Dosage & Administration
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Korlym Prescribing Information
Mifepristone is a potent antagonist of progesterone and cortisol via the progesterone and glucocorticoid (GR-II) receptors, respectively. The antiprogestational effects will result in the termination of pregnancy. Pregnancy must therefore be excluded before the initiation of treatment with KORLYM and prevented during treatment and for one month after stopping treatment by the use of a non-hormonal medically acceptable method of contraception unless the patient has had a surgical sterilization, in which case no additional contraception is needed. Pregnancy must also be excluded if treatment is interrupted for more than 14 days in females of reproductive potential.
KORLYM (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:
- KORLYM should not be used in the treatment of patients with type 2 diabetes unless it is secondary to Cushing's syndrome.
Testing Prior to and During KORLYM Administration
Obtain a negative pregnancy test in females of reproductive potential prior to initiating treatment with KORLYM or if treatment is interrupted for more than 14 days [see Contraindications , Warnings and Precautions , Use in Specific Populations ].
Adult Dosage
The recommended starting dose is 300 mg orally once daily. KORLYM must be given as a single daily dose. KORLYM should always be taken with a meal. Patients should swallow the tablet whole. Do not split, crush, or chew tablets.
Dosing and titration
The daily dose of KORLYM may be increased in 300 mg increments. The dose of KORLYM may be increased to a maximum of 1200 mg once daily but should not exceed 20 mg/kg per day. Increases in dose should not occur more frequently than once every 2-4 weeks. Decisions about dose increases should be based on a clinical assessment of tolerability and degree of improvement in Cushing's syndrome manifestations. Changes in glucose control, anti-diabetic medication requirements, insulin levels, and psychiatric symptoms may provide an early assessment of response (within 6 weeks) and may help guide early dose titration. Improvements in cushingoid appearance, acne, hirsutism, striae, and body weight occur over a longer period of time and, along with measures of glucose control, may be used to determine dose changes beyond the first 2 months of therapy. Careful and gradual titration of KORLYM accompanied by monitoring for recognized adverse reactions [See Warnings and Precautions and ] may reduce the risk of severe adverse reactions. Dose reduction or even dose discontinuation may be needed in some clinical situations. If KORLYM treatment is interrupted, it should be reinitiated at the lowest dose (300 mg). If treatment was interrupted because of adverse reactions, the titration should aim for a dose lower than the one that resulted in treatment interruption.
Dosing in Renal Impairment
No change in initial dose of KORLYM is required in renal impairment. The maximum dose should be limited to 600 mg. [See Renal Impairment and Clinical Pharmacology ]
Dosing in Hepatic Impairment
No change in the initial dose of KORLYM is required in mild to moderate hepatic impairment. The maximum dose should be limited to 600 mg. KORLYM should not be used in severe hepatic impairment. [See Hepatic Impairment and Clinical Pharmacology ]
Concomitant Administration with CYP3A Inhibitors
Ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir and fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole may increase exposure to mifepristone. KORLYM should be used in combination with strong CYP3A inhibitors only when necessary. [See Warnings and Precautions , Drug Interactions ]
Administration of KORLYM to patients already being treated with strong CYP3A inhibitors:
- Start at a dose of 300 mg. If clinically indicated, titrate to a maximum of 900 mg.
Administration of strong CYP3A inhibitors to patients already being treated with KORLYM:
- Adjust the dose of KORLYM according to Table 1.
| Current dose of KORLYM | Adjustment to dose of KORLYM if adding a strong CYP3A inhibitor |
| 300 mg | No change |
| 600 mg | Reduce dose to 300 mg. If clinically indicated, titrate to a maximum of 600 mg |
| 900 mg | Reduce dose to 600 mg. If clinically indicated, titrate to a maximum of 900 mg |
| 1200 mg | Reduce dose to 900 mg |
Tablets: 300 mg
Oval shaped, light yellow to yellow tablets debossed with “Corcept” on one side and “300” on the other side. The tablets are not scored.
