Korlym

Korlym can cause serious side effects including:

• See “Drug Precautions”
• reduced effects of adrenal hormones (adrenal insufficiency). Korlym stops an adrenal hormone in your body called cortisol from working. Tell your doctor right away if you have any symptoms of adrenal insufficiency. Symptoms may include:
  • unusual tiredness or weakness
  • nausea
  • fatigue
  • low blood pressure (hypotension)
  • low blood sugar (hypoglycemia)
• low blood potassium (hypokalemia). Your doctor should check the level of potassium in your blood before you start taking mifepristone and while you take it. Tell your doctor if you have any signs of low potassium. Signs may include:
  • muscle weakness, aches, or cramps
  • abnormal or irregular heartbeats (palpitations)
• bleeding from the vagina. Korlym may cause the lining of your uterus to become thick and may cause your uterus to bleed. Tell your doctor right away about any bleeding from your vagina that is not normal for you.
• problems with the electrical system of your heart (QT interval prolongation).
• worsening of symptoms of other medical problems that are treated with corticosteroids when you take corticosteroids and Korlym at the same time.

The most common side effects of Korlym include:

• nausea
• fatigue
• headache
• low potassium in your blood
• pain in your arms and legs (arthralgia)
• vomiting
• swelling of your arms and legs (peripheral edema)
• high blood pressure
• dizziness
• decreased appetite
• thickening of the lining of the uterus (endometrial hypertrophy)

Tell your doctor if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of Korlym. For more information, ask your doctor or pharmacist.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Get emergency medical help if you have signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Stop using Korlym and call your doctor at once if you have:

• nausea, unusual weakness, tired feeling;

• abnormal vaginal bleeding;

• a light-headed feeling, like you might pass out;

• new or worsening medical problems;

• low blood sugar--headache, hunger, weakness, sweating, confusion, irritability, dizziness, fast heart rate, or feeling jittery;

• low potassium--leg cramps, irregular heartbeats, fluttering in your chest, muscle weakness or limp feeling; or

• increased blood pressure--severe headache, blurred vision, pounding in your neck or ears, anxiety, nosebleed.

Common side effects may include:

• nausea, vomiting, loss of appetite;

• low potassium;

• tired feeling;

• headache, dizziness;

• joint pain;

• thickened lining of your uterus;

• swelling in your hands or feet;

• changes in your menstrual periods; or

• high blood pressure.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

This section provides information on the proper use of a number of products that contain mifepristone. It may not be specific to Korlym. Please read with care.

This medicine should come with a Medication Guide. Read and follow these instructions carefully. Ask your doctor if you have any questions.

For patients using Mifeprex® tablets:

• This medicine is given only by your doctor. You will not be allowed to take it at home. The entire treatment requires three visits to your doctor.
• At the first visit, you will be given one mifepristone tablet. Two days later at the second visit, you will be given four tablets of another medicine called misoprostol. Two weeks later at the third visit, your doctor will check to make sure you are no longer pregnant. This may include an ultrasound exam (sonogram).
• This medicine will cause you to bleed and have cramps for about 2 to 4 weeks. Call your doctor if you have little or no vaginal bleeding after receiving the medicine.
• It is sometimes necessary to have a surgical abortion to completely end the pregnancy. You may also need to have surgery if there is any tissue left in your uterus after treatment with mifepristone.
• Tell your doctor if you are using an intrauterine device (IUD). It must be removed first before using this medicine.

For patients using Korlym™ tablets:

• Your doctor will tell you how much of this medicine to use and how often. Your dose may need to be changed several times in order to find out what works best for you. Do not use more medicine or use it more often than your doctor tells you to.
• Swallow the tablet whole. Do not break, crush, or chew it. Take this medicine with a meal.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For oral dosage form (tablets):
  • For termination of pregnancy (70 days or less) taken together with misoprostol:
    • Adults—200 milligrams (mg) as a single dose on Day 1. This is followed 2 days later by 800 micrograms (mcg) (four-200 mcg tablets) of misoprostol as a single dose placed in the cheeks.
    • Children—Use is not recommended.
  • For treatment of hyperglycemia in patients with Cushing's syndrome:
    • Adults—At first, 300 milligrams (mg) once a day. Your doctor may increase your dose as needed. However, the dose is usually not more than 1200 mg per day.
    • Children—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

• Tell all of your health care providers that you take Korlym. This includes your doctors, nurses, pharmacists, and dentists.
• Have blood work checked as you have been told by the doctor. Talk with the doctor.
• Avoid grapefruit and grapefruit juice.
• This medicine may affect how much of some other drugs are in your body. If you are taking other drugs, talk with your doctor. You may need to have your blood work checked more closely while taking this medicine with your other drugs.
• Birth control pills and other hormone-based birth control may not work as well to prevent pregnancy. Use some other kind of birth control also, like a condom, when taking Korlym and for 1 month after care ends.
• If you get pregnant while taking this medicine or within 1 month after your last dose, call your doctor right away.

