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Mifepristone

Pronunciation

(mi FE pris tone)

Index Terms

  • RU-38486
  • RU-486

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Korlym: 300 mg [contains fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake]

Mifeprex: 200 mg

Brand Names: U.S.

  • Korlym
  • Mifeprex

Pharmacologic Category

  • Abortifacient
  • Antineoplastic Agent, Hormone Antagonist
  • Antiprogestin
  • Cortisol Receptor Blocker

Pharmacology

Mifepristone is a synthetic steroid. At low doses, it competitively binds to the intracellular progesterone receptor, blocking the effects of progesterone. When used for the termination of pregnancy, this leads to contraction-inducing activity in the myometrium. In the absence of progesterone, mifepristone acts as a partial progesterone agonist. At high doses used for the treatment of hyperglycemia in patients with Cushing’s syndrome, mifepristone blocks the effect of cortisol at the glucocorticoid receptor (antagonizes the effects of cortisol on glucose metabolism) while at the same time increasing circulating cortisol concentrations.

Absorption

Oral: Rapid

Metabolism

Hepatic via CYP3A4 to three metabolites (active)

Excretion

Feces (83%); urine (9%)

Time to Peak

Oral: 90 minutes; Range: Single dose: 1-2 hours, Multiple doses: 1-4 hours

Half-Life Elimination

Single dose: Terminal: 18 hours following a slower phase where 50% eliminated between 12-72 hours; Multiple doses (600 mg/day): 85 hours

Protein Binding

98% to albumin and α1-acid glycoprotein

Use: Labeled Indications

Korlym: To control hyperglycemia occurring secondary to hypercortisolism in patients with endogenous Cushing’s syndrome who have type 2 diabetes mellitus or glucose intolerance and who failed surgery or who are not surgical candidates

Mifeprex: Medical termination of intrauterine pregnancy, through day 49 of pregnancy. Patients may need treatment with misoprostol and possibly surgery to complete therapy.

Use: Unlabeled

Termination of pregnancy ≤63 days of pregnancy

Contraindications

Hypersensitivity to mifepristone or any component of the formulation

Korlym™ (additional contraindications): Concomitant use of lovastatin, simvastatin, or CYP3A substrates with a narrow therapeutic range (eg, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinine, sirolimus, tacrolimus); concomitant use of systemic corticosteroids for serious medical conditions (eg, immunosuppression following organ transplant); women with a history of unexplained vaginal bleeding, or endometrial hyperplasia with atypia or endometrial carcinoma; pregnancy

Mifeprex® (additional contraindications): Hypersensitivity to misoprostol; chronic adrenal failure; porphyrias; hemorrhagic disorder or concurrent anticoagulant therapy; pregnancy termination >49 days; intrauterine device (IUD) in place; ectopic pregnancy or undiagnosed adnexal mass; concurrent long-term corticosteroid therapy; inadequate or lack of access to emergency medical services; inability to understand effects and/or comply with treatment

Dosing: Adult

Hyperglycemia in patients with Cushing syndrome (Korlym): Oral: Initial dose: 300 mg once daily. Dose may be increased in 300 mg increments at intervals of ≥2-4 weeks based on tolerability and symptom control. Maximum dose: 1200 mg once daily, not to exceed 20 mg/kg/day. If treatment is interrupted, reinitiate at 300 mg daily or a dose lower than the dose that caused the treatment to be stopped if interruption due to adverse reactions

Dosage adjustment with concurrent use of strong CYP450 inhibitor therapy (eg, ketoconazole): Maximum dose 300 mg/day

Termination of pregnancy (Mifeprex): Oral: Treatment consists of 3 office visits by the patient; the patient must read medication guide and sign patient agreement prior to treatment:

Day 1 (mifepristone administration): 600 mg (three 200 mg tablets) taken as a single dose under physician supervision

Day 3 (misoprostol administration): Patient must return to the health care provider 2 days following administration of mifepristone; unless abortion has occurred (confirmed using ultrasound or clinical examination): Misoprostol 400 mcg (two 200 mcg tablets); Note: Patient may need treatment for cramps or gastrointestinal symptoms at this time

Day 14 (post-treatment exam): Patient must return to the health care provider ~14 days after administration of mifepristone; confirm complete termination of pregnancy by ultrasound or clinical exam. Surgical termination is recommended to manage treatment failures.

