Dosing & Uses
Dosage Forms & Strengths
relugolix/estradiol/norethindrone
tablet
- 40mg/1mg/0.5mg
Uterine Fibroids
Fixed-dose combination tablet indicated for management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women
Take 1 tablet (relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg) PO qDay
Start as early as possible after onset of menses but no later than 7 days after menses has started
Recommended total duration of treatment is 24 months
Endometriosis Pain
Indicated for moderate-to-severe pain associated with endometriosis in premenopausal females
Take 1 tablet (relugolix 40 mg/estradiol 1 mg/norethindrone 0.5 mg) PO qDay
Start as early as possible after onset of menses, but no later than 7 days after menses has started
Recommended total duration of treatment is 24 months
Dosage Modifications
Coadministration with P-gp inhibitors
- Avoid coadministration with oral P-gp inhibitors
- If use is unavoidable, take relugolix/estradiol/norethindrone first and separate dosing by at 6 hr
Renal impairment
- Estradiol and norethindrone: Not studied
-
Relugolix
- Mild-to-severe (CrCl 15-89 mL/min): No dosage adjustment required
- End-stage renal disease with or without hemodialysis: Not studied
Hepatic impairment
- Contraindicated
- Use of estradiol (E2) in patients with hepatic impairment is expected to increase exposure to E2 and increase the risk of E2-associated adverse reactions
Dosing Considerations
Before initiating
- Verify pregnancy status in females of reproductive potential
- Discontinue hormonal contraceptives
Limitation of use
- Limit use to 24 months due to risk of continued bone loss that may be irreversible
Safety and efficacy not established
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Contraindicated (3)
- fezolinetant
estradiol will increase the level or effect of fezolinetant by affecting hepatic enzyme CYP1A2 metabolism. Contraindicated. Fezolinetant AUC and peak plasma concentration are increased if coadministered with drugs that are weak, moderate, or strong CYP1A2 inhibitors
- mifepristone
mifepristone will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Contraindicated.
- ospemifene
ospemifene, estradiol. Either increases effects of the other by pharmacodynamic synergism. Contraindicated.
Serious - Use Alternative (53)
- acitretin
acitretin decreases effects of norethindrone by unknown mechanism. Contraindicated. Contraceptive failure may result.
- anastrozole
estradiol decreases effects of anastrozole by pharmacodynamic antagonism. Contraindicated. Estrogen may diminish the pharmacologic action of anastrozole. Coadministration not recommended.
- antithrombin alfa
estradiol decreases effects of antithrombin alfa by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- antithrombin III
estradiol decreases effects of antithrombin III by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- apalutamide
apalutamide will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed.
apalutamide will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of apalutamide, a strong CYP3A4 inducer, with drugs that are CYP3A4 substrates can result in lower exposure to these medications. Avoid or substitute another drug for these medications when possible. Evaluate for loss of therapeutic effect if medication must be coadministered. Adjust dose according to prescribing information if needed. - argatroban
estradiol decreases effects of argatroban by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- belzutifan
belzutifan will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Coadministration of belzutifan with hormonal contraceptives may lead to contraceptive failure or increased breakthrough bleeding. Advise females of reproductive potential to use effective nonhormonal contraception. Based on animal studies, belzutifan can cause fetal harm.
- bemiparin
estradiol decreases effects of bemiparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- bivalirudin
estradiol decreases effects of bivalirudin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- bosentan
bosentan will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- brigatinib
brigatinib will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Brigatinib induces CYP3A4 in vitro. Coadministration of hormonal contraceptives with brigatinib can result in decreased concentrations and loss of efficacy. Brigatinib can cause fetal harm. Women should use an effective nonhormonal method of contraception during treatment and for at least 4 months after the last brigatinib dose.
- carbamazepine
carbamazepine will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
carbamazepine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. - cimetidine
cimetidine will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- efavirenz
efavirenz will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- clarithromycin
clarithromycin will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- dalteparin
estradiol decreases effects of dalteparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- enoxaparin
estradiol decreases effects of enoxaparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- enzalutamide
enzalutamide will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
enzalutamide will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. - erdafitinib
erdafitinib will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug. If coadministration unavoidable, separate administration by at least 6 hr before or after administration of P-gp substrates with narrow therapeutic index.
