Dosing & Uses
Dosage Forms & Strengths
tablet
- 1mg
- 5mg
- 10mg
Cushing Disease
Indicated for Cushing disease in adults for whom pituitary surgery is not an option or has not been curative
Initial: 2 mg PO BID
Titration
- Initially, titrate by 1-2 mg BID, no more frequently than q2weeks based on rate of cortisol changes, individual tolerability, and improvement in Cushing disease signs and symptoms
- If patient tolerates 10 mg PO BID and continues to have elevated 24-hr urine free cortisol (UFC) levels >ULN, titrate dosage further by 5 mg BID q2week
- Monitor cortisol levels from at least two 24-hour UFC collections q1-2weeks until adequate clinical response maintained
Maintenance
- Individualize maintenance dose according to cortisol levels and signs/symptoms
- Maintenance dosage varied from 2-7 mg BID in clinical trials
- Maximum recommended maintenance dose: 30 mg BID
- Once maintenance dose achieved, monitor cortisol levels at least every 1-2 months or as indicated
Dosage Modifications
Interruptions or modifications
- Decrease or temporarily discontinue if UFC levels fall below target range, there is a rapid decrease in cortisol levels, and/or symptoms of hypocortisolism occur; if necessary, initiate glucocorticoid
- Stop osilodrostat and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency
- If treatment is interrupted, reinitiate at lower dose when cortisol levels are within target ranges and symptoms have resolved
Renal impairment
- No dose adjustment required
- Caution in interpreting UFC levels with moderate-to-severe renal impairment, owing to reduced UFC excretion
Hepatic impairment
- Mild (Child-Pugh A): No dose adjustment required
- Moderate (Child-Pugh B): Reduce initial dose to 1 mg BID
- Severe (Child-Pugh C): Reduce initial dose to 1 mg qHS
- May require more frequent adrenal function monitoring during dose titration in all patients with hepatic impairment
Dosing Considerations
Correct hypokalemia and hypomagnesemia before initiating
Obtain baseline ECG; repeat ECG within 1 week after treatment initiation, and as clinically indicated thereafter
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (1)
- lefamulin
lefamulin will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated. Lefamulin is contraindicated with CYP3A substrates know to prolong the QT interval.
Serious - Use Alternative (16)
- adagrasib
adagrasib, osilodrostat. Either increases effects of the other by QTc interval. Avoid or Use Alternate Drug. Each drug prolongs the QTc interval, which may increased the risk of Torsade de pointes, other serious arryhthmias, and sudden death. If coadministration unavoidable, more frequent monitoring is recommended for such patients.
- amisulpride
amisulpride and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- buprenorphine buccal
buprenorphine buccal and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- buprenorphine subdermal implant
buprenorphine subdermal implant and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- buprenorphine transdermal
buprenorphine transdermal and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- buprenorphine, long-acting injection
buprenorphine, long-acting injection and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- carbamazepine
carbamazepine will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- ceritinib
ceritinib will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- dofetilide
dofetilide and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- fexinidazole
fexinidazole and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Avoid coadministration of fexinidazole with drugs known to block potassium channels or prolong QT interval.
fexinidazole will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Fexinidazole inhibits CYP3A4. Coadministration may increase risk for adverse effects of CYP3A4 substrates. - fosphenytoin
fosphenytoin will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- grapefruit
grapefruit will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- mobocertinib
mobocertinib and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. If coadministration unavoidable, reduce mobocertinib dose and monitor QTc interval more frequently.
- primidone
primidone will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- ribociclib
ribociclib and osilodrostat both increase QTc interval. Avoid or Use Alternate Drug. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- tucatinib
tucatinib will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid concomitant use of tucatinib with CYP3A substrates, where minimal concentration changes may lead to serious or life-threatening toxicities. If unavoidable, reduce CYP3A substrate dose according to product labeling.