Termination of pregnancy (off-label dosing): Mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 to 48 hours later (ACOG, 2014; FIGO, 2011).

Dosing: Geriatric

Hyperglycemia in patients with Cushing syndrome: Refer to adult dosing.

Dosing: Renal Impairment

Hyperglycemia in patients with Cushing syndrome: Maximum dose 600 mg daily; Note: Following doses of 1200 mg daily for 7 days in patients with severe renal impairment (CrCl <30 mL/minute), exposure to mifepristone and its metabolites was increased and a large variability in exposure was observed.

Termination of pregnancy: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied)

Dosing: Hepatic Impairment

Hyperglycemia in patients with Cushing syndrome:

Mild-to-moderate impairment: Maximum dose 600 mg daily

Severe impairment: Use is not recommended

Note: Following single and multiple doses of 600 mg/day in patients with moderate hepatic impairment (Child-Pugh class B), a large variability in exposure to mifepristone and its metabolites was observed.

Termination of pregnancy: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution due to CYP3A4 metabolism.

Administration

Hyperglycemia in patients with Cushing syndrome: Administer as a single daily dose with a meal. Tablets should be swallowed whole, not crushed, split, or chewed.

Termination of pregnancy: To be taken as a single dose under physician supervision

Hazardous agent; use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Storage

Store at room temperature of 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Monitor therapy

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Androgens: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol. Monitor therapy

Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Apixaban: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Apixaban. Monitor therapy

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

Astemizole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

Avanafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil. Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor or temporarily stopping budesonide therapy during CYP3A4 inhibitor use. Monitor patients closely for signs/symptoms of corticosteroid excess. Consider therapy modification

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Consider therapy modification

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Avoid combination

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Contraceptives (Estrogens): Mifepristone may diminish the therapeutic effect of Contraceptives (Estrogens). Mifepristone may increase the serum concentration of Contraceptives (Estrogens). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment. Consider therapy modification

Contraceptives (Progestins): Mifepristone may diminish the therapeutic effect of Contraceptives (Progestins). Mifepristone may increase the serum concentration of Contraceptives (Progestins). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment. Consider therapy modification

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): Mifepristone may diminish the therapeutic effect of Corticosteroids (Systemic). Mifepristone may increase the serum concentration of Corticosteroids (Systemic). Management: Avoid mifepristone in patients who require long-term corticosteroid treatment of serious illnesses or conditions (e.g., for immunosuppression following transplantation). Corticosteroid effects may be reduced by mifepristone treatment. Avoid combination

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

CycloSPORINE (Systemic): Mifepristone may increase the serum concentration of CycloSPORINE (Systemic). Management: Avoid cyclosporine during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

CYP2B6 Substrates: Mifepristone may increase the serum concentration of CYP2B6 Substrates. Monitor therapy

CYP2C8 Substrates: Mifepristone may increase the serum concentration of CYP2C8 Substrates. Management: Use CYP2C8 substrates at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

CYP2C9 Substrates: Mifepristone may increase the serum concentration of CYP2C9 Substrates. Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Mifepristone. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Mifepristone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 300 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication. Consider therapy modification

CYP3A4 Substrates: Mifepristone may increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Dasatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dexketoprofen: May diminish the therapeutic effect of Mifepristone. Monitor therapy

Digoxin: Mifepristone may increase the serum concentration of Digoxin. Management: Measure serum digoxin concentration 1-2 weeks following mifepristone initiation, and in accordance with normal clinical practice thereafter, adjusting dose as needed. Monitor therapy

