Precautions

PRECAUTIONS – Q & A

What important PRECAUTION information should a patient know about medical abortion with mifepristone and misoprostol?

PRECAUTIONS on the drug’s labeling should provide a concise summary of the most clinically significant information that would affect decisions about whether to prescribe a drug, recommendations for patient monitoring that are critical to safe use of the drug, and measures that can be taken to prevent or mitigate harm. ⁽¹⁾

Patients should understand the Precautions and Warnings sections of the prescribing information that describes:⁽¹⁾

• clinically significant adverse reactions (including any that are potentially fatal, are serious even if infrequent, or can be prevented through appropriate use of the drug),
• other safety hazards (including those that are expected from pharmacological class or those resulting from drug/drug interactions),
• limitations in use imposed by them, and steps to be taken if they occur.  

For More Information:

• Mifeprex (Mifepristone) Prescribing Information
• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information
• Mifeprex (mifepristone) Information
• Misoprostol (marketed as Cytotec) Information

GENERAL

General Precautions: Mifepristone ⁽²⁾

Treatment with Mifeprex (mifepristone) and misoprostol for the termination of pregnancy requires three office visits by the patient. (see DOSAGE AND ADMINISTRATION)

Mifeprex is available only in single dose packaging. Three 200 mg tablets (600 mg) of Mifeprex are taken in a single oral dose. (see DOSAGE AND ADMINISTRATION)

Administration must be under the supervision of a qualified physician (see DOSAGE AND ADMINISTRATION).

Mifeprex may be administered only in a clinic, medical office, or hospital, by or under the supervision of a physician, able to assess the gestational age of an embryo and to diagnose ectopic pregnancies.

Physicians must also be able to provide surgical intervention in cases of incomplete abortion or severe bleeding, or have made plans to provide such care through others, and be able to assure patient access to medical facilities equipped to provide blood transfusions and resuscitation, if necessary.

The use of Mifeprex (mifepristone) is assumed to require the same preventive measures as those taken prior to and during surgical abortion to prevent rhesus immunization.

There are no data on the safety and efficacy of mifepristone in women with chronic medical conditions such as:

• cardiovascular, hypertensive, hepatic, respiratory or renal disease;
• insulin-dependent diabetes mellitus; severe anemia or heavy smoking.

Women who are more than 35 years of age and who also smoke 10 or more cigarettes per day should be treated with caution because such patients were generally excluded from clinical trials of mifepristone.

Although there is no clinical evidence, the effectiveness of Mifeprex (mifepristone) may be lower if misoprostol is administered more than two days after mifepristone administration.

General Precautions: Misoprostol ⁽³⁾

Caution should be employed when administering Cytotec (misoprostol) to patients with pre-existing cardiovascular disease.

More Information – Off-label Use of Misoprostol for Medical Abortion:

Misoprostol is used off-label for a variety of indications in the practice of obstetrics and gynecology, including cervical ripening before surgical procedures, treatment of postpartum hemorrhage, medical management of miscarriage, induction of labor and medical abortion. ⁽⁴⁾

Although misoprostol is not approved by the US Food and Drug Administration (FDA) for these indications, including medical abortion, in 2002, pregnancy was removed from the label as an absolute contraindication to misoprostol use. ⁽⁴⁾

FDA is aware that questions have been raised about the use of misoprostol, a drug indicated for the prevention of NSAID (nonsteroidal anti-inflammatory drugs, including aspirin)–induced gastric ulcers, in the medical abortion regimen with mifepristone, without a separate approval and labeling of misoprostol for this use. ⁽⁵⁾

The FDA routinely approves new drugs to be used with products already approved without requiring a change to the labeling of the previously approved drug. ⁽⁵⁾

Despite sufficient evidence justifying some off-label practices, lack of FDA approval means that off-label uses are not given the same degree of scientific scrutiny as labeled indications. ⁽⁶⁾

 If there are substantial safety concerns about approved (FDA) indications and dosages, there is even greater uncertainty with regard to off-label uses. ⁽⁷⁾

For More Information:

• Mifeprex (Mifepristone) Prescribing Information
• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information

INFORMATION FOR PATIENTS

Information for Patients Precautions: Mifepristone ⁽²⁾

Patients should be fully advised of the treatment procedure and its effects.

Patients should be given a copy of the MEDICATION GUIDE and the PATIENT AGREEMENT. (Additional copies of the MEDICATION GUIDE and the PATIENT AGREEMENT are available by contacting Danco Laboratories at 1-877-4 Early Option) (1-877-432-7596).

Patients should be advised to review both the MEDICATION GUIDE and the PATIENT AGREEMENT, and should be given the opportunity to discuss them and obtain answers to any questions they may have prior to receiving Mifeprex (mifepristone).