Monitor Closely (196)
- albuterol
osilodrostat and albuterol both increase QTc interval. Use Caution/Monitor.
albuterol and osilodrostat both increase QTc interval. Use Caution/Monitor. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval - alfuzosin
osilodrostat and alfuzosin both increase QTc interval. Use Caution/Monitor.
alfuzosin and osilodrostat both increase QTc interval. Use Caution/Monitor. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval - amiodarone
osilodrostat and amiodarone both increase QTc interval. Use Caution/Monitor.
- amisulpride
osilodrostat and amisulpride both increase QTc interval. Use Caution/Monitor. ECG monitoring is recommended if coadministered.
- amitriptyline
osilodrostat and amitriptyline both increase QTc interval. Use Caution/Monitor.
- amobarbital
amobarbital will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- anagrelide
osilodrostat and anagrelide both increase QTc interval. Use Caution/Monitor.
- apalutamide
apalutamide will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- apomorphine
osilodrostat and apomorphine both increase QTc interval. Use Caution/Monitor.
- arformoterol
osilodrostat and arformoterol both increase QTc interval. Use Caution/Monitor.
- aripiprazole
osilodrostat and aripiprazole both increase QTc interval. Use Caution/Monitor.
- arsenic trioxide
osilodrostat and arsenic trioxide both increase QTc interval. Use Caution/Monitor.
- artemether
osilodrostat and artemether both increase QTc interval. Use Caution/Monitor.
- artemether/lumefantrine
osilodrostat and artemether/lumefantrine both increase QTc interval. Use Caution/Monitor.
- asenapine
osilodrostat and asenapine both increase QTc interval. Use Caution/Monitor.
- asenapine transdermal
asenapine transdermal and osilodrostat both increase QTc interval. Use Caution/Monitor. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- atazanavir
atazanavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- atomoxetine
osilodrostat and atomoxetine both increase QTc interval. Use Caution/Monitor.
- azithromycin
osilodrostat and azithromycin both increase QTc interval. Use Caution/Monitor.
- bedaquiline
osilodrostat and bedaquiline both increase QTc interval. Use Caution/Monitor.
- bosentan
bosentan will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- bosutinib
osilodrostat and bosutinib both increase QTc interval. Use Caution/Monitor.
- buprenorphine
osilodrostat and buprenorphine both increase QTc interval. Use Caution/Monitor.
- butabarbital
butabarbital will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- butalbital
butalbital will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- capecitabine
osilodrostat and capecitabine both increase QTc interval. Use Caution/Monitor.
- carbamazepine
carbamazepine will decrease the level or effect of osilodrostat by Other (see comment). Modify Therapy/Monitor Closely. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with strong CYP3A4 and/or CYP2B6 inducers. Adjust dose of osilodrostat if necessary.
- ceritinib
osilodrostat and ceritinib both increase QTc interval. Use Caution/Monitor.
- chloramphenicol
chloramphenicol will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- chloroquine
osilodrostat and chloroquine both increase QTc interval. Use Caution/Monitor.
chloroquine and osilodrostat both increase QTc interval. Use Caution/Monitor. - chlorpromazine
osilodrostat and chlorpromazine both increase QTc interval. Use Caution/Monitor.
- ciprofloxacin
osilodrostat and ciprofloxacin both increase QTc interval. Use Caution/Monitor.
- citalopram
osilodrostat and citalopram both increase QTc interval. Use Caution/Monitor.
- clarithromycin
clarithromycin will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
osilodrostat and clarithromycin both increase QTc interval. Use Caution/Monitor. - clofazimine
osilodrostat and clofazimine both increase QTc interval. Use Caution/Monitor.
- clozapine
osilodrostat and clozapine both increase QTc interval. Use Caution/Monitor.
- cobicistat
cobicistat will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- conivaptan
conivaptan will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- crizotinib
osilodrostat and crizotinib both increase QTc interval. Use Caution/Monitor.
- dabrafenib
dabrafenib will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
osilodrostat and dabrafenib both increase QTc interval. Use Caution/Monitor. - darunavir
darunavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- dasatinib
osilodrostat and dasatinib both increase QTc interval. Use Caution/Monitor.