Dihydroergotamine: Mifepristone may increase the serum concentration of Dihydroergotamine. Management: Avoid dihydroergotamine during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

Eplerenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone. Avoid combination

Ergotamine: Mifepristone may increase the serum concentration of Ergotamine. Management: Avoid ergotamine during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Estazolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam. Monitor therapy

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

FentaNYL: Mifepristone may increase the serum concentration of FentaNYL. Management: Avoid fentanyl during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Monitor therapy

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification

Fluvastatin: Mifepristone may increase the serum concentration of Fluvastatin. Management: Use fluvastatin at the lowest recommended dose, and monitor closely for adverse effects (including myopathy), during and in the 2 weeks following mifepristone treatment. Consider therapy modification

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when starting this combination. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

Herbs (Hypoglycemic Properties): May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Monitor therapy

Highest Risk QTc-Prolonging Agents: Mifepristone may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lovastatin: Mifepristone may increase the serum concentration of Lovastatin. Management: Avoid lovastatin during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

MAO Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: Mifepristone may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Osimertinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Osimertinib. Avoid combination

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

Pegvisomant: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Mifepristone may enhance the QTc-prolonging effect of Pimozide. Mifepristone may increase the serum concentration of Pimozide. Management: Avoid pimozide during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): Mifepristone may enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

QuiNIDine: Mifepristone may enhance the QTc-prolonging effect of QuiNIDine. Mifepristone may increase the serum concentration of QuiNIDine. Management: Avoid quinidine during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Quinolone Antibiotics: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolone Antibiotics may diminish the therapeutic effect of Blood Glucose Lowering Agents. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Monitor therapy

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Salicylates: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

Saxagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Saxagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Monitor therapy

Sildenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sildenafil. Management: Use of sildenafil for pulmonary hypertension should be avoided with strong CYP3A4 inhibitors. When used for erectile dysfunction, starting adult dose should be reduced to 25 mg. Maximum adult dose with ritonavir or cobicistat is 25 mg per 48 hours. Consider therapy modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: Mifepristone may increase the serum concentration of Simvastatin. Management: Avoid simvastatin during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Sirolimus: Mifepristone may increase the serum concentration of Sirolimus. Management: Avoid sirolimus during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

St John's Wort: May decrease the serum concentration of Mifepristone. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): Mifepristone may enhance the QTc-prolonging effect of Tacrolimus (Systemic). Mifepristone may increase the serum concentration of Tacrolimus (Systemic). Management: Avoid tacrolimus during and 2 weeks following mifepristone for treatment of hyperglycemia in Cushing's syndrome. The interaction magnitude could be lower with single doses used to terminate pregnancy, but neither effect has been studied clinically. Avoid combination

Tadalafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tadalafil. Management: Recommendations regarding use of tadalafil in patients also receiving strong CYP3A4 inhibitors may vary based on indication and/or international labeling. Consult appropriate product labeling. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Tenoxicam: May diminish the therapeutic effect of Mifepristone. Avoid combination

Terfenadine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Vardenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vardenafil. Management: Recommendations regarding concomitant use of vardenafil with strong CYP3A4 inhibitors may vary depending on brand name (e.g., Levitra, Staxyn) or by international labeling. See full drug interaction monograph for details. Consider therapy modification

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Monitor therapy

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Test Interactions

hCG levels will not be useful to confirm pregnancy termination until at least 10 days following mifepristone treatment

When used for the treatment of hyperglycemia in patients with Cushing’s syndrome, serum cortisol concentrations remain elevated and may increase, and cannot be used for monitoring.