- fexinidazole
fexinidazole will increase the level or effect of norethindrone 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.
- erythromycin base
erythromycin base will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- erythromycin ethylsuccinate
erythromycin ethylsuccinate will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- erythromycin lactobionate
erythromycin lactobionate will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- erythromycin stearate
erythromycin stearate will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- fexinidazole
fexinidazole will increase the level or effect of estradiol 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.
- fondaparinux
estradiol decreases effects of fondaparinux by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- fosphenytoin
fosphenytoin will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- givosiran
givosiran will increase the level or effect of estradiol by affecting hepatic enzyme CYP1A2 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP1A2 substrates with givosiran. If unavoidable, decrease the CYP1A2 substrate dosage in accordance with approved product labeling.
- heparin
estradiol decreases effects of heparin by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- idelalisib
idelalisib will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates
idelalisib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Idelalisib is a strong CYP3A inhibitor; avoid coadministration with sensitive CYP3A substrates - ivosidenib
ivosidenib will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternative therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs.
ivosidenib will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration of sensitive CYP3A4 substrates with ivosidenib or replace with alternate therapies. If coadministration is unavoidable, monitor patients for loss of therapeutic effect of these drugs. - lesinurad
lesinurad decreases effects of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use additional methods of nonhormonal contraception. Do not rely on hormonal contraception alone when taking lesinurad.
- nefazodone
nefazodone will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- lorlatinib
lorlatinib will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Monitor response to estrogens and progestins whenever a CYP3A4 inducer is added to or discontinued, and adjust hormone dosage as necessary. For adequate protection against conception, advise additional or alternative nonhormonal birth control during coadministration with CY3A4 inducers and beyond discontinuation of the CYP3A4 inducers for ~for 3 plasma half-lives.
- lumacaftor/ivacaftor
lumacaftor/ivacaftor will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- mavacamten
mavacamten will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Progestin and ethinyl estradiol are CYP3A4 substrates. Mavacamten may decrease systemic exposures of ethinyl estradiol and progestin, which may lead to contraceptive failure or an increase in breakthrough bleeding. Advise patients to use a contraceptive method that is not affected by CYP450 enzyme induction (eg, intrauterine system) or add nonhormonal contraception (eg, condoms) during coadministration and for 4 months after last mavacamten dose.
- mitotane
mitotane will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- pacritinib
estradiol will decrease the level or effect of pacritinib by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- phenindione
estradiol decreases effects of phenindione by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- phenobarbital
phenobarbital will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- phenytoin
phenytoin will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- primidone
primidone will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- protamine
estradiol decreases effects of protamine by pharmacodynamic antagonism. Contraindicated. Risk of thromboembolic disorders.
- quinidine
quinidine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Avoid or Use Alternate Drug.
- rifabutin
rifabutin will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
rifabutin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. - rifampin
rifampin decreases levels of norethindrone by increasing metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
rifampin will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Use of nonhormonal contraceptives advised
rifampin will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. - St John's Wort
St John's Wort will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- rifapentine
rifapentine will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- sugammadex sodium
sugammadex sodium decreases effects of norethindrone by receptor binding competition. Avoid or Use Alternate Drug. In vitro binding studies showed that sugammadex may bind to progestogen, thereby decreasing progestogen exposure. Therefore, a sugammadex bolus dose is considered to be equivalent to missing dose(s) of hormonal contraceptives containing an estrogen or progestogen. If an oral contraceptive is taken on the same day of sugammadex, or the patient has a transdermal or implant hormonal contraceptive, the patient must use an additional, nonhormonal contraceptive method or back-up method of contraception (eg, condoms and spermicides) for the next 7 days.
- tipranavir
tipranavir will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug.
- topiramate
topiramate will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Avoid coadministration unless benefit outweighs risk. When coadministered, hormonal contraceptives are not a reliable method of effective birth control. Concomitant use may increase incidence of menstruation associated adverse effects (amenorrhea, dysmenorrhea, menorrhagia).
