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Mifepristone (Mifegyn, Korlym) - Uses, Dose, Side effects, MOA

Mifepristone or RU-486 is a progesterone antagonist that is used in combination with misoprostol for the medical termination of pregnancy.

Mifepristone Uses:

Korlym:
- It is used to treat adult patients with endogenous Cushing syndrome who have diabetes mellitus or glucose intolerance and have high blood sugars that are a result of elevated cortisol levels. Additionally, it is utilised to treat individuals who have undergone unsuccessful surgical procedures or who are not the right candidates.
- Its use in hyperglycemia is limited by the fact that it cannot be used in patients with diabetes mellitus which is caused by other causes than hypercortisolism.
Mifeprex:
- This is also used in the termination of pregnancy which is more than 70 days but only be used in combination with misoprostol.
Off Label Use of Mifepristone in Adults:
- Termination of early pregnancy.

Mifepristone Dose in Adults:

Mifepristone Dose for treating Hyperglycemia in patients with Cushing syndrome (Korlym): Oral:

The initial dose is 300 mg once day, and depending on tolerance and symptom control, the dose may be increased in 300 mg increments at intervals of more than 2 to 4 weeks.
The daily intake should not be more than 20 mg/kg, with a maximum of 1,200 mg.
If therapy is terminated due to unfavourable side effects, restart it at 300 mg daily or a dose lower than that which prompted the stoppage.
Korlym dosage adjustment in patients receiving powerful CYP3A inhibitor medication already:
- Once daily, 300 mg is the recommended starting dose; this dose may be increased to whatever level is clinically necessary (900 mg is the daily maximum).
Korlym dosage adjustment in individuals who need to start taking a potent CYP3A inhibitor.:
- No dosage adjustment is required if the current dose is 300 mg per day.
- Reduce the dose to 300 mg once daily if the daily dose is already 600 mg. However, the dose can be increased to a maximum of 600 mg once daily if clinically necessary.
- If the dosage is now 900 mg/day, reduce it to 600 mg once daily. If clinically necessary, increase it to a maximum of 900 mg once day.
- Reduce the dose to 900 mg once daily if it is now 1,200 mg/day.

Dose for terminating intrauterine pregnancy (Mifeprex): Oral:

Treatment includes 3 visits by the patient.
- Day 1 (mifepristone administration):
  - 200 mg, single dose.
- Day 2 or 3 (misoprostol administration):
  - Within 24 to 48 hours of taking mifepristone, administer misoprostol 800 mcg buccally.
  - Two 200 mcg tablets are placed in each cheek pouch along with instructions to hold them there for 30 minutes. Any leftovers can be dissolved in water or another liquid and ingested.

Note: At this point, the patient could require therapy for cramping or other gastrointestinal issues.

Day 7 to 14 (post-treatment exam):
- On the seventh to fourteenth day following the administration of mifepristone, the patient must go back to the doctor to verify that the pregnancy has been fully terminated and to gauge the severity of bleeding.
- If ejection has not yet taken place but the pregnancy is not progressing, another dose of mifepristone together with misoprostol 800 mcg buccal might be administered.
- Women who decide to utilise a repeat dose of misoprostol should schedule a follow-up appointment with their doctor in about 7 days to determine whether they will experience a complete abortion.
- If total termination has not yet happened, surgery is necessary.

Dose for terminating pregnancy (off-label dosing):

After taking 200 mg of mifepristone orally, women receive 800 mcg of misoprostol vaginally 24 to 48 hours later.

Mifepristone (Mifegyn) Dose in early pregnancy loss (off-label): Oral:

After taking 200 mg of mifepristone orally, misoprostol is administered vaginally 24 hours later.

Use in Children:

Not indicated.

Mifepristone Pregnancy Category: X

Mifepristone in pregnancy is contraindicated if it is used to treat hyperglycemia associated with Cushing syndrome.
Korlym[US Boxed Warning]
- Mifepristone acts as a powerful antagonizing agent for progesterone (GR-II), and cortisol (CP) via the progesterone, glucocorticoid(GR-II), respectively.
- The antiprogesterone effects can cause the termination of pregnancy.
- If mifepristone is being used to treat hyperglycemia in women suffering from Cushing syndrome, it must be ruled out that pregnancy has occurred.
- Patients should use contraception throughout treatment, and for one month after the end of the treatment.
- The pregnancy must be ruled out before you can resume treatment after a 14-day interruption.
Mifeprex
- Although there are approved indications for using this medicine during pregnancy, it can be used to end pregnancies.
- If treatment is unsuccessful, there is a danger of foetal deformity.
- Pregnancy can occur in sexually active women before the first period after treatment.
- It is important to start appropriate contraception as soon as possible after termination of pregnancy or before any sexual intercourses are resumed.

