Myfembree (relugolix/estradiol/norethindrone acetate)

Relugolix/estradiol/norethindrone is available as fixed combination tablets containing relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg.

Dosage of norethindrone is expressed in terms of norethindrone acetate.

Administer relugolix/estradiol/norethindrone orally once daily with or without food at approximately the same time each day. The first dose should be given as soon as possible after the onset of menses within 7 days of the start of menses. The recommended total duration of treatment is 24 months.

If a dose of relugolix/estradiol/norethindrone is missed, take the dose as soon as possible within the same day, and then resume the regular dosing schedule on the following day.

Avoid concomitant use of P-glycoprotein (P-gp) inhibitors. If concomitant use cannot be avoided, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor.

Store relugolix/estradiol/norethindrone tablets at 15-30degreesC.

No dosing information is available for this tab.

Relugolix is a substrate of cytochrome P-450 (CYP) isoenzymes 3A and 2C8, and an inducer of 3A and 2B6. Relugolix does not inhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4; it does not induce 1A2.

Relugolix is a substrate of P-glycoprotein (P-gp), but not breast cancer resistance protein (BCRP); the drug inhibits P-gp and BCRP. Relugolix does not inhibit organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter 1 (OAT1), OAT3, organic cation transporter 2 (OCT2), multidrug and toxin extrusion (MATE) 1, MATE2-K, or bile salt exporter pump (BSEP).

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Agents Affecting Plasma Cortisol Levels/Cosyntropin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

CLINICAL EFFECTS: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of cosyntropin states accuracy of diagnosis using the cosyntropin diagnostic test may be complicated by concomitant medications affecting plasma cortisol levels.(1) Agents affecting plasma cortisol levels and recommendation to stop prior to cosyntropin diagnostic test include: - Glucocorticoids: May elevate plasma cortisol levels. Stop these drugs on the day of testing. Long-acting glucocorticoids may need to be stopped for a longer period before testing. - Spironolactone: May elevate plasma cortisol levels. Stop spironolactone on the day of testing. - Estrogen: May elevate plasma total cortisol levels. Discontinue estrogen containing drugs 4 to 6 weeks prior to testing to allow cortisol binding globulin levels to return to levels within the reference range. Alternatively, concomitant measurement of cortisol binding globulin at the time of testing can be done; if cortisol binding globulin levels are elevated, plasma total cortisol levels are considered inaccurate.(1)

DISCUSSION: Concurrent use of agents affecting plasma cortisol levels may impact the accuracy of the cosyntropin diagnostic test.(1)

Cyp1a2 Inhibitors/Fezolinetant

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1-4)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4)

DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include acyclovir, allopurinol, artemisinin, belumosudil, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, valacyclovir, verapamil, and zileuton.(5-7)

Cyp3a4 Inducers/Zuranolone

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of zuranolone.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in a loss of zuranolone efficacy.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of zuranolone with CYP3A4 inducers.(1)

DISCUSSION: Coadministration of zuranolone with rifampin decreased the maximum concentration (Cmax) by 0.31-fold and area-under-curve (AUC) by 0.15-fold.(1) Strong CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort. Moderate CYP3A4 inducers linked to this monograph include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib. Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Estrogenic Agents/Tranexamic Acid (Oral)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Tranexamic acid is an antifibrinolytic and estrogen-containing hormonal contraceptives are known to increase the risk of venous thromboembolism and arterial thromboses, including stroke and myocardial infarction. Concurrent use may increase the risk of these events.(1)

CLINICAL EFFECTS: Concurrent use of tranexamic acid in patients taking estrogen-containing agents or hormonal contraceptives may increase the risk of embolisms.(1)

PREDISPOSING FACTORS: The risk of thrombosis may be even greater in women who are obese or smoke, especially smokers over age 35.(1)

PATIENT MANAGEMENT: The concurrent use of oral tranexamic and and estrogen-containing hormonal contraception is contraindicated.(1) It would be prudent to follow this restriction with estrogen-replacement therapy as well.

DISCUSSION: There are no clinical trial data on the risk of concurrent therapy with tranexamic acid and hormonal contraceptives. There have been postmarketing reports of venous and arterial thrombotic events in women receiving combination therapy.(1) Women taking hormonal contraception were excluded from safety and efficacy trials of tranexamic acid.(1)

Estrogens/Selected Anti-Aromatase Agents

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Aromatase inhibitors(1-6) and inactivators(7-10) treat breast cancer by inhibiting estrogen synthesis therefore lowering serum estrone and estradiol levels. In postmenopausal women, androgens are metabolized to estrogens via the primary pathway of the aromatase enzyme.

CLINICAL EFFECTS: Concurrent administration of estrogen may decrease the effectiveness of aromatase inhibitors.(1-6)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The Canadian,(1) UK,(2) and US(3) manufacturers of anastrozole state that estrogen containing therapies should not be used during anastrozole therapy. The Australian,(7) Canadian,(8) UK,(9) and US(10) manufacturers of exemestane state that exemestane should not be administered with estrogen containing therapies. The Canadian(4) and UK(5) manufacturer of letrozole state that estrogen containing therapies should be avoided during letrozole therapy.

DISCUSSION: Many breast cancers have estrogen receptors and their growth can be stimulated by estrogen. Anastrozole is a potent and selective non-steroidal aromatase inhibitor that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of anastrozole.(1-3) Exemestane is a steroidal aromatase inactivator that lowers serum estradiol levels. Concurrent use of estrogen may diminish the effects of exemestane.(7-10)

Estrogens/Sodium Tetradecyl Sulfate

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Patients taking estrogen-containing hormonal contraceptives or hormone replacement therapy have a higher risk of clotting problems.(1)

CLINICAL EFFECTS: Use of sodium tetradecyl sulfate on patients taking estrogen-containing hormonal contraceptives or hormone replacement therapy may increase the risk of deep vein thrombosis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of sodium tetradecyl sulfate states that its use in patients taking contraceptives or hormone replacement therapy is contraindicated.(2)

DISCUSSION: Factors which may increase the risk of deep vein thrombosis after sclerotherapy should be avoided.(1) Therefore, its use in patients taking estrogen-containing contraceptives or hormone replacement therapy is contraindicated.(2)

Selected Cyp1a2 Inhibitors/Rasagiline (> 0.5 Mg)

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2)

DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Cyp3a4 Inducers/Erlotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Inducers of CYP3A4 may induce the metabolism of erlotinib.(1)

CLINICAL EFFECTS: Concurrent or recent use of a CYP3A4 inducer may result in decreased levels and effectiveness of erlotinib.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid the concurrent use of CYP3A4 inducers in patients receiving therapy with erlotinib. Consider the use of alternative agents with less enzyme induction potential.(1) Consider increasing the dosage of erlotinib by 50 mg increments as tolerated at two week intervals (to a maximum of 450 mg) while closely monitoring the patient. The highest dosage studied with concurrent rifampin is 450 mg. If the dosage of erlotinib is increased, it will need to be decreased when the inducer is discontinued.(1)

