NDC 43393-001 Mifepristone

Mifepristone

NDC Product Code 43393-001

NDC Code: 43393-001

Proprietary Name: Mifepristone What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Mifepristone What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.


Product Characteristics
Color(s):
YELLOW (C48330)
Shape: ROUND (C48348)
Size(s):
11 MM
Imprint(s):
S

Code Structure
  • 43393 - Genbiopro Inc
    • 43393-001 - Mifepristone

NDC 43393-001-06

Package Description: 6 CARTON in 1 PACKAGE > 1 BLISTER PACK in 1 CARTON > 1 TABLET in 1 BLISTER PACK (43393-001-01)

NDC Product Information

Mifepristone with NDC 43393-001 is a a human prescription drug product labeled by Genbiopro Inc. The generic name of Mifepristone is mifepristone. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Genbiopro Inc

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.


Mifepristone Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • MIFEPRISTONE 200 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
  • STARCH, CORN (UNII: O8232NY3SJ)
  • POVIDONE, UNSPECIFIED (UNII: FZ989GH94E)
  • MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Progestational Hormone Receptor Antagonists - [MoA] (Mechanism of Action)
  • Progestin Antagonist - [EPC] (Established Pharmacologic Class)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Genbiopro Inc
Labeler Code: 43393
FDA Application Number: ANDA091178 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: ANDA - A product marketed under an approved Abbreviated New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 05-01-2019 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2020 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Mifepristone Product Label Images

Mifepristone Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

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, 200mg use. No causal relationship between the use of Mifepristone tablets, 200mg 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, 200mg 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, 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 she experiences sustained fever, severe abdominal pain, prolonged heavy bleeding, or syncope, or if she experiences abdominal pain or discomfort, or general malaise (including weakness, nausea, vomiting or diarrhea) for more than 24 hours after taking misoprostol.Advise the patient to take the Medication Guide with her if she visits an emergency room or a healthcare provider who did not prescribe Mifepristone tablets, 200mg so that the provider knows that she is undergoing a medical abortion.

1 Indications And Usage

Mifepristone tablets, 200mg is indicated, in a regimen with misoprostol, for the medical termination of intrauterine pregnancy through 70 days gestation.

2.1 Dosing Regimen

For purposes of this treatment, pregnancy is dated from the first day of the last menstrual period. The duration of pregnancy may be determined from menstrual history and clinical examination. Assess the pregnancy by ultrasonographic scan if the duration of pregnancy is uncertain or if ectopic pregnancy is suspected.
Remove any intrauterine device (“IUD”) before treatment with Mifepristone tablets, 200mg begins [see Contraindications (4)].
The dosing regimen for Mifepristone tablets, 200mg and misoprostol is:
Mifepristone 200mg orally + misoprostol 800mcg buccally• Day One: Mifepristone 200mg Administration One 200mg tablet of Mifepristone is taken in a single oral dose.• Day Two or Three: Misoprostol Administration (minimum 24-hour interval between, Mifepristone and misoprostol)

Four 200mcg tablets (total dose 800mcg) of misoprostol are taken by the buccal route. Tell the patient to place two 200mcg misoprostol tablets in each cheek pouch (the area between the cheek and gums) for 30 minutes and then swallow any remnants with water or another liquid (see Figure 1).Patients taking Mifepristone tablets, 200mg must take misoprostol within 24 to 48 hours after taking Mifepristone. The effectiveness of the regimen may be lower if misoprostol is administered less than 24 hours or more than 48 hours after Mifepristone administration. Because most women will expel the pregnancy within 2 to 24 hours of taking misoprostol [see Clinical Studies (14)], discuss with the patient an appropriate location for her to be when she takes the misoprostol, taking into account that expulsion could begin within 2 hours of administration.