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
• Very bad dizziness or passing out.
• Very bad headache.
• Shortness of breath.
• Feeling very tired or weak.
• A fast heartbeat.
• Very upset stomach or throwing up.
• Signs of low potassium levels like muscle pain or weakness, muscle cramps, or a heartbeat that does not feel normal.
• Signs of high or low blood pressure like very bad headache or dizziness, passing out, change in eyesight.
• Vaginal bleeding that is not normal.
• Anxiety.
• Chest pain or pressure.
• Swelling in the arms or legs.
• Not able to sleep.
• Low blood sugar can happen. The chance of low blood sugar may be raised when Korlym is used with other drugs for high blood sugar (diabetes). Signs may be dizziness, headache, feeling sleepy, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do if you get low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.
• A type of abnormal heartbeat (prolonged QT interval) can happen with this medicine. Call your doctor right away if you have a fast heartbeat, a heartbeat that does not feel normal, or if you pass out.

Pregnancy

Korlym is contraindicated in women who are pregnant. Pregnancy must be excluded before the initiation of treatment with Korlym or if treatment is interrupted for more than 14 days in females of reproductive potential. Non-hormonal contraceptives should be used during and one month after stopping treatment in all women of reproductive potential. [See Use in Specific Populations 8.8]

Drugs Metabolized by CYP3A

Korlym is contraindicated in patients taking simvastatin, lovastatin, and CYP3A substrates with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, due to an increased risk of adverse events. [See Drug Interactions (7.1) and Clinical Pharmacology (12.3)]

Corticosteroid Therapy Required for Lifesaving Purposes

Korlym is contraindicated in patients who require concomitant treatment with systemic corticosteroids for serious medical conditions or illnesses (e.g., immunosuppression after organ transplantation) because Korlym antagonizes the effect of glucocorticoids.

Women with Risk of Vaginal Bleeding or Endometrial Changes

Korlym is contraindicated in the following:

• Women with a history of unexplained vaginal bleeding
• Women with endometrial hyperplasia with atypia or endometrial carcinoma

Known Hypersensitivity to Mifepristone

Korlym is contraindicated in patients with prior hypersensitivity reactions to mifepristone or to any of the product components.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

Safety data on the use of Korlym are available from 50 patients with Cushing's syndrome enrolled in an uncontrolled, open-label, multi-center trial (Study 400). Forty-three patients had Cushing's disease and all except one had previously undergone pituitary surgery. Four patients had ectopic ACTH secretion, and three had adrenal carcinoma. Patients were treated for up to 24 weeks. A dose of 300 mg per day was administered for the initial 14 days; thereafter, the dose could be escalated in increments of 300 mg per day based on assessments of tolerability and clinical response. Doses were escalated up to 900 mg per day for patients <60 kg, or 1200 mg per day for patients >60 kg.

The most frequently reported adverse reactions (reported in ≥20% of patients, regardless of relationship to Korlym) were nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, and endometrial hypertrophy. Drug-related adverse events resulted in dose interruption or reduction in study drug in 40% of patients.

The adverse reactions that occurred in ≥10% of the Cushing's syndrome patients receiving Korlym, regardless of relationship to Korlym, are shown in Table 1.

Laboratory Tests

Reductions in high density lipoprotein-cholesterol (HDL-C) levels have been observed following treatment with Korlym. In study subjects that experienced declines in HDL-C, levels returned to baseline following discontinuation of drug. The clinical significance of the treatment-related reduction in HDL-C levels in patients with Cushing's syndrome is not known.

In a study of patients with Cushing's syndrome, hypokalemia was observed in 44% of subjects during treatment with Korlym. In these cases, hypokalemia responded to treatment with potassium supplementation and/or mineralocorticoid antagonist therapy (e.g., spironolactone or eplerenone). Hypokalemia should be corrected prior to initiating Korlym. [See Warnings and Precautions (5.2)]

Elevations of thyroid-stimulating hormone (TSH) were seen in subjects treated with Korlym. Of the 42 subjects with detectable TSH at baseline, eight (19%) had increases in TSH above the normal range, while remaining asymptomatic. The TSH levels returned to normal in most patients without intervention when Korlym was discontinued at the end of the study.