- tucatinib
tucatinib will increase the level or effect of norethindrone 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.
tucatinib will increase the level or effect of estradiol 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. - voxelotor
voxelotor will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.
voxelotor will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Avoid or Use Alternate Drug. Voxelotor increases systemic exposure of sensitive CYP3A4 substrates. Avoid coadministration with sensitive CYP3A4 substrates with a narrow therapeutic index. Consider dose reduction of the sensitive CYP3A4 substrate(s) if unable to avoid.
Monitor Closely (85)
- albiglutide
estradiol decreases effects of albiglutide by pharmacodynamic antagonism. Use Caution/Monitor. Estradiol may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. Monitor for glycemic control in diabetic patients.
- amikacin
amikacin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- amiodarone
amiodarone will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- amobarbital
amobarbital will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
amobarbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - amoxicillin
amoxicillin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- atazanavir
atazanavir, norethindrone. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Atazanavir may increase or decrease levels of norethindrone. Use alternatives if available.
- apalutamide
apalutamide will decrease the level or effect of estradiol by increasing elimination. Use Caution/Monitor. Apalutamide induces UGT and may decrease systemic exposure of drugs that are UGT substrates.
- aprepitant
aprepitant will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- armodafinil
armodafinil will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- artemether/lumefantrine
artemether/lumefantrine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- atazanavir
atazanavir, estradiol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Atazanavir may increase or decrease levels of estradiol. Use alternatives if available.
- atorvastatin
atorvastatin will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- azithromycin
azithromycin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.
- aztreonam
aztreonam will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- belzutifan
belzutifan will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. If unable to avoid coadministration of belzutifan with sensitive CYP3A4 substrates, consider increasing the sensitive CYP3A4 substrate dose in accordance with its prescribing information.
- bosentan
bosentan will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- bosutinib
bosutinib increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- budesonide
budesonide will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- butabarbital
butabarbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- butalbital
butalbital will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- cannabidiol
cannabidiol, estradiol. affecting hepatic enzyme CYP1A2 metabolism. Modify Therapy/Monitor Closely. Owing to the potential for both CYP1A2 induction and inhibition with the coadministration of CYP1A2 substrates and cannabidiol, consider reducing dosage adjustment of CYP1A2 substrates as clinically appropriate.
- cefaclor
cefaclor will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cefadroxil
cefadroxil will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cefamandole
cefamandole will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cefazolin
cefazolin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cefepime
cefepime will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cefixime
cefixime will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cefpirome
cefpirome will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cefprozil
cefprozil will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- ceftazidime
ceftazidime will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- ceftibuten
ceftibuten will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- cenobamate
cenobamate will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate.
cenobamate will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Increase dose of CYP3A4 substrate, as needed, when coadministered with cenobamate. - cephalexin
cephalexin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- clobazam
clobazam will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Clobazam is a weak CYP3A4 inducer; effectiveness of hormonal contraceptives may be diminished when given concurrently with clobazam. Additional non-hormonal forms of contraception are recommended.
- ceritinib
ceritinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- chloramphenicol
chloramphenicol increases levels of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. May increase side effects.
- chlorhexidine oral
chlorhexidine oral will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- ciprofloxacin
ciprofloxacin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- clarithromycin
clarithromycin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.
clarithromycin will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. - clindamycin
clindamycin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- clotrimazole
clotrimazole will decrease the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- colesevelam
colesevelam decreases levels of norethindrone by drug binding in GI tract. Use Caution/Monitor. Administer oral contraceptives containing norethindrone/ethinyl estradiol at least 4 hr before colesevelam to avoid decreased absorption.
- conivaptan
conivaptan will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- cortisone
cortisone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- crofelemer
crofelemer increases levels of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed.
crofelemer increases levels of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Crofelemer has the potential to inhibit CYP3A4 at concentrations expected in the gut; unlikely to inhibit systemically because minimally absorbed. - cyclosporine
cyclosporine will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
cyclosporine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. - dabrafenib
dabrafenib will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.