Mifepristone use during breastfeeding:

Breast milk contains Mifepristone.
The manufacturers recommend that the clinical benefits for mother and infant exposed to the product should outweigh any risks. A decision should then be made.
Korlym: According to the manufacturer, it is important to avoid breastfeeding infants. It is recommended that you pump and discard milk for 18-21 days (or 6 to 6 half-lives) following treatment.

Mifepristone Dose in Kidney Disease:

Hyperglycemia with Cushing syndrome:
- The daily maximum dose is 600 mg.
Terminating intrauterine pregnancy:
- Studies have not indicated that the dose should be adjusted for the aforementioned indication.

Mifepristone (Mifegyn) Dose in Liver disease:

Hyperglycemia with Cushing syndrome:
- The maximum dose for mild to severe impairment is 600 mg administered once daily.
- Its Use is not advised in cases of severe impairment.

Note: Mifepristone and its metabolites were exposed to patients with mild hepatic impairment (Child-Pugh class B) following single and multiple doses of 600 mg per day.

Termination of intrauterine pregnancy:
- With CYP3A4 inhibitors, it is advised against use. However, no dose modifications are investigated.

Adverse events occur when treating hyperglycemia in patients with Cushing syndrome.

Common Side Effects of Mifepristone:

Cardiovascular:
- Peripheral Edema
- Hypertension
Central Nervous System:
- Fatigue
- Headache
- Dizziness
- Pain
Endocrine & Metabolic:
- Hypokalemia
- Abnormal Thyroid Function Test
Gastrointestinal:
- Abdominal Cramps
- Nausea
- Vomiting
- Decreased Appetite
- Diarrhea
- Xerostomia
Genitourinary:
- Uterine Cramps
- Endometrium Disease
- Vaginal Hemorrhage
Neuromuscular & Skeletal:
- Arthralgia
- Back Pain
- Myalgia
- Limb Pain
Respiratory:
- Dyspnea
- Sinusitis
- Nasopharyngitis

Less Common Side Effects of Mifepristone:

Cardiovascular:
- Edema
- Pitting Edema
- Syncope
Central Nervous System:
- Anxiety
- Drowsiness
- Flank Pain
- Malaise
- Insomnia
- Rigors
Dermatologic:
- Pruritus
- Skin Rash
Endocrine & Metabolic:
- Hypoglycemia
- Increased Serum Triglycerides
- Increased Thirst
- Adrenocortical Insufficiency
Gastrointestinal:
- Anorexia
- Constipation
- Abdominal Pain
- Gastroesophageal Reflux Disease
- Dyspepsia
Genitourinary:
- Uterine Hemorrhage
- Vaginitis
- Leukorrhea
- Pelvic Pain
- Endometriosis
- Salpingitis
- Pelvic Inflammatory Disease
Hematologic & Oncologic:
- Decreased Hemoglobin
- Anemia
Infection:
- Viral Infection
Neuromuscular & Skeletal:
- Musculoskeletal Chest Pain
- Weakness
- Leg Pain
Miscellaneous:
- Fever

Side effects of Mifepristone (Mifegyn) Frequency not defined:

Endocrine & metabolic:
- Decreased HDL cholesterol

Contraindications to Mifepristone:

Hypersensitivity can be a serious contraindication.

Korlym (extra contraindications) (additional contraindications). simvastatin or lovastatin use concurrently.
Narrow therapeutic range CYP3A substrates, such as cyclosporine (dihydroergotamine), ergotamine (ergotamine), pimozide (quinine), and trolomimus (sirolimus).
To preserve lives, combine with systemic corticosteroids (eg, immunosuppression after an organ transplant).
women who have a history of endometrial cancer, endometrial hyperplasia, or undetected breakthrough bleeding
Pregnancy.

Mifeprex (additional contraindications).

If you have hypersensitivity, it is better to stay away from prostaglandins like misoprostol.
It is best to avoid using it in cases of chronic adrenal insufficiency.
Hemorrhagic illness and ongoing anticoagulant treatment
An implanted intrauterine device.
Undiagnosed adnexal mass
Ectopic pregnancy.
Long-term corticosteroid therapy.