- degarelix
osilodrostat and degarelix both increase QTc interval. Use Caution/Monitor.
- desflurane
osilodrostat and desflurane both increase QTc interval. Use Caution/Monitor.
- desipramine
osilodrostat and desipramine both increase QTc interval. Use Caution/Monitor.
- deutetrabenazine
osilodrostat and deutetrabenazine both increase QTc interval. Use Caution/Monitor. At the maximum recommended dose, deutetrabenazine does not prolong QT interval to a clinically relevant extent. Certain circumstances may increase risk of torsade de pointes and/or sudden death in association with drugs that prolong the QTc interval (eg, bradycardia, hypokalemia or hypomagnesemia, coadministration with other drugs that prolong QTc interval, presence of congenital QT prolongation).
- disopyramide
osilodrostat and disopyramide both increase QTc interval. Use Caution/Monitor.
- divalproex sodium
osilodrostat will decrease the level or effect of divalproex sodium by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.
- dofetilide
osilodrostat and dofetilide both increase QTc interval. Use Caution/Monitor.
- dolasetron
osilodrostat and dolasetron both increase QTc interval. Use Caution/Monitor.
- donepezil
osilodrostat and donepezil both increase QTc interval. Use Caution/Monitor.
- doxepin
osilodrostat and doxepin both increase QTc interval. Use Caution/Monitor.
- dronedarone
osilodrostat and dronedarone both increase QTc interval. Use Caution/Monitor.
- droperidol
osilodrostat and droperidol both increase QTc interval. Use Caution/Monitor.
- efavirenz
efavirenz will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
osilodrostat and efavirenz both increase QTc interval. Use Caution/Monitor. - eliglustat
osilodrostat and eliglustat both increase QTc interval. Use Caution/Monitor.
- encorafenib
osilodrostat and encorafenib both increase QTc interval. Use Caution/Monitor.
- entrectinib
osilodrostat and entrectinib both increase QTc interval. Use Caution/Monitor.
- enzalutamide
enzalutamide will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- eribulin
osilodrostat and eribulin both increase QTc interval. Use Caution/Monitor.
- erythromycin base
osilodrostat and erythromycin base both increase QTc interval. Use Caution/Monitor.
- erythromycin ethylsuccinate
osilodrostat and erythromycin ethylsuccinate both increase QTc interval. Use Caution/Monitor.
- erythromycin lactobionate
osilodrostat and erythromycin lactobionate both increase QTc interval. Use Caution/Monitor.
- erythromycin stearate
osilodrostat and erythromycin stearate both increase QTc interval. Use Caution/Monitor.
- escitalopram
osilodrostat and escitalopram both increase QTc interval. Use Caution/Monitor.
escitalopram and osilodrostat both increase QTc interval. Use Caution/Monitor. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval - etravirine
etravirine will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- ezogabine
osilodrostat and ezogabine both increase QTc interval. Use Caution/Monitor.
- fingolimod
osilodrostat and fingolimod both increase QTc interval. Use Caution/Monitor.
- flecainide
osilodrostat and flecainide both increase QTc interval. Use Caution/Monitor.
- floxuridine
osilodrostat and floxuridine both increase QTc interval. Use Caution/Monitor.
- fluconazole
osilodrostat and fluconazole both increase QTc interval. Use Caution/Monitor.
- fluoxetine
osilodrostat and fluoxetine both increase QTc interval. Use Caution/Monitor.
- fluphenazine
osilodrostat and fluphenazine both increase QTc interval. Use Caution/Monitor.
- formoterol
osilodrostat and formoterol both increase QTc interval. Use Caution/Monitor.
- foscarnet
osilodrostat and foscarnet both increase QTc interval. Use Caution/Monitor.
- fosphenytoin
fosphenytoin will decrease the level or effect of osilodrostat by Other (see comment). Modify Therapy/Monitor Closely. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with strong CYP3A4 and/or CYP2B6 inducers. Adjust dose of osilodrostat if necessary.
