Mifepristone

WARNING: SERIOUS AND SOMETIMES FATAL INFECTIONS OR BLEEDING Serious and sometimes fatal infections and bleeding occur very rarely following spontaneous, surgical, and medical abortions, including following Mifepristone Tablets, 200 mg use. No causal relationship between the use of Mifepristone Tablets, 200 mg and misoprostol and these events has been established. Atypical Presentation of Infection. Patients with serious bacterial infections (e.g., Clostridium sordellii ) and sepsis can present without fever, bacteremia, or significant findings on pelvic examination following an abortion. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise. A high index of suspicion is needed to rule out serious infection and sepsis [see Warnings and Precautions ( 5.1 )] Bleeding. Prolonged heavy bleeding may be a sign of incomplete abortion or other complications and prompt medical or surgical intervention may be needed. Advise patients to seek immediate medical attention if they experience prolonged heavy vaginal bleeding [see Warnings and Precautions ( 5.2 )] . Because of the risks of serious complications described above, Mifepristone Tablets, 200 mg is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Mifepristone REMS Program [see Warnings and Precautions ( 5.3 )] . Before prescribing mifepristone tablets, inform the patient about the risk of these serious events. Ensure that the patient knows whom to call and what to do, including going to an Emergency Room if none of the provided contacts are reachable, if they experience sustained fever, severe abdominal pain, prolonged heavy bleeding, or syncope, or if they experience abdominal pain or discomfort, or general malaise (including weakness, nausea, vomiting, or diarrhea) for more than 24 hours after taking misoprostol. WARNING: SERIOUS AND SOMETIMES FATAL INFECTIONS OR BLEEDING See full prescribing information for complete boxed warning. Serious and sometimes fatal infections and bleeding occur very rarely following spontaneous, surgical, and medical abortions, including following Mifepristone Tablets, 200 mg use . Atypical Presentation of Infection. Patients with serious bacterial infections and sepsis can present without fever, bacteremia or significant findings on pelvic examination. A high index of suspicion is needed to rule out serious infection and sepsis. ( 5.1 ) Bleeding. Prolonged heavy bleeding may be a sign of incomplete abortion or other complications and prompt medical or surgical intervention may be needed. ( 5.2 ) Mifepristone Tablets, 200 mg is only available through a restricted program called the Mifepristone REMS Program ( 5.3 ). Before prescribing Mifepristone Tablets, 200 mg, inform the patient about these risks. Ensure the patient knows whom to call and what to do if they experience sustained fever, severe abdominal pain, prolonged heavy bleeding, or syncope, or if they experience abdominal pain or discomfort or general malaise for more than 24 hours after taking misoprostol.

5 WARNINGS AND PRECAUTIONS Ectopic pregnancy: Exclude before treatment. ( 5.4 ) Rhesus immunization: Prevention needed as for surgical abortion. ( 5.5 ) 5.1 Infection and Sepsis As with other types of abortion, cases of serious bacterial infection, including very rare cases of fatal septic shock, have been reported following the use of Mifepristone Tablets, 200 mg [see Boxed Warning ] . Healthcare providers evaluating a patient who is undergoing a medical abortion should be alert to the possibility of this rare event. A sustained (> 4 hours) fever of 100.4°F or higher, severe abdominal pain, or pelvic tenderness in the days after a medical abortion may be an indication of infection. A high index of suspicion is needed to rule out sepsis (e.g., from Clostridium sordellii ) if a patient reports abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting or diarrhea) more than 24 hours after taking misoprostol. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise. No causal relationship between Mifepristone Tablets, 200 mg and misoprostol use and an increased risk of infection or death has been established. Clostridium sordellii infections have also been reported very rarely following childbirth (vaginal delivery and caesarian section), and in other gynecologic and non-gynecologic conditions. 5.2 Uterine Bleeding Uterine bleeding occurs in almost all patients during a medical abortion. 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. Counsel patients to seek immediate medical attention if they experience prolonged heavy vaginal bleeding following a medical abortion [see Boxed Warning ] . Women should expect to experience vaginal bleeding or spotting for an average of 9 to 16 days. Women report experiencing heavy bleeding for a median duration of 2 days. Up to 8% of all subjects may experience some type of bleeding for 30 days or more. In general, the duration of bleeding and spotting increased as the duration of the pregnancy increased. Decreases in hemoglobin concentration, hematocrit, and red blood cell count may occur in patient who bleed heavily. Excessive uterine bleeding usually requires treatment by uterotonics, vasoconstrictor drugs, surgical uterine evacuation, administration of saline infusions, and/or blood transfusions. Based on data from several large clinical trials, vasoconstrictor drugs were used in 4.3% of all subjects, there was a decrease in hemoglobin of more than 2 g/dL in 5.5% of subjects, and blood transfusions were administered to ≤0.1% of subjects. Because heavy bleeding requiring surgical uterine evacuation occurs in about 1% of patients, special care should be given to patients with hemostatic disorders, hypocoagulability, or severe anemia. 5.3 Mifepristone REMS Program Mifepristone Tablets, 200 mg is available only through a restricted program under a REMS called the Mifepristone REMS Program, because of the risks of serious complications [see Warnings and Precautions ( 5.1 , 5.2 )]. Notable requirements of the Mifepristone REMS Program include the following: Prescribers must be certified with the program by completing the Prescriber Agreement Form. Patients must sign a Patient Agreement Form. Mifepristone Tablets, 200 mg must only be dispensed to patients by or under the supervision of a certified prescriber, or by certified pharmacies on prescriptions issued by certified prescribers. Further information is available at 1-866-718-0098. 5.4 Ectopic Pregnancy Mifepristone Tablets, 200 mg is contraindicated in patients with a confirmed or suspected ectopic pregnancy because mifepristone tablets is not effective for terminating ectopic pregnancies [see Contraindications ( 4 )] . Healthcare providers should remain alert to the possibility that a patient who is undergoing a medical abortion could have an undiagnosed ectopic pregnancy because some of the expected symptoms experienced with a medical abortion (abdominal pain, uterine bleeding) may be similar to those of a ruptured ectopic pregnancy. The presence of an ectopic pregnancy may have been missed even if the patient underwent ultrasonography prior to being prescribed mifepristone tablets, 200 mg. Patients who became pregnant with an IUD in place should be assessed for ectopic pregnancy. 5.5 Rhesus Immunization The use of Mifepristone Tablets, 200 mg is assumed to require the same preventive measures as those taken prior to and during surgical abortion to prevent rhesus immunization.