- dabrafenib
dabrafenib will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely.
- dapsone
dapsone will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- darifenacin
darifenacin will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- darunavir
darunavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- dasatinib
dasatinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- deferasirox
deferasirox will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- demeclocycline
demeclocycline will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- dexamethasone
dexamethasone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- DHEA, herbal
DHEA, herbal will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- diltiazem
diltiazem will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- doxycycline
doxycycline will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- dronedarone
dronedarone will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
dronedarone will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. - efavirenz
efavirenz will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- elagolix
elagolix will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed.
elagolix decreases levels of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Modify Therapy/Monitor Closely. Elagolix is a weak-to-moderate CYP3A4 inducer. Monitor CYP3A substrates if coadministered. Consider increasing CYP3A substrate dose if needed. - eliglustat
eliglustat increases levels of estradiol by P-glycoprotein (MDR1) efflux transporter. Modify Therapy/Monitor Closely. Monitor therapeutic drug concentrations, as indicated, or consider reducing the dosage of the P-gp substrate and titrate to clinical effect.
- encorafenib
encorafenib, norethindrone. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.
- encorafenib
encorafenib, estradiol. affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Encorafenib both inhibits and induces CYP3A4 at clinically relevant plasma concentrations. Coadministration of encorafenib with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents.
- ertapenem
ertapenem will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- erythromycin base
erythromycin base will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.
erythromycin base will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. - erythromycin ethylsuccinate
erythromycin ethylsuccinate will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.
erythromycin ethylsuccinate will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. - erythromycin lactobionate
erythromycin lactobionate will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.
erythromycin lactobionate will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. - erythromycin stearate
erythromycin stearate will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Modify Therapy/Monitor Closely.
erythromycin stearate will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor. - eslicarbazepine acetate
eslicarbazepine acetate will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- etravirine
etravirine will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
etravirine will decrease the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - exemestane
estradiol decreases effects of exemestane by pharmacodynamic antagonism. Use Caution/Monitor. Estrogens or estrogen-containing products, including combined oral contraceptives, should not be given concomitantly with exemestane; these drugs could interfere with the pharmacologic action and efficacy of exemestane.
- fedratinib
fedratinib will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.
- exenatide injectable solution
estradiol, exenatide injectable solution. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide. .
- exenatide injectable suspension
estradiol, exenatide injectable suspension. Other (see comment). Use Caution/Monitor. Comment: Oral contraceptives may decrease hypoglycemic effects of antidiabetics by impairing glucose tolerance. The effect of exenatide to slow gastric emptying may reduce the extent and rate of oral medications that require rapid GI absorption. Advise patients to take oral contraceptives at least 1 hr before exenatide.
- fedratinib
fedratinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Adjust dose of drugs that are CYP3A4 substrates as necessary.
- felodipine
felodipine will increase the level or effect of estradiol by P-glycoprotein (MDR1) efflux transporter. Use Caution/Monitor.
- fexinidazole
fexinidazole will increase the level or effect of estradiol by affecting hepatic enzyme CYP1A2 metabolism. Use Caution/Monitor.
- fleroxacin
fleroxacin will decrease the level or effect of estradiol by altering intestinal flora. Applies only to oral forms of hormone. Low risk of contraceptive failure. Use Caution/Monitor.
- fluconazole
fluconazole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- fludrocortisone
fludrocortisone will decrease the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- fosamprenavir
fosamprenavir, norethindrone. unspecified interaction mechanism. Use Caution/Monitor. Variable effect on norethindrone. Use non-hormonal contraception.
fosamprenavir will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. - fosaprepitant
fosaprepitant will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor.
- gallium Ga 68 PSMA-11
relugolix will decrease the level or effect of gallium Ga 68 PSMA-11 by unspecified interaction mechanism. Modify Therapy/Monitor Closely. Androgen deprivation therapy and other therapies targeting the androgen pathway may result in changes in the uptake of gallium Ga 68 PSMA-11 in prostate cancer. The effect of ADT on the performance of gallium Ga 68 PSMA-11 is unknown.