Patients should be advised to take their MEDICATION GUIDE with them if they visit an emergency room or another health care provider who did not prescribe Mifeprex, so that provider will be aware that the patient is undergoing a medical abortion.

Each Patient Must Understand:

• the necessity of completing the treatment schedule, including a follow-up visit approximately 14 days after taking Mifeprex;
• that vaginal bleeding and uterine cramping probably will occur;
• that prolonged heavy vaginal bleeding is not proof of a complete abortion;
• that if the treatment fails, there is a risk of fetal malformation;
• that medical abortion treatment failures are managed by surgical termination;
• and the steps to take in an emergency situation, including precise instructions and a telephone number that she can call if she has any problems or concerns.

Another pregnancy can occur following termination of pregnancy and before resumption of normal menses.

Contraception can be initiated as soon as the termination of the pregnancy has been confirmed, or before the woman resumes sexual intercourse.

Patient information is included with each package of Mifeprex (see MEDICATION GUIDE).

Information for Patients Precautions:* Misoprostol ⁽³⁾

• Cytotec is intended for administration along with nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, to decrease the chance of developing an NSAID-induced gastric ulcer.
• Cytotec should be taken only according to the directions given by a physician.
• If the patient has questions about or problems with Cytotec, the physician should be contacted promptly

 See Boxed WARNINGS.

• Cytotec (misoprostol) administration to women who are pregnant can cause abortion, premature birth, or birth defects.
• Uterine rupture has been reported when Cytotec was administered in pregnant women to induce labor or induce abortion beyond the eighth week of pregnancy (see also PRECAUTIONS and LABOR and DELIVERY).
• Patients must be advised of the abortifacient property and warned not to give the drug to others.

 *(Excerpts from Cytotec (misoprostol) labeling)

For More Information:

• Mifeprex (Mifepristone) Prescribing Information
• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information

SPECIAL NOTE FOR WOMEN – MISOPROSTOL

Special Note for Women Precautions: Cytotec (misoprostol) ⁽³⁾

Cytotec may cause abortion (sometimes incomplete), premature labor, or birth defects if given to pregnant women. (See Patient Information and Boxed Warnings)

Patient Information and Boxed Warning:* Misoprostol ⁽³⁾

• Cytotec is indicated for reducing the risk of NSAID (nonsteroidal antiinflammatory drugs, including aspirin)–induced gastric ulcers in patients at high risk of complications from gastric ulcer.
• Cytotec can cause abortion (sometimes incomplete which could lead to dangerous bleeding and require hospitalization and surgery), premature birth, or birth defects.
• Cytotec has been reported to cause the uterus to rupture (tear) when given after the eighth week of pregnancy. Rupture (tearing) of the uterus can result in severe bleeding, hysterectomy, and/or maternal or fetal death.
• Cytotec may cause diarrhea, abdominal cramping, and/or nausea in some people.
• Patients must be advised of the abortifacient property of misoprostol and warned not give the drug to anyone else.

*(Excerpts from Cytotec (misoprostol) labeling)

For More Information:

• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information

PEDIATRIC USE

Pediatric Use Precautions: Mifepristone ⁽²⁾

Safety and effectiveness of Mifeprex (mifepristone) in pediatric patients have not been established.

Pediatric Use Precautions: Misoprostol ⁽³⁾

Safety and effectiveness of Cytotec (misoprostol) in pediatric patients have not been established.

More Information – Pediatric FDA Approval Process:

Pediatric population(s) and pediatric patient(s) are defined as the pediatric age group, from birth to 16 years, including age groups often called neonates, infants, children, and adolescents. ⁽¹⁾

On May 17, 2006, Janet Woodcock, M.D., Deputy Commissioner of the FDA testified before the House Committee on Government Reform, Subcommittee on Criminal Justice, Drug Policy and Human Resources the following: ⁽⁵⁾

• The clinical trials in the NDA (New Drug Application) excluded patients younger than 18 years old, and the labeling states that the safety and efficacy in this age group have not been studied. ⁽⁵⁾
• In the case of Mifeprex (mifepristone), there was no scientific reason to expect menstruating females under 18 years of age to have a different physiological outcome with the approved Mifeprex regimen from women 18 years of age and older. ⁽⁵⁾

FDA requirements for pediatric approval:

• The pediatric use of mifepristone for medical abortion must be supported by evidence from adequate and well-controlled studies of mifepristone in adults that supports a finding of substantial evidence of effectiveness in the pediatric population.