Adverse Reactions

Adverse events associated with treatment of hyperglycemia in patients with Cushing’s syndrome:

>10%:

Cardiovascular: Peripheral edema (26%), hypertension (24%)

Central nervous system: Fatigue (48%), headache (44%), dizziness (22%), pain (14%)

Endocrine & metabolic: Hypokalemia (34% to 44%), endometrial hypertrophy (38%), thyroid function tests abnormal (18%)

Gastrointestinal: Nausea (48%), vomiting (26%), appetite decreased (20%), xerostomia (18%), diarrhea (12%)

Genitourinary: Vaginal bleeding (14%)

Neuromuscular & skeletal: Arthralgia (30%), back pain (16%), myalgia (14%), extremity pain (12%)

Respiratory: Dyspnea (16%), sinusitis (14%), nasopharyngitis (12%)

5% to 10%:

Cardiovascular: Edema, pitting edema

Central nervous system: Anxiety (10%), somnolence (10%), insomnia, malaise

Endocrine & metabolic: Hypoglycemia, triglycerides increased

Gastrointestinal: Anorexia (10%), constipation (10%), abdominal pain, GI reflux

Genitourinary: Vaginal hemorrhage, metrorrhagia

Neuromuscular & skeletal: Flank pain, malaise, musculoskeletal chest pain, weakness

Miscellaneous: Thirst

<5% or frequency not defined: Adrenal insufficiency (4%), pruritus (4%), rash (4%), HDL cholesterol decreased

Adverse events associated with treatment for termination of pregnancy: Note: Vaginal bleeding and uterine cramping are expected to occur when this medication is used to terminate a pregnancy; ~90% of women using this medication for this purpose also report adverse reactions on day 3 after the procedure. Bleeding or spotting occurs in most women for a period of 9-16 days. Up to 8% of women will experience some degree of bleeding or spotting for 30 days or more. In some cases, bleeding may be prolonged and heavy, potentially leading to hypovolemic shock.

Central nervous system: Headache (2% to 31%), dizziness (1% to 12%)

Gastrointestinal: Abdominal pain (cramping) (96%), nausea (43% to 61%), vomiting (18% to 26%), diarrhea (12% to 20%)

Genitourinary: Uterine cramping (83%)

1% to 10%:

Cardiovascular: Syncope (1%)

Central nervous system: Fatigue (10%), fever (4%), insomnia (3%), anxiety (2%), fainting (2%)

Gastrointestinal: Dyspepsia (3%)

Genitourinary: Uterine hemorrhage (5%), vaginitis (3%), pelvic pain (2%), endometriosis/salpingitis/pelvic inflammatory disease (1%)

Hematologic: Decreased hemoglobin >2 g/dL (6%), anemia (2%), leukorrhea (2%)

Neuromuscular & skeletal: Back pain (9%), rigors (3%), leg pain (2%), weakness (2%)

Respiratory: Sinusitis (2%)

Miscellaneous: Viral infection (4%)

<1% (Limited to important or life-threatening): Adult respiratory distress syndrome (ADRS), allergic reaction including urticaria and hives, bacterial infection (including an ectopic bacteria such as Clostridium sordellii), Crohn's disease (exacerbation), disseminated intravascular coagulopathy (DIC), dyspnea, hematometra, hypotension, lightheadedness, loss of consciousness, MI, pancreatitis (acute), pelvic infection, postabortal infection, QT prolongation, ruptured ectopic pregnancy, sepsis, septic shock, sickle cell crisis (exacerbation), tachycardia, toxic shock syndrome

ALERT: U.S. Boxed Warning

Bacterial infections (Mifeprex):

Serious and sometimes fatal infections and bleeding occur very rarely following spontaneous, surgical, and medical abortions, including following mifepristone use. No causal relationship between the use of mifepristone and misoprostol and these reactions has been established. Before prescribing mifepristone, inform the patient about the risk of these serious events and discuss the Medication Guide and the Patient Agreement. Ensure that the patient knows whom to call and what to do, including going to an emergency room, if none of the provided contacts are reachable, if she experiences sustained fever, severe abdominal pain, prolonged heavy bleeding, or syncope, or if she experiences abdominal pain or discomfort or general malaise (including weakness, nausea, vomiting, or diarrhea) more than 24 hours after taking misoprostol.