- iloperidone
iloperidone increases levels of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Use Caution/Monitor. Iloperidone is a time-dependent CYP3A inhibitor and may lead to increased plasma levels of drugs predominantly eliminated by CYP3A4.
Minor (37)
- acetazolamide
acetazolamide will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
acetazolamide will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. - amitriptyline
estradiol, amitriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- anastrozole
anastrozole will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- amoxapine
estradiol, amoxapine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- anastrozole
anastrozole will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- androstenedione
androstenedione increases effects of estradiol by pharmacodynamic synergism. Minor/Significance Unknown.
- boron
boron increases levels of estradiol by altering metabolism. Minor/Significance Unknown.
- clomipramine
estradiol, clomipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- cyanocobalamin
estradiol decreases levels of cyanocobalamin by altering metabolism. Minor/Significance Unknown.
- cyclophosphamide
cyclophosphamide will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
cyclophosphamide will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown. - desipramine
estradiol, desipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- larotrectinib
larotrectinib will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- dosulepin
estradiol, dosulepin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- doxepin
estradiol, doxepin. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- folic acid
estradiol decreases levels of folic acid by altering metabolism. Minor/Significance Unknown.
- imipramine
estradiol, imipramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- isoniazid
isoniazid will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- L-methylfolate
estradiol decreases levels of L-methylfolate by altering metabolism. Minor/Significance Unknown.
- larotrectinib
larotrectinib will increase the level or effect of estradiol by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- levoketoconazole
levoketoconazole will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- lofepramine
estradiol, lofepramine. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- magnesium chloride
estradiol decreases levels of magnesium chloride by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.
- magnesium citrate
estradiol decreases levels of magnesium citrate by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.
- magnesium hydroxide
estradiol decreases levels of magnesium hydroxide by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.
- magnesium oxide
estradiol decreases levels of magnesium oxide by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.
- magnesium sulfate
estradiol decreases levels of magnesium sulfate by Other (see comment). Minor/Significance Unknown. Comment: Magnesium shifted from blood to tissue storage.
- maprotiline
estradiol, maprotiline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- metyrapone
estradiol decreases effects of metyrapone by unspecified interaction mechanism. Minor/Significance Unknown.
- mycophenolate
mycophenolate decreases effects of estradiol by unknown mechanism. Minor/Significance Unknown. Clinical significance unclear.
- nortriptyline
estradiol, nortriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- phytoestrogens
phytoestrogens decreases effects of estradiol by pharmacodynamic antagonism. Minor/Significance Unknown.
- pleurisy root
pleurisy root decreases effects of estradiol by unspecified interaction mechanism. Minor/Significance Unknown. Theoretical interaction.
- protriptyline
estradiol, protriptyline. Mechanism: unspecified interaction mechanism. Minor/Significance Unknown. Estrogens and progestins may decr tricyclic antidepressant effects, while increasing TCA plasma concentration and adverse effects.
- pyridoxine
estradiol decreases levels of pyridoxine by altering metabolism. Minor/Significance Unknown.
- pyridoxine (Antidote)
estradiol decreases levels of pyridoxine (Antidote) by altering metabolism. Minor/Significance Unknown.
- ribociclib
ribociclib will increase the level or effect of norethindrone by affecting hepatic/intestinal enzyme CYP3A4 metabolism. Minor/Significance Unknown.
- ropinirole
estradiol increases levels of ropinirole by unspecified interaction mechanism. Minor/Significance Unknown.
