4.1. Therapeutic indications

Etcamah in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, or abemaciclib) is indicated for the treatment of adult patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer upon detection of ESR1‑mutation and without disease progression during first-line endocrine therapy in combination with a CDK4/6 inhibitor (for biomarker based patient-selection, see section 4.2 and 5.1).

In pre- or peri-menopausal women and in men, Etcamah plus a CDK4/6 inhibitor should be combined with a luteinizing hormone releasing hormone (LHRH) agonist or antagonist.

4.2. Posology and method of administration

Treatment should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.

Patient selection

Patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer on first-line endocrine treatment should be selected for treatment based on the presence of ESR1‑mutations in plasma or tumour specimen collected every 3 months until an ESR1-mutation has been detected, and which should be assessed by a CE-marked in vitro diagnostic (IVD) medical device with the corresponding intended purpose (see section 5.1). If a CE-marked IVD is not available, an alternative validated test should be used.

Posology

The recommended dose of Etcamah in combination with a CDK4/6 inhibitor is 75 mg once daily. The CDK4/6 inhibitor should be continued at the same dose at the time of initiation with Etcamah as when the ESR1m was detected.

Please also refer to the summary of product characteristics (SmPC) of the CDK4/6 inhibitor or LHRH agonist or antagonist for the recommended dosing information. If the CDK4/6 inhibitor is permanently discontinued, Etcamah should also be discontinued.

Treatment duration

Treatment with Etcamah should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

Missed dose

If a dose of Etcamah is missed, it can be taken immediately within 6 hours after the time it is usually taken. After more than 6 hours, the dose should be skipped for that day. The next dose of Etcamah should be taken at the usual time.

Vomiting

If the patient vomits, an additional dose should not be taken. The next dose of Etcamah should be taken at the usual time.

Monitoring for Etcamah in combination with CDK4/6 inhibitors

For the combination of Etcamah with a CDK4/6 inhibitor, ECG should be assessed before initiating treatment, at approximately day 8 and day 15 of the first cycle, and then as clinically indicated. Thereafter, monitoring during combination treatment should be performed according to the recommendations in the SmPC of the co-administered CDK4/6 inhibitor. In case of QTc prolongation during treatment, more frequent ECG monitoring is recommended.

In addition, for the combination of Etcamah with ribociclib, treatment should be initiated only in patients with QTcF values less than 450 msec, and analysis of electrolytes should be performed before initiating combination treatment, at day 15 and as clinically indicated. Refer to the ribociclib SmPC for dose modification guidelines and other relevant safety information.

Dose adjustments

Treatment with Etcamah may be temporarily interrupted and/or discontinued to manage adverse reactions per dose modification guideline provided in Table 1.

Table 1 Recommended dose modification for Etcamah

ADL = Activities of daily living; AE = Adverse Event; CTCAE = Common Terminology Criteria for Adverse Events; NCI = National Cancer Institute.

a. Bradycardia includes bradycardia and sinus bradycardia.

b. Visual effects include photopsia, vision blurred, visual impairment, diplopia, and photophobia of eye disorders MedDRA SOC, and visual perseveration of nervous system disorders MedDRA SOC.

No clinically relevant pharmacokinetic interaction was observed when camizestrant was co-administered with abemaciclib or palbociclib. When camizestrant 75 mg was administered in combination with ribociclib, camizestrant exposure increased to levels comparable to those observed with a 150 mg monotherapy dose (see section 4.9).

Special populations

Elderly

No dose adjustment of camizestrant is required for elderly patients (see section 5.2).

Renal impairment

No dose adjustment of camizestrant is required for patients with mild or moderate renal impairment. Etcamah is not recommended for patients with severe renal impairment (see section 5.2).

Hepatic impairment

No dose adjustment of camizestrant is required for patients with mild (NCI criteria) hepatic impairment. As a precautionary measure, the use of camizestrant in patients with moderate and severe hepatic impairment should be avoided. Patients with mild hepatic impairment are allowed to take camizestrant (see sections 4.4 and 5.2).

Paediatric population

The safety and efficacy of camizestrant in children aged 0‑18 years has not been established. No data are available.

Method of administration

Oral use.

The tablet should be swallowed whole with water and may be taken with or without food, at approximately the same time each day. Etcamah should not be ingested if it is broken, cracked, or otherwise not intact. The tablet should not be chewed, crushed, dissolved, or divided because these methods have not been studied in clinical studies.