DISCUSSION: Pretreatment and concurrent therapy with rifampin increased erlotinib clearance by 3-fold and decreased the erlotinib area-under-curve (AUC) by 66% to 80%. This is equivalent to a dose of about 30 mg to 50 mg in NSCLC.(1) In a study, pretreatment with rifampin for 11 days decreased the AUC of a single 450 mg dose of erlotinib to 57.6% of the AUC observed with a single 150 mg dose of erlotinib.(1) In a case report, coadministration of phenytoin (180mg daily) and erlotinib (150mg daily) increased the phenytoin concentration from 8.2mcg/ml to 24.2mcg/ml and decreased the erlotinib concentration 12-fold (from 1.77mcg/ml to 0.15mcg/ml) and increased the erlotinib clearance by 10-fold (from 3.53 L/h to 41.7 L/h).(2) In a study, concurrent use of sorafenib (400 mg twice daily) and erlotinib (150 mg daily) decreased the concentration minimum (Cmin), concentration maximum (Cmax), and AUC of erlotinib.(3) In an animal study, concurrent use of dexamethasone and erlotinib decreased the AUC of erlotinib by 0.6-fold.(4) Strong inducers of CYP3A4 include: barbiturates, encorafenib, enzalutamide, fosphenytoin, ivosidenib, mitotane, phenobarbital, phenytoin, primidone, rifampin, and rifapentine.(5,6) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, sotorasib, telotristat, thioridazine, and tovorafenib.(5,6) Weak inducers of CYP3A4 include: amprenavir, armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dicloxacillin, echinacea, eslicarbazepine, flucloxacillin, garlic, genistein, ginkgo, ginseng, glycyrrhizin, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(5,6)

Estrogen Replacement Therapy/Lamotrigine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogens increase glucuronidation mediated metabolism of lamotrigine. Lamotrigine may modestly induce the metabolism of estrogens.(1,2)

CLINICAL EFFECTS: Concurrent use of lamotrigine and estrogens may result in decreased levels and effectiveness of both agents. Increased seizure rates have been reported in patients taking lamotrigine for epilepsy.(1,2)

PREDISPOSING FACTORS: Increased seizure risk is more likely in when lamotrigine is used as monotherapy for treatment of epilepsy. The risk for an increase in seizure rate is lower in patients already stabilized on a combination of lamotrigine and an enzyme inducing agent such as carbamazepine, phenytoin, phenobarbital, or primidone.

PATIENT MANAGEMENT: Monitor closely the clinical effectiveness of lamotrigine with concurrent use of estrogen replacement therapy. Dose adjustment may be necessary.(1) During initiation of lamotrigine therapy, no adjustments to the recommended lamotrigine dose escalation guidelines are recommended in patients taking estrogen.(1) Dose adjustments will be necessary in most patients who start or stop an estrogen in patients taking maintenance doses of lamotrigine. The lamotrigine dosage may need to be increased by as much as 2-fold according to clinical response when estrogen or estrogen-containing contraceptives are initiated in patients NOT taking other drugs which induce glucuronidation such as carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin. If estrogen is discontinued, the dosage of lamotrigine may need to be decreased by 50%.(1) Initiate changes in lamotrigine dosage at the same time estrogen containing products are started or stopped.(1) In patients also taking carbamazepine, phenytoin, phenobarbital, primidone, lopinavir/ritonavir, atazanavir/ritonavir, or rifampin, no lamotrigine maintenance dosage adjustments should be necessary if estrogen is initiated or discontinued.(1)

DISCUSSION: In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) increased lamotrigine clearance by 2-fold, with a mean decrease in lamotrigine area-under-curve (AUC) and maximum concentration (Cmax) by 52% and 39%, respectively. Serum trough lamotrigine levels were two-fold higher at the end of the week of inactive tablets when compared to lamotrigine levels at the end of the active hormonal cycle. This effect should be expected in women not taking carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.(1) In a study in 16 females, concurrent ethinylestradiol (30 mcg) and levonorgestrel (150 mcg) with lamotrigine (300 mg per day) had no effect on ethinylestradiol levels. Levonorgestrel AUC and Cmax decreased by 19% and 12%, respectively. Though there was no hormonal evidence of ovulation, there was some loss of suppression of the hypothalamic-pituitary-ovarian axis.(1) In a study, mean steady-state lamotrigine levels were 13 micro mol/L in 22 women taking oral contraceptives compared to 28 micro mol/L in 30 women who were not taking oral contraceptives. The lamotrigine dose/body weight/ plasma concentration was 2.1 L/kg/day in patients taking oral contraceptives compared to 0.8 L/kg/day in patients without oral contraceptives.(3) One set of authors reported seven cases of decreased lamotrigine levels in patients receiving oral contraceptives. Lamotrigine levels were decreased by 41% to 64%, average 49%. Most patients either experienced increased seizure frequency or recurrence of seizures after the addition of the oral contraceptive, or increased lamotrigine adverse effects following the discontinuation of the oral contraceptive.(4) A study in 45 females compared lamotrigine pharmacokinetics in patients taking an ethinyl estradiol-containing contraceptive (n=11) to patients taking a progestin-only contraceptive (n=16) and to patients taking no contraceptives (n=18). The lamotrigine serum concentration to dose ratio was significantly lower in patients taking ethinyl estradiol-containing contraceptives. There was no significant difference between patients taking progestin-only contraceptives and those using no contraceptives.(5) In a double-blind, placebo-controlled study, women with epilepsy were treated with lamotrigine monotherapy, or lamotrigine plus oral contraceptive. After 21 days, the mean dose-corrected lamotrigine concentration was 84% higher in the monotherapy group verses the combined treatment group.(6) Another study in 8 epileptic females assessed the pharmacokinetics of lamotrigine in combination with hormonal contraceptives. Serum samples were drawn on days 18 and 21 of hormonal contraceptive therapy and during days 5 and 7 of the placebo week (hormonal contraceptive free week). Analysis found statistically significant elevations (approximately 27%) in lamotrigine plasma concentrations during the hormone-free week, than during cycle intake.(7) In a study, 22 enrolled females took lamotrigine titrated up to 300 mg/d for a period of 130 days and either combined it with an oral contraceptive or took lamotrigine monotherapy. Both ethinyl estradiol and lamotrigine serum levels were drawn in the presence or absence of combined therapy. Laboratory serum data showed the ratios of lamotrigine AUC (0-24h) and Cmax at 0.48 for coadministration (lamotrigine plus oral contraceptive) and a ratio of 0.61 for lamotrigine monotherapy.(8)

