Side Effects of Mifeprex (mifepristone)

Mifeprex (mifepristone) is a synthetic steroid with antiprogesterone and antiglucocorticoid effects used to terminate pregnancy and to treat people with Cushing syndrome. 

Progesterone is a female hormone and the principal progestational hormone. Progesterone prepares the uterus (the womb) to receive and sustain the fertilized egg and is an important hormone for sustaining pregnancy. 

Mifeprex terminates early pregnancy by blocking the activity of progesterone at progesterone receptors. It also stimulates contraction of the uterus. Early pregnancy is considered to be 49 days (7 weeks) since the last menstrual period began. Mifeprex must be used in combination with misoprostol for the purpose of termination of pregnancy. 

Cortisol is a metabolite of the hormone cortisone, and is an essential factor in many processes including the proper metabolism of starches, and it is the major natural glucocorticoid in humans. People with Cushing syndrome produce too much cortisol, and, among many other effects, develop high glucose (sugar) levels in the blood. Mifeprex reduces blood glucose levels in people with Cushing syndrome by blocking the activity of cortisol.

Common side effects of Mifeprex include

• vaginal bleeding,
• cramping,
• nausea,
• vomiting,
• diarrhea,
• dizziness,
• back pain, and
• tiredness. 

Serious side effects of Mifeprex include

• allergic reactions,
• low blood pressure,
• loss of consciousness,
• infections after abortion,
• ruptured ectopic pregnancy,
• shortness of breath,
• rapid heartbeat, and
• collection of blood in the uterus (hematometra).

Drug interactions of Mifeprex include ketoconazole, itraconazole, erythromycin, and grapefruit juice, which may increase blood levels of Mifeprex by inhibiting the enzyme responsible for metabolizing (breaking down) Mifeprex.

• Rifampin, dexamethasone, St. John's wort, phenytoin, phenobarbital, and carbamazepine may decrease blood levels of Mifeprex by increasing the activity of the enzyme responsible for metabolizing Mifeprex and decrease the effectiveness of Mifeprex.
• Mifeprex may inhibit liver enzymes which are responsible for the metabolism of various drugs, resulting in increased blood levels of these drugs. 

Mifeprex is used for the termination of pregnancy through the 49th day of pregnancy. Otherwise, it should not be used during pregnancy because it will terminate the pregnancy. 

Mifeprex is secreted into breast milk. Due to the risk of adverse effects, breastfeeding mothers should decide whether to discontinue breastfeeding or Mifeprex.

Commonly reported side effects include

• vaginal bleeding,
• cramping,
• nausea,
• vomiting,
• diarrhea,
• dizziness,
• back pain, and
• tiredness.

Less common but severe side effects include

• allergic reactions,
• low blood pressure,
• loss of consciousness,
• infections after abortion,
• ruptured ectopic pregnancy,
• shortness of breath,
• rapid heartbeat (tachycardia), and
• hematometra (collection of blood in the uterus).

The following adverse reactions are described in greater detail in other sections:

• Infection and sepsis
• Uterine bleeding

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Information presented on common adverse reactions relies solely on data from U.S. studies, because rates reported in non-U.S. studies were markedly lower and are not likely generalizable to the U.S. population.

In three U.S. clinical studies totaling 1,248 women through 70 days gestation who used mifepristone 200 mg orally followed 24-48 hours later by misoprostol 800 mcg buccally, women reported adverse reactions in diaries and in interviews at the follow-up visit.

These studies enrolled generally healthy women of reproductive age without contraindications to mifepristone or misoprostol use according to the Mifeprex product label.

Gestational age was assessed prior to study enrollment using the date of the woman's last menstrual period, clinical evaluation, and/or ultrasound examination.

About 85% of patients report at least one adverse reaction following administration of Mifeprex and misoprostol, and many can be expected to report more than one such reaction. The most commonly reported adverse reactions (>15%) were

• nausea,
• weakness,
• fever/chills,
• vomiting,
• headache,
• diarrhea, and
• dizziness (see Table 1).