4.3. Contraindications

Breast-feeding (see section 4.6).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.5. Interaction with other medicinal products and other forms of interaction

Camizestrant is a reversible inhibitor of CYP3A4/5 and CYP2B6 and cause inhibition of drug transporters P-gp, BCRP and OATP1B1. Camizestrant is a potent, time-dependent, irreversible inhibitor of CYP2C9 and CYP2C19. Camizestrant is a substrate for CYP3A4/5 and P‑gp.

Effects of other medicinal products on camizestrant

CYP3A4/5 inducers

The exposure to camizestrant is expected to decrease if co-administered with moderate and strong CYP3A4/5 inducers. Clinically, a single 75 mg camizestrant dose co-administered orally with repeat doses of carbamazepine, a strong CYP3A4/5 inducer, resulted in camizestrant geometric mean ratios for C_max and AUC of 0.41 [90% CI: 0.37,0.46] and 0.29 [90% CI: 0.28,0.32], respectively. The co-administration of camizestrant and a strong CYP3A4/5 inducer (including but not limited to: carbamazepine, phenytoin, rifampicin and St John's Wort) should be avoided. An alternative medicinal product with no or weak potential to induce CYP3A4/5 should be considered.

When co-administering camizestrant in combination with ribociclib, plus a moderate CYP3A4/5 inducer (including but not limited to: e.g. bosentan, nafcillin, modafinil and phenobarbital), no dose adjustment of camizestrant is necessary. When co-administering camizestrant in combination with abemaciclib or palbociclib, the use of such moderate CYP3A4/5 inducers should be avoided by switching to an alternate concomitant drug product (see section 5.2).

CYP3A4/5 inhibitors

In a clinical study, concomitant use of itraconazole, a strong CYP3A4/5 inhibitor, increased camizestrant geometric mean C_max and AUC_inf by 1.37-fold and 1.90-fold, respectively. Camizestrant in combination with ribociclib should be avoided in patients taking strong CYP3A4/5 inhibitors. In addition, caution should be exercised when combining camizestrant and ribociclib in combination with weak (e.g., chlorzoxazone and fosaprepitant) and moderate (e.g., aprepitant and diltiazem) CYP3A4/5 inhibitors.

Effects of camizestrant on other medicinal products

CYP2C9 and CYP2C19 substrates

In vitro data in conjunction with mechanistic static modelling show that camizestrant is a potent irreversible, time-dependent inhibitor of both CYP2C9 and CYP2C19. This means that the inhibition is irreversible and in order to reinstate functionality, the enzymes need to be synthesised again. Therefore, camizestrant is expected to increase the exposure levels of medicinal products that are substrates of CYP2C9 and/or CYP2C19. No in vivo clinical data is available. Medicinal products that are sensitive substrates (including but not limited to: clobazam, omeprazole, pantoprazole and proguanil) or substrates with narrow therapeutic index of CYP2C9 and/or CYP2C19 (including but not limited to: phenytoin and warfarin) should be stopped at least 2 weeks before the first dose of Etcamah and not used for at least 2 weeks after the last dose of Etcamah.

The co-administration of camizestrant and moderately sensitive substrates of CYP2C9 (including but not limited to: flurbiprofen, siponimod and glyburide) and/or CYP2C19 (including but not limited to: esomeprazole, voriconazole and lansoprazole) may be allowed with caution; however, alternative medicinal products should be considered if possible.

CYP3A4/5 substrates

In a clinical study, concomitant use of camizestrant increased midazolam, a sensitive CYP3A4/5 substrate, geometric mean C_max by 1.50‑fold and AUC by 1.99‑fold respectively, therefore, camizestrant is a weak inhibitor of CYP3A4/5. Camizestrant should be used with caution when co-administered with sensitive CYP3A4/5 substrates (including but not limited to: budesonide, buspirone, dronedarone, ivabradine, lurasidone, midazolam, quetiapine, sildenafil and simvastatin). Narrow therapeutic index CYP3A4/5 substrates (e.g. alfentanil and fentanyl) may require dose adjustment and should be monitored closely.

OATP1B1 sensitive substrates

In vitro data show that camizestrant is an inhibitor of OATP1B1. Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of OATP1B1 including but not limited to glyburide, and lovastatin. No in vivo clinical data is available. Medicinal products which have a narrow therapeutic index and are sensitive substrates of OATP1B1 should be avoided. Those medicinal products which are sensitive substrates of OATP1B1 are permitted but caution should be exercised and patients monitored closely for possible drug interactions.