Estrogenic Agents/Tranexamic Acid (Injectable)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Tranexamic acid is an antifibrinolytic and estrogen-containing hormonal contraceptives are known to increase the risk of venous thromboembolism and arterial thromboses, including stroke and myocardial infarction. Concurrent use may increase the risk of these events.(1,2)

CLINICAL EFFECTS: Concurrent use of tranexamic acid in patients taking estrogen-containing agents or hormonal contraceptives may increase the risk of embolisms.(1,2)

PREDISPOSING FACTORS: The risk of thrombosis may be even greater in women who are obese or smoke, especially smokers over age 35.(1)

PATIENT MANAGEMENT: The concurrent use of injectable tranexamic and and estrogen-containing hormonal contraception or estrogen replacement therapy should be approached with caution.(1)

DISCUSSION: There are no clinical trial data on the risk of concurrent therapy with tranexamic acid and hormonal contraceptives. There have been postmarketing reports of venous and arterial thrombotic events in women receiving combination therapy with oral tranexamic acid.(2) Women taking hormonal contraception were excluded from safety and efficacy trials of oral tranexamic acid.(2)

Estrogens/Tizanidine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogen containing hormonal contraceptives or hormone replacement therapy may decrease the clearance of tizanidine by inhibiting CYP1A2.(1)

CLINICAL EFFECTS: Concurrent use of tizanidine and estrogen containing hormonal contraceptives or hormone replacement therapy may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function.

PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The manufacturer states that routine administration of tizanidine and estrogen containing hormonal contraceptives or hormone replacement therapy should be avoided.(1) If concurrent use is necessary, tizanidine should be initiated with a 2 mg dose and increased 2-4 mg daily based on patient response to therapy.(1) If adverse reactions such as hypotension, bradycardia, or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(1)

DISCUSSION: In a retrospective analysis of population pharmacokinetic data, women taking oral contraceptives with tizanidine has a 50% lower clearance compared to women not on oral contraceptives.(1) In fifteen women using oral contraceptives, tizanidine (4 mg) increased the area-under-curve (AUC) and peak plasma tizanidine concentration, 3.9-fold and 3.0-fold respectively, compared to placebo. In one patient, the AUC of tizanidine exceeded twenty times the AUC of the placebo group.(3)

Estrogens/Tofacitinib (>=20 Mg Daily)

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Estrogens increase the risk of thrombosis, and combining estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may place patients at high risk of thromboembolism.(1-3)

CLINICAL EFFECTS: Concurrent use of estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may increase the incidence of pulmonary embolism and death.(1-3)

PREDISPOSING FACTORS: Additional risk factors include advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.(1)

PATIENT MANAGEMENT: The European manufacturer states that the 10 mg twice daily dose of tofacitinib is not recommended in patients who are on combined hormonal contraceptives or hormone replacement therapy, or who are otherwise at high risk of pulmonary embolism, unless there are no suitable alternatives.(4) Patients at high risk of pulmonary embolism should be switched to alternative therapies. For the treatment of rheumatoid arthritis and psoriatic arthritis, the dose of tofacitinib should be limited to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4) The US FDA and Health Canada have not placed use restrictions specifically on concurrent use of tofacitinib with hormonal contraceptives or hormone replacement therapy. Both agencies advise avoiding tofacitinib in patients at increased risk of thrombosis. The US and Canadian manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile idiopathic arthritis. For the treatment of ulcerative colitis, the lowest effective dose for the shortest duration possible is recommended. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis and discontinue tofacitinib in patients with symptoms of thrombosis.(5-7) There is currently no use restriction on the combination of estrogens with lower doses of tofacitinib (less than 20 mg daily).

DISCUSSION: In an ongoing open-label study comparing the safety of tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5 mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123 patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years, respectively). All-cause mortality was also higher in the tofacitinib 10 mg twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28 deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9 deaths/3,323 patient-years, respectively).(3)

Progestin Replacement Therapy/Ulipristal

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity.(1)(2)

CLINICAL EFFECTS: Concurrent use of ulipristal may make progesterone products ineffective.(1,2) These agents may also make ulipristal ineffective.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Products containing progestin should not be used within 12 days of ulipristal discontinuation.(3)

DISCUSSION: Ulipristal is a progesterone receptor modulator and binds to the progesterone receptor with high affinity, thus it may interfere with the efficacy of progestin products.(1-3) These products may also make ulipristal ineffective.(3)

Relugolix-Hormonal Combinations/Dual P-Gp & Strong 3A4 Induc

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Relugolix, estradiol, and norethindrone are substrates of the intestinal P-glycoprotein (P-gp) efflux transporter and are primarily metabolized by CYP3A4. Agents that induce both P-gp and CYP3A4 may reduce the plasma levels of relugolix, estradiol, and norethindrone.(1)

CLINICAL EFFECTS: Concurrent or recent use of P-gp and strong CYP3A4 inducers may result in decreased levels and effectiveness of relugolix, estradiol, and norethindrone.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Avoid use of relugolix-estradiol-norethindrone with combined P-gp and strong CYP3A4 inducers.(1)

DISCUSSION: Coadministration with rifampin (P-gp and strong CYP3A4 inducer) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 55% and 23%, respectively.(1) Dual P-gp and CYP3A4 inducers linked to this monograph include: apalutamide, carbamazepine, fosphenytoin, phenytoin, rifampin, rifapentine, and St. John's wort.(2,3)

Relugolix/P-Glycoprotein (P-Gp) Inhibitors

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter. Inhibitors of P-gp may increase the absorption of relugolix.(1)

CLINICAL EFFECTS: The concurrent administration of relugolix with an inhibitor of P-glycoprotein may result in elevated levels of relugolix and adverse effects, including hot flashes, skin flushing, musculoskeletal pain, hyperglycemia, acute renal injury, transaminitis, arrhythmias, and hemorrhage.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of relugolix states that the coadministration of relugolix with P-gp inhibitors should be avoided. If the P-gp inhibitor is to be used short-term, relugolix may be held for up to 2 weeks. If treatment with relugolix is interrupted for longer than 7 days, resume relugolix with a loading dose of 360 mg on the first day, followed by 120 mg once daily.(1) If coadministration with a P-gp inhibitor cannot be avoided, relugolix should be taken at least 6 hours before the P-gp inhibitor. Monitor the patient more frequently for adverse events.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Coadministration of relugolix with erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 6.2-fold. Voriconazole (a strong CYP3A4 inhibitor) did not have a clinically significant effect on the pharmacokinetics of relugolix.(1) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil, mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline, schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Estrogen/Raloxifene

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Raloxifene binds to estrogen receptors and activates certain estrogenic pathways while blocking others.(1)

CLINICAL EFFECTS: The concurrent use of raloxifene and estrogen may increase the risk of estrogen-related toxicities (bloating, vaginal bleeding, mood changes, cardiovascular events, thromboembolism, and breast cancer) and antagonize the anti-estrogenic effects of raloxifene.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of raloxifene does not recommend the use of systemic estrogen or hormone replacement therapy with raloxifene.(1)

DISCUSSION: Information on the interaction between raloxifene and estrogen is lacking and the manufacturer of raloxifene states that the concurrent use of these medications has not been studied in prospective clinical trials.(1)

Estrogens/Selected Anticonvulsants; Barbiturates

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Enzyme induction, causing increased hepatic metabolism of estrogens.