For More Information:

• Mifeprex (Mifepristone) Prescribing Information
• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information
• Mifepristone: Approval Process and Postmarketing Activities

LABORATORY TESTS

Laboratory Tests Precautions: Mifepristone ⁽²⁾

Clinical examination is necessary to confirm the complete termination of pregnancy after the treatment procedure. Changes in quantitative human Chorionic Gonadotropin (hCG) levels will not be decisive until at least 10 days after the administration of Mifeprex.

A continuing pregnancy can be confirmed by ultrasonographic scan.

The existence of debris in the uterus following the treatment procedure will not necessarily require surgery for its removal.

Decreases in hemoglobin concentration, hematocrit and red blood cell count occur in some women who bleed heavily. Hemoglobin decreases of more than 2 g/dL occurred in 5.5% of subjects during the French clinical trials of mifepristone and misoprostol.

Clinically significant changes in serum enzyme (serum glutamic oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT), alkaline phosphatase, gamma-glutamyltransferase (GT)) activities were rarely reported.

For More Information:

• Mifeprex (Mifepristone) Prescribing Information

DRUG INTERACTIONS

Drug Interactions Precautions: Mifepristone ⁽²⁾

Although specific drug or food interactions with mifepristone have not been studied, on the basis of this drug’s metabolism by CYP 3A4, it is possible that:

• ketoconazole, itraconazole, erythromycin, and grapefruit juice may inhibit its metabolism (increasing serum levels of mifepristone).
•  rifampin, dexamethasone, St. John’s Wort, and certain anticonvulsants (phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum levels of mifepristone).

Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum levels of drugs that are CYP 3A4 substrates.

Due to the slow elimination of mifepristone from the body, such interaction may be observed for a prolonged period after its administration.

Therefore, caution should be exercised when mifepristone is administered with drugs that are CYP 3A4 substrates and have narrow therapeutic range, including some agents used during general anesthesia.

For More Information:

• Mifeprex (Mifepristone) Prescribing Information

CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY

Carcinogenesis, Mutagenesis, Impairment of Fertility Precautions: Mifepristone ⁽²⁾

No long-term studies to evaluate the carcinogenic potential of mifepristone have been performed.

Results from studies conducted in vitro and in animals have revealed no genotoxic potential for mifepristone.

Among the tests carried out were: Ames test with and without metabolic activation; gene conversion test in Saccharomyces cerevisiae D4 cells; forward mutation in Schizosaccharomyces pompe P1 cells; induction of unscheduled DNA synthesis in cultured HeLa cells; induction of chromosome aberrations in CHO cells; in vitro test for gene mutation in V79 Chinese hamster lung cells; and micronucleus test in mice.

The pharmacological activity of mifepristone disrupts the estrus cycle of animals, precluding studies designed to assess effects on fertility during drug administration. Three studies have been performed in rats to determine whether there were residual effects on reproductive function after termination of the drug exposure.

In rats, administration of the lowest oral dose of 0.3 mg/kg/day caused severe disruption of the estrus cycles for the three weeks of the treatment period. Following resumption of the estrus cycle, animals were mated and no effect on reproductive performance was observed.

In a neonatal exposure study in rats, the administration of a subcutaneous dose of mifepristone up to 100 mg/kg on the first day after birth had no adverse effect on future reproductive function in males or females.

The onset of puberty was observed to be slightly premature in female rats neonatally exposed to mifepristone. In a separate study in rats, oviduct and ovary malformations in female rats, delayed male puberty, deficient male sexual behavior, reduced testicular size, and lowered ejaculation frequency were noted after exposure to mifepristone (1 mg every other day) as neonates.

For More Information:

• Mifeprex (Mifepristone) Prescribing Information

PREGNANCY

Pregnancy Precautions: Mifepristone ⁽²⁾

Mifepristone is indicated for use in the termination of pregnancy (through 49 days' pregnancy) and has no other approved indication for use during pregnancy.

For More Information:

• Mifeprex (Mifepristone) Prescribing Information

TERATOGENIC EFFECTS

Teratogenic Effects Precautions: Mifepristone ⁽²⁾

The risk of abnormal embryo or fetal development due to mifepristone and misoprostol exposure in an ongoing pregnancy.

Human Data

As of September 2000, over 620,000 women in Europe had taken mifepristone in combination with a prostaglandin to terminate pregnancy. Among these 620,000 women, about 415,000 received mifepristone together with misoprostol. As of May 2000, a total of 82 cases had been reported in which women with on-going pregnancies after using mifepristone alone or mifepristone followed by misoprostol declined to have a surgical procedure at that time. These cases are summarized in Table 2.

Table 2: Reported Cases (as of May 2000) of On-going Pregnancies Not Terminated by Surgical Abortion at the End of Treatment with Mifepristone Alone or with Mifepristone-Misoprostol

Several reports in the literature indicate that prostaglandins, including misoprostol, may have teratogenic effects in human beings

• Skull defects, cranial nerve palsies, delayed growth and psychomotor development, facial malformation and limb defects have all been reported after exposure during the first trimester.