2.2 Patient Management Following Misoprostol Administration

  • During the period immediately following the administration of misoprostol, the patient may need medication for cramps or gastrointestinal symptoms [see Adverse Reactions (6)].Give the patient:Instructions on what to do if significant discomfort, excessive vaginal bleeding or other adverse reactions occurA phone number to call if she has questions following the administration of the misoprostolThe name and phone number of the healthcare provider who will behandling emergencies.

2.3 Post-Treatment Assessment: Day 7 To 14

Patients should follow-up with their healthcare provider approximately 7 to 14 days after the administration of Mifepristone. This assessment is very important to confirm that complete termination of pregnancy has occurred and to evaluate the degree of bleeding. Termination can be confirmed by medical history, clinical examination, human Chorionic Gonadotropin (hCG) testing, or ultrasonographic scan. Lack of bleeding following treatment usually indicates failure; however, prolonged or heavy bleeding is not proof of a complete abortion.
The existence of debris in the uterus (e.g., if seen on ultrasonography) following the treatment procedure will not necessarily require surgery for its removal.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 women may experience some type of bleeding for more than 30 days. Persistence of heavy or moderate vaginal bleeding at the time of follow-up, however, could indicate an incomplete abortion.If complete expulsion has not occurred, but the pregnancy is not ongoing, women may be treated with another dose of misoprostol 800mcg buccally. There have been rare reports of uterine rupture in women who took Mifepristone tablets, 200mg and misoprostol, including women with prior uterine rupture or uterine scar and women who received multiple doses of misoprostol within 24 hours. Women who choose to use a repeat dose of misoprostol should have a follow-up visit with their healthcare provider in approximately 7 days to assess for complete termination.Surgical evacuation is recommended to manage ongoing pregnancies after medical abortion [see Use in Specific Populations (8.1)]. Advise the patient whether you will provide such care or will refer her to another provider as part of counseling prior to prescribing Mifepristone tablets, 200mg.

2.4 Contact For Consultation

For consultation 24 hours a day, 7 days a week with an expert in mifepristone, call GenBioPro, Inc. at 1-855-MIFEINFO (1-855-643-3463).

3 Dosage Forms And Strengths

Tablets containing 200mg of Mifepristone each, supplied as 1 tablet on one blister card. Mifepristone tablets are light yellow in color, circular, bio-convex tablets, approximately 11mm in diameter and imprinted on one side with “S.”

4 Contraindications

  • Administration of Mifepristone tablets, 200mg and misoprostol for the termination of pregnancy (the “treatment procedure”) is contraindicated in patients with any of the following conditions: -Confirmed or suspected ectopic pregnancy or undiagnosed adnexal mass (the treatment procedure will not be effective to terminate an ectopic pregnancy) [see Warnings and Precautions (5.4)]-Chronic adrenal failure (risk of acute renal insufficiency)-Concurrent long-term corticosteroid therapy (risk of acute renal insufficiency)-History of allergy to mifepristone, misoprostol, or other prostaglandins (allergic reactions including anaphylaxis, angioedema, rash, hives, and itching have been reported [see Adverse Reactions (6.2)])-Hemorrhagic disorders or concurrent anticoagulant therapy (risk of heavy bleeding)-Inherited porphyrias (risk of worsening or of precipitation of attacks)Use of Mifepristone tablets, 200mg and misoprostol for termination of intrauterine pregnancy is contraindicated in patients with an intrauterine device (“IUD”) in place (the IUD might interfere with pregnancy termination). If the IUD is removed, Mifepristone tablets, 200mg may be used.

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, 200mg [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, 200mg 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 women 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 2g/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, 200mg is available only through a restricted program 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 FormPatients must sign a Patient Agreement FormMifepristone tablets, 200mg must be dispensed to patients only in certain healthcare settings, specifically clinics, medical offices and hospitals by or under the supervision of a certified prescriberFurther information is available at 1-855-MIFEINFO (1-855-643-3463).

5.4 Ectopic Pregnancy

Mifepristone tablets, 200mg is contraindicated in patients with a confirmed or suspected ectopic pregnancy because mifepristone 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, 200mg.Women who became pregnant with an IUD in place should be assessed for ectopic pregnancy.