CLINICAL EFFECTS: Decreased effectiveness of estrogens may lead to spotting, breakthrough bleeding, vaginitis and may increase the risk for osteoporosis.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Increasing the dose of estrogen may be sufficient.

DISCUSSION: Decreased effectiveness of estrogens characterized by spotting, breakthrough bleeding or vaginitis have been documented during concurrent administration of barbiturates and hydantoins. Primidone is metabolized to phenobarbital. Additionally, lowered estrogen levels may increase the risk of osteoporosis. Often, patients are receiving multiple anticonvulsant drugs making it difficult to quantify the frequency of this interaction. However, decreases in the area under the plasma concentration-time curves for ethinyl estradiol and levonorgestrel have been documented during concurrent administration of phenytoin.

Estrogens/Selected Human Immunoglobulins

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of human immunoglobulin with estrogens may have additive effects on clotting mechanisms.(1)

CLINICAL EFFECTS: Concurrent use of human immunoglobulin with estrogens may increase the risk of thrombosis. Thrombosis may occur regardless of the route of administration of the immunoglobulin.(1)

PREDISPOSING FACTORS: Additional risk factors include advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes).(1)

PATIENT MANAGEMENT: For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1)

DISCUSSION: Thrombosis has been associated with the use of human immunoglobulin and may occur without the presence of risk factors and regardless of the route of administration of the immunoglobulin. Risk factors known to increase the risk of thrombosis include the use of estrogens, advanced age, prolonged immobilization, hypercoagulable states, history of arterial or venous thrombosis, indwelling central vascular catheter, hyperviscosity and cardiovascular risk factors (e.g. coronary artery disease, hypertension, diabetes). For patients at risk of thrombosis, administer the minimum concentration of immunoglobulin available at the minimum rate of infusion practicable. Ensure that patients are adequately hydrated before immunoglobulin is infused. Patients should be monitored for signs and symptoms of thrombosis. Assess blood viscosity in patients at risk for hyperviscosity. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis.(1)

Estrogens/Thyroid Preparations

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens increase thyroxine-binding globulin (TBG) levels by increasing its biosynthesis and decreasing its clearance.(1) Hypothyroid patients who start estrogens may be unable to compensate for this increase and may have decreased serum free T4 (FT4) concentrations and increased TSH.(1,2)

CLINICAL EFFECTS: The coadministration of thyroid preparations and estrogens may result in decreased levels and clinical effects of thyroid hormones.(1-4)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients taking thyroid preparations and who start or stop estrogens should be monitored for changes in thyroid function. The dosage of the thyroid preparation may need to be increased.(1-4)

DISCUSSION: In a prospective observational study, 25 post-menopausal women with hypothyroidism on stable levothyroxine therapy for at least 9 months started on estrogen replacement therapy. After 12 weeks, mean serum FT4 levels decreased significantly from 1.7 +/- 0.4 ng/dL to 1.4 +/-0.3 mg/dL and TSH increased significantly from 0.9 +/-1.1 to 3.2 +/- 3.1 milli-units/L.(1)

Estrogens/Tofacitinib (<20 Mg Daily)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens increase the risk of thrombosis, and combining estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may place patients at high risk of thromboembolism.(1-3)

CLINICAL EFFECTS: Concurrent use of estrogens with a higher dose of tofacitinib (greater than or equal to 10 mg twice daily, or 20 mg/day) may increase the incidence of pulmonary embolism and death.(1-3)

PREDISPOSING FACTORS: Additional risk factors include advanced age, obesity (BMI greater than 30), smoking, prolonged immobilization, heart failure, hypercoagulable states, history of venous thromboembolism, malignancy, and major surgery.(1)

PATIENT MANAGEMENT: The European manufacturer states that the 10 mg twice daily dose of tofacitinib is not recommended in patients who are on combined hormonal contraceptives or hormone replacement therapy, or who are otherwise at high risk of pulmonary embolism.(4) Patients at high risk of pulmonary embolism should be switched to alternative therapies. For the treatment of rheumatoid arthritis and psoriatic arthritis, the dose of tofacitinib should be limited to 5 mg twice daily or tofacitinib XR 11 mg daily.(1-4) The US FDA and Health Canada have not placed use restrictions specifically on concurrent use of tofacitinib with hormonal contraceptives or hormone replacement therapy. Both agencies advise avoiding tofacitinib in patients at increased risk of thrombosis. The US and Canadian manufacturers recommend against a dosage of tofacitinib 10 mg twice daily or weight-based equivalent twice daily or tofacitinib XR 22 mg once daily for rheumatoid arthritis, psoriatic arthritis, or polyarticular-course juvenile idiopathic arthritis. For the treatment of ulcerative colitis, the lowest effective dose for the shortest duration possible is recommended. Counsel patients on the risk of thrombosis and its signs and symptoms. Instruct patients to promptly report any symptoms of thrombosis and discontinue tofacitinib in patients with symptoms of thrombosis.(5-7) There is currently no use restriction on the combination of estrogens with lower doses of tofacitinib (less than 20 mg daily).

DISCUSSION: In an ongoing open-label study comparing the safety of tofacitinib 5 mg twice daily, tofacitinib 10 mg twice daily, and a tumor necrosis factor (TNF) inhibitor in rheumatoid arthritis patients 50 years old and older, the incidence of pulmonary embolism (PE) was 6-fold higher in the tofacitinib 10 mg twice daily arm and 3-fold higher in the tofacitinib 5 mg twice daily arm compared to the TNF inhibitor arm (17 cases/3,123 patient-years, 9 cases/3,317 patient-years, and 3 cases/3,319 patient-years, respectively). All-cause mortality was also higher in the tofacitinib 10 mg twice daily and 5 mg twice daily arms compared to the TNF inhibitor arm (28 deaths/3,140 patient-years, 19 deaths/3,324 patient-years, and 9 deaths/3,323 patient-years, respectively).(3)

Estrogens/Xanthine Derivatives

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Estrogens may inhibit the hepatic microsomal enzymes responsible for the metabolism of the theophyllines.

CLINICAL EFFECTS: Concurrent use of estrogens may result in an increase in the pharmacologic effects of xanthine derivatives as a result of elevated serum levels. Signs and symptoms of theophylline toxicity including anorexia, nausea, vomiting, nervousness, agitation, headache, tachycardia, arrhythmias, and convulsions.

