured ectopic (tubal)
pregnancy. The other two deaths (one in
September, 2003, and the other in January, 2004)
were associated with septic shock. The
MedWatch reports for the three deaths were reported
to FDA in October, 2001, September,
2003, and August, 2004, respectively. The coroner’s
report for the January, 2004 death
indicated that the patient terminated her pregnancy
with methotrexate. However, information
subsequently submitted by the healthcare provider
indicated that the patient had in fact
received mifepristone and misoprostol, not
methotrexate. Danco Laboratories was not
notified by the healthcare provider about this death
until August, 2004, after which they
notified FDA.
- What further action will FDA take regarding
Mifeprex?
The revised labeling will provide physicians and
patients with important information so that
they can respond and possibly prevent rare but
serious complications that may occur with any
abortion. FDA monitors postmarketing reports and
will continue to closely monitor safety
reports associated with the use of Mifeprex and
misoprostol and may take further action.
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Date created: November 16, 2004, updated July 19, 2005
