MIFEPRISTONE Drug Interactions: What You Need to Know

INTERACTIONS Based on the long terminal half-life of mifepristone after reaching steady state, at least 2 weeks should elapse after cessation of mifepristone before initiating or increasing the dose of any interacting concomitant medication. Drugs metabolized by CYP3A: Administer drugs that are metabolized by CYP3A at the lowest dose when used with mifepristone ( 7.1 ). CYP3A inhibitors: Caution should be used when mifepristone is used with strong CYP3A inhibitors. Limit mifepristone dose to 900 mg per day when used with strong CYP3A inhibitors ( 7.2 ). CYP3A inducers: Do not use mifepristone with CYP3A inducers ( 7.3 ). Drugs metabolized by CYP2C8/2C9: Use the lowest dose of CYP2C8/2C9 substrates when used with mifepristone ( 7.4 ). Drugs metabolized by CYP2B6: Use of mifepristone should be done with caution with bupropion and efavirenz ( 7.5 ). Hormonal contraceptives: Do not use with mifepristone ( 7.6 ).

7.1 Drugs Metabolized by CYP3A Because mifepristone is an inhibitor of CYP3A, concurrent use of mifepristone with a drug whose metabolism is largely or solely mediated by CYP3A is likely to result in increased plasma concentrations of the drug. Discontinuation or dose reduction of such medications may be necessary with mifepristone coadministration. Mifepristone increased the exposure to simvastatin and simvastatin acid significantly in healthy subjects. Concomitant use of simvastatin or lovastatin is contraindicated because of the increased risk of myopathy and rhabdomyolysis <span class="opacity-50 text-xs">[see Contraindications ( 4.2 ), Clinical Pharmacology 12.3 ]</span> . The exposure of other substrates of CYP3A with narrow therapeutic ranges, such as cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus, may be increased by concomitant administration with mifepristone. Therefore, the concomitant use of such CYP3A substrates with mifepristone is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4.2 )]</span> . Other drugs with similar high first pass metabolism in which CYP3A is the primary route of metabolism should be used with extreme caution if coadministered with mifepristone. The lowest possible dose and/or a decreased frequency of dosing must be used with therapeutic drug monitoring when possible. Use of alternative drugs without these metabolic characteristics is advised when possible with concomitant mifepristone. If drugs that undergo low first pass metabolism by CYP3A or drugs in which CYP3A is not the major metabolic route are coadministered with mifepristone, use the lowest dose of concomitant medication necessary, with appropriate monitoring and follow-up <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.2 CYP3A Inhibitors Medications that inhibit CYP3A could increase plasma mifepristone concentrations and dose reduction of mifepristone may be required. 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. Caution should be used when strong CYP3A inhibitors are prescribed in combination with mifepristone. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. The dose of mifepristone should be limited to 900 mg, and strong inhibitors of CYP3A should be used only when necessary <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.4 ), Warnings &amp; Precautions ( 5.6 ), and Clinical Pharmacology ( 12.3 )]</span> .

7.3 CYP3A Inducers No medications that induce CYP3A have been studied when coadministered with mifepristone. Avoid coadministration of mifepristone and CYP3A inducers such as rifampin, rifabutin, rifapentin, phenobarbital, phenytoin, carbamazepine, and St. John’s wort.

7.4 Drugs Metabolized by CYP2C8/2C9 Because mifepristone is an inhibitor of CYP2C8/2C9, concurrent use of mifepristone with a drug whose metabolism is largely or solely mediated by CYP2C8/2C9 is likely to result in increased plasma concentrations of the drug. Mifepristone significantly increased exposure of fluvastatin, a typical CYP2C8/2C9 substrate, in healthy subjects. When given concomitantly with mifepristone, drugs that are substrates of CYP2C8/2C9 (including non-steroidal anti-inflammatory drugs, warfarin, and repaglinide) should be used at the smallest recommended doses, and patients should be closely monitored for adverse effects <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.5 Drugs Metabolized by CYP2B6 Mifepristone is an inhibitor of CYP2B6 and may cause significant increases in exposure of drugs that are metabolized by CYP2B6 such as bupropion and efavirenz. Since no study has been conducted to evaluate the effect of mifepristone on substrates of CYP2B6, the concomitant use of bupropion and efavirenz should be undertaken with caution <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

7.6 Use of Hormonal Contraceptives Mifepristone is a progesterone-receptor antagonist and will interfere with the effectiveness of hormonal contraceptives. Therefore, non-hormonal contraceptive methods should be used [See Use In Specific Populations (8.3)] .