PREDISPOSING FACTORS: Smoking.

PATIENT MANAGEMENT: Patients receiving concurrent estrogens should be monitored for elevated xanthine levels and signs of toxicity. Adjust dosages accordingly.

DISCUSSION: Although there are no reports of toxicity due to concurrent administration of oral contraceptives and theophylline, use of this combination has been associated with a decrease in the plasma clearance and an increase in the elimination half-life of theophylline. One study involving a small number of patients found that low dose oral contraceptive administration (i.e., 35 mcg) for up to 9 months, did not alter the pharmacokinetics of theophylline. Other studies demonstrate the effect of caffeine, a xanthine alkaloid chemically similar to theophylline, when administered to patients taking oral contraceptives or hormone replacement. Concomitant administration resulted in decreased caffeine metabolism by ethinyl estradiol's metabolic inhibition. A study of 20 healthy women evaluated the effect of caffeine elimination prior to and during one cycle of oral contraception. Compared to pretreatment values, it was determined that clearance of caffeine was reduced by approximately 55%. Another study evaluated the pharmacokinetics of caffeine in seven women receiving an oral depot contraceptive containing ethinyl estradiol. After six months, the oral contraceptive was found to significantly decrease the elimination half-life of caffeine: half-life prior to therapy was 4.9h, and after oral contraceptive therapy, the half-life of caffeine increased to 8.0h.

Hormonal Contraceptives; Estrogens/Corticosteroids

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: It is speculated that hormonal contraceptives and estrogens inhibit hepatic metabolism of some corticosteroids as well as endogenous cortisol. Competitive protein binding may also contribute to elevations in serum corticosteroids.

CLINICAL EFFECTS: Concurrent use of hormonal contraceptives or estrogens may result in an increase in the therapeutic and toxic effects of corticosteroids.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent hormonal contraceptives or estrogen should be observed for symptoms of corticosteroid toxicity. A lower corticosteroid dose may be required.

DISCUSSION: In a study in 6 healthy females controlled on long-term oral contraceptives, subjects received either a placebo or high and low-dose prednisolone (0.53 and 0.14 mg/Kg iv). Both dosages of prednisolone decreased the total clearance, unbound clearance, and volume of distribution (Vd) at maximum concentration (Cmax) of total drug. Significant increases in half-life for free and unbound prednisolone and hydrocortisone concentrations were also observed in comparison to the placebo group. In a study in 8 females controlled on oral contraceptive therapy, 8 females not receiving contraceptive therapy, and 8 males, each subject received prednisolone 40 mg iv. The plasma clearance of total prednisolone in females on OC was 96 ml/min, which was significantly lower than those in both the male and female (205 and 187 ml/min, respectively) control groups. Prednisolone half-life and mean residence times were increased. The oral contraceptive group had a significantly higher (2-fold) concentration of transcortin, resulting in lower clearance, decreased Vd, and a 2-fold increase in the area-under-curve (AUC) for prednisolone. A clinical trial demonstrated the interaction between prednisolone (20 mg) and oral contraceptives containing ethinyl estradiol (30 mcg). The oral contraceptive users had an average plasma concentration of prednisolone 131% higher compared to the control group, and plasma cortisol levels were suppressed by approximately 90%. No differences were reported for ethinyl estradiol levels. In a study in 8 females taking oral contraceptives and 8 females who were were not, subjects received IV doses of prednisolone at 0.1 mg/Kg and 1.0 mg/Kg. Free prednisolone clearance was reduced by approximately 30% in the contraceptive receiving subjects compared to the control group, and plasma cortisol concentrations were reduced 2-fold compared to the control group. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Moderate And Weak Cyp3a4 Inducers/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may accelerate the metabolism of tacrolimus.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of tacrolimus.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and adjusting tacrolimus dose if needed. Monitor clinical response closely.(1)

DISCUSSION: A 13-year-old cystic fibrosis patient with a history of liver transplant on stable doses of tacrolimus underwent 2 separate courses of nafcillin therapy (a moderate CYP3A4 inducer). During the 1st course of nafcillin, his tacrolimus levels started to fall 3 days after starting nafcillin, became undetectable at day 8, and recovered to therapeutic levels without a change in tacrolimus dose 5 days after discontinuation of nafcillin. During the 2nd course of nafcillin, tacrolimus level became undetectable 4 days after starting nafcillin and recovered 3 days after stopping nafcillin.(2) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, elagolix, etravirine, lesinurad, lorlatinib, mavacamten, modafinil, nafcillin, repotrectinib, telotristat, and tovorafenib.(3,4) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, nevirapine, oritavancin, omaveloxolone, oxcarbazepine, pioglitazone, relugolix, rufinamide, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vinblastine, and zanubrutinib.(3,4)

Moderate And Weak Cyp3a4 Inducers/Ubrogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate or weak CYP3A4 inducers may induce the metabolism of ubrogepant.(1)

CLINICAL EFFECTS: Concurrent use of a moderate or weak CYP3A4 inducer may result in decreased levels and effectiveness of ubrogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with moderate or weak CYP3A4 inducers. Initial dose of ubrogepant should be 100 mg. If a second dose is needed, the dose of ubrogepant should be 100 mg.(1)

DISCUSSION: Coadministration of ubrogepant with rifampin, a strong CYP3A4 inducer, resulted in an 80% reduction in ubrogepant exposure. No dedicated drug interaction studies were conducted to assess concomitant use with moderate or weak CYP3A4 inducers. Dose adjustment for concomitant use of ubrogepant with moderate or weak CYP3A4 inducers is recommended based on a conservative prediction of 50% reduction in exposure of ubrogepant.(1) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pexidartinib, rifabutin, telotristat, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, bexarotene, brigatinib, brivaracetam, clobazam, danshen, dexamethasone, dicloxacillin, echinacea, elafibranor, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, relugolix, repotrectinib, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Moderate And Weak Cyp3a4 Inhibitors/Tacrolimus