BCRP sensitive substrates

In vitro data show that camizestrant is an inhibitor of Breast Cancer Resistance Protein (BCRP). Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of BCRP. No in vivo clinical data is available. Those medicinal products that are sensitive substrates of BCRP e.g. rosuvastatin, sulfasalazine and sofosbuvir, are permitted but caution should be exercised and patients monitored closely for possible drug interactions. Medicinal products that have a narrow therapeutic index and are sensitive substrates of BCRP should be avoided.

P-gp sensitive substrates

In vitro data show that camizestrant is an inhibitor of P-glycoprotein (P-gp). Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of P-gp including but not limited to: edoxaban, digoxin, fexofenadine and dabigatran etexilate. No in vivo clinical data is available. Medicinal products which have a narrow therapeutic index and are sensitive substrates of P-gp should be avoided. Those medicinal products which are sensitive substrates of P-gp are permitted but caution should be exercised and patients monitored closely for possible drug interactions.

CYP2B6 sensitive substrates

In vitro data show that camizestrant is an inhibitor of Cytochrome P450 2B6 (CYP2B6). Therefore, camizestrant may increase the exposure levels of medicinal products that are substrates of CYP2B6. No in vivo clinical data are available. Those medicinal products that are sensitive substrates of CYP2B6 including but not limited to: bupropion, nevirapine, ketamine, and cyclophosphamide should be avoided. All other CYP2B6 substrates are permitted but caution should be exercised and patients monitored closely for possible drug interactions.

Medicinal products known to prolong the QT interval

Camizestrant in combination with ribociclib has been studied clinically, a non-fatal Torsades de Pointes was observed in a patient with bradycardia and QTc prolongation for camizestrant in combination with ribociclib. It is recommended to monitor patients clinically and adjust doses as specified in the approved ribociclib SmPC. Co-administration of other medicinal products known to prolong the QT interval and/or have a known risk of Torsades de Pointes (e.g. ciprofloxacin, levofloxacin, ondansetron, escitalopram, venlafaxine, fluconazole, chloroquine, halofantrine, clarithromycin, azithromycin, haloperidol, methadone, moxifloxacin, bepridil, and pimozide) should be avoided. If concomitant use cannot be avoided, monitor ECGs as clinically indicated (see section 4.2).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Based on its mechanism of action and preclinical data, camizestrant may cause foetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving camizestrant. A pregnancy test should be performed and verified as negative on women of childbearing potential prior to initiating treatment and re-testing should be considered throughout treatment.

Contraception in males and females

Women of childbearing potential and men with women partners of childbearing potential have to use effective contraception during treatment with camizestrant and for the following periods after completion of treatment with camizestrant: at least 4 weeks for females and 1 week for males.

Pregnancy

There are no data from the use of camizestrant in pregnant women. Studies in animals have shown reproductive toxicity, including embryo lethality and dystocia (see section 5.3). Based on animal data and its mechanism of action, camizestrant should not be used during pregnancy unless the clinical condition of the women requires treatment with camizestrant.

Breast-feeding

It is not known whether camizestrant and its metabolites are excreted in human milk. Based on animal data (see section 5.3), a risk to the breast‑fed child cannot be excluded. Breast-feeding must be discontinued prior to treatment with camizestrant and must not be resumed until 4 weeks following the last dose (see section 4.3).

Fertility

There are no data on the effect of camizestrant on human fertility. Results from animal studies have shown that camizestrant has marked effects on male and female reproductive organs in mice, rats and dogs and functional effects on female and male fertility in rats (see section 5.3).

4.7. Effects on ability to drive and use machines

Etcamah in combination with a CDK4/6 inhibitor, has a minor influence on the ability to drive and use machines as the combination may cause fatigue and dizziness (see section 4.8). Etcamah, may cause transient visual effects in the peripheral vision consisting mainly of photopsia, which has no or negligible influence on the ability to drive. However, patients who experience these symptoms should be advised to observe caution when driving or operating machinery.

4.9. Overdose

There is no specific treatment in the event of Etcamah overdose. No Maximum Tolerated Dose (MTD) was reached in the phase I studies in which patients received a daily monotherapy dose up to 450 mg. The safety profile of patients treated with once daily doses of 150 mg Etcamah was consistent with the established safety profile of Etcamah at the recommended 75 mg once daily dose (see section 4.8). In case of suspected overdose, patients should be closely monitored and treated symptomatically, if necessary.