- fostemsavir
osilodrostat and fostemsavir both increase QTc interval. Use Caution/Monitor. QTc prolongation reported with higher than recommended doses of fostemsavir.
- gadoterate meglumine
osilodrostat and gadoterate meglumine both increase QTc interval. Use Caution/Monitor.
- gemifloxacin
osilodrostat and gemifloxacin both increase QTc interval. Use Caution/Monitor.
- gemtuzumab
osilodrostat and gemtuzumab both increase QTc interval. Use Caution/Monitor.
- gepirone
gepirone and osilodrostat both increase QTc interval. Modify Therapy/Monitor Closely.
- gilteritinib
gilteritinib and osilodrostat both increase QTc interval. Use Caution/Monitor. Dose dependent QT prolongation - avoid drugs known to prolong the QT interval
- glasdegib
osilodrostat and glasdegib both increase QTc interval. Use Caution/Monitor.
- goserelin
osilodrostat and goserelin both increase QTc interval. Use Caution/Monitor.
- granisetron
osilodrostat and granisetron both increase QTc interval. Use Caution/Monitor.
- haloperidol
osilodrostat and haloperidol both increase QTc interval. Use Caution/Monitor.
- hydroxychloroquine sulfate
osilodrostat and hydroxychloroquine sulfate both increase QTc interval. Use Caution/Monitor.
hydroxychloroquine sulfate and osilodrostat both increase QTc interval. Use Caution/Monitor. - hydroxyzine
osilodrostat and hydroxyzine both increase QTc interval. Use Caution/Monitor.
- ibutilide
osilodrostat and ibutilide both increase QTc interval. Use Caution/Monitor.
- idelalisib
idelalisib will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- iloperidone
osilodrostat and iloperidone both increase QTc interval. Use Caution/Monitor.
- indacaterol, inhaled
osilodrostat and indacaterol, inhaled both increase QTc interval. Use Caution/Monitor.
- indinavir
indinavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- inotuzumab
osilodrostat and inotuzumab both increase QTc interval. Use Caution/Monitor.
- isoflurane
osilodrostat and isoflurane both increase QTc interval. Use Caution/Monitor.
- isoniazid
isoniazid will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- itraconazole
itraconazole will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
osilodrostat and itraconazole both increase QTc interval. Use Caution/Monitor. - ivosidenib
ivosidenib will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
osilodrostat and ivosidenib both increase QTc interval. Use Caution/Monitor. - ketoconazole
ketoconazole will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- lapatinib
osilodrostat and lapatinib both increase QTc interval. Use Caution/Monitor.
- lefamulin
osilodrostat and lefamulin both increase QTc interval. Use Caution/Monitor.
- lenacapavir
lenacapavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Lencapavir may increase CYP3A4 substrates initiated within 9 months after last SC dose of lenacapavir, which may increase potential risk of adverse reactions of CYP3A4 substrates.
- lenvatinib
osilodrostat and lenvatinib both increase QTc interval. Use Caution/Monitor.
- leuprolide
osilodrostat and leuprolide both increase QTc interval. Use Caution/Monitor.
- levalbuterol
osilodrostat and levalbuterol both increase QTc interval. Use Caution/Monitor.
- levofloxacin
osilodrostat and levofloxacin both increase QTc interval. Use Caution/Monitor.
- levoketoconazole
levoketoconazole will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- lithium
osilodrostat and lithium both increase QTc interval. Use Caution/Monitor.
- lofexidine
osilodrostat and lofexidine both increase QTc interval. Use Caution/Monitor.
- loperamide
osilodrostat and loperamide both increase QTc interval. Use Caution/Monitor.
- lopinavir
lopinavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
osilodrostat and lopinavir both increase QTc interval. Use Caution/Monitor. - lorlatinib
lorlatinib will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- lumacaftor/ivacaftor
lumacaftor/ivacaftor will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- macimorelin
osilodrostat and macimorelin both increase QTc interval. Use Caution/Monitor.
- mefloquine
osilodrostat and mefloquine both increase QTc interval. Use Caution/Monitor.