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Moderate and weak inhibitors of CYP3A4 may inhibit the metabolism of tacrolimus.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inhibitor may result in elevated levels of and toxicity from tacrolimus, including nephrotoxicity, neurotoxicity, and prolongation of the QTc interval and life-threatening cardiac arrhythmias, including torsades de pointes.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsade de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of tacrolimus recommends monitoring tacrolimus whole blood trough concentrations and reducing tacrolimus dose if needed.(1) Consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study of 26 renal transplant recipients, conjugated estrogens 3.75 mg daily increased the tacrolimus dose-corrected concentration of tacrolimus by 85.6%. Discontinuation of the conjugated estrogens led to a decrease in tacrolimus concentration of 46.6%.(3) A case report describes a 65-year-old kidney transplant recipient who was stable on tacrolimus 9 mg per day with trough levels of 5 to 7.5 ng/mL. Ten days after starting on estradiol gel 0.5 mg per day, her tacrolimus level rose to 18.3 ng/mL and serum creatinine (Scr) rose from 1.1 mg/dL at baseline to 2 mg/dL. Tacrolimus dose was reduced by 60%, and trough levels and Scr normalized after two weeks.(4) A study of 16 healthy volunteers found that elbasvir 50 mg/grazoprevir 200 mg daily increased the area-under-curve (AUC) of tacrolimus by 43%, while the maximum concentration (Cmax) of tacrolimus was decreased by 40%.(5) An analysis of FAERS data from 2004-2017, found a significant association between transplant rejection and concurrent use of tacrolimus and clotrimazole (reporting odds ratio 1.92, 95% CI). A retrospective study of 7 heart transplant patients on concurrent tacrolimus and clotrimazole troche showed a significant correlation between tacrolimus trough concentration and AUC after clotrimazole discontinuation. Tacrolimus clearance and bioavailability after clotrimazole discontinuation was 2.2-fold greater (0.27 vs. 0.59 L/h/kg) and the trough concentration decreased from 6.5 ng/mL at 1 day to 5.3 ng/mL at 2 days after clotrimazole discontinuation.(7) A retrospective study of 26 heart transplant patients found that discontinuation of concurrent clotrimazole with tacrolimus in the CYP3A5 expresser group had a 3.3-fold increase in apparent oral clearance and AUC of tacrolimus (0.27 vs. 0.89 L/h/kg) compared to the CYP3A5 non expresser group with a 2.2-fold mean increase (0.18 vs. 0.39 L/h/kg).(8) A study of 6 adult kidney transplant recipients found that clotrimazole (5-day course) increased the tacrolimus AUC 250% and the blood trough concentrations doubled (27.7 ng/ml versus 27.4 ng/ml). Tacrolimus clearance decreased 60% with coadministration of clotrimazole.(9) A case report describes a 23-year-old kidney transplant recipient who was stable on tacrolimus 5 mg twice daily, mycophenolate mofetil 30 mg daily, prednisone (30 mg daily tapered over time to 5 mg), and clotrimazole troche 10 mg four times daily. Discontinuation of clotrimazole resulted in a decrease in tacrolimus trough levels from 13.7 ng/ml to 5.4 ng/ml over a period of 6 days. Clotrimazole was restarted with tacrolimus 6 mg resulting in an increased tacrolimus level of 19.2 ng/ml.(10) A retrospective study in 95 heart transplant recipients on concurrent clotrimazole and tacrolimus found a median tacrolimus dose increase of 66.7% was required after clotrimazole discontinuation. Tacrolimus trough concentration was found to have decreased 42.5% after clotrimazole discontinuation.(11) A retrospective study in 65 pancreas transplant patients on concurrent tacrolimus, clotrimazole, cyclosporine, and prednisone found that clotrimazole discontinuation at 3 months after transplantation may cause significant tacrolimus trough level reductions.(12) A case report describes a 6-year-old kidney transplant recipient who was on a regimen of tacrolimus and mycophenolate mofetil. The patient was started letermovir 240 mg via G-tube 2 months post kidney transplant. One week after starting letermovir, the routine tacrolimus level showed a supratherapeutic concentration of 22.9 ng/L. A 36% dose reduction of tacrolimus was required. Upon discontinuation of letermovir, the tacrolimus level decreased by 42%.(13) Moderate CYP3A4 inhibitors linked to this monograph include: berotralstat, conivaptan, fluvoxamine, lenacapavir, letermovir, netupitant, nirogacestat, sevabertinib, stiripentol, and tofisopam.(6) Weak CYP3A4 inhibitors linked to this monograph include: avacopan, baikal skullcap, berberine, bicalutamide, blueberry, brodalumab, camizestrant, chlorzoxazone, cimetidine, cranberry juice, daclatasvir, daridorexant, delavirdine, diosmin, elinzanetant, estrogens, flibanserin, fostamatinib, ginkgo biloba, givinostat, glecaprevir/pibrentasvir, goldenseal, grazoprevir, isoniazid, istradefylline, ivacaftor, lacidipine, lazertinib, linagliptin, lomitapide, lumateperone, lurasidone, peppermint oil, piperine, propiverine, ranitidine, resveratrol, rimegepant, simeprevir, sitaxsentan, skullcap, ticagrelor, tolvaptan, trofinetide, viloxazine, and vonoprazan-amoxicillin.(6)

Moderate Cyp1a2 Inhibitors/Pirfenidone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Pirfenidone is primarily metabolized by CYP1A2 which is responsible for about 50% of its conversion to inactive drug. CYP2C9, 2C19, 2D6 and 2E1 are additional minor contributors to pirfenidone metabolism.(1) Inhibitors of CYP1A2 may inhibit the metabolism of pirfenidone.(1)

CLINICAL EFFECTS: Concurrent pirfenidone use with moderate inhibitors of CYP1A2 may lead to increased systemic concentrations and toxicity from pirfenidone, including serious liver injury.(1)

PREDISPOSING FACTORS: A greater risk of adverse events may result from concomitant treatment with strong or moderate inhibitors of one or more other CYP isoenzymes involved in the metabolism of pirfenidone such as CYP2C9 (e.g. amiodarone, fluconazole), CYP2C19 (e.g. fluconazole, fluoxetine, ticlopidine) and CYP2D6 (e.g. fluoxetine, paroxetine).(1) The magnitude of this interaction may be reduced in cigarette smokers. Cigarette smoking induces production of CYP1A2 and, in the absence of a CYP1A2 inhibitor, leads to decreased systemic concentrations of pirfenidone.(1)

PATIENT MANAGEMENT: The manufacturer of pirfenidone states that for concurrent use with moderate inhibitors of CYP1A2, dose reduction is recommended. Reduce the dose of pirfenidone to two-267 mg capsules three times a day (total daily dose of 1602 mg/day).(1) Combinations of strong or moderate CYP1A2 inhibitors with strong or moderate CYP2C9, CYP2C19, and/or CYP2D6 inhibitors should be discontinued prior to and avoided during pirfenidone treatment.(1)

DISCUSSION: Pirfenidone is converted to inactive metabolites prior to elimination. CYP1A2 is responsible for approximately half of this metabolism. In an interaction study conducted in non-smokers and smokers, coadministration of pirfenidone with fluvoxamine (a strong CYP1A2 inhibitor), an agent which inhibits multiple pirfenidone elimination pathways (CYP1A2, CYP2C9, CYP2C19), led to an approximately 4-fold and 7-fold, respectively, increase in pirfenidone exposure.(1) In a single-dose study in 27 healthy subjects, coadministration of 801 mg of pirfenidone and 750 mg of ciprofloxacin on Day 6 (ciprofloxacin was dosed at 750 mg twice daily from Day 2 to Day 7) increased the exposure to pirfenidone by 81%.(1) Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(2)

Oral Estrogens/Growth Hormone

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Growth hormone (somatropin or lonapegsomatropin-tcgd) binds to growth hormone receptors and stimulates Janus activating tyrosine kinases (JAK 1 and 2) and signal transducer activators of transcription (STAT1, STAT3, STAT5) to increase gene transcription and metabolism to produce and secrete insulin like growth factor-1 (IGF-1). IGF-1 promotes cell growth, proliferation, and survival. Estrogens block STAT phosphorylation and inhibit IGF-1 secretion and production.(1,2) Higher quantities of growth hormone are required to raise serum IGF-1 concentrations to the normal range.