5.5 Rhesus Immunization

The use of Mifepristone tablets, 200mg 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)]

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 US studies, because rates reported in non-US studies were markedly lower and are not likely generalizable to the US population. In three US clinical studies totaling 1,248 women through 70 days gestation who used mifepristone 200mg orally followed 24-48 hours later by misoprostol 800mcg 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, 200mg 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, 200mg 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, 200mg 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, 200mg and misoprostol as used in the treatment procedure. Most women 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 US clinical studies with incidence >15% of women.Table 1 Adverse Reactions Reported in Women Following Administration of Mifepristone (oral) and Misoprostol (buccal) in US Clinical StudiesAdverse Reaction# US studiesNumber of Evaluable WomenRange of frequency (%)Upper Gestational Age of Studies Reporting OutcomeNausea31,24851-75%70 daysWeakness263055-58%63 daysFever/chills141448%63 daysVomiting31,24837-48%70 daysHeadache263041-44%63 daysDiarrhea31,24818-43%70 daysDizziness263039-41%63 daysOne 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 US and four non-US clinical studies, totaling 30,966 women through 70 days gestation who used mifepristone 200mg orally followed 24-48 hours later by misoprostol 800mcg buccally. Serious adverse reaction rates were similar between US and non-US studies, so rates from both US and non-US studies are presented. In the US studies, one studied women through 56 days gestation, four through 63 days gestation, and one through 70 days gestation, while in the non-US 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 US and non-US studies is presented in Table 2.
Table 2 Serious Adverse Reactions Reported in Women Following Administration of Mifepristone (oral) and Misoprostol (buccal) in US and Non-US Clinical StudiesNR= Not reported
*This outcome represents a single patient who experienced death related to sepsis.
Adverse ReactionUS Non-US# of studiesNumber of Evaluable WomenRange offrequency (%)# of studiesNumber of Evaluable WomenRange of frequency (%)Transfusion417,7740.03-0.5%312,1340-0.1%Sepsis1 629 0.2% 1 11,155 <0.01%*ER visit2 1,043 2.9-4.6%1 95 0 Hospitalization Related to Medical Abortion3 14,339 0.04-0.6% 3 1,286 0-0.7% Infection without sepsis1 216 0 1 11,155 0.2% HemorrhageNR 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, 200mg 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: anemiaImmune system disorders: allergic reaction (including anaphylaxis, angioedema, hives, rash, itching)Psychiatric disorders: anxietyCardiac disorders: tachycardia (including racing pulse, heart palpitations, heart pounding)Vascular disorders: syncope, fainting, loss of consciousness, hypotension (including orthostatic), light-headednessRespiratory, thoracic and mediastinal disorders: shortness of breathGastrointestinal disorders: dyspepsiaMusculoskeletal, connective tissue and bone disorders: back pain, leg pain Reproductive system and breast disorders: uterine rupture, ruptured ectopic pregnancy, hematometra, leukorrheaGeneral disorders and administration site conditions: pain

7.1 Drugs That May Reduce Mifepristone Tablets, 200Mg Exposure (Effect Of Cyp 3A4 Inducers On Mifepristone Tablets, 200Mg)

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 [see Dosage and Administration (2.3)] to verify that treatment has been successful.

7.2 Drugs That May Increase Mifepristone Tablets, 200Mg Exposure (Effect Of Cyp 3A4 Inhibitors On Mifepristone Tablets, 200Mg)

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). Mifepristone tablets, 200mg should be used with caution in patients currently or recently treated with CYP 3A4 inhibitors.

7.3 Effects Of Mifepristone Tablets, 200Mg On Other Drugs (Effect Of Mifepristone Tablets, 200Mg On Cyp 3A4substrates)

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 a narrow therapeutic range.