- methadone
osilodrostat and methadone both increase QTc interval. Use Caution/Monitor.
- midostaurin
osilodrostat and midostaurin both increase QTc interval. Use Caution/Monitor.
- mifepristone
mifepristone will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
osilodrostat and mifepristone both increase QTc interval. Use Caution/Monitor. - mirtazapine
osilodrostat and mirtazapine both increase QTc interval. Use Caution/Monitor.
- mitotane
mitotane will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- moxifloxacin
osilodrostat and moxifloxacin both increase QTc interval. Use Caution/Monitor.
- nafcillin
nafcillin will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- nefazodone
nefazodone will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- nelfinavir
nelfinavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- nevirapine
nevirapine will decrease the level or effect of osilodrostat by affecting hepatic enzyme CYP2B6 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP2B6 inducers. Adjust dose of osilodrostat if necessary.
- nilotinib
osilodrostat and nilotinib both increase QTc interval. Use Caution/Monitor.
- nortriptyline
osilodrostat and nortriptyline both increase QTc interval. Use Caution/Monitor.
- ofloxacin
osilodrostat and ofloxacin both increase QTc interval. Use Caution/Monitor.
- olanzapine
osilodrostat and olanzapine both increase QTc interval. Use Caution/Monitor.
- olodaterol inhaled
osilodrostat and olodaterol inhaled both increase QTc interval. Use Caution/Monitor.
- ondansetron
osilodrostat and ondansetron both increase QTc interval. Use Caution/Monitor.
- osimertinib
osilodrostat and osimertinib both increase QTc interval. Use Caution/Monitor.
- oxaliplatin
osilodrostat and oxaliplatin both increase QTc interval. Use Caution/Monitor.
- ozanimod
ozanimod and osilodrostat both increase QTc interval. Modify Therapy/Monitor Closely. The potential additive effects on heart rate, treatment with ozanimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties.
- paliperidone
osilodrostat and paliperidone both increase QTc interval. Use Caution/Monitor.
- panobinostat
osilodrostat and panobinostat both increase QTc interval. Use Caution/Monitor.
- pasireotide
osilodrostat and pasireotide both increase QTc interval. Use Caution/Monitor.
- pazopanib
osilodrostat and pazopanib both increase QTc interval. Use Caution/Monitor.
- pentamidine
osilodrostat and pentamidine both increase QTc interval. Use Caution/Monitor.
- pentobarbital
pentobarbital will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- phenobarbital
phenobarbital will decrease the level or effect of osilodrostat by Other (see comment). Modify Therapy/Monitor Closely. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with strong CYP3A4 and/or CYP2B6 inducers. Adjust dose of osilodrostat if necessary.
- phenytoin
phenytoin will decrease the level or effect of osilodrostat by Other (see comment). Modify Therapy/Monitor Closely. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with strong CYP3A4 and/or CYP2B6 inducers. Adjust dose of osilodrostat if necessary.
- pimavanserin
osilodrostat and pimavanserin both increase QTc interval. Use Caution/Monitor.
- pimozide
osilodrostat and pimozide both increase QTc interval. Use Caution/Monitor.
- pitolisant
osilodrostat and pitolisant both increase QTc interval. Use Caution/Monitor.
- posaconazole
posaconazole will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- primaquine
osilodrostat and primaquine both increase QTc interval. Use Caution/Monitor.
- primidone
primidone will decrease the level or effect of osilodrostat by Other (see comment). Modify Therapy/Monitor Closely. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with strong CYP3A4 and/or CYP2B6 inducers. Adjust dose of osilodrostat if necessary.
- procainamide
osilodrostat and procainamide both increase QTc interval. Use Caution/Monitor.
- propofol
osilodrostat and propofol both increase QTc interval. Use Caution/Monitor.
- quetiapine
osilodrostat and quetiapine both increase QTc interval. Use Caution/Monitor.
- quinidine
osilodrostat and quinidine both increase QTc interval. Use Caution/Monitor.