Vaginal Bleeding and Endometrial Changes

In Study 400, the thickness of the endometrium increased from a mean of 6.14 mm at baseline (n=23) to 15.7 mm at end-of-trial (n=18) in premenopausal women; in postmenopausal women the increase was from 2.75 mm (n=6) to 7.35 mm (n=8). Endometrial thickness above the upper limit of normal was reported in 10/26 females who had baseline and end-of-trial transvaginal ultrasound (38%). The endometrial thickness returned to the normal range in 3 out of 10 patients 6 weeks after treatment cessation at the end of the study. Vaginal bleeding occurred in 5 out of 35 females (14%). Two of five subjects with vaginal bleeding had normal endometrial thickness. Endometrial biopsies were performed in six patients; five of these patients had endometrial thickening. No endometrial carcinoma was detected in the sampled cases.

Additional Data from Clinical Trials

The following are adverse events that were reported in Study 400 at frequencies of ≥ 5% to 10%, and may be related to Korlym's mechanism of action:

Gastrointestinal disorders: gastroesophageal reflux, abdominal pain

General disorders and administration site conditions: asthenia, malaise, edema, pitting edema, thirst

Investigations: blood triglycerides increased

Metabolism and nutrition disorders: hypoglycemia

Musculoskeletal and connective tissue disorders: muscular weakness, flank pain, musculoskeletal chest pain

Psychiatric disorders: insomnia

Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia [See Warnings and Precautions (5.3)]

Adrenal Insufficiency

Adrenal insufficiency was reported in two subjects (4%) in Study 400. The most typical symptoms of adrenal insufficiency were nausea and decreased appetite. No hypotension or hypoglycemia was reported during the events. Adrenal insufficiency resolved in both cases with Korlym interruption and /or dexamethasone administration.

Rash

Generalized, maculo-papular rash was reported in 2 subjects (4%) in Study 400. Two additional subjects developed pruritus (4%). None resulted in discontinuation of Korlym, and all the events resolved by the end of the study.

Postmarketing Experience

The following adverse reaction has been identified during post approval use of Korlym. 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.

Korlym (mifepristone) is a cortisol receptor blocker for oral administration. The chemical name of mifepristone is 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4, 9-dien-3-one. The chemical formula is C29H35NO2; the molecular weight is 429.60, and the structural formula is:

Mifepristone demonstrates a pH-related solubility profile. The greatest solubility is achieved in acidic media (~ 25 mg/mL at pH 1.5) and solubility declines rapidly as the pH is increased. At pH values above 2.5 the solubility of mifepristone is less than 1 mg/mL.

Each Korlym tablet for oral use contains 300 mg of mifepristone. The inactive ingredients of Korlym tablets are silicified microcrystalline cellulose, sodium starch glycolate, hydroxypropylcellulose, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide, triacetin, D&C yellow 10 aluminum lake, polysorbate 80, and FD&C yellow 6 aluminum lake.

Cushing's Syndrome

An uncontrolled, open-label, 24-week, multicenter clinical study was conducted to evaluate the safety and efficacy of Korlym in the treatment of endogenous Cushing's syndrome. The study enrolled 50 subjects with clinical and biochemical evidence of hypercortisolemia despite prior surgical treatment and radiotherapy. The reasons for medical treatment were failed surgery, recurrence of disease, and poor medical candidate for surgery. Forty-three patients (86%) had Cushing's disease, four patients (8%) had ectopic ACTH secretion, and three (6%) had adrenal carcinoma. Baseline characteristics included: mean age of 45 years (range 26 to 71), mean BMI of 36 kg/m2 (range 24 to 66), mean weight 100 kg (range 61 to 199), and mean waist circumference was 119 cm (range 89 to 178); 70% were female; 84% were white and 16% were black or African American. Baseline mean urinary free cortisol level was 365 μg per 24 hr.

Patients belonged to one of two cohorts: a “diabetes” cohort (29 patients, 26 with type 2 diabetes and 3 with glucose intolerance), and a “hypertension” cohort (21 patients). Efficacy was evaluated separately in the two cohorts. Korlym treatment was started in all patients at a dose of 300 mg once a day. The study protocol allowed an increase in dose to 600 mg after 2 weeks, and then by additional 300 mg increments every 4 weeks to a maximum of 900 mg per day for patients <60 kg, or 1200 mg per day for patients >60 kg, based on clinical tolerance and clinical response.

