Mifepristone
Generic: MIFEPRISTONE
Basic Information
Manufacturer
Corcept Therapeutics Incorporated
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
63c068cd-9370-460f-829b-70e8c7ebe91e
Indications & Usage
1 INDICATIONS AND USAGE Mifepristone is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery.
LIMITATIONS OF USE: Mifepristone should not be used in the treatment of patients with type 2 diabetes unless it is secondary to Cushing's syndrome.
Mifepristone is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery ( 1 ).
Important Limitations of Use: Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing's syndrome.
LIMITATIONS OF USE: Mifepristone should not be used in the treatment of patients with type 2 diabetes unless it is secondary to Cushing's syndrome.
Mifepristone is a cortisol receptor blocker indicated to control hyperglycemia secondary to hypercortisolism in adult patients with endogenous Cushing's syndrome who have type 2 diabetes mellitus or glucose intolerance and have failed surgery or are not candidates for surgery ( 1 ).
Important Limitations of Use: Do not use for the treatment of type 2 diabetes mellitus unrelated to endogenous Cushing's syndrome.
Adverse Reactions
6 ADVERSE REACTIONS Most common adverse reactions in Cushing's syndrome (≥ 20%): nausea, fatigue, headache, decreased blood potassium, arthralgia, vomiting, peripheral edema, hypertension, dizziness, decreased appetite, endometrial hypertrophy ( 6 ).
To report suspected adverse reactions, contact Corcept Therapeutics at 1-855-844-3270 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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 mifepristone 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 mifepristone) 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 mifepristone, regardless of relationship to mifepristone, are shown in Table 2 .
Table 2.
Treatment Emergent Adverse Events Occurring in ≥10% of Cushing's Syndrome Patients Receiving mifepristone Body System/Adverse Reaction Percent (%) of Patients Reporting Event (n = 50) *The denominator was 26 females who had baseline and end-of-trial transvaginal ultrasound Gastrointestinal disorders Nausea 48 Vomiting 26 Dry mouth 18 Diarrhea 12 Constipation 10 General disorders and administration/site conditions Fatigue 48 Edema peripheral 26 Pain 14 Nervous system disorders Headache 44 Dizziness 22 Somnolence 10 Musculoskeletal and connective tissue disorders Arthralgia 30 Back pain 16 Myalgia 14 Pain in extremity 12 Investigations Blood potassium decreased 34 Thyroid function test abnormal 18 Infections and infestations Sinusitis 14 Nasopharyngitis 12 Metabolism and nutrition disorders Decreased appetite 20 Anorexia 10 Vascular disorders Hypertension 24 Reproductive system and breast disorders Endometrial hypertrophy 38* Respiratory, thoracic, and mediastinal disorders Dyspnea 16 Psychiatric disorders Anxiety 10 Laboratory Tests Reductions in high density lipoprotein-cholesterol (HDL-C) levels have been observed following treatment with mifepristone.
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 mifepristone.
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 mifepristone.
[See Warnings and Precautions ( 5.2 )] Elevations of thyroid-stimulating hormone (TSH) were seen in subjects treated with mifepristone.
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 mifepristone 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 mifepristone'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 mifepristone 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 mifepristone, and all the events resolved by the end of the study.
6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of mifepristone.
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.
- Angioedema
To report suspected adverse reactions, contact Corcept Therapeutics at 1-855-844-3270 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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 mifepristone 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 mifepristone) 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 mifepristone, regardless of relationship to mifepristone, are shown in Table 2 .
Table 2.
Treatment Emergent Adverse Events Occurring in ≥10% of Cushing's Syndrome Patients Receiving mifepristone Body System/Adverse Reaction Percent (%) of Patients Reporting Event (n = 50) *The denominator was 26 females who had baseline and end-of-trial transvaginal ultrasound Gastrointestinal disorders Nausea 48 Vomiting 26 Dry mouth 18 Diarrhea 12 Constipation 10 General disorders and administration/site conditions Fatigue 48 Edema peripheral 26 Pain 14 Nervous system disorders Headache 44 Dizziness 22 Somnolence 10 Musculoskeletal and connective tissue disorders Arthralgia 30 Back pain 16 Myalgia 14 Pain in extremity 12 Investigations Blood potassium decreased 34 Thyroid function test abnormal 18 Infections and infestations Sinusitis 14 Nasopharyngitis 12 Metabolism and nutrition disorders Decreased appetite 20 Anorexia 10 Vascular disorders Hypertension 24 Reproductive system and breast disorders Endometrial hypertrophy 38* Respiratory, thoracic, and mediastinal disorders Dyspnea 16 Psychiatric disorders Anxiety 10 Laboratory Tests Reductions in high density lipoprotein-cholesterol (HDL-C) levels have been observed following treatment with mifepristone.
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 mifepristone.
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 mifepristone.
[See Warnings and Precautions ( 5.2 )] Elevations of thyroid-stimulating hormone (TSH) were seen in subjects treated with mifepristone.
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 mifepristone 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 mifepristone'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 mifepristone 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 mifepristone, and all the events resolved by the end of the study.
6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of mifepristone.
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.
- Angioedema