Camizestrant

A non-fatal Torsades de Pointes was observed in a patient with bradycardia and QTc prolongation for camizestrant in combination with ribociclib. Considering bradycardia in the context of potential QTc prolongation may increase the risk of arrhythmia, caution should be exercised when administering camizestrant in combination with agents known to cause QTc prolongation, e.g. ribociclib.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Etcamah is not recommended for patients with severe renal impairment.

Camizestrant is metabolised by the liver. Patients with impaired hepatic function are expected to have increased exposure to camizestrant. As a precautionary measure, the use of camizestrant in patients with moderate and severe hepatic impairment should be avoided.

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.

There are no data from the use of camizestrant in pregnant women. Studies in animals have shown reproductive toxicity, including embryo lethality and dystocia. 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.

It is not known whether camizestrant and its metabolites are excreted in human milk. Based on animal data, 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.

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.

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.

Camizestrant 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. Camizestrant, 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.

Summary of the safety profile

The summary of the safety profile of camizestrant is based on pooled data from 263 patients who received camizestrant in combination with a CDK4/6 inhibitor in phase III (SERENA-6) and phase I (SERENA-1) studies.

The most common adverse reactions (≥15%) for camizestrant in combination with a CDK4/6 inhibitor were neutropenia (59.7%), visual effects (40.7%), infections (38.4%), diarrhoea (21.3%), nausea (21.3%), anaemia (21.3%), fatigue (20.5%) bradycardia (19.8%) and leukopenia (15.6%). Among these, ADRs identified for camizestrant were visual effects (40.7%) and bradycardia (19.8%).

The common Grade 3 or 4 adverse reactions (≥2%) for camizestrant in combination with a CDK4/6 inhibitor were neutropenia (46.4%), leukopenia (9.1%), anaemia (3.4%), infections (3.4%) and alanine aminotransferase increase (2.3%).

The common serious adverse reactions (≥1%) reported in patients receiving camizestrant in combination with a CDK4/6 inhibitor included infections (3.4%) and pyrexia (1.1%).

Adverse reactions leading to treatment discontinuation of camizestrant in patients receiving camizestrant in combination with a CDK4/6 inhibitor were neutropenia (0.4%) and electrocardiogram QT prolonged (0.4%).

The most common adverse reactions (≥2%) leading to dose modification of camizestrant in patients receiving camizestrant in combination with a CDK4/6 inhibitor were infections (6.8%), neutropenia (6.5%), bradycardia (4.2%), electrocardiogram QT prolonged (3.4%), diarrhoea (2.3%), vomiting (2.3%) and visual effects (2.3%).

Tabulated list of adverse reactions

Adverse drug reactions identified for camizestrant in the camizestrant and CDK4/6 inhibitors combination are visual effects and bradycardia. Also included in Table 2 are adverse reactions, and their respective incidence, identified for the camizestrant and CDK4/6 inhibitors combination in the camizestrant in combination with a CDK4/6 inhibitor pool (n=263).

In SERENA-6, the median duration of exposure to camizestrant in combination with a CDK4/6 inhibitor was 15.54 months and to AI in combination with a CDK4/6 inhibitor was 7.36 months. The adverse reaction frequencies from clinical studies are based on all-cause adverse event frequencies, where a proportion of the events for an adverse reaction may have causes other than the drug, such as the disease, other medication or unrelated causes.

Adverse reactions are listed by MedDRA System Organ Class (SOC) and by descending frequency of the MedDRA grouped term. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1 000 to <1/100); rare (≥1/10 000 to <1/1 000); very rare (<1/10 000) and not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

Adverse drug reactions reported in the camizestrant and CDK4/6 inhibitor combination (n=263)^a:

^a Graded according to National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.
^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. In addition to camizestrant, vision blurred is an ADR for palbociclib and photopsia is an ADR for abemaciclib.
^c Bradycardia includes bradycardia and sinus bradycardia.
^d All PTs under the Infections and Infestation SOC.
^e ADR for camizestrant and palbociclib combination.
^f ADR for camizestrant and abemaciclib combination.
^g ADR for camizestrant and ribociclib combination.
^h Neutropenia includes neutropenia and neutrophil count decreased.
ⁱ Anaemia includes anaemia, anaemia macrocytic and iron deficiency anaemia.
^j Leukopenia includes leukopenia and white blood cell count decreased.
^k Thrombocytopenia includes thrombocytopenia and platelet count decreased.

Description of selected adverse reaction

Bradycardia

Among the 19.8% patients with bradycardia reported, 85% patients had bradycardia reported as asymptomatic CTCAE Grade 1, while the remaining 15% had Grade 2 adverse reactions reported. Bradycardia exhibited a time-dependent onset where a gradual decrease in heart rate can reach a stable nadir at approximately 14 days and generally recovered following treatment cessation in a similar time course.

Bradycardia in the presence of drug-induced QTc prolongation has the potential to increase the risk of arrhythmia. QTc prolongation has been reported as an adverse reaction in 18 patients (6.8%) within the camizestrant and CDK4/6 inhibitor combination (see table). Of those, 14 were reported as Grade 1 or Grade 2; 3 were reported as Grade 3 and a Torsades de Pointes (Grade 4) was observed in a patient with bradycardia and QTc prolongation for camizestrant in combination with ribociclib in a phase 1 study. The Grade 3 and 4 events were in combination with ribociclib. Additional monitoring is recommended.

Visual effects

Of the 40.7% patients who reported visual effects, the majority (92.5%) experienced CTCAE Grade 1 adverse reactions, while 6.5% patients experienced CTCAE Grade 2 adverse reactions and 0.9% CTCAE Grade 3 adverse reaction (photopsia) occurred. The most common visual effect was photopsia (24.0%). The median time to the onset of the first visual effect was 9 days. Visual effects ADRs were typically intermittent, of brief duration, and not continuous throughout the day. Visual effects were reported not to worsen over time in patients. Ophthalmological review of patients reporting visual effects showed no evidence of structural effects on the eye or clinically meaningful changes in visual acuity attributed to camizestrant.