8.1 Pregnancy

Risk SummaryMifepristone is indicated, in a regimen with misoprostol, for the medical termination of intrauterine pregnancy through 70 days gestation. Risks to pregnant women are discussed throughout the labeling.Refer to misoprostol labeling for risks to pregnant women with the use of misoprostol.
The risk of adverse developmental outcomes with a continued pregnancy after a failed pregnancy termination with Mifepristone tablets,
200mg in a regimen with misoprostol is unknown; however, the process of a failed pregnancy termination could disrupt normal embryo-fetal
development and result in adverse developmental effects. Birth defects have been reported with a continued pregnancy after a failed
pregnancy termination with Mifepristone tablets, 200mg in a regimen with misoprostol. In animal reproduction studies, increased fetal losses
were observed in mice, rats, and rabbits and skull deformities were observed in rabbits with administration of mifepristone at doses lower than
the human exposure level based on body surface area.DataAnimal DataIn teratology studies in mice, rats and rabbits at doses of 0.25 to 4.0mg/kg (less than 1/100 to approximately 1/3 the human exposure based on body surface area), 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 inhibition of progesterone action.

8.2 Lactation

Mifepristone tablets, 200mg is present in human milk. Limited data demonstrate undetectable to low levels of the drug in human milk with the relative (weight-adjusted) infant dose 0.5% or less as compared to maternal dosing. There is no information on the effects of Mifepristone tablets, 200mg in a regimen with misoprostol in a breastfed infant or on milk production. Refer to misoprostol labeling for lactation information with the use of misoprostol. The developmental and health benefits of breast-feeding should be considered along with any potential adverse effects on the breast-fed child from Mifepristone tablets, 200mg in a regimen with misoprostol.

8.4 Pediatric Use

Safety and efficacy of Mifepristone tablets, 200mg have been established in pregnant females. Data from a clinical study of Mifepristone tablets, 200mg that included a subset of 322 females under age 17 demonstrated a safety and efficacy profile similar to that observed in adults.

10 Overdosage

No serious adverse reactions were reported in tolerance studies in healthy non-pregnant female and healthy male subjects where
mifepristone was administered in single doses greater than 1,800mg (ninefold the recommended dose for medical abortion). If a patient
ingests a massive overdose, she should be observed closely for signs of adrenal failure.

11 Description

Mifepristone tablets each contain 200mg of mifepristone, a synthetic steroid with antiprogestational effects. The tablets are light yellow in color, circular, bi-convex, and are intended for oral administration only. The tablets include the inactive ingredients colloidal silicon dioxide, corn starch, povidone, microcrystalline cellulose, and magnesium stearate.Mifepristone is a substituted 19-nor steroid compound chemically designated as 11ß-[p- (Dimethylamino) phenyl]-17ß-hydroxy-
17-(1-propynyl) estra-4,9-dien-3-one. Its empirical formula is C29H35NO2. Its structural formula is:The compound is a yellow powder with a molecular weight of 429.6 and a melting point of 192- 196°C. It is freely soluble in methanol, chloroform and acetone and poorly soluble in water, hexane and isopropyl ether.

12.1 Mechanism Of Action

The anti-progestational activity of mifepristone results from competitive interaction with progesterone at progesterone-receptor sites. Based on studies with various oral doses in several animal species (mouse, rat, rabbit, and monkey), the compound inhibits the activity of endogenous or exogenous progesterone, resulting in effects on the uterus and cervix that, when combined with misoprostol, result in termination of an intrauterine pregnancy.During pregnancy, the compound sensitizes the myometrium to the contraction-inducing activity of prostaglandins.

12.2 Pharmacodynamics

Use of Mifepristone tablets, 200mg in a regimen with misoprostol disrupts pregnancy by causing decidual necrosis, myometrial contractions, and cervical softening, leading to the expulsion of the products of conception.Doses of 1mg/kg or greater of mifepristone have been shown to antagonize the endometrial and myometrial effects of progesterone in women.Antiglucocorticoid and antiandrogenic activity: Mifepristone also exhibits antiglucocorticoid and weak antiandrogenic activity. The activity of the glucocorticoid dexamethasone in rats was inhibited following doses of 10 to 25mg/kg of mifepristone. Doses of 4.5mg/kg or greater in human beings resulted in a compensatory elevation of adrenocorticotropic hormone (ACTH) and cortisol. Antiandrogenic activity was observed in rats following repeated administration of doses from 10 to 100mg/kg.