The frequency of adverse reactions varies between studies and may be dependent on many factors, including the patient population and gestational age.

Abdominal pain/cramping is expected in all medical abortion patients and its incidence is not reported in clinical studies. Treatment with Mifeprex and misoprostol is designed to induce uterine bleeding and cramping to cause termination of an intrauterine pregnancy.

Uterine bleeding and cramping are expected consequences of the action of Mifeprex and misoprostol as used in the treatment procedure. Most women can expect bleeding more heavily than they do during a heavy menstrual period.

Table 1 lists the adverse reactions reported in U.S. clinical studies with incidence >15% of women.

Table 1: Adverse Reactions Reported in Women Following Administration of Mifepristone (oral) and Misoprostol (buccal) in U.S. Clinical Studies

One study provided gestational-age stratified adverse reaction rates for women who were 57-63 and 64-70 days; there was little difference in frequency of the reported common adverse reactions by gestational age.

Information on serious adverse reactions was reported in six U.S. and four non-U.S. clinical studies, totaling 30,966 women through 70 days gestation who used mifepristone 200 mg orally followed 24-48 hours later by misoprostol 800 mcg buccally. Serious adverse reaction rates were similar between U.S. and non-U.S. studies, so rates from both U.S. and non-U.S. studies are presented.

In the U.S. studies, one studied women through 56 days gestation, four through 63 days gestation, and one through 70 days gestation, while in the non-U.S. studies, two studied women through 63 days gestation, and two through 70 days gestation.

Serious adverse reactions were reported in <0.5% of women. Information from the U.S. and non-U.S. studies is presented in Table 2.

Table 2: Serious Adverse Reactions Reported in Women Following Administration of Mifepristone (oral) and Misoprostol (buccal) in U.S. and Non-U.S. Clinical Studies

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Mifeprex and misoprostol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Infections and infestations: post-abortal infection (including endometritis, endomyometritis, parametritis, pelvic infection, pelvic inflammatory disease, salpingitis)

Blood and the lymphatic system disorders: anemia

Immune system disorders: allergic reaction (including anaphylaxis, angioedema, hives, rash, itching)

Psychiatric disorders: anxiety

Cardiac disorders: tachycardia (including racing pulse, heart palpitations, heart pounding)

Vascular disorders: syncope, fainting, loss of consciousness, hypotension (including orthostatic), light-headedness

Respiratory, thoracic and mediastinal disorders: shortness of breath

Gastrointestinal disorders: dyspepsia

Musculoskeletal, connective tissue and bone disorders: back pain, leg pain

Reproductive system and breast disorders: uterine rupture, ruptured ectopic pregnancy, hematometra, leukorrhea

General disorders and administration site conditions: pain

Drugs That May Reduce Mifeprex Exposure (Effect Of CYP 3A4 Inducers On Mifeprex)

• CYP450 3A4 is primarily responsible for the metabolism of mifepristone. CYP3A4 inducers such as rifampin, dexamethasone, St. John's Wort, and certain anticonvulsants (such as phenytoin, phenobarbital, carbamazepine) may induce mifepristone metabolism (lowering serum concentrations of mifepristone).
• Whether this action has an impact on the efficacy of the dose regimen is unknown. Refer to the follow-up assessment to verify that treatment has been successful.

Drugs That May Increase Mifeprex Exposure (Effect Of CYP 3A4 Inhibitors On Mifeprex)

• 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 concentrations of mifepristone).
• Mifeprex should be used with caution in patients currently or recently treated with CYP 3A4 inhibitors.

Effects Of Mifeprex On Other Drugs (Effect Of Mifeprex On CYP 3A4 Substrates)

• Based on in vitro inhibition information, coadministration of mifepristone may lead to an increase in serum concentrations 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.