Orserdu (elacestrant HCl)

Dosage of elacestrant hydrochloride is expressed in terms of elacestrant.

If adverse reactions occur during elacestrant therapy, temporary interruption, dosage reduction, and/or permanent discontinuance of the drug may be necessary. If dosage modification is required, reduce the dosage of elacestrant as described below (see Table 1).

Table 1. Recommended Dosage Reduction for Elacestrant Toxicity.

Dosage Reduction Level Recommended Dosage First dose reduction 258 mg (three 86 mg tablets) orally once daily Second dose reduction 172 mg (two 86 mg tablets) orally once daily

Permanently discontinue elacestrant if further dose reduction below 172 mg is required.

Recommended dosage modifications for adverse reactions based on severity are listed below (see Table 2).

Table 2. Recommended Dosage Modifications for Elacestrant Adverse Reactions.

Severity Recommendation Grade 1 Continue at current dosage level. Grade 2 Consider interruption until recovery to grade 1 or less or baseline, then resume at the same dosage level Grade 3 Interrupt therapy until recovery to grade 1 or less or baseline, then resume at the next lower dosage level If grade 3 toxicity recurs, interrupt therapy until recovery to grade 1 or less or baseline, then resume therapy reduced by another dosage level Grade 4 Interrupt therapy until recovery to grade 1 or less or baseline, then resume therapy reduced by 1 dosage level. If grade 4 or intolerable adverse reaction recurs, permanently discontinue elacestrant.

Administer orally once daily at approximately the same time each day.

Administer elacestrant with food to reduce nausea and vomiting.

Swallow tablets whole; do not chew, crush, or split prior to swallowing. Do not take any tablets that are broken, cracked, or look damaged.

If a dose is missed for >6 hours or vomiting occurs, skip the dose and take the next dose on the following day at its regularly scheduled time.

Store tablets at 20-25degreesC (excursions permitted between 15-30degreesC).

No dosing information is available for this tab.

Elacestrant is primarily metabolized by cytochrome P-450 (CYP) isoenzyme 3A4, and by isoenzymes 2C9 and 2A6 to a lesser extent.

Elacestrant is a CYP3A4 substrate. Elacestrant is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A. Elacestrant is not an inducer of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, or CYP3A.

Elacestrant is an inhibitor of P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP).

Elacestrant is a substrate for organic anion transporting polypeptide (OATP) 2B1, but not P-gp.

Elacestrant does not inhibit organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 2, OCT1, OATP1B1, OATP1B3, multidrug and toxin extrusion (MATE) 1, MATE2K, or OATP2B1.

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

Elacestrant/Strong And Moderate Cyp3a4 Inducers

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: Elacestrant is metabolized by CYP3A4. Strong and moderate inducers of CYP3A4 may increase the metabolism of elacestrant.(1)

CLINICAL EFFECTS: Concurrent use of a strong or moderate inducer of CYP3A4 may result in decreased levels and effectiveness of elacestrant.(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 elacestrant states avoid concomitant use of elacestrant with strong or moderate CYP3A4 inducers.(1) The US manufacturer of elacestrant does not provide dose modification recommendations with strong and moderate CYP3A4 inducers. The Australian and UK manufacturers of elacestrant state concomitant use of strong or moderate CYP3A4 inducers should be avoided and an alternative concomitant medicinal product with no or minimal potential to induce CYP3A4 should be considered. If a strong or moderate CYP3A4 inducer must be used for a short duration of time (i.e. less than or equal to 3 days) or intermittently (i.e. treatment periods less than or equal to 3 days separated by at least 2 weeks or 1 week + 5 half-lives of the CYP3A4 inducer, whichever is longer), continue elacestrant without increasing the dose.(2,3)

DISCUSSION: Coadministration of 200 mg dose of elacestrant with rifampin (a strong CYP3A inducer) decreased the maximum concentration (Cmax) and area-under-curve (AUC) of elacestrant by 73% and 86%, respectively.(1) Efavirenz is predicted to decrease the Cmax and AUC of elacestrant by 44 to 63% and 55% to 73%, respectively.(1) Strong inducers of CYP3A4 include: apalutamide, barbiturates, carbamazepine, encorafenib, enzalutamide, fosphenytoin, ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, primidone, rifampin, rifapentine, and St. John's wort.(4,5) Moderate inducers of CYP3A4 include: belzutifan, bosentan, cenobamate, dabrafenib, dipyrone, efavirenz, elagolix, etravirine, fexinidazole, lesinurad, lorlatinib, mavacamten, mitapivat, modafinil, nafcillin, pacritinib, pexidartinib, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(4,5)