Patients with serious bacterial infections (eg, Clostridium sordelli) and sepsis can present without fever, bacteremia, or significant findings on pelvic examination following an abortion. Very rarely, deaths have been reported in patients who presented without fever, with or without abdominal pain, but with leukocytosis with a marked left shift, tachycardia, hemoconcentration, and general malaise. A high index of suspicion is needed to rule out serious infection and sepsis.

Medication guide (Mifeprex):

Advise patients to take their Medication Guide with them if they visit an emergency room or another health care provider who did not prescribe mifepristone, so that provider will be aware that the patient is undergoing a medical abortion.

Bleeding (Mifeprex):

Prolonged heavy bleeding may be a sign of incomplete abortion or other complications, and prompt medical or surgical intervention may be needed. Advise patients to seek immediate medical attention if they experience prolonged heavy vaginal bleeding.

Termination of pregnancy (Korlym):

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 be excluded before the initiation of treatment with mifepristone and prevented during treatment and for 1 month after stopping treatment by the use of a nonhormonal, 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.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal insufficiency: When used for the treatment of hyperglycemia in patients with Cushing’s syndrome, adrenal insufficiency may occur. Serum cortisol concentrations remain elevated and may increase, and cannot be used for monitoring. If signs and symptoms of adrenal insufficiency occur (eg, fatigue, hypoglycemia, hypotension, nausea, weakness), discontinue mifepristone and administer glucocorticoids (high doses may be needed). Following resolution, treatment may be resumed at a lower dose; evaluate patient for precipitating causes (eg, infection, trauma).

• Bacterial infections: [U.S. Boxed Warning]: When used for the termination of pregnancy, bacterial infections have been reported following use of this product and may have an atypical presentation. In rare cases, these infections may be serious and/or fatal, with septic shock as a potential complication. A causal relationship has not been established. Sustained fever, abdominal pain, or pelvic tenderness should prompt evaluation; however, healthcare professionals are warned that atypical presentations of serious infection without these symptoms have also been noted. Patients presenting with nausea, vomiting, diarrhea, or weakness, with or without abdominal pain or fever, should be evaluated for serious bacterial infection when symptoms occur >24 hours after taking misoprostol. Treatment with antibiotics, including coverage for anaerobic bacteria (eg, Clostridium sordellii) should be initiated. Patients with Cushing’s syndrome may be at risk for opportunistic infections such as Pneumocystis jiroveci pneumonia.

• Bleeding: Regardless of indication, endometrial proliferation is promoted by mifepristone, resulting in endometrial thickening, cystic dilation of endometrial glands, and vaginal bleeding. [U.S. Boxed Warning]: When used for the termination of pregnancy, patients should be counseled to seek medical attention in cases of excessive bleeding. Bleeding occurs and should be expected (average 9-16 days, may be ≥30 days). In some cases, bleeding may be prolonged and heavy and may be a sign of incomplete abortion or other complications, potentially leading to hypovolemic shock; the manufacturer cites soaking through 2 thick sanitary pads per hour for 2 consecutive hours as an example of excessive bleeding. Bleeding may require blood transfusion (rare), curettage, saline infusions, and/or vasoconstrictors. Patients should be instructed to seek medical attention if prolonged heavy vaginal bleeding occurs. When used for termination of pregnancy, use is contraindicated in women with hemorrhagic disorders or those using anticoagulants; use caution in women with severe anemia, hypocoagulability or hemostatic disorders. When used for the treatment of hyperglycemia in patients with Cushing’s syndrome, use caution in women with hemorrhagic disorders or women using anticoagulants and evaluate unexplained vaginal bleeding; use is contraindicated with a history of unexplained vaginal bleeding.