Adverse Effects
>10%
Uterine fibroids
- Hot flush, hyperhidrosis, or night sweats (10.6%)
Endometriosis Pain
- Headache (33%)
- Increased total cholesterol (200 to <240 mg/dL) (13.6%)
- Vasomotor symptoms (13.2%)
1-10%
Uterine fibroids
- Increased total cholesterol 130 to <160 mg/dL (9.3%)
- Abnormal uterine bleeding (6.3%)
- Alopecia (3.5%)
- Libido decreased (3.1%)
- Irritability (2-3%)
- Dyspepsia (2-3%)
- Breast cyst (2-3%)
- Depression (2.4%)
- Irritability (2.4%)
- Increased total cholesterol >240 mg/dL (1.7%)
- Increased total cholesterol 160 to <190 mg/dL (1.5%)
- Anxiety (1.2%)
Endometriosis pain
- Mood disorders (9.1%)
- Abnormal uterine bleeding (6.7%)
- Nausea (6%)
- Back pain (4.8%)
- Decreased sexual desire and arousal (4.3%)
- Arthralgia (3.6%)
- Fatigue (3.1%)
- Dizziness (3.1%)
- Diarrhea (2.4%)
- Peripheral edema (2.2%)
- Vulvovaginal dryness (2.2%)
<1%
Uterine fibroids
- Low trauma fractures (defined as a fall from standing height or less) (0.6%)
- Increased total cholesterol ≥190 mg/dL (0.5%)
- Uterine myoma expulsion (0.4%)
- Uterine leiomyoma (prolapse) (0.4%)
Frequency Not Defined
Suicidal ideation
Postmarketing Reports
Immune system disorders: Anaphylactoid reaction
Skin and SC tissue disorders: Drug eruption
Neoplasms, benign, malignant, and unspecified: Uterine leiomyoma degeneration
Respiratory, thoracic, and mediastinal disorders: Pulmonary embolism
Warnings
Black Box Warnings
Thromboembolic disorders and vascular events
- Estrogen and progestin combination products, including relugolix/estradiol/norethindrone, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism (PE), deep vein thrombosis (DVT), stroke, and myocardial infarction (MI), especially in women at increased risk for these events
- Contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women aged ≥35 years who smoke or women with uncontrolled hypertension
Contraindications
Pregnancy
Osteoporosis
Current or history of breast cancer or other hormone-sensitive malignancies
Hepatic impairment or disease
Undiagnosed abnormal uterine bleeding
Hypersensitivity to drug or its components
High risk of arterial, venous thrombotic, or thromboembolic disorder
-
Examples include women aged ≥35 years who smoke and known to have
- Current or history of DVT or PE
- Vascular disease (eg, cerebrovascular disease, coronary artery disease, peripheral vascular disease)
- Thrombogenic valvular or thrombogenic rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease, atrial fibrillation)
- Inherited or acquired hypercoagulopathies
- Uncontrolled hypertension
- Headaches with focal neurological symptoms or migraine headaches with aura
Cautions
Hypersensitivity reactions, including anaphylactoid reactions, urticaria and angioedema, reported; contraindicated with history of hypersensitivity reactions to relugolix or any component; immediately discontinue if a hypersensitivity reaction occurs
Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease; discontinue therapy if signs or symptoms of gallbladder disease or jaundice occur; assess the risk-benefit of continuing therapy for women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy
New or worsening hypertension occurred; continue to monitor blood pressure (BP) and stop therapy if BP rises significantly
Women may experience amenorrhea or a reduction in the amount, intensity, or duration of menstrual bleeding, which may delay the ability to recognize pregnancy; perform pregnancy testing if pregnancy is suspected and discontinue treatment if pregnancy is confirmed
Based on animal studies and mechanism of action, early pregnancy loss may occur
Uterine fibroid prolapse and uterine fibroid expulsion reported; advise women with known or suspected submucosal uterine fibroids about the possibility of uterine fibroid prolapse or expulsion and to contact their physician if severe bleeding and/or cramping occur during treatment
Discontinue therapy if a hormone-sensitive malignancy is diagnosed; surveillance measures in accordance with standard of care (eg, breast examinations, mammography) are recommended; use of estrogen alone or estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation
Thromboembolic disorders and vascular events
- Estrogen and progestin combinations, including estradiol/norethindrone acetate, increase the risk of thrombotic or thromboembolic disorders, including PE, DVT, stroke, and MI, especially in women at high risk for these events
- Risk is greatest among women aged ≥35 years who smoke, and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity
- Discontinue therapy at least 4-6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization, if feasible
-
Discontinue therapy immediately
- If an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected
- If there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions, and evaluate for retinal vein thrombosis, as these have been reported in patients receiving estrogens and progestins
Bone loss
- Bone mineral density (BMD) loss may occur; may be greater with increasing duration of use and may not be completely reversible after stopping treatment
- Consider benefits and risks of treatment in patients with a history of a low trauma fracture or risk factors for osteoporosis or bone loss, including taking medications that may decrease BMD (eg, systemic or long-term inhaled corticosteroids, anticonvulsants, or long-term use of proton pump inhibitors)
- Assessment of BMD by dual-energy X-ray absorptiometry is recommended at baseline and periodically thereafter
- Supplementation with calcium and vitamin D was not studied but may be beneficial for patients with inadequate dietary intake
- Impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown
Depression, mood disorders, and suicidal ideation
- Depression (including depression, mood swings, and depressed mood), irritability, anxiety, and suicidal ideation occurred
- Promptly evaluate patients with mood changes and depressive symptoms, shortly after initiating treatment, to determine whether the risks of continued therapy outweigh the benefits
- Refer patients with new or worsening depression, anxiety, or other mood changes to a mental health professional, as appropriate
- Advise patients to seek immediate medical attention for suicidal ideation and behavior
- Reevaluate the benefits and risks of continuing therapy if such events occur
Hepatic impairment and transaminase elevations
- Contraindicated in patients with known hepatic impairment or disease
- Steroid hormones may be poorly metabolized in patients with impaired liver function
- Elevations [≥3x ULN] in ALT and AST reported
- Instruct women to promptly seek medical attention for symptoms or signs that may reflect liver injury (eg, jaundice, right upper abdominal pain)
- Consider discontinuing treatment if acute liver test abnormalities until liver tests return to normal and cause is ruled out
Alopecia
- Alopecia, hair loss, and hair thinning reported
- Consider discontinuing if hair loss becomes a concern
- No specific pattern of hair loss was described
- Majority of affected women completed study with reported hair loss ongoing
- Unknown if hair loss is reversible
Effects on carbohydrate and lipid metabolism
- May decrease glucose tolerance and result in increased blood glucose concentrations; consider more frequent monitoring in women with prediabetes and diabetes
- Estrogen therapy may be associated with elevated triglycerides, leading to pancreatitis, in women with pre-existing hypertriglyceridemia
- Increases in total cholesterol and low-density lipoprotein cholesterol (LDL-C) reported
- Monitor lipid levels and consider discontinuing if hypercholesterolemia or hypertriglyceridemia worsens
Drug interaction overview
- Relugolix: Substrate of CYP3A (primarily) and CYP2C8 (minor); substrate of P-gp; inhibitor of BCRP and P-gp
-
Laboratory results
- Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy; use of estrogen and progestin combinations may raise serum concentrations of binding proteins (eg, thyroid-binding globulin, corticosteroid-binding globulin), which may reduce free thyroid or corticosteroid hormone levels
- Use of estrogen and progestin may also affect the levels of sex hormone–binding globulin (SHBG) and coagulation factors
-
P-gp inhibitors
- Avoid coadministration
- Coadministration increases relugolix AUC and peak plasma concentration; if unable to avoid, adjust time between dosing relugolix and the P-gp inhibitor
-
Combined P-gp and strong CYP3A inducers
- Avoid coadministration
- If use is unavoidable, separate dosing
- Coadministration decreases AUC and peak plasma concentration of relugolix, estradiol, and/or norethindrone
Pregnancy & Lactation
Pregnancy
Contraindicated
Based on findings from animal studies and its mechanism of action, early pregnancy loss may occur
Discontinue if pregnancy occurs during treatment
Limited human data with use in pregnant females are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes
Perform pregnancy testing if pregnancy is suspected during treatment and discontinue treatment if pregnancy is confirmed
Contraception for females of reproductive potential