Warnings and precautions

Insufficiency of the adrenals:
- When it is used to treat hyperglycemia in Cushing syndrome patients, adrenal insufficiency may occur.
- The serum cortisol levels are still elevated and could increase, so monitoring is not recommended.
- If adrenal insufficiency symptoms (eg fatigue, hypoglycemia and hypotension, nausea, weakness) are present, discontinue mifepristone treatment and start high-dose glucocorticoids.
- After the Addison's crisis is resolved, treatment can be restarted at a lower dose.
- It is important to evaluate the patient for any precipitating causes (eg. infection or trauma).
Bacterial diseases: [US Boxed Warn]
- Clostridium sordellii, a bacterium that can be transmitted to the uterus by using this product for the termination or reversal of pregnancy has been reported. This product can cause unusual symptoms.
- These infections can be fatal in rare cases.Septic shock is a possible complication.
- It has not been proven that there is a causal relationship.
- An evaluation should be made if you have a fever greater than 38 degrees Celsius (100.4 degrees Fahrenheit) that lasts more than four hours, abdominal pain, or tenderness in the pelvis.
- Healthcare professionals have noticed that some patients have presented with serious infections without these symptoms.
- If symptoms persist for more than 24hrs after misoprostol was administered, patients with nausea, vomiting, diarrhea or weakness should be examined for a serious bacterial infection.
- Cushing syndrome patients may be at high risk of developing opportunistic infections like Pneumocystis jarovecii pneumonia.
Bleeding
- Mifepristone can cause endometrial hyperplasia regardless of its indication.
- This results in endometrial thickening and cystic dilation endometrial glands. It also causes vaginal bleeding.
- [US Boxed Warning]Patients should be advised to seek medical attention if they are using the procedure for termination of pregnancy.
- Bleeding is normal and to be expected. It can last from 9 to 16 days on average, but may last for more than 30.
- Sometimes bleeding can be excessive and prolonged in some cases. This could be an indication of incomplete abortions or other complications.
- Hypovolemic shock can result. Excessive bleeding is defined as soaking through 2x2x2x2x2x2x2 sanitary pads for 2 consecutive hours.
- Transfusions may be required due to severe bleeding, curettage or saline injections and/or vasoconstrictors.
- If there is persistent heavy vaginal bleeding, patients should be directed to seek medical attention.
- Women with hemorhagic conditions or anticoagulants should not use this medication to eliminate pregnancy.
- Women with hemostatic, severe anemia, and hypercoagulability should be cautious.
- Women who experience persistent, unexplained vaginal bleeding should not use Mifepristone.
Hypokalemia
- Patients with Cushing syndrome may experience hyperglycemia at any stage of therapy.
- Before starting treatment, ensure that you have the correct potassium levels. You should monitor your potassium levels.
Extension of QT
- QT prolongation due to dose-related QT prolongation is possible. It should not be taken with any QT-prolonging medication.
Cardiovascular disease
- Mifepristone doesn't reduce serum cortisol levels, so mineralocorticoid receptors may be activated in cardiac tissue.
- Patients with heart failure or CAD should exercise caution.
Diabetes:
- Its efficacy in patients with IDDM has yet to be established.
Hepatic impairment
- Patients with mild hepatic impairment may be exposed to harmful products in a variable dose of up to 600mg/day
Renal impairment
- Patients with severe renal impairment were more likely to be exposed to mifepristone or its metabolites.
- There was also a greater variability in exposure in patients with Cushing syndrome, who received multiple doses of the drug.