CLINICAL EFFECTS: Oral estrogens may reduce the IGF-1 response to growth hormone (somatropin and lonapegsomatropin-tcgd).(1-9)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of somatropin states a larger dose of somatropin may be required to achieve the treatment goal.(3-9) The manufacturer of lonapegsomatropin-tcgd states adults of any age concurrently taking oral estrogen should increase the dose of lonapegsomatropin-tcgd to 2.1 mg once weekly.(3) The American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for growth hormone deficiency states that higher recombinant human growth hormone (rhGH) doses are advised in women on oral estrogen therapy and that switching women to transdermal estrogen patches may allow lower rhGH doses to be used for equivalent IGF-1 responses.(10)

DISCUSSION: A prospective study compared growth hormone replacement requirements in women with elevated estrogen (on oral estrogen), women without elevated estrogen (no estrogen therapy or on transdermal estrogen), and growth hormone treated adult hypopituitary males. Women on oral estrogen required 10.6 +/-0.7 mcg/kg/day or 867 +/- 45 mcg/day growth hormone, women not taking oral estrogen required 5.0 +/- 0.7 mcg/kg/day or 424 +/-57 mcg/day, and men required 4.1 +/- 0.6 mcg/kg/day or 376 +/-49 mcg/day.(1) A randomized cross-over study compared one month of treatment with ethinyl estradiol (20 mcg), conjugated equine estrogen (1.25 mg Premarin), and estradiol valerate (2 mg). All three formulations resulted in a significant reduction in IGF-1 levels compared to baseline.(11) A study compared IGF-1 concentrations in premenopausal women and postmenopausal women before and after 2 months of cyclical replacement therapy with either oral ethinyl estradiol (20 mcg daily) or transdermal 17 beta-estradiol (100 mcg patch applied twice weekly). Oral ethinyl estradiol significantly reduced circulating IGF-1 (0.70 +/- 0.09 to 0.47 +/- 0.04 units/mL, P < 0.02) levels. Transdermal 17-beta estradiol increased IGF-1 levels (0.86 +/- 0.15 to 1.10 +/- 0.14 units/mL, P < 0.005).(12) In a clinical trial, somapacitan administered once weekly was compared to somatropin once daily injections in patients with and without oral estrogen replacement therapy. Patients with oral estrogen therapy were administered 2 mg/wk compared to 1 mg/wk for patients without estrogen replacement therapy. Observed doses after titration for somapacitan and somatropin were highest for females on oral estrogen.(13) An open-label, randomized crossover study in growth hormone deficient women compared oral estrogen with transdermal estrogen treatment while on growth hormone. Women received incremental doses of growth hormone (0.5, 1.0, 2.0 units/day for 1 week; increased to next dose each week) for 8 weeks and estradiol valerate (2 mg/day) or transdermal estrogen patches (Estraderm-TTS 100 mcg). IGF-1 levels were significantly reduced during oral estrogen treatment and rose dose-dependently during growth hormone administration by a lower magnitude compared with transdermal treatment (change in IGF-1: 109 +/-43% vs. 135 +/-41%).(14)

Selected Cyp1a2 Inhibitors/Rasagiline (<= 0.5 Mg)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of rasagiline.(1)

CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from rasagiline.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rasagiline states that patients receiving concurrent therapy with an inhibitor of CYP1A2 should receive no more than 0.5 mg of rasagiline daily.(1) Concurrent therapy with vemurafenib may require extended monitoring for interaction onset and severity because steady-state levels of vemurafenib are not attained for approximately 15 days.(2)

DISCUSSION: In a study in 12 healthy subjects, ciprofloxacin (500 mg twice daily) increased the area-under-curve (AUC) of rasagiline (2 mg twice daily) by 83%.(1) Strong CYP1A2 inhibitors linked to this monograph include: angelica root, ciprofloxacin, enasidenib, enoxacin, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, and vemurafenib.(3-5)

Selected Moderate-Weak Cyp3a4 Inducers/Exemestane

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: CYP3A4 inducers may induce the metabolism of exemestane.(1)

CLINICAL EFFECTS: Concurrent use of a CYP3A4 inducer may result in decreased levels and effectiveness of exemestane.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The US manufacturer of exemestane recommends that patients receiving concurrent therapy with a strong CYP3A4 inducer receive 50 mg of exemestane daily after a meal.(1) It may be prudent to consider a dosage increase for patients receiving weaker CYP3A4 inducers.

DISCUSSION: In a study in 10 healthy postmenopausal subjects, pretreatment with rifampin (a strong CYP3A4 inducer, 600 mg daily for 14 days) decreased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of exemestane (25 mg) by 54% and 41%, respectively.(1) Strong inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 80% or more and include: carbamazepine, enzalutamide, mitotane, phenobarbital, phenytoin, rifabutin, rifampin, and St. John's wort.(1-3) Moderate inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 50-80% and include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat ethyl, thioridazine, and tovorafenib.(2,3) Weak inducers of CYP3A4 would be expected to decrease the AUC of a sensitive 3A4 substrate by 20-50% and include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, elafibranor, enasidenib, eslicarbazepine, floxacillin, garlic, gingko, ginseng, glycyrrhizin, lorlatinib, meropenem-vaborbactam, methylprednisolone, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, sunvozertinib, suzetrigine, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(2,3)

Strong And Moderate Cyp1a2 Inhibitors/Ropinirole

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Ropinirole is a CYP1A2 substrate. Strong and moderate CYP1A2 inhibitors may decrease the metabolism of ropinirole.(1-3)

CLINICAL EFFECTS: The concurrent administration of strong or moderate CYP1A2 inhibitors and ropinirole may result in elevated levels of ropinirole, increased clinical effects, and signs of toxicity.(1-3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In patients receiving strong or moderate CYP1A2 inhibitors who are started on ropinirole, ropinirole may be titrated to effect according to the manufacturer's dosage instructions. If the strong or moderate CYP1A2 inhibitor is started or discontinued in a patient receiving ropinirole, the dosage of ropinirole may need to be adjusted.(1-2)