- quinine
osilodrostat and quinine both increase QTc interval. Use Caution/Monitor.
- quizartinib
quizartinib, osilodrostat. Either increases effects of the other by QTc interval. Modify Therapy/Monitor Closely. Monitor patients more frequently with ECG if coadministered with QT prolonging drugs.
- ranolazine
osilodrostat and ranolazine both increase QTc interval. Use Caution/Monitor.
- ribociclib
osilodrostat and ribociclib both increase QTc interval. Use Caution/Monitor.
ribociclib will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - rifabutin
rifabutin will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- rifampin
rifampin will decrease the level or effect of osilodrostat by Other (see comment). Use Caution/Monitor. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with strong CYP3A4 and/or CYP2B6 inducers. Adjust dose of osilodrostat if necessary.
rifampin will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - rifapentine
rifapentine will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- rilpivirine
osilodrostat and rilpivirine both increase QTc interval. Use Caution/Monitor.
- risperidone
osilodrostat and risperidone both increase QTc interval. Use Caution/Monitor.
- ritonavir
ritonavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- romidepsin
osilodrostat and romidepsin both increase QTc interval. Use Caution/Monitor.
- rucaparib
rucaparib will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Adjust dosage of CYP3A4 substrates, if clinically indicated.
- salmeterol
osilodrostat and salmeterol both increase QTc interval. Use Caution/Monitor.
- saquinavir
saquinavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
osilodrostat and saquinavir both increase QTc interval. Use Caution/Monitor. - secobarbital
secobarbital will decrease the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Monitor cortisol concentration and patient?s signs and symptoms during coadministration or discontinuation with strong CYP3A4 inducers. Adjust dose of osilodrostat if necessary.
- selpercatinib
selpercatinib and osilodrostat both increase QTc interval. Use Caution/Monitor.
- sertraline
osilodrostat and sertraline both increase QTc interval. Use Caution/Monitor.
- siponimod
osilodrostat and siponimod both increase QTc interval. Use Caution/Monitor.
- solifenacin
osilodrostat and solifenacin both increase QTc interval. Use Caution/Monitor.
- sorafenib
osilodrostat and sorafenib both increase QTc interval. Use Caution/Monitor.
- sotalol
osilodrostat and sotalol both increase QTc interval. Use Caution/Monitor.
- stiripentol
stiripentol, osilodrostat. Other (see comment). Modify Therapy/Monitor Closely. Comment: Stiripentol is both an inhibitor and inducer of CYP2B6, and CYP3A4. Osilodrostat is a CYP3A4 and CYP2B6 subtrate. Monitor cortisol concentration and patient?s signs and symptoms during coadministration and discontinuation with stiripentol. Adjust dose of osilodrostat if necessary.
- sunitinib
osilodrostat and sunitinib both increase QTc interval. Use Caution/Monitor.
- tacrolimus
osilodrostat and tacrolimus both increase QTc interval. Use Caution/Monitor.
- telavancin
osilodrostat and telavancin both increase QTc interval. Use Caution/Monitor.
- terbutaline
osilodrostat and terbutaline both increase QTc interval. Use Caution/Monitor.
- tetrabenazine
osilodrostat and tetrabenazine both increase QTc interval. Use Caution/Monitor.
- theophylline
osilodrostat will increase the level or effect of theophylline by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.
- thioridazine
osilodrostat and thioridazine both increase QTc interval. Use Caution/Monitor.
- tipranavir
tipranavir will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
- tizanidine
osilodrostat will increase the level or effect of tizanidine by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.
- toremifene
osilodrostat and toremifene both increase QTc interval. Use Caution/Monitor.
- trazodone
osilodrostat and trazodone both increase QTc interval. Use Caution/Monitor.
- triclabendazole
osilodrostat and triclabendazole both increase QTc interval. Use Caution/Monitor.
- triptorelin
osilodrostat and triptorelin both increase QTc interval. Use Caution/Monitor.
- valbenazine
valbenazine and osilodrostat both increase QTc interval. Use Caution/Monitor.