• Hypokalemia: May occur at any time during therapy when used to control hyperglycemia in patients with Cushing’s syndrome. Correct hypokalemia prior to initiation of treatment; monitor potassium levels closely with therapy.

• QT prolongation: May prolong the QTc interval (dose related); use caution with other QT-prolonging agents.

Disease-related concerns:

• Cardiovascular disease: When used for the termination of pregnancy, safety and efficacy have not been established for use in women with chronic cardiovascular disease as well as hypertension. Because mifepristone does not reduce serum cortisol concentrations, mineralocorticoid receptors in cardiac tissue may be activated; use caution in patients with Cushing’s syndrome who also have heart failure or coronary vascular disease.

• Diabetes: Safety and efficacy have not been established for use in insulin-dependent diabetes mellitus.

• Hepatic impairment: In patients with moderate hepatic impairment, a large variability in exposure to mifepristone and its metabolites was observed at doses of 600 mg/day. Safety and efficacy have not been established for use in women with hepatic impairment when used as a single dose for the termination of pregnancy.

• Renal impairment: In patients with severe renal impairment, exposure to mifepristone and its metabolites was increased and a large variability in exposure was observed following multiple doses used in patients with Cushing’s syndrome. Safety and efficacy have not been established for use in women with renal impairment when used as a single dose for the termination of pregnancy.

• Respiratory disease: Safety and efficacy have not been established for use in women with respiratory disease when used as a single dose for the termination of pregnancy.

Concurrent drug therapy issues:

• Corticosteroids: Use of mifepristone for the treatment of hyperglycemia in patients with Cushing’s syndrome may antagonize the effects of steroids used for other conditions. Use is contraindicated when steroids are required for lifesaving indications.

• High potential for drug interactions: High potential for drug interactions exists when used for the treatment of hyperglycemia in patients with Cushing’s syndrome. Refer to drug interactions for detailed information. The potential for drug interactions was not specifically studied following a single dose for the termination of pregnancy.

Special populations:

• Pregnancy: [U.S. Boxed Warning]: Use of mifepristone will result in termination of pregnancy. When used to control hyperglycemia in women with Cushing’s syndrome, pregnancy must be excluded prior to initiation of therapy. Nonhormonal contraception must be used during treatment and for 1 month after discontinuation of therapy unless the patient has had surgical sterilization. Pregnancy must be excluded if treatment is interrupted for ≥14 days.

• Smokers: Use with caution in patients who are heavy smoker (>10 cigarettes/day); these patients were excluded from clinical trials when used as a single dose for the termination of pregnancy.

• Women >35 years: Use with caution in women >35 years of age; these patients were excluded from clinical trials when used as a single dose for the termination of pregnancy.

Special handling:

• Hazardous agent: Use appropriate precautions for handling and disposal (NIOSH 2014 [group 3]).

Other warnings/precautions:

• Confirmation of terminated pregnancy: When used for the termination of pregnancy, confirmation of pregnancy termination by clinical exam or ultrasound must be made 14 days following treatment. Manufacturer recommends surgical termination of pregnancy when medical termination fails or is not complete. Prescriber should determine in advance whether they will provide such care themselves or through other providers. Preventive measures to prevent rhesus immunization must be taken prior to surgical abortion.

• Ectopic pregnancy: Ultrasound should be used if an ectopic pregnancy is suspected or if duration of pregnancy is uncertain. Ultrasonography may not identify all ectopic pregnancies, and healthcare providers should be alert for signs and symptoms which may be related to undiagnosed ectopic pregnancy in any patient who receives mifepristone. Mifepristone is not effective in terminating ectopic pregnancies.

• Experienced physician: When used for the termination of pregnancy, to be administered only by physicians who can date pregnancy, diagnose ectopic pregnancies, provide access to surgical abortion (if needed), and can provide access to emergency care. Medication will be distributed directly to these physicians following signed agreement with the distributor. Must be administered under supervision by the qualified physician.