Animal Data

Teratology studies in mice, rats and rabbits at doses of 0.25 to 4.0 mg/kg (less than 1/100 to approximately 1/3 the human exposure level based on body surface area) were carried out. Because of the antiprogestational activity of mifepristone, fetal losses were much higher than in control animals.

Skull deformities were detected in rabbit studies at approximately 1/6 the human exposure, although no teratogenic effects of mifepristone have been observed to date in rats or mice. These deformities were most likely due to the mechanical effects of uterine contractions resulting from decreased progesterone levels.

Teratogenic Effects Precautions: Misoprostol ⁽³⁾

See Boxed WARNINGS.

Congenital anomalies sometimes associated with fetal death have been reported subsequent to the unsuccessful use of misoprostol as an abortifacient, but the drug's teratogenic mechanism has not been demonstrated.

Several reports in the literature associate the use of misoprostol during the first trimester of pregnancy with:

• skull defects,
• cranial nerve palsies,
• facial malformations,
• and limb defects.

Cytotec is not fetotoxic or teratogenic in rats and rabbits at doses 625 and 63 times the human dose, respectively.

For More Information:

• Mifeprex (Mifepristone) Prescribing Information
• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information

NONTERATOGENIC EFFECTS

Nonteratogenic Effects Precautions: Mifepristone ⁽²⁾

How the use of mifepristone and misoprostol disrupts pregnancy.

The indication for use of Mifeprex in conjunction with misoprostol is for the termination of pregnancy through 49 days' duration of pregnancy (as dated from the first day of the last menstrual period).

These drugs together disrupt pregnancy by:

• causing decidual necrosis,
• myometrial contractions and cervical softening,
• leading to the expulsion of the products of conception.

Nonteratogenic Effects Precautions:* Misoprostol ⁽³⁾

See Boxed WARNINGS.

Cytotec may endanger pregnancy (may cause abortion) and thereby cause harm to the fetus when administered to a pregnant woman.

Cytotec may produce uterine contractions, uterine bleeding, and expulsion of the products of conception.

Abortions caused by Cytotec may be incomplete.

*(Excerpts from Cytotec (misoprostol) labeling)

For More Information:

• Mifeprex (Mifepristone) Prescribing Information
• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information

LABOR & DELIVERY

Labor and Delivery Precautions:* Misoprostol ⁽³⁾

Cytotec (misoprostol) can induce or augment uterine contractions.

Vaginal administration of Cytotec, outside of its approved indication, has been used as a cervical ripening agent, for the induction of labor and for treatment of serious postpartum hemorrhage in the presence of uterine atony.

A major adverse effect of the obstetrical use of Cytotec is the hyperstimulation of the uterus which may progress to:

• uterine tetany with marked impairment of uteroplacental blood flow,
• uterine rupture (requiring surgical repair, hysterectomy, and/or salpingo-oophorectomy),
• or amniotic fluid embolism.

Pelvic pain, retained placenta, severe genital bleeding, shock, fetal bradycardia, and fetal and maternal death have been reported.

There may be an increased risk of uterine tachysystole, uterine rupture, meconium passage, meconium staining of amniotic fluid, and Cesarean delivery due to uterine hyperstimulation with the use of higher doses of Cytotec, including the manufactured 100 mcg tablet.

The risk of uterine rupture increases with advancing gestational ages and with prior uterine surgery, including Cesarean delivery. Grand multiparity also appears to be a risk factor for uterine rupture.

The effect of Cytotec on later growth, development, and functional maturation of the child when Cytotec is used for cervical ripening or induction of labor has not been established.

*(Excerpts from Cytotec (misoprostol) labeling)

For More Information:

• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information
   

NURSING MOTHERS

Nursing Mothers Precautions: Mifepristone ⁽²⁾

It is not known whether mifepristone is excreted in human milk. Many hormones with a similar chemical structure, however, are excreted in breast milk.

Since the effects of mifepristone on infants are unknown, breast-feeding women should consult with their health care provider to decide if they should discard their breast milk for a few days following administration of the medications (mifepristone and misoprostol).

Nursing Mothers Precautions: Misoprostol ⁽³⁾

Misoprostol is rapidly metabolized in the mother to misoprostol acid, which is biologically active and is excreted in breast milk. There are no published reports of adverse effects of misoprostol in breast-feeding infants of mothers taking misoprostol.

Caution should be exercised when misoprostol is administered to a nursing woman.

For More Information:

• Mifeprex (Mifepristone) Prescribing Information
• Cytotec (misoprostol tablets) U.S. Physician Prescribing Information