Administration of Mifepristone Tablets, 200 mg 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 adrenal insufficiency) Concurrent long-term corticosteroid therapy (risk of acute adrenal 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, 200 mg 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, 200 mg may be used. Confirmed/suspected ectopic pregnancy or undiagnosed adnexal mass ( 4 ) Chronic adrenal failure ( 4 ) Concurrent long-term corticosteroid therapy ( 4 ) History of allergy to mifepristone, misoprostol, or other prostaglandins ( 4 ) Hemorrhagic disorders or concurrent anticoagulant therapy ( 4 ) Inherited porphyria ( 4 ) Intrauterine device (IUD) in place ( 4 )

AND PRECAUTIONS Adrenal insufficiency : Patients should be closely monitored for signs and symptoms of adrenal insufficiency ( 5.1 ). Hypokalemia : Hypokalemia should be corrected prior to treatment and monitored for during treatment ( 5.2 ). Vaginal bleeding and endometrial changes : Women may experience endometrial thickening or unexpected vaginal bleeding. Use with caution if patient also has a hemorrhagic disorder or is on anti-coagulant therapy ( 5.3 ). QT interval prolongation : Avoid use with QT interval-prolonging drugs, or in patients with potassium channel variants resulting in a long QT interval ( 5.4 ). Use of Strong CYP3A Inhibitors : Concomitant use can increase mifepristone plasma levels. Use only when necessary and limit mifepristone dose to 900 mg ( 5.6 ).

5.1 Adrenal Insufficiency Patients receiving mifepristone may experience adrenal insufficiency. Because serum cortisol levels remain elevated and may even increase during treatment with mifepristone, serum cortisol levels do not provide an accurate assessment of hypoadrenalism in patients receiving mifepristone. Patients should be closely monitored for signs and symptoms of adrenal insufficiency, including weakness, nausea, increased fatigue, hypotension, and hypoglycemia. If adrenal insufficiency is suspected, discontinue treatment with mifepristone immediately and administer glucocorticoids without delay. High doses of supplemental glucocorticoids may be needed to overcome the glucocorticoid receptor blockade produced by mifepristone. Factors considered in deciding on the duration of glucocorticoid treatment should include the long half-life of mifepristone (85 hours). Treatment with mifepristone at a lower dose can be resumed after resolution of adrenal insufficiency. Patients should also be evaluated for precipitating causes of hypoadrenalism (infection, trauma, etc.).

5.2 Hypokalemia In a study of patients with Cushing’s syndrome, hypokalemia was observed in 44% of subjects during treatment with mifepristone. Hypokalemia should be corrected prior to initiating mifepristone. During mifepristone administration, serum potassium should be measured 1 to 2 weeks after starting or increasing the dose of mifepristone and periodically thereafter. Hypokalemia can occur at any time during mifepristone treatment. Mifepristone-induced hypokalemia should be treated with intravenous or oral potassium supplementation based on event severity. If hypokalemia persists in spite of potassium supplementation, consider adding mineralocorticoid antagonists.

5.3 Vaginal Bleeding and Endometrial Changes Being an antagonist of the progesterone receptor, mifepristone promotes unopposed endometrial proliferation that may result in endometrium thickening, cystic dilatation of endometrial glands, and vaginal bleeding. Mifepristone should be used with caution in women who have hemorrhagic disorders or are receiving concurrent anticoagulant therapy. Women who experience vaginal bleeding during mifepristone treatment should be referred to a gynecologist for further evaluation.

5.4 QT Interval Prolongation Mifepristone and its metabolites block IKr. Mifepristone prolongs the QTc interval in a dose-related manner. There is little or no experience with high exposure, concomitant dosing with other QT- prolonging drugs, or potassium channel variants resulting in a long QT interval <span class="opacity-50 text-xs">[see Warnings &amp; Precautions ( 5.6 )]</span> . To minimize risk, the lowest effective dose should always be used.

5.5 Exacerbation/Deterioration of Conditions Treated with Corticosteroids Use of mifepristone in patients who receive corticosteroids for other conditions (e.g., autoimmune disorders) may lead to exacerbation or deterioration of such conditions, as mifepristone antagonizes the desired effects of glucocorticoid in these clinical settings. For medical conditions in which chronic corticosteroid therapy is lifesaving (e.g., immunosuppression in organ transplantation), mifepristone is contraindicated <span class="opacity-50 text-xs">[see Contraindications ( 4.3 )]</span> .

5.6 Use of Strong CYP3A Inhibitors Mifepristone should be used with caution in patients taking ketoconazole and other strong inhibitors of CYP3A, such as itraconazole, nefazodone, ritonavir, nelfinavir, indinavir, atazanavir, amprenavir, fosamprenavir, clarithromycin, conivaptan, lopinavir/ritonavir, posaconazole, saquinavir, telithromycin, or voriconazole, as these could increase the concentration of mifepristone in the blood. The benefit of concomitant use of these agents should be carefully weighed against the potential risks. Mifepristone should be used in combination with strong CYP3A inhibitors only when necessary, and in such cases the dose should be limited to 900 mg per day <span class="opacity-50 text-xs">[see Warnings &amp; Precautions ( 5.4 ), Drug Interactions (7.2), and Clinical Pharmacology ( 12.3 )]</span> .

5.7 Pneumocystis jiroveci Infection Patients with endogenous Cushing’s syndrome are at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia during mifepristone treatment. Patients may present with respiratory distress shortly after initiation of mifepristone. Appropriate diagnostic tests should be undertaken and treatment for Pneumocystis jiroveci should be considered.

5.8 Potential Effects of Hypercortisolemia Mifepristone does not reduce serum cortisol levels. Elevated cortisol levels may activate mineralocorticoid receptors which are also expressed in cardiac tissues. Caution should be used in patients with underlying heart conditions including heart failure and coronary vascular disease.

5.9 Risk of Allergic Reactions due to Tartrazine This product contains FD&amp;C Yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&amp;C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.