• Medication guide: [U.S. Boxed Warning]: When used for the termination of pregnancy, patients undergoing treatment with mifepristone should be instructed to bring their medication guide with them when an obtaining treatment from an emergency room or healthcare provider that did not prescribe the medication initially in order to identify that they are undergoing a medical abortion.

• Patient education: [U.S. Boxed Warning]: When used for the termination of pregnancy, patient must be instructed of the treatment procedure and expected effects. A signed agreement form must be kept in the patient's file. Physicians may obtain patient agreement forms, physician enrollment forms, and medical consultation directly from Danco Laboratories at 1-877-432-7596. Prescriber should also give the patient clear instructions on whom to call and what to do in the event of an emergency following administration of therapy.

• Pregnancy dating: Pregnancy is dated from day 1 of last menstrual period (presuming a 28-day cycle, ovulation occurring midcycle). Pregnancy duration can be determined using menstrual history and clinical examination. Ultrasound should be used if duration of pregnancy is uncertain.

• Reporting of adverse effects: When used for the termination of pregnancy, adverse effects (including blood transfusions, hospitalization, ongoing pregnancy, and other major complications) must be reported in writing to the medication distributor.

Monitoring Parameters

Treatment of hyperglycemia in patients with Cushing’s syndrome: Signs and symptoms of adrenal insufficiency (serum cortisol concentrations will not be accurate); thyroid function; serum potassium (1-2 weeks after initiating dose or dose increase, then periodically thereafter); serum glucose and psychiatric symptoms (may show response to therapy within 6 weeks); cushingoid appearance (acne, hirsutism, striae, weight may take >2 months of therapy to show improvement); vaginal ultrasound in women (annually)

Termination of pregnancy: Clinical exam and/or ultrasound to confirm complete termination of pregnancy; hemoglobin, hematocrit, and red blood cell count in cases of heavy bleeding. Consider CBC in any patient who reports nausea, vomiting, or diarrhea and weakness with or without abdominal pain, and without fever or other signs of infection more than 24 hours after administration of misoprostol.

Pregnancy Risk Factor

X

Pregnancy Considerations

Use of mifepristone in a pregnant woman will result in fetal loss. In addition, skull deformities were observed in rabbit reproduction studies and were most likely due to uterine contractions.

Korlym: [U.S. Boxed Warning]: Use of mifepristone will result in termination of pregnancy. When used to control hyperglycemia in women with Cushing’s syndrome, pregnancy must be excluded prior to initiation of therapy. Nonhormonal contraception must be used during treatment and for 1 month after discontinuation of therapy unless the patient has had surgical sterilization. Pregnancy must be excluded if treatment is interrupted for ≥14 days.

Mifeprex: This medication is used to terminate pregnancy; there are no approved treatment indications for its use during pregnancy. In addition, skull defects, cranial nerve palsies, delayed growth and psychomotor development, facial malformations and limb defects have been reported following prostaglandin exposure (including misoprostol). If treatment fails, there is a risk of fetal malformation. In sexually active women, pregnancy can occur prior to the first menstrual period following treatment. Appropriate contraception can be started as soon as termination of pregnancy is confirmed or before sexual intercourse is resumed.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, chills, abdominal cramps, constipation, lack of appetite, dry mouth, heartburn, joint pain, pharyngitis, or rhinitis. Have patient report immediately to prescriber signs of infection, severe abdominal pain, bleeding, tachycardia, passing out, severe vaginal bleeding (soaking two pads per hour), severe nausea, vomiting, severe diarrhea, loss of strength and energy, severe dizziness, severe headache, shortness of breath, difficulty breathing, vaginitis, pelvic pain, signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), vision changes, anxiety, back pain, angina, swelling of arms or legs, insomnia, or signs of low blood sugar (dizziness, headache, fatigue, feeling weak, shaking, a fast heartbeat, confusion, hunger, or sweating) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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