Pregnancy
Risk Summary
KORLYM is contraindicated in pregnancy because the use of KORLYM results in pregnancy loss. There are no data that assess the risk of birth defects in women exposed to KORLYM during pregnancy. Available data limited to exposure following a single dose of mifepristone during pregnancy showed a higher rate of major birth defects compared to the general population comparator (See Data). Mifepristone administered to pregnant mice, rats, and rabbits during organogenesis caused pregnancy loss in all species at clinically relevant doses based on body surface area comparisons (See Data). The inhibition of both endogenous and exogenous progesterone by mifepristone at the progesterone receptor results in pregnancy loss. If KORLYM is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. [See Contraindications ]
The estimated risk of fetal loss is elevated in patients with active Cushing's syndrome (24-30%), and the risk of major birth defects is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively.
Data
Human Data
There are no data on long term exposure to mifepristone in pregnancy. Available data are limited to exposure to a single dose of mifepristone for pregnancy termination. In a prospective study in France of 46 pregnancies exposed to a single dose of mifepristone alone and 59 pregnancies exposed to a single dose of mifepristone and misoprostol, the overall major birth defect rate (4%) was greater than the general population background rate of 2 to 3% (2 birth defects in each group). There was no pattern of birth defects identified.
Animal Data
Reproductive studies were performed in mice, rats and rabbits at doses of 0.25 to 4.0 mg/kg (less than human exposure at the maximum clinical dose, based on body surface area). Because of the anti-progestational activity of mifepristone, fetal losses were much higher than in control animals. Skull deformities were detected in rabbit studies at less than human exposure, although mifepristone did not cause any adverse developmental effects in rats or mice during organogenesis. These deformities were most likely due to the mechanical effects of uterine contractions resulting from antagonism of the progesterone receptor.
Lactation
Risk Summary
Mifepristone is present in human milk, however, there are no data on the amount of mifepristone in human milk, the effects on the breastfed infant, or the effects on milk production during long term use of mifepristone (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for KORLYM and any potential adverse effects on the breastfed child from KORLYM or from the underlying maternal condition.
Clinical Considerations
To minimize exposure to a breastfed infant, women who discontinue or interrupt KORLYM treatment may consider pumping and discarding milk during treatment and for 18-21 days (5-6 half-lives) after the last dose, before breastfeeding.
Data
Available published data based on intake of a single dose of 600 mg of mifepristone in 10 breastfeeding women who were 6-12 months postpartum showed a small amount in breast milk (the estimated relative infant dose was 0.5%). The half-life of mifepristone is longer with repeat dosing compared to a single dose; therefore, there may be greater exposure with long term use.
Females and Males of Reproductive Potential
Pregnancy Testing
Due to its anti-progestational activity, KORLYM causes pregnancy loss. Perform pregnancy testing before the initiation of treatment with KORLYM or if treatment is interrupted for more than 14 days in females of reproductive potential.
Contraception
Recommend non-hormonal contraception for the duration of treatment and for one month after stopping treatment . KORLYM interferes with the effectiveness of hormonal contraceptives. [See Drug Interactions ]
Pediatric Use
Safety and effectiveness of KORLYM in pediatric patients have not been established.
Geriatric Use
Clinical studies with KORLYM did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger people.
Renal Impairment
The maximum dose should not exceed 600 mg per day in renally impaired patients. [See Clinical Pharmacology ]
Hepatic Impairment
In patients with mild to moderate hepatic impairment, the maximum dose should not exceed 600 mg per day. The pharmacokinetics of mifepristone in patients with severe hepatic impairment has not been studied, and KORLYM should not be used in these patients. [See Clinical Pharmacology ]
KORLYM is contraindicated in:
- Pregnancy [See Dosage and Administration , Use in Specific Populations ]
- Patients taking drugs metabolized by CYP3A such as 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 and Clinical Pharmacology ]
- Patients receiving systemic corticosteroids for lifesaving purposes (e.g., immunosuppression after organ transplantation) because KORLYM antagonizes the effect of glucocorticoids.
- Women with a history of unexplained vaginal bleeding or with endometrial hyperplasia with atypia or endometrial carcinoma.
- Patients with known hypersensitivity to mifepristone or to any of the product components.