Mifepristone: Drug Interaction

Risk Factor C (Monitor therapy)
Alosetron	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron.
Androgens	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Exceptions: Danazol.
Antidiabetic Agents	May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents.
Benperidol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Benperidol.
Betamethasone (Ophthalmic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Betamethasone (Ophthalmic).
Bictegravir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bictegravir.
Bortezomib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib.
Bosentan	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
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.
Bosentan	CYP2C9 Inhibitors (Moderate) 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.
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.
Brinzolamide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide.
Budesonide (Nasal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal).
Budesonide (Oral Inhalation)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation).
Calcifediol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol.
Cannabidiol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabidiol.
Cannabis	CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased.
Cannabis	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased.
Carvedilol	CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased.
Cinacalcet	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cinacalcet.
Clofazimine	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
CloZAPine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Codeine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Codeine.
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).
CYP2B6 Substrates (High risk with Inhibitors)	MiFEPRIStone may increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors).
CYP3A4 Inducers (Moderate)	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
CYP3A4 Inhibitors (Moderate)	May decrease the metabolism of CYP3A4 Substrates (High risk with Inhibitors).
Deferasirox	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
DexAMETHasone (Ophthalmic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of DexAMETHasone (Ophthalmic).
Dexketoprofen	May diminish the therapeutic effect of MiFEPRIStone.
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.
Dofetilide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dofetilide.
Doxercalciferol	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol.
Dronabinol	CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol.
Dronabinol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol.
Dutasteride	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride.
Enfortumab Vedotin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Enfortumab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased.
Estrogen Derivatives	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estrogen Derivatives.
Evogliptin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Evogliptin.
Fosnetupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Fostamatinib	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fostamatinib.
Galantamine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Galantamine.
Grapefruit Juice	May increase the serum concentration of MiFEPRIStone.
Herbs (Hypoglycemic Properties)	May enhance the hypoglycemic effect of HypoglycemiaAssociated Agents.
Hypoglycemia-Associated Agents	May enhance the hypoglycemic effect of other HypoglycemiaAssociated Agents.
Ifosfamide	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide.
Imatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib.
Imidafenacin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin.
Lacosamide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide.
Levamlodipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levamlodipine.
Levobupivacaine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine.
Lornoxicam	CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Lornoxicam.
Lumefantrine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumefantrine.
Maitake	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Meperidine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Meperidine.
Monoamine Oxidase Inhibitors	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Naldemedine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naldemedine.
Nalfurafine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nalfurafine.
Netupitant	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Ospemifene	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene.
Oxybutynin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin.
Parecoxib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib.
Paricalcitol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol.
Pegvisomant	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Pimecrolimus	CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus.
Polatuzumab Vedotin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Polatuzumab Vedotin. Exposure to unconjugated MMAE, the cytotoxic small molecule component of polatuzumab vedotin, may be increased.
Pranlukast	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast.
Propafenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Prothionamide	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
QT-prolonging Agents (Highest Risk)	QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk.
Quinolones	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents. Quinolones 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.
Ramelteon	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon.
Repaglinide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure.
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.
Rilpivirine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rilpivirine.
RomiDEPsin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin.
Salicylates	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Sarilumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
Selective Serotonin Reuptake Inhibitors	May enhance the hypoglycemic effect of Blood Glucose Lowering Agents.
Sibutramine	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Sibutramine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sibutramine.
Siltuximab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
SORAfenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib.
Tasimelteon	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon.
Tenoxicam	May diminish the therapeutic effect of MiFEPRIStone.
Tetrahydrocannabinol	CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol.
Tetrahydrocannabinol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol.
Tetrahydrocannabinol and Cannabidiol	CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol. Specifically, concentrations of tetrahydrocannabinol may be increased.
Tetrahydrocannabinol and Cannabidiol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol and Cannabidiol.
Tocilizumab	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers).
TraMADol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol.
Upadacitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Upadacitinib.
Vilanterol	May increase the serum concentration of CYP3A4 Inhibitors (Strong).
Vindesine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine.
Zolpidem	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zolpidem.
Risk Factor D (Consider therapy modification)
Abemaciclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Abemaciclib. Management: In patients taking abemaciclib at a dose of 200 mg or 150 mg twice daily, reduce the dose to 100 mg twice daily when combined with strong CYP3A4 inhibitors. In patients taking abemaciclib 100 mg twice daily, decrease the dose to 50 mg twice daily.
Alitretinoin (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor.
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.
ALPRAZolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of ALPRAZolam. Management: Consider using an alternative agent that is less likely to interact. If combined, monitor for increased therapeutic/toxic effects of alprazolam if combined with a strong CYP3A4 inhibitor.
ARIPiprazole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details.
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.
Avatrombopag	MiFEPRIStone may increase the serum concentration of Avatrombopag. Management: Management of this interaction varies based on avatrombopag indication. Dose adjustments are required for patients using avatrombopag for chronic immune thrombocytopenia. See monograph for details.
Bedaquiline	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit duration of concurrent use of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued use outweighs the possible risks. Monitor for toxic effects of bedaquiline. Exceptions discussed in separate monographs.
Brexpiprazole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer.
Brigatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brigatinib. Management: Avoid concurrent use of brigatinib with strong CYP3A4 inhibitors when possible. If combination cannot be avoided, reduce the brigatinib dose by approximately 50%, rounding to the nearest tablet strength (ie, from 180 mg to 90 mg, or from 90 mg to 60 mg).
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.
BusPIRone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of BusPIRone. Management: Limit the buspirone dose to 2.5 mg daily and monitor patients for increased buspirone effects/toxicities if combined with strong CYP3A4 inhibitors.
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.
Cabozantinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details.
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.
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. Exceptions discussed in separate monographs.
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.
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. See full monograph for details.
Conivaptan	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 600 mg/day when combined with conivaptan. Monitor for increased mifepristone toxicity regardless of dose or indication.
Copanlisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Copanlisib. Management: If concomitant use of copanlisib and strong CYP3A4 inhibitors cannot be avoided, reduce the copanlisib dose to 45 mg. Monitor patients for increased copanlisib effects/toxicities.
Crizotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Management: Avoid concomitant use of crizotinib and strong CYP3A4 inhibitors whenever possible. If combined use cannot be avoided, decrease the crizotinib dose to 250 mg daily. Exceptions are discussed in separate monographs.
CYP2C9 Substrates (High risk with Inhibitors)	MiFEPRIStone may increase the serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Management: Use CYP2C9 substrates at the lowest recommended dose, and monitor closely for adverse effects, during and in the 2 weeks following mifepristone treatment.
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 900 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication.
CYP3A4 Substrates (High risk with Inhibitors)	MiFEPRIStone may increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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.
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.
Dasatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: This combination should be avoided if possible. If combined, dasatinib dose reductions are recommended. See full monograph for details. Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Delamanid	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Delamanid. Management: Increase ECG monitoring frequency if delamanid is combined with strong CYP3A4 inhibitors due to the risk for QTc interval prolongation. Continue frequent ECG assessments throughout full delamanid treatment period. Exceptions discussed separately.
Diclofenac (Systemic)	CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Diclofenac (Systemic). Management: Consider using a reduced dose of diclofenac when used together with moderate CYP2C9 inhibitors. Arthrotec (diclofenac and misoprostol) prescribing information recommends a maximum dose of 50 mg twice daily.
DOCEtaxel	CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOCEtaxel. Management: Avoid the concomitant use of docetaxel and strong CYP3A4 inhibitors when possible. If combined use is unavoidable, consider a 50% docetaxel dose reduction and monitor for increased docetaxel toxicities.
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.
Drospirenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Management: Drospirenone use is contraindicated specifically when the strong CYP3A4 inhibitors atazanavir and cobicistat are administered concurrently. Caution should be used when drospirenone is coadministered with other strong CYP3A4 inhibitors.
Duvelisib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Duvelisib. Management: Reduce the dose of duvelisib to 15 mg twice a day when used together with a strong CYP3A4 inhibitor.
Elagolix	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Elagolix. Management: Use of the elagolix 200 mg twice daily dose with a strong CYP3A4 inhibitor for longer than 1 month is not recommended. Limit combined use of the elagolix 150 mg once daily dose with a strong CYP3A4 inhibitor to a maximum of 6 months.
Eliglustat	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details.
Encorafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Encorafenib. Management: Avoid concomitant use of encorafenib and strong CYP3A4 inhibitors whenever possible. If concomitant administration is unavoidable, decrease the encorafenib dose. See monograph for details.
Entrectinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Entrectinib. Management: Avoid strong CYP3A4 inhibitors during treatment with entrectinib. Reduce dose to 100 mg/day if combination cannot be avoided in adults and those 12 yrs of age or older with a BSA of at least 1.5 square meters. No alternative dosing provided for others.
Erdafitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erdafitinib. Management: Avoid concomitant use of erdafitinib and strong CYP3A4 inhibitors when possible. If combined, monitor closely for erdafitinib adverse reactions and consider dose modifications accordingly.
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).
Estrogen Derivatives (Contraceptive)	MiFEPRIStone may diminish the therapeutic effect of Estrogen Derivatives (Contraceptive). MiFEPRIStone may increase the serum concentration of Estrogen Derivatives (Contraceptive). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment.
Eszopiclone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression).
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.
Fedratinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fedratinib. Management: Consider alternatives when possible. If used together, decrease fedratinib dose to 200 mg/day. After the inhibitor is stopped, increase fedratinib to 300 mg/day for the first 2 weeks and then to 400 mg/day as tolerated.
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.
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.
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.
Fosamprenavir	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 600 mg/day when combined with fosamprenavir. Monitor for increased mifepristone toxicity regardless of dose or indication.
Gilteritinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gilteritinib. Management: Consider alternatives to the use of a strong CYP3A4 inhibitor with gilteritinib. If the combination cannot be avoided, monitor more closely for evidence of gilteritinib toxicities.