- valproic acid
osilodrostat will decrease the level or effect of valproic acid by affecting hepatic enzyme CYP2C19 metabolism. Use Caution/Monitor.
- vandetanib
osilodrostat and vandetanib both increase QTc interval. Use Caution/Monitor.
- vardenafil
osilodrostat and vardenafil both increase QTc interval. Use Caution/Monitor.
- vemurafenib
osilodrostat and vemurafenib both increase QTc interval. Use Caution/Monitor.
- voclosporin
voclosporin, osilodrostat. Either increases effects of the other by QTc interval. Use Caution/Monitor.
- voriconazole
voriconazole will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Reduce dose of osilodrostat, a CYP3A4 substrate, by half when coadministered with a strong CYP3A4 inhibitor.
osilodrostat and voriconazole both increase QTc interval. Use Caution/Monitor. - vorinostat
osilodrostat and vorinostat both increase QTc interval. Use Caution/Monitor.
- ziprasidone
osilodrostat and ziprasidone both increase QTc interval. Use Caution/Monitor.
Minor (4)
- acetazolamide
acetazolamide will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- anastrozole
anastrozole will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- cyclophosphamide
cyclophosphamide will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- larotrectinib
larotrectinib will increase the level or effect of osilodrostat by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
Adverse Effects
>10%
Adrenal insufficiency (43.1%)
Fatigue (38.7%)
Nausea (37.2%)
Headache (30.7%)
Edema (21.2%)
Nasopharyngitis (19.7%)
Vomiting (19%)
Arthralgia (17.5%)
Back pain (15.3%)
Rash (15.3%)
Diarrhea (14.6%)
Blood corticotrophin increased (13.9%)
Dizziness (13.9%)
Abdominal pain (13.1%)
Hypokalemia (12.4%)
Myalgia (12.4%)
Decreased appetite (11.7%)
Hormone level abnormal (11.7%)
Hypotension (11.7%)
Urinary tract infection (11.7%)
Blood testosterone increased (10.9%)
Pyrexia (10.9%)
Anemia (10.2%)
Cough (10.2%)
Hypertension (10.2%)
Influenza (10.2%)
1-10%
Hirsutism (9.5%)
Acne (8.8%)
Dyspepsia (8%)
Insomnia (8%)
Anxiety (7.3%)
Depression (7.3%)
Gastroenteritis (7.3%)
Malaise (6.6%)
Tachycardia (6.6%)
Alopecia (5.8%)
Transaminases increased (4.4%)
ECG QT prolongation (3.6%)
Syncope (1.5%)
Warnings
Contraindications
None
Cautions
Hypocortisolism
- Osilodrostat lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency
- Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, dizziness; significant lowering may result in hypotension, abnormal electrolyte levels, and hypoglycemia
- Can occur at any time during treatment; evaluate for precipitating causes of hypocortisolism (eg, infection, physical stress)
- Monitor 24-hr urine free cortisol (UFC), serum or plasma cortisol, and signs/symptoms
- Decrease or temporarily discontinue osilodrostat if UFC levels fall below target range, there is a rapid decrease in cortisol levels, and/or symptoms of hypocortisolism occur
- Stop osilodrostat and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency
- Reinitiate at lower dose when urine free, serum, or plasma cortisol levels are within target range, and/or patient symptoms have resolved
- After discontinuation, cortisol suppression may persist beyond the 4 hr drug half-life
QTc prolongation
- Associated with dose-dependent QT interval prolongation (maximum mean estimated QTcF increase of up to 5.3 ms at 30 mg), which may cause cardiac arrhythmias
- Obtain baseline ECG with QTc interval measurement before initiating and monitor QTc interval thereafter
- Correct hypokalemia and/or hypomagnesemia before initiating and monitor periodically during treatment; correct electrolyte abnormalities if indicated
- Consider temporary discontinuation if QTc interval >480 ms
- Caution with risk factors for QT prolongation, (eg, congenital long QT syndrome, CHF, bradyarrhythmias, uncorrected electrolyte abnormalities, other drugs known to prolong QT) and consider more frequent ECG monitoring
Elevated adrenal hormone precursors and androgens