Elacestrant/Strong And Moderate Cyp3a4 Inhibitors

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 CYP3A4 may inhibit the metabolism of elacestrant.(1)

CLINICAL EFFECTS: Concomitant use of a strong or moderate CYP3A4 inhibitor increases elacestrant plasma concentrations, which may increase the incidence and severity of adverse reactions.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of elacestrant states avoid concomitant use of strong or moderate CYP3A4 inhibitors with elacestrant.(1) The US manufacturer of elacestrant does not provide dose modification recommendations with strong and moderate CYP3A4 inhibitors. The Australian and UK manufacturers state concomitant use of strong or moderate CYP3A4 inhibitors should be avoided and an alternative concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. If concomitant use of a strong CYP3A4 inhibitor is unavoidable, the elacestrant dose should be reduced to 172 mg once daily with careful monitoring of tolerability. Subsequent dose reduction to 86 mg once daily may be considered with moderate CYP3A4 inhibitors based on tolerability. If the CYP3A4 inhibitor is discontinued, the elacestrant dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 5 half-lives of the CYP3A4 inhibitor).(2,3)

DISCUSSION: Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased elacestrant area-under-curve (AUC) and maximum concentration (Cmax) by 5.3-fold and 4.4-fold, respectively.(1) Coadministration of fluconazole (a moderate CYP3A4 inhibitor) is predicted to increase elacestrant AUC and Cmax by 2.3-fold and 1.6-fold, respectively.(1) Strong inhibitors of CYP3A4 include: adagrasib, boceprevir, ceritinib, clarithromycin, cobicistat, ensitrelvir, idelalisib, indinavir, itraconazole, josamycin, ketoconazole, levoketoconazole, lonafarnib, lopinavir, mibefradil, mifepristone, nefazodone, nelfinavir, nirmatrelvir, paritaprevir, posaconazole, relacorilant, ribociclib, saquinavir, telaprevir, telithromycin, tipranavir, troleandomycin, tucatinib, and voriconazole.(4,5) Moderate CYP3A4 inhibitors include: amprenavir, aprepitant, atazanavir, avacopan, berotralstat, clofazimine, conivaptan, crizotinib, darunavir, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fluconazole, fluvoxamine, fosamprenavir, fosnetupitant, imatinib, isavuconazonium, oral lefamulin, lenacapavir, letermovir, netupitant, nilotinib, nirogacestat, rilzabrutinib, schisandra, stiripentol, tofisopam, treosulfan, verapamil, and voxelotor.(4,5)

Estrogen Receptor Blockers (Erbs)/Fluoroestradiol F-18

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: Drugs that bind to the estrogen receptor (ER) may compete with the binding of radioactive diagnostic agent fluoroestradiol F-18.(1)

CLINICAL EFFECTS: Concurrent use of estrogen receptor blockers such as selective estrogen receptor modulators (SERMs) and selective estrogen receptor down-regulators (SERDs) may reduce the detection of ER-positive lesions with fluoroestradiol F-18.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Before administering fluoroestradiol F-18, discontinue drugs that bind to the ER, such as SERMs and SERDs, for at least 5 biological half-lives.(1) The following washout periods apply when discontinuing ERBs, prior to fluoroestradiol F-18 administration: - Bazedoxifene = 7 days - Clomiphene = 25 days - Elacestrant = 11 days - Enclomiphene = 25 days - Fulvestrant = 28 weeks - Imlunestrant = 7 days - Ospemifene = 5 days - Raloxifene = 7 days - Tamoxifen = 8 weeks - Toremifene = 5 weeks

DISCUSSION: The following ERBs are linked to this monograph: SERDs: elacestrant, imlunestrant, and fulvestrant. SERMs: bazedoxifene, clomiphene, enclomiphene, ospemifene, raloxifene, tamoxifen and toremifene.

There are no severe interactions for this drug.