DISCUSSION: In a study in 12 subjects, the concurrent administration of ropinirole with ciprofloxacin resulted in increases in the maximum concentration (Cmax) and area-under-curve (AUC) of ropinirole by 84% and 60%, respectively. The major pathway for ropinirole metabolism has been shown to be CYP1A2.(1-3) Strong CYP1A2 inhibitors linked to this monograph include: Angelica dahurica, enasidenib, enoxacin, and fluvoxamine. Moderate CYP1A2 inhibitors linked to this monograph include: capmatinib, centanafadine, ciprofloxacin, dipyrone, fexinidazole, genistein, estrogen-containing contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine.(4)

Weak Cyp3a4 Inducers/Atogepant

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Weak CYP3A4 inducers may increase the metabolism of atogepant by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of weak CYP3A4 inducers with atogepant may result in decreased levels and clinical effectiveness of atogepant.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: The manufacturer of atogepant recommends that patients on concomitant weak CYP3A4 inducers receive atogepant 30 mg or 60 mg once daily for prevention of episodic migraines and receive atogepant 60 mg once daily for prevention of chronic migraines.(1) Patients receiving concurrent therapy with CYP3A4 inducers and atogepant should be observed for decreased clinical effectiveness.

DISCUSSION: In a study of healthy subjects, rifampin, a strong CYP3A4 inducer, decreased the area-under-curve (AUC) and maximum concentration (Cmax) of atogepant by 60% and 30%, respectively. Topiramate, a weak CYP3A4 inducer, decreased atogepant AUC and Cmax by 25% and 24%, respectively.(1) Weak CYP3A4 inducers linked to this monograph include: armodafinil, aumolertinib, bexarotene, brigatinib, brivaracetam, clobazam, danshen, darolutamide, dexamethasone, dicloxacillin, echinacea, eslicarbazepine, floxacillin, garlic, genistein, ginseng, glycyrrhizin, methylprednisolone, mobocertinib, nevirapine, omaveloxolone, oritavancin, oxcarbazepine, pioglitazone, pitolisant, quercetin, relugolix, rufinamide, sarilumab, sulfinpyrazone, tazemetostat, tecovirimat, terbinafine, ticlopidine, topiramate, troglitazone, vemurafenib, vinblastine, and zanubrutinib.(1,2)

*High risk of arterial, venous thrombotic, or thromboembolic disorders.

*Pregnancy.

*Known osteoporosis.

*Current or history of breast cancer or other hormone-sensitive malignancies.

*Known hepatic impairment or disease.

*Undiagnosed abnormal uterine bleeding.

*Known hypersensitivity to relugolix, estradiol, norethindrone acetate, or any components in the formulation.

• Acute myocardial infarction
• Carcinoma of breast
• Cerebrovascular accident
• Deep venous thrombosis
• Disease of liver
• Endometrial carcinoma
• Estrogen-dependent neoplasm
• Osteoporosis
• Pregnancy
• Pulmonary thromboembolism
• Thrombophilia

• Bed-ridden
• Coronary artery disease
• Depression
• Family history of malignant tumor of breast
• Hereditary angioedema
• Hypertension
• Hypothyroidism
• Invasive surgical procedure
• Malignant neoplasm of the ovary
• Osteopenia
• Papilledema
• Retinal thrombosis
• Suicidal ideation
• Tobacco smoker

• Diabetes mellitus
• Gallbladder disease
• Hyperglycemia
• Hyperlipidemia
• Hypertriglyceridemia
• Unspecified lump in breast

The most common adverse reactions (incidence >=3%) reported with relugolix/estradiol/norethindrone in women with heavy menstrual bleeding associated with uterine fibroids are vasomotor symptoms, uterine bleeding, alopecia, and decreased libido.

The most common adverse reactions (incidence >=3%) reported with relugolix/estradiol/norethindrone in women with moderate to severe pain associated with endometriosis are headache, vasomotor symptoms, mood disorders, abnormal uterine bleeding, nausea, toothache, back pain, decreased sexual desire and arousal, arthralgia, fatigue, and dizziness.

More Frequent

• Osteopenia

Less Frequent

• Hypertension

Rare or Very Rare

• Anaphylaxis
• Angioedema
• Cholecystitis
• Hypersensitivity drug reaction
• Increased alanine transaminase
• Increased aspartate transaminase
• Suicidal ideation
• Thromboembolic disorder
• Thrombotic disorder
• Uterine leiomyoma degeneration

More Frequent

• Abnormal vaginal bleeding
• Alopecia
• Drug-induced hot flash
• Hyperhidrosis
• Libido changes
• Night sweats

Less Frequent

• Depression
• Hypercholesterolemia
• Hypertriglyceridemia
• Irritability
• Symptoms of anxiety

Rare or Very Rare

• Hyperglycemia
• Pelvic pain
• Urticaria

No enhanced messaging available.

Safety and efficacy of relugolix/estradiol/norethindrone combination therapy have not been established in pediatric patients.

Relugolix/estradiol/norethindrone is contraindicated during pregnancy. Relugolix/estradiol/norethindrone can cause early pregnancy loss in humans based on its mechanism of action and animal findings. If pregnancy occurs during treatment, the fixed-combination drug should be discontinued.

Human data are insufficient to determine the risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes associated with relugolix/estradiol/norethindrone.

In pregnant rabbits, oral exposure to relugolix at exposures equivalent to approximately half of the maximum recommended human dose (40 mg) during organogenesis resulted in spontaneous abortion and total litter loss. However, in rabbits and rats, relugolix exposures ranging from approximately 0.5 to 300 times the human exposure at recommended dosages did not result in fetal malformations.

No increase in genital or non-genital birth defects has been identified with exposure to estrogens (e.g., estradiol) and progestins (e.g., norethindrone) before conception or during early pregnancy based on data from epidemiologic studies and meta-analyses.

MYFEMBREE Pregnancy Exposure Registry tracks pregnancy outcomes in women exposed to relugolix/estradiol/norethindrone during pregnancy. Patients and providers are encouraged to report exposures during pregnancy by calling 1-855-428-0707.

Relugolix is distributed into milk in rats. It is not known whether relugolix or its metabolites are distributed into human milk, but drugs present in the milk of animals are likely to be present in human milk also. Estrogen and progestin have been detected in the breast milk of women treated with these drugs. Estrogen plus progestin therapy can reduce milk production; reduction in milk production can occur at any time, but is less likely after breastfeeding is well established. The developmental and health benefits of breastfeeding, the clinical importance of the therapy to the woman, and any potential adverse effects to the nursing infants should be considered when making treatment decisions.

The manufacturer makes no specific dosage recommendations for geriatric patients.

Clinical trials evaluating relugolix/estradiol/norethindrone combination therapy did not include any patients 65 years of age or older.