- Use effective nonhormonal contraception during treatment and for 1 week following discontinuation
- Avoid concomitant use of hormonal contraceptives
- Use of estrogen-containing hormonal contraceptives may increase the risk of estrogen-associated adverse events and is expected to decrease the efficacy of relugolix/estradiol/norethindrone
Animal data
- Oral administration of relugolix in pregnant rabbits during organogenesis resulted in spontaneous abortion and total litter loss at relugolix exposures about half those at the maximum recommended human dose (MRHD) of 40 mg
- In both rabbits and rats, no fetal malformations were present at any dose level tested, which were associated with relugolix exposures of about half and ~300x exposures in women at the MRHD, respectively
Pregnant exposure registry
- Registry monitors pregnancy outcomes in women exposed to therapy during pregnancy
- Pregnant females exposed to relugolix/estradiol/norethindrone and healthcare providers are encouraged to call the MYFEMBREE Pregnancy Exposure Registry at 1-(855) 428-0707
Lactation
There are no data on presence of relugolix or its metabolites in human milk, effects on the breastfed children, or effects on milk production
Relugolix was detected in milk of lactating rats
When a drug is present in animal milk, it is likely that the drug will be present in human milk
Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen plus progestin therapy and can reduce milk production in breastfeeding women
Reduction can occur at any time but is less likely to occur once breastfeeding is well established
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
Relugolix
- Gonadotropin-releasing hormone (GnRH) receptor antagonist; binds to and blocks GnRH receptors in the anterior pituitary gland
- Blocking GnRH receptors decreases the release of gonadotropins (ie, luteinizing hormone, follicle-stimulating hormone), thereby decreasing the downstream production of estrogen and progesterone by the ovaries in women
Estradiol and norethindrone
- Estradiol: Addition of exogenous estradiol may reduce the increase in bone resorption and resultant bone loss that can occur due to a decrease in circulating estrogen concentrations from relugolix alone
- Norethindrone: Protect the uterus from the potential adverse endometrial effects of unopposed estrogen
Absorption
Absolute bioavailability of relugolix is 62%
Steady-state reached at
- Relugolix: 12 days
- Estradiol and norethindrone: 14 days
Peak plasma concentration
- Relugolix: 26 ng/mL
- Unconjugated estradiol: 28 ng/mL
- Norethindrone: 3.6 ng/mL
Peak plasma time
- Relugolix: 2 hr
- Unconjugated estradiol: 7 hr
- Norethindrone: 1 hr
AUC
- Relugolix: 198.1 ng·hr/mL
- Unconjugated estradiol: 818.7 ng·hr/mL
- Norethindrone: 17.5 ng·hr/mL
Distribution
Blood/plasma ratio: 0.78 (relugolix)
Protein bound
- Relugolix: 68-71%; albumin (primarily), alpha1-acid glycoprotein (less extent)
- Estradiol circulates in the blood bound to SHBG (36-37%) and to albumin (61%), while only ~1-2% is unbound
- Norethindrone binds to a similar extent to SHBG (36%) and to albumin (61%)
Metabolism
Relugolix: Metabolized primarily by CYP3A and to lesser extent by CYP2C8 in vitro
Estradiol: Converted reversibly to estrone, and both can be converted to estriol, which is a major urinary metabolite; estrogens also undergo enterohepatic recirculation due to sulfate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the intestine followed by reabsorption
Norethindrone: Undergoes extensive biotransformation, primarily by reduction, in addition to sulfation, glucuronidation, and oxidation, respectively, by sulfotransferases, glucuronosyltransferases, and CYP enzymes, including CYP3A4; majority of metabolites in the circulation are sulfates, with glucuronides accounting for most of the urinary metabolites
Elimination
Excretion
- Relugolix: Feces (81%; 4.2% unchanged); urine (4.1%; 2.2% unchanged)
- Estradiol: Urine as glucuronide and sulfate conjugates
- Norethindrone: Primarily excreted in urine as various polar metabolites
Administration
Oral Administration
Take with or without food at approximately the same time
Missed dose: Take dose as soon as possible on the same day and then resume regular dosing schedule and time the next day
Storage
Store at 15-30ºC (59-86ºF)
Dispose unused medication via a take-back option if available
Otherwise, follow FDA instructions for disposing medication in the household trash, www.fda.gov/drugdisposal
Do NOT flush down the toilet
Images
Formulary
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