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

P-Glycoprotein (P-Gp) Inhibitors/Digoxin

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of digoxin at the levels of intestinal absorption, renal tubular secretion, and biliary-intestinal secretion.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels and toxicities of digoxin.(1) Symptoms of digoxin toxicity can include anorexia, nausea, vomiting, headache, fatigue, malaise, drowsiness, generalized muscle weakness, disorientation, hallucinations, visual disturbances, and arrhythmias.

PREDISPOSING FACTORS: Low body weight, advanced age, impaired renal function, hypokalemia, hypercalcemia, and/or hypomagnesemia may increase the risk of digoxin toxicity.

PATIENT MANAGEMENT: Monitor digoxin concentrations before initiating concomitant use with P-gp inhibitors and continue monitoring serum digoxin concentrations as recommended in the prescribing information for digoxin.(1) When digoxin levels are expected to be increased by over 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 30-50% or by modifying the dosing frequency to reduce digoxin concentrations.(1) When digoxin levels are expected to be increased by less than 50%, the manufacturer of digoxin recommends decreasing the dose of digoxin by approximately 15-30% or by modifying the dosing frequency to reduce digoxin concentrations.(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: Digoxin is a known substrate of P-gp. Inhibitors of P-gp may increase toxicity of digoxin.(1) In a clinical study, elacestrant increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.1-fold and 1.3-fold, respectively.(3,4) In another clinical study, imlunestrant increased the area-under-curve (AUC) and maximum concentration (Cmax) of digoxin by 1.4-fold and 1.6-fold, respectively.(5) In another clinical study, maribavir increased the AUC and Cmax of digoxin by 1.2-fold and 1.25-fold, respectively.(6) Inhibitors of P-gp linked to this monograph include: abrocitinib, aumolertinib, capmatinib, daraxonrasib, elacestrant, enzalutamide, imlunestrant, maribavir, selpercatinib, sparsentan, sotorasib, vepdegestrant, and vibegron.(2-8)

*None.

• Child-pugh class C hepatic impairment
• Lactation

• Child-pugh class B hepatic impairment
• Disease of liver
• Pregnancy

• Hypercholesterolemia
• Hypertriglyceridemia

Adverse effects (including laboratory abnormalities) reported in >=10% of patients receiving elacestrant were musculoskeletal pain, nausea, vomiting, increased cholesterol, increased AST/ALT, increased triglycerides, fatigue, decreased hemoglobin, decreased sodium, increased creatinine, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flush, and dyspepsia.

More Frequent

• Increased alanine transaminase
• Increased aspartate transaminase

More Frequent

• Acute abdominal pain
• Anemia
• Anorexia
• Constipation
• Diarrhea
• Drug-induced hot flash
• Dyspepsia
• Fatigue
• Headache disorder
• Hypercholesterolemia
• Hypertriglyceridemia
• Hyponatremia
• Musculoskeletal pain
• Nausea
• Vomiting

Less Frequent

• Cough
• Dizziness
• Dyspnea
• Gastroesophageal reflux disease
• Insomnia
• Skin rash

No enhanced messaging available.

Safety and efficacy of elacestrant in pediatric patients have not been established.

Elacestrant use during pregnancy can cause fetal harm based on findings in an animal study and the mechanism of action of the drug.

Human data on elacestrant use during pregnancy are not available to determine the drug-associated risk. Administration of oral elacestrant to pregnant rats during the period of organogenesis resulted in structural abnormalities and embryofetal death at maternal exposures below the recommended dose based on AUC. Maternal toxicity (reduced weight gain, low food consumption, red vulvar discharge) was also observed in rats.

Verify pregnancy status in females of reproductive potential prior to initiating elacestrant. Apprise patients of the potential hazard to the fetus if elacestrant is used during pregnancy.

It is unknown whether elacestrant distributes into human milk, or affects milk production or the breast-fed infant.

Because of the potential for serious adverse reactions in breast-fed infants, advise women to not breast-feed during treatment with elacestrant and for 1 week after the last dose.

The manufacturer makes no specific dosage recommendations for geriatric patients.

In the EMERALD trial, 43 and 17% of patients were >=65 and >=75 years of age. There were no overall differences in the safety or efficacy of elacestrant between patients >=65 years and younger adults. There was an insufficient number of patients >=75 years of age to assess age-related differences in safety or efficacy.

No clinically important differences in elacestrant pharmacokinetics were observed based on age (range 24-89 years).