- Osilodrostat blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors (11-deoxy cortisol and 11-deoxycorticosterone) and androgens
- Elevated 11-deoxycorticosterone levels may activate mineralocorticoid receptors and cause hypokalemia, edema, and hypertension
- Correct hypokalemia before initiating
- Monitor for hypokalemia, worsening hypertension, and edema
- Treat osilodrostat-induced hypokalemia with IV or oral potassium supplementation based on event severity; if hypokalemia persists despite potassium supplementation, consider adding mineralocorticoid antagonists; osilodrostat dose reduction or discontinuation may be necessary
- Accumulation of androgens may lead to hirsutism, hypertrichosis, and acne (in females)
Drug interaction overview
-
Strong CYP3A4 inhibitors
- Osilodrostat is a substrate of CYP3A4 substrate (major)
- Reduce osilodrostat dose by 50% if coadministered with strong CYP3A4 inhibitors
-
Strong CYP3A4 and/or CYP2B6 inducers
- Osilodrostat is a substrate of CYP3A4 (major) and CYP2B6 (moderate)
- Coadministration with strong CYP3A4 and/or CYP2B6 inducers may decrease osilodrostat concentration and reduce efficacy
- Discontinuation of strong CYP3A4 and/or CYP2B6 inducers while using osilodrostat may increase osilodrostat concentration and the related adverse effects
-
CYP1A2 and CYP2C19 substrates
- Osilodrostat showed inhibition potential on CYP1A2 and CYP2C19 in clinical studies
- Caution if coadministered with CYP1A2 or CYP2C19 substrates with a narrow therapeutic index
-
QTc prolonging drugs
- Osilodrostat is associated with dose-dependent QT interval prolongation
- Caution if coadministered with other drugs known to prolong QT interval
Pregnancy & Lactation
Pregnancy
Data are not available regarding use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
There are risks to the mother and fetus associated with active Cushing syndrome during pregnancy
Clinical considerations
- Active Cushing syndrome during pregnancy associated with increased risk of maternal and fetal morbidity and mortality (including gestational diabetes, gestational hypertension, preeclampsia, maternal death, miscarriage, fetal loss, preterm birth)
Animal data
- No adverse developmental outcomes observed in reproduction studies in pregnant rats and rabbits when exposed during organogenesis at doses that produced maternal exposures of 7 and 0.5 times the 30-mg BID maximum clinical dose, by AUC
- In rabbits, exposures associated with maternal toxicity at 7 times the maximum clinical dose resulted in decreased fetal viability
- No adverse developmental outcomes were observed in a prenatal and postnatal development study with administration to pregnant rats from organogenesis through lactation at 8 times the 30-mg BID maximum clinical dose
Lactation
Data are not available regarding presence in human or animal milk, effects on breastfed infants, or effects on milk production
Because of potential for serious adverse effects (eg, adrenal insufficiency), do not breastfeed during treatment and for at least 1 week after discontinuing drug
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
Orally administered steroidogenesis inhibitor of 11-beta-hydroxylase, an enzyme that catalyzes the final step of cortisol synthesis in the adrenal cortex
Absorption
Peak plasma time: 1 hr
Distribution
Protein bound: 36.4%
Vd: 100 L
Metabolism
Multiple CYP enzymes (ie, CYP3A4, CYP2B6, CYP2D6) and UDP-glucuronosyltransferases contribute to metabolism
No single enzyme contributes >25% to total clearance
Metabolites are not expected to contribute to the pharmacological effect
Elimination
Half-life: 4 hr
Excretion: 90.6% urine (5.2% as unchanged); 1.58% feces
Administration
Oral Administration
May take with or without food
Missed dose: Take next dose at the regularly scheduled time
Storage
Store at room temperature of 68-77ºF (20-25ºC); excursions permitted to 15-30ºC (59-86ºF)
Protect from moisture
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Formulary
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