12.3 Pharmacokinetics

Mifepristone is rapidly absorbed after oral ingestion with non-linear pharmacokinetics for Cmax after single oral doses of 200mg and 600mg in healthy subjects.AbsorptionThe absolute bioavailability of a 20mg mifepristone oral dose in women of childbearing age is 69%. Following oral administration of a single dose of 600mg, mifepristone is rapidly absorbed, with a peak plasma concentration of 1.98 ± 1.0mg/L occurring approximately 90 minutes after ingestion.Following oral administration of a single dose of 200mg in healthy men (n=8), mean Cmax was1.77 ± 0.7mg/L occurring approximately 45 minutes after ingestion. Mean AUC0-∞ was 25.8± 6.2mg*hr/L.DistributionMifepristone is 98% bound to plasma proteins, albumin, and 1-acid glycoprotein. Binding to the latter protein is saturable, and the drug displays nonlinear kinetics with respect to plasma concentration and clearance.EliminationFollowing a distribution phase, elimination of mifepristone is slow at first (50% eliminated between 12 and 72 hours) and then becomes more rapid with a terminal elimination half-life of 18 hours.MetabolismMetabolism of mifepristone is primarily via pathways involving N-demethylation and terminal hydroxylation of the 17-propynyl chain. In vitro studies have shown that CYP450 3A4 is primarily responsible for the metabolism. The three major metabolites identified in humans are: (1) RU 42 633, the most widely found in plasma, is the N-monodemethylated metabolite; (2) RU 42 848, which results from the loss of two methyl groups from the 4-dimethylaminophenyl in position 11ß; and (3) RU 42 698, which results from terminal hydroxylation of the 17-propynyl chain.ExcretionBy 11 days after a 600mg dose of tritiated compound, 83% of the dr ug has been accounted for by the feces and 9% by the urine. Serum concentrations are undetectable by 11 days.Specific PopulationsThe effects of age, hepatic disease and renal disease on the safety, efficacy and pharmacokinetics of mifepristone have not been investigated.

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

CarcinogenesisNo long-term studies to evaluate the carcinogenic potential of mifepristone have been performed.MutagenesisResults 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.Impairment of FertilityIn rats, administration of 0.3mg/kg mifepristone per 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 effects on reproductive performance were observed.

14 Clinical Studies

Safety and efficacy data from clinical studies of mifepristone 200mg orally followed 24-48 hours later by misoprostol 800mcg buccally through 70 days gestation are reported below. Success was defined as the complete expulsion of the products of conception without the need for surgical intervention. The overall rates of success and failure, shown by reason for failure based on 22 worldwide clinical studies (including 7 US studies) appear in Table 3.The demographics of women who participated in the US clinical studies varied depending on study location and represent the racial and ethnic variety of American females. Females of all reproductive ages were represented, including females less than 18 and more than 40 years of age; most were 27 years or younger.Table 3 Outcome Following Treatment with Mifepristone (oral) and Misoprostol (buccal) Through 70 Days GestationUS TrialsNon-US TrialsN16,79418,425Complete Medical Abortion97.4%96.2%Surgical Intervention*2.6%3.8%Ongoing Pregnancy**0.7%0.9%* Reasons for surgical intervention include ongoing pregnancy, medical necessity, persistent or heavy bleeding after treatment, patient request, or incomplete expulsion.** Ongoing pregnancy is a subcategory of surgical intervention, indicating the percent of women who have surgical intervention
due to an ongoing pregnancy.The results for clinical studies that reported outcomes, including failure rates for ongoing pregnancy, by gestational age are presented in Table 4.
Table 4 Outcome by Gestational Age Following Treatment with Mifepristone and Misoprostol (buccal) for US and Non-US Clinical Studies <49 days 50-56 days 57-63 days 64-70 days N % Number of Evaluable Studies N % Number of Evaluable Studies N % Number of Evaluable Studies N % Number of Evaluable Studies Complete medical abortion12,04698.1103,94196.872,29494.7947992.74 Surgical intervention for ongoing pregnancy10,2720.363,7880.862,211284533.13One clinical study asked subjects through 70 days gestation to estimate when they expelled the pregnancy, with 70% providing data. Of these, 23-38% reported expulsion within 3 hours and over 90% within 24 hours of using misoprostol.