Glasdegib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Glasdegib. Management: Consider alternatives to this combination when possible. If the combination must be used, monitor closely for evidence of QT interval prolongation and other adverse reactions to glasdegib.
GuanFACINE	CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination.
Iloperidone	CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor.
Istradefylline	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Istradefylline. Management: Limit the maximum istradefylline dose to 20 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased istradefylline effects/toxicities.
Ivacaftor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for productspecific recommendations.
Ivosidenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivosidenib. Management: Avoid use of a strong CYP3A4 inhibitor with ivosidenib whenever possible. When combined use is required, reduce the ivosidenib dose to 250 mg once daily. Drugs listed as exceptions are discussed in further detail in separate drug interaction monographs.
Ixabepilone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone.
Larotrectinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Larotrectinib. Management: Avoid use of strong CYP3A4 inhibitors with larotrectinib. If this combination cannot be avoided, reduce the larotrectinib dose by 50%. Increase to previous dose after stopping the inhibitor after a period of 3 to 5 times the inhibitor half-life.
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.
Lorlatinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lorlatinib. Management: Avoid use of lorlatinib with strong CYP3A4 inhibitors. If the combination cannot be avoided, reduce the lorlatinib dose from 100 mg once daily to 75 mg once daily, or from 75 mg once daily to 50 mg once daily.
Lorlatinib	May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences.
Manidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Manidipine. Management: Consider avoiding concomitant use of manidipine and strong CYP3A4 inhibitors. If combined, monitor closely for increased manidipine effects and toxicities. Manidipine dose reductions may be required.
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.
Midostaurin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Exceptions are discussed in separate monographs.
Mirodenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination.
Nilotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Management: Avoid if possible. If combination needed, decrease nilotinib to 300 mg once/day for patients with resistant or intolerant Ph+ CML or to 200 mg once/day for patients with newly diagnosed Ph+ CML in chronic phase. Exceptions discussed in separate monograph.
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 possible. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 100 mg twice daily.
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.
Panobinostat	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor.
PAZOPanib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib adult dose to 400 mg. Further dose reductions may also be required.
Pexidartinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pexidartinib. Management: Avoid use of pexidartinib with strong CYP3A4 inhibitors if possible. If combined use cannot be avoided, the pexidartinib dose should be reduced. Decrease 800 mg or 600 mg daily doses to 200 mg twice daily. Decrease doses of 400 mg/day to 200 mg/day.
Pimavanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Management: Decrease the pimavanserin dose to 10 mg daily when combined with strong CYP3A4 inhibitors.
Piperaquine	CYP3A4 Inhibitors (Strong) may enhance the QTc-prolonging effect of Piperaquine. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Piperaquine. Management: Avoid concomitant use of piperaquine and strong CYP3A4 inhibitors when possible. If the combination cannot be avoided, frequent ECG monitoring is recommended due to the risk for QTc prolongation. Exceptions are discussed separately.
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.
Progestins (Contraceptive)	MiFEPRIStone may diminish the therapeutic effect of Progestins (Contraceptive). MiFEPRIStone may increase the serum concentration of Progestins (Contraceptive). Management: Women of childbearing potential should use an effective, nonhormonal means of contraception during and 4 weeks following mifepristone treatment.
QUEtiapine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce quetiapine to one-sixth of regular dose after starting strong CYP3A4 inhibitor. In those on strong CYP3A4 inhibitors, start quetiapine at lowest dose and up-titrate as needed. Exceptions discussed separately.
Reboxetine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine.
Ribociclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ribociclib. Management: Avoid use of ribociclib with strong CYP3A4 inhibitors when possible; if combined use cannot be avoided, reduce ribociclib dose to 400 mg once daily. Exceptions are discussed in separate monographs.
Ruxolitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details.
SAXagliptin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Limit the saxagliptin dose to 2.5 mg daily when combined with strong CYP3A4 inhibitors. When using the saxagliptin combination products saxagliptin/dapagliflozin or saxagliptin/dapagliflozin/metformin, avoid use with strong CYP3A4 inhibitors.
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.
Solifenacin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Solifenacin. Management: Limit solifenacin doses to 5 mg daily when combined with strong CYP3A4 inhibitors.
Stiripentol	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). 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.
SUFentanil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUFentanil. Management: If a strong CYP3A4 inhibitor is initiated in a patient on sufentanil, consider a sufentanil dose reduction and monitor for increased sufentanil effects and toxicities (eg, respiratory depression).
SUNItinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of SUNItinib. Management: Avoid when possible. If such a combination cannot be avoided, sunitinib dose decreases are recommended, and vary by indication. See full monograph for details.
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.
Temsirolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Temsirolimus. Management: Avoid concomitant use of temsirolimus and strong CYP3A4 inhibitors whenever possible. If combined, decrease temsirolimus dose to 12.5 mg per week and monitor patients for increased temsirolimus effects and toxicities.
Tezacaftor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tezacaftor. Management: When combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor alone should be administered.
Thiotepa	CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Thiotepa. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Thiotepa. Management: Thiotepa prescribing information recommends avoiding concomitant use of thiotepa and strong CYP3A4 inhibitors. If concomitant use is unavoidable, monitor for adverse effects and decreased efficacy.
Tofacitinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Tofacitinib dose reductions are recommended when combined with strong CYP3A4 inhibitors. Recommended dose adjustments vary by tofacitinib formulation and therapeutic indication. See full monograph for details.
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.
Toremifene	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Management: Use of toremifene with strong CYP3A4 inhibitors should be avoided if possible. If coadministration is necessary, monitor for increased toremifene toxicities, including QTc interval prolongation. Exceptions are discussed in separate monograph.
TraZODone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraZODone. Management: Consider the use of a lower trazodone dose and monitor for increased trazodone effects (eg, sedation, QTc prolongation) if combined with strong CYP3A4 inhibitors.
Valbenazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Valbenazine. Management: Reduce the valbenazine dose to 40 mg daily when combined with strong CYP3A4 inhibitors.
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.
Vemurafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Management: Avoid concurrent use of vemurafenib with strong CYP3A4 inhibitors when possible. Consider use of an alternative that is not a strong inhibitor of CYP3A4 as clinically appropriate.
Venetoclax	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: This combination is contraindicated during venetoclax initiation and ramp-up in patients with CLL/SLL. Reduced venetoclax doses are required during ramp-up for patients with AML, and reduced doses are required for all patients during maintenance therapy.
Vilazodone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg daily in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor.
Voxelotor	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Voxelotor. Management: Avoid concomitant use of voxelotor and strong CYP3A4 inhibitors. If concomitant use is unavoidable, reduce the voxelotor dose to 1,000 mg once daily.
Zanubrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zanubrutinib. Management: Decrease the zanubrutinib dose to 80 mg once daily during coadministration with a strong CYP3A4 inhibitor. Further dose adjustments may be required for zanubrutinib toxicities, refer to prescribing information for details.
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.
Zuclopenthixol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity.
Risk Factor X (Avoid combination)
Acalabrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Acalabrutinib.
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.
Alfuzosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin.
Anticoagulants	MiFEPRIStone may enhance the adverse/toxic effect of Anticoagulants. Specifically, the risk of bleeding may be increased.
Aprepitant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant.
Astemizole	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Astemizole. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Asunaprevir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir.
Avanafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avanafil.
Avapritinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Avapritinib.
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.
Barnidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine.
Blonanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin.
Bosutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib.
Bromocriptine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine.
Budesonide (Systemic)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic).
Cobimetinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib.
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.
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.
CYP3A4 Inducers (Strong)	May decrease the serum concentration of MiFEPRIStone.
Dabrafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib.
Dapoxetine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine.
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.
Domperidone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Dronedarone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Eletriptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan.
Eplerenone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eplerenone.
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.
Everolimus	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus.
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.
Flibanserin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin.
Fluticasone (Nasal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal).
Fosaprepitant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fosaprepitant.
Fusidic Acid (Systemic)	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
Halofantrine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
Ibrutinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: Avoid concomitant use of ibrutinib and strong CYP3A4 inhibitors. If a strong CYP3A4 inhibitor must be used short-term (eg, anti-infectives for 7 days or less), interrupt ibrutinib therapy until the strong CYP3A4 inhibitor is discontinued.
Idelalisib	May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors).
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.
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.
Ivabradine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine.
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.
Lefamulin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets and strong inhibitors of CYP3A4.
Lemborexant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lemborexant.
Lercanidipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine.
Lomitapide	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide.
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.
Lumateperone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lumateperone.
Lurasidone	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone.
Macitentan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan.
Naloxegol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol.
Neratinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Neratinib.
NiMODipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine.
Nisoldipine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine.
Palbociclib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib.
Phenylbutazone	May diminish the therapeutic effect of MiFEPRIStone. Management: Phenylbutazone should not be used for 8-12 days following mifepristone administration.
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.
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.
Radotinib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Radotinib.
Ranolazine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine.
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.
Regorafenib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib.
Rupatadine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Rupatadine.
Salmeterol	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol.
Silodosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin.
Simeprevir	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir.
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.
Siponimod	MiFEPRIStone may increase the serum concentration of Siponimod. Management: Coadministration of siponimod with miferpristone, a moderate inhibitor of CYP2C9 and a strong inhibitor of CYP3A4 is not recommended.
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.
Sonidegib	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib.
St John's Wort	May decrease the serum concentration of MiFEPRIStone.
Suvorexant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant.
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.
Tamsulosin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin.
Terfenadine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Terfenadine. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs.
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.
Tolvaptan	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan.
Trabectedin	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin.
Triazolam	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Triazolam.
Ubrogepant	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ubrogepant.
Udenafil	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil.
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.
VinCRIStine (Liposomal)	CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal).
Vinflunine	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine.
Vorapaxar	CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar.