Results in the diabetes cohort

Patients in the diabetes cohort underwent standard oral glucose tolerance tests at baseline and periodically during the clinical study. Anti-diabetic medications were allowed but had to be kept stable during the trial and patients had to be on stable anti-diabetic regimens prior to enrollment. The primary efficacy analysis for the diabetes cohort was an analysis of responders. A responder was defined as a patient who had a ≥ 25% reduction from baseline in glucose AUC. The primary efficacy analysis was conducted in the modified intent-to-treat population (n=25) defined as all patients who received a minimum of 30 days on Korlym. Fifteen of 25 patients (60%) were treatment responders (95% CI: 39%,78%).

Mean HbA1c was 7.4% in the 24 patients with HbA1c values at baseline and Week 24. For these 24 patients mean reduction in HbA1c was 1.1% (95% CI -1.6, -0.7) from baseline to the end of the trial. Fourteen of 24 patients had above normal HbA1c levels at baseline, ranging between 6.7% and 10.4%; all of these patients had reductions in HbA1c by the end of the study (range -0.4 to -4.4%) and eight of 14 patients (57%) normalized HbA1c levels at trial end. Antidiabetic medications were reduced in 7 of the 15 DM subjects taking antidiabetic medication and remained constant in the others.

Results in the hypertension cohort

There were no changes in mean systolic and diastolic blood pressures at the end of the trial relative to baseline in the modified intent-to-treat population (n=21).

Signs and symptoms of Cushing's syndrome in both cohorts

Individual patients showed varying degrees of improvement in Cushing's syndrome manifestations such as cushingoid appearance, acne, hirsutism, striae, psychiatric symptoms, and excess total body weight. Because of the variability in clinical presentation and variability of response in this open label trial, it is uncertain whether these changes could be ascribed to the effects of Korlym.

This medication guide provides information about the Korlym brand of mifepristone. Mifeprex is another brand of mifepristone that is not covered in this medication guide.

Korlym can harm an unborn baby or cause a miscarriage. Do not use if you are pregnant. You will need to have a negative pregnancy test before you start taking mifepristone, or if you restart the medication after not taking it for longer than 2 weeks.

You should not take Korlym if you have unexplained vaginal bleeding, endometrial hyperplasia or a certain type of uterine cancer, if you are pregnant, or if you take steroid medications because of a serious illness or condition (such as an organ transplant).

There are many other drugs that should not be used together with mifepristone. Tell your doctor about all other medicines you use.

Before you take this medicine, tell your doctor if you have liver or kidney disease, heart disease, heart failure, coronary artery disease, high blood pressure, endometriosis, a problem with your thyroid or adrenal glands, or an autoimmune disorder.

Applies to mifepristone: oral tablet

Along with its needed effects, mifepristone (the active ingredient contained in Korlym) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking mifepristone:

• Excessively heavy vaginal bleeding
• unusual tiredness or weakness

• Chest pain or discomfort
• confusion
• cough or hoarseness
• fast, weak pulse
• fever or chills
• lower back or side pain
• pain or discomfort in the arms, jaw, back, or neck
• painful or difficult urination
• pale, cold, or clammy skin
• shortness of breath
• sudden increase in stomach or shoulder pain
• sweating
• unusual or large amount of vaginal bleeding

Some side effects of mifepristone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Abdominal or stomach pain or uterine cramping
• back pain
• diarrhea
• dizziness
• headache
• nausea or vomiting

• Acid or sour stomach
• anxiety
• belching
• cough
• fainting or lightheadedness when getting up from a lying or sitting position
• fever
• flu-like symptoms
• headache
• heartburn
• increased clear or white vaginal discharge
• indigestion
• itching of the vagina or genital area
• lack or loss of strength
• pain during sexual intercourse
• pain or tenderness around the eyes and cheekbones
• pale skin
• shaking chills
• stomach discomfort, upset, or pain
• stuffy or runny nose
• tightness of the chest
• trouble sleeping
• troubled breathing
• troubled breathing, exertional
• unusual bleeding or bruising

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 this drug in a regimen with misoprostol in a breastfed infant or on milk production. The developmental and health benefits of breast-feeding should be considered along with any potential adverse effects on the breast-fed child from this drug in a regimen with misoprostol.

Termination of Pregnancy: -Use should be avoided. For control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance: -A decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Yes Comments: The effects in the nursing infant are unknown.

LactMed Record Number

816

Last Revision Date

20150310

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