6 ADVERSE REACTIONS The following adverse reactions are described in greater detail in other sections: Infection and sepsis [ see Warnings and Precautions ( 5.1 )] Uterine bleeding [ see Warnings and Precautions ( 5.2 )] Most common adverse reactions (>15%) are nausea, weakness, fever/chills, vomiting, headache, diarrhea, and dizziness. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Evita Solutions LLC at 1-866-718-0098 or medical@evitasolutionsllc.com or www.medicalabortionpill.com or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 to 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 Mifepristone Tablets, 200 mg 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 Mifepristone Tablets, 200 mg 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 Mifepristone Tablets, 200 mg 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 Mifepristone Tablets, 200 mg and misoprostol as used in the treatment procedure. Most patients can expect bleeding more heavily than they do during a heavy menstrual period [see Warnings and Precautions ( 5.2 )] . 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 Adverse Reaction # U.S. studies Number of Evaluable Women Range of frequency (%) Upper Gestational Age of Studies Reporting Outcome Nausea 3 1,248 51-75% 70 days Weakness 2 630 55-58% 63 days Fever/chills 1 414 48% 63 days Vomiting 3 1,248 37-48% 70 days Headache 2 630 41-44% 63 days Diarrhea 3 1,248 18-43% 70 days Dizziness 2 630 39-41% 63 days One study provided gestational-age stratified adverse reaction rates for women who were 57 to 63 and 64 to 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 to 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 NR= Not reported * This outcome represents a single patient who experienced death related to sepsis. Adverse Reaction U.S. Non-U.S. # of studies Number of Evaluable Women Range of frequency (%) # of studies Number of Evaluable Women Range of frequency (%) Transfusion 4 17,774 0.03-0.5% 3 12,134 0-0.1% Sepsis 1 629 0.2% 1 11,155 <0.01% * ER visit 2 1,043 2.9-4.6% 1 95 0 Hospitalization Related to Medical Abortion 3 14,339 0.04-0.6% 3 1,286 0-0.7% Infection without sepsis 1 216 0 1 11,155 0.2% Hemorrhage NR NR NR 1 11,155 0.1% 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of Mifepristone Tablets, 200 mg 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

<table width="85%"><tbody><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Adverse Reaction</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"># U.S. studies </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Number of Evaluable Women </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Range of frequency (%) </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Upper Gestational Age of Studies Reporting Outcome </content></td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Nausea</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1,248</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">51-75%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">70 days</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Weakness</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">2</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">630</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">55-58%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">63 days</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Fever/chills</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">414</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">48%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">63 days</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Vomiting</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1,248</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">37-48%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">70 days</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Headache</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">2</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">630</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">41-44%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">63 days</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Diarrhea</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1,248</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">18-43%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">70 days</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Dizziness</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">2</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">630</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">39-41%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">63 days</td></tr></tbody></table>

<table width="85%"><tfoot><tr styleCode="First Last"><td colspan="3" align="left" valign="top"><paragraph styleCode="First Footnote">NR= Not reported</paragraph><paragraph>^*This outcome represents a single patient who experienced death related to sepsis. </paragraph></td></tr></tfoot><tbody><tr><td rowspan="2" align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Adverse Reaction </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">U.S.</content></td><td colspan="5" align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Non-U.S.</content></td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"># of studies</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Number of Evaluable Women</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Range of frequency (%) </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold"># of studies </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Number of Evaluable Women </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Range of frequency (%) </content></td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Transfusion</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">4</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">17,774</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0.03-0.5%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">12,134</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0-0.1%</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Sepsis</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">629</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0.2%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">11,155</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">&lt;0.01% ^*</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">ER visit</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">2</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1,043</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">2.9-4.6%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">95</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Hospitalization Related to Medical Abortion </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">14,339</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0.04-0.6%</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">3</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1,286</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0-0.7%</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Infection without sepsis </content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">216</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">11,155</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0.2%</td></tr><tr><td align="center" styleCode="Botrule Lrule Rrule Toprule"><content styleCode="bold">Hemorrhage</content></td><td align="center" styleCode="Botrule Lrule Rrule Toprule">NR</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">NR</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">NR</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">1</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">11,155</td><td align="center" styleCode="Botrule Lrule Rrule Toprule">0.1%</td></tr></tbody></table>