Monitoring parameters:

Treating hyperglycemia in patients with Cushing syndrome:
- Symptoms of adrenal insufficiency as serum cortisol concentrations will not be accurate.
Thyroid function tests.
Serum potassium levels 1 to 2 weeks after initiating dose or dose increase then periodically thereafter.
Serum glucose and psychiatric symptoms. It may show response to therapy within 6 weeks.
Cushingoid appearance can be seen and features like acne, hirsutism, striae, weight may take >2 months of therapy to show improvement.
Vaginal ultrasound in women should be performed annually.

Pregnancy-related uses:

Prior to termination of pregnancy, confirm pregnancy and Rh status.
Hemoglobin levels should be assessed.

Following the procedure:

Clinical exam, human Chorionic Gonadotropin (hCG) testing, and ultrasound should be done to confirm complete termination of pregnancy.
Hemoglobin, hematocrit, and red blood cell count should be closely observed 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.
When used for medical management of early pregnancy loss, evaluate Rh status as transfusions may be required.
Evaluate response to treatment within 7 days after the first dose.

How to administer Mifepristone?

Hyperglycemia with Cushing syndrome:

One dose per day should be given with food.
The tablets should not be chewed, divided, or crushed before being swallowed whole.

Terminating intrauterine pregnancy:

Before starting mifepristone therapy, remove any intrauterine devices.
Give misoprostol buccally and mifepristone orally.
Mifepristone should be given orally on day 1 under the guidance of a licenced physician.
Give the patient the provider's name and phone number so they can contact them in case of queries or emergencies.

Mechanism of action of Mifepristone (Mifegyn):

Mifepristone can be described as a synthetic steroid.
It can competely bind to the intracellular progesterone-receptor at low doses and block the effects of progesterone.
This is used to terminate a pregnancy and causes contraction-inducing activity within the myometrium.
Mifepristone is a partial progesterone antagonist in the absence of progesterone.
Mifepristone is used to treat hyperglycemia in Cushing's syndrome patients at high doses.
It counteracts the effects of cortisol on glucose metabolism by blocking cortisol action at the glucocorticoid receptor.
Increasing the levels of cortisol in the blood.

Absorption: Oral:

Rapid

Protein binding:

98% to albumin and α -acid glycoprotein

Metabolism:

Hepatic via CYP3A4 to three metabolites (active)

Bioavailability:

Oral: 69%

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

Time to peak: Oral:

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

Excretion:

Feces (83%);
urine (9%)

International Brand Names of Mifepristone:

Korlym
Mifeprex
Abortom
Apano
Ginepriston
Mefaprix
Mifegyn
Mifegyne
Mifestad
Mifolian
Miropriston
Nopreg Pill
Si Mi An
Unwanted
Zacafemyl

Mifepristone Brand Names in Pakistan:

No Brands Available in Pakistan.

Mifepristone (Mifegyn, Korlym) - Uses, Dose, Side effects, MOA

Mifepristone Uses:

Off Label Use of Mifepristone in Adults:

Mifepristone Dose in Adults:

Mifepristone Dose for treating Hyperglycemia in patients with Cushing syndrome (Korlym): Oral:

Korlym dosage adjustment in patients receiving powerful CYP3A inhibitor medication already:

Korlym dosage adjustment in individuals who need to start taking a potent CYP3A inhibitor.:

Dose for terminating intrauterine pregnancy (Mifeprex): Oral:

Day 1 (mifepristone administration):

Day 2 or 3 (misoprostol administration):

Day 7 to 14 (post-treatment exam):

Dose for terminating pregnancy (off-label dosing):

Mifepristone (Mifegyn) Dose in early pregnancy loss (off-label): Oral:

Use in Children:

Mifepristone Pregnancy Category: X

Mifepristone use during breastfeeding:

Mifepristone Dose in Kidney Disease:

Hyperglycemia with Cushing syndrome:

Terminating intrauterine pregnancy:

Mifepristone (Mifegyn) Dose in Liver disease:

Hyperglycemia with Cushing syndrome:

Termination of intrauterine pregnancy:

Common Side Effects of Mifepristone:

Cardiovascular:

Central Nervous System:

Endocrine & Metabolic:

Gastrointestinal:

Genitourinary:

Neuromuscular & Skeletal:

Respiratory:

Less Common Side Effects of Mifepristone:

Cardiovascular:

Central Nervous System:

Dermatologic:

Endocrine & Metabolic:

Gastrointestinal:

Genitourinary:

Hematologic & Oncologic:

Infection:

Neuromuscular & Skeletal:

Miscellaneous:

Side effects of Mifepristone (Mifegyn) Frequency not defined:

Endocrine & metabolic:

Contraindications to Mifepristone:

Warnings and precautions

Insufficiency of the adrenals:

Bacterial diseases: [US Boxed Warn]

Bleeding

Hypokalemia

Extension of QT

Cardiovascular disease

Diabetes:

Hepatic impairment

Renal impairment

Monitoring parameters:

How to administer Mifepristone?

Mechanism of action of Mifepristone (Mifegyn):

International Brand Names of Mifepristone:

Mifepristone Brand Names in Pakistan:

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