1. Clinical Overview
Mifepristone is a synthetic steroid with potent antiprogestogenic and antiglucocorticoid activity. In the 10mg strength, it is primarily used for the medical management of 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. It acts as a competitive antagonist at progesterone and glucocorticoid (type II) receptors.
| Onset | Duration | Bioavailability |
|---|---|---|
| Clinical effects on cortisol levels are typically observed within 2 weeks of initiation. | The pharmacodynamic effects persist for 24-72 hours after a single dose, but clinical management requires daily dosing. | Approximately 69% following oral administration. |
2. Mechanism of Action
Mifepristone is a competitive antagonist at the progesterone receptor (PR) and the glucocorticoid receptor (GR). For Cushing's syndrome, its therapeutic effect is primarily due to blocking the glucocorticoid receptor (type II). This prevents cortisol from binding to its receptor, thereby inhibiting the downstream effects of cortisol excess, such as insulin resistance and hyperglycemia.
3. Indications & Uses
- Control of 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.
4. Dosage & Administration
Adult Dosage: Starting dose is 300 mg once daily (i.e., 30 tablets of 10mg each). Dose may be increased in 300 mg increments based on clinical response and tolerability. Maximum recommended dose is 1200 mg (120 tablets of 10mg) once daily. Dose adjustments should not be made more frequently than every 2-4 weeks.
Administration: Administer orally once daily with a meal. Swallow tablets whole with a glass of water. Do not crush, split, or chew. The high pill burden (e.g., 30-120 tablets per dose) must be carefully managed; adherence aids may be necessary. Consistent timing relative to meals is recommended.
5. Side Effects
Common side effects may include:
- Nausea
- Fatigue
- Headache
- Decreased appetite
- Arthralgia (joint pain)
- Vomiting
- Edema (peripheral swelling)
- Dizziness
- Hypertension
- Hypokalemia
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Ketoconazole, Itraconazole, Clarithromycin | Strong CYP3A4 inhibitors - Significantly increase mifepristone plasma levels. Contraindicated. | Contraindicated |
| Rifampicin, Carbamazepine, Phenytoin, St. John's Wort | Strong CYP3A4 inducers - Significantly decrease mifepristone plasma levels, reducing efficacy. | Major |
| Simvastatin, Lovastatin | Increased statin levels, raising risk of myopathy/rhabdomyolysis. Contraindicated. | Contraindicated |
| Warfarin | Mifepristone may potentiate anticoagulant effect; increased INR monitoring required. | Major |
| Corticosteroids (e.g., Prednisolone, Dexamethasone) | Mifepristone antagonizes their effect; higher doses of corticosteroids may be needed for stress coverage. | Major |
| Fentanyl, Cyclosporine, Sirolimus, Tacrolimus | Increased levels of these narrow-therapeutic-index drugs. Contraindicated or requires extreme caution. | Contraindicated/Major |
7. Patient Counselling
- DO take the medication exactly as prescribed, with food.
- DO use a highly effective non-hormonal method of contraception during and for 1 month after therapy.
- DO inform all your doctors and surgeons that you are on this medication, especially before any surgery.
- DO monitor your blood glucose and blood pressure regularly as advised.
- DONT take with grapefruit or grapefruit juice.
- DONT start any new medication, including over-the-counter drugs, herbal supplements (especially St. John's Wort), without consulting your doctor.
- DONT crush, split, or chew the tablets.
8. Toxicology & Storage
Overdose: Expected symptoms would be an extension of its pharmacologic effects: severe nausea, vomiting, profound fatigue, hypotension, adrenal insufficiency, and potentially severe hypokalemia. Vaginal bleeding may occur in women.
Storage: Store at room temperature (15°C to 30°C). Protect from light and moisture. Keep in the original blister pack or container. Keep out of reach of children and pets.