16 How Supplied/Storage And Handling

Mifepristone tablets, 200mg is only available through a restricted program called the Mifepristone REMS Program [see Warnings and Precautions (5.3)]Mifepristone tablets, 200mg is supplied as light yellow, circular, bi-convex, uncoated tablets debossed with “S” on one side and plain on other side. Each tablet contains 200mg of mifepristone. One tablet is individually blistered on one blister card that is packaged in an individual package (National Drug Code 43393-001-01).Store at 25°C (77°F); excursions permitted to 15 to 30°C (59 to 86°F) [see USP Controlled Room Temperature].

17 Patient Counseling Information

  • Advise the patient to read the FDA-approved patient labeling (Medication Guide), included with each package of Mifepristone tablets, 200mg. Additional copies of the Medication Guide are available by contacting GenBioPro, Inc., at 1-855-MIFEINFO (1-855-643-3463) or from www.MIFEINFO.com.Serious Infections and BleedingInform the patient that uterine bleeding and uterine cramping will occur [see Warnings and Precautions (5.2)].Advise the patient that serious and sometimes fatal infections and bleeding can occur very rarely [see Warnings and Precautions (5.1, 5.2)].Mifepristone tablets, 200mg are only available through a restricted program called the Mifepristone REMS Program [see Warnings and Precautions (5.3)]. Under the Mifepristone REMS Program:
  • Patients must sign a Patient Agreement Form.Mifepristone tablets, 200mg is only available in clinics, medical offices and hospitals and not through retail pharmacies.Provider Contacts and Actions in Case of ComplicationsEnsure 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, or if she experiences complications including prolonged heavy bleeding, severe abdominal pain, or sustained fever [see Boxed Warning].Advise the patient to take the Medication Guide with her if she visits an emergency room or another healthcare provider who did not prescribe Mifepristone tablets, 200mg, so that the provider will be aware that the patient is undergoing a medical abortion with Mifepristone tablets, 200mg.Compliance with Treatment Schedule and Follow-up AssessmentAdvise the patient that it is necessary to complete the treatment schedule; including a follow-up assessment approximately 7 to14 days after taking Mifepristone tablets, 200mg [see Dosage and Administration (2.3)].Explain that:
  • Prolonged heavy vaginal bleeding is not proof of a complete abortion,if the treatment fails and the pregnancy continues, the risk of fetal malformation is unknown,it is recommended that ongoing pregnancy be managed by surgical termination [see Dosage and Administration (2.3)]. Advise the patient whether you will provide such care or will refer her to another provider.Subsequent FertilityInform the patient that another pregnancy can occur following medical abortion and before resumption of normal menses.Inform the patient that contraception can be initiated as soon as pregnancy expulsion has been confirmed, or before she resumes sexual intercourse.Manufactured for:
  • GenBioPro, Inc.
  • P.O. Box 32011
  • Las Vegas, NV 89103
  • 1-855-MIFEINFO (1-855-643-3463)
  • Www.MIFEINFO.com

Package Label

NDC 43393-001-01Mifepristone Tablet200 mg1 TabletNDC 43393-001-01Mifepristone Tablet200 mgRx Only1 TabletNDC 43393-001-06Mifepristone Tablet200 mgRx OnlyContains 6 Cartons Each Carton Contains 1 Tablet

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