VERZENIOS Film-coated tablet Ref.[7607] Active ingredients: Abemaciclib

Neutropenia

Neutropenia was reported in patients receiving abemaciclib. Dose modification is recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2). Fatal events of neutropenic sepsis occurred in <1% of patients with metastatic breast cancer. Patients should be instructed to report any episode of fever to their healthcare provider.

Infections/infestations

Infections were reported in patients receiving abemaciclib plus endocrine therapy at a higher rate than in patients treated with endocrine therapy. Lung infection was reported in patients receiving abemaciclib without concurrent neutropenia. Fatal events occurred in <1% of patients with metastatic breast cancer. Patients should be monitored for signs and symptoms of infection and treated as medically appropriate.

Venous thromboembolism

Venous thromboembolic events were reported in patients treated with abemaciclib plus endocrine therapy. Patients should be monitored for signs and symptoms of deep vein thrombosis and pulmonary embolism and treated as medically appropriate. Based on the grade of VTE, abemaciclib may require dose modification (see section 4.2).

Arterial Thromboembolic Events

A potential increased risk for serious arterial thromboembolic events (ATEs), including ischemic stroke and myocardial infarction, has been observed in metastatic breast cancer studies when abemaciclib was administered in combination with endocrine therapies. The benefits and risks of continuing abemaciclib in patients who experience a serious ATE should be considered.

Increased aminotransferases

Increases in ALT and AST were reported in patients receiving abemaciclib. Based on the level of ALT or AST elevation, abemaciclib may require dose modification (see section 4.2).

Diarrhoea

Diarrhoea is the most common adverse reaction. Across clinical studies, median time to onset of the first diarrhoea event was approximately 6 to 8 days, and median duration of diarrhoea was 7 to 12 days (Grade 2) and 5 to 8 days (Grade 3). Diarrhoea can be associated with dehydration. Patients should start treatment with antidiarrhoeal agents such as loperamide at the first sign of loose stools, increase oral fluids and notify their healthcare provider. Dose modification is recommended for patients who develop ≥ Grade 2 diarrhoea (see section 4.2).

ILD/Pneumonitis

ILD/pneumonitis was reported in patients receiving abemaciclib. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis and treated as medically appropriate. Based on the grade of ILD/pneumonitis, abemaciclib may require dose modification (see section 4.2). Permanently discontinue abemaciclib in patients with Grade 3 or 4 ILD/pneumonitis.

Concomitant use of inducers of CYP3A4

Concomitant use of CYP3A4 inducers should be avoided due to the risk of decreased efficacy of abemaciclib (see section 4.5).

Visceral crisis

There are no data on the efficacy and safety of abemaciclib in patients with visceral crisis.

Lactose

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Effects of other medicinal products on the pharmacokinetics of abemaciclib

Abemaciclib is primarily metabolised by CYP3A4.

CYP3A4 inhibitors

Co-administration of abemaciclib with CYP3A4 inhibitors can increase plasma concentrations of abemaciclib. In patients with advanced and/or metastatic cancer, co-administration of the CYP3A4 inhibitor clarithromycin resulted in a 3.4-fold increase in the plasma exposure of abemaciclib and a 2.5-fold increase in the combined unbound potency adjusted plasma exposure of abemaciclib and its active metabolites.

Use of strong CYP3A4 inhibitors together with abemaciclib should be avoided. If strong CYP3A4 inhibitors need to be co-administered, the dose of abemaciclib should be reduced (see section 4.2), followed by careful monitoring of toxicity. Examples of strong CYP3A4 inhibitors include, but not limited to: clarithromycin, itraconazole, ketoconazole, lopinavir/ritonavir, posaconazole or voriconazole. Avoid grapefruit or grapefruit juice.

No dose adjustment is necessary for patients treated with moderate or weak CYP3A4 inhibitors. There should, however, be close monitoring for signs of toxicity.

CYP3A4 inducers

Co-administration of abemaciclib with the strong CYP3A4 inducer rifampicin decreased the plasma concentration of abemaciclib by 95% and unbound potency adjusted plasma concentration of abemaciclib plus its active metabolites by 77% based on AUC_0-∞. Concomitant use of strong CYP3A4 inducers (including, but not limited to: carbamazepine, phenytoin, rifampicin and St. John’s wort) should be avoided due to the risk of decreased efficacy of abemaciclib.

Effects of abemaciclib on the pharmacokinetics of other medicinal products

Medicinal products that are substrates of transporters

Abemaciclib and its major active metabolites inhibit the renal transporters organic cation transporter 2 (OCT2), multidrug and extrusion toxin protein (MATE1), and MATE2-K. In vivo interactions of abemaciclib with clinically relevant substrates of these transporters, such as dofetilide or creatinine, may occur (see section 4.8). In a clinical drug interaction study with metformin (substrate of OCT2, MATE1 and 2) co-administered with 400 mg abemaciclib, a small but not clinically relevant increase (37%) in metformin plasma exposure was observed. This was found to be due to reduced renal secretion with unaffected glomerular filtration.

In healthy subjects, co-administration of abemaciclib and the P-glycoprotein (P-gp) substrate loperamide resulted in an increase in loperamide plasma exposure of 9% based on AUC_0-∞ and 35% based on C_max. This was not considered to be clinically relevant. However, based on the in vitro inhibition of P-gp and breast cancer resistance protein (BCRP) observed with abemaciclib, in vivo interactions of abemaciclib with narrow therapeutic index substrates of these transporters, such as digoxin or dabigatran etexilate, may occur.

In a clinical study in patients with breast cancer, there was no clinically-relevant pharmacokinetic drug interaction between abemaciclib and anastrozole, fulvestrant, exemestane, letrozole or tamoxifen.

It is currently unknown whether abemaciclib may reduce the effectiveness of systemically acting hormonal contraceptives.

Women of childbearing potential/Contraception in females

Women of childbearing potential should use highly effective contraception methods (e.g. double-barrier contraception) during treatment and for at least 3 weeks after completing therapy (see section 4.5).

Pregnancy

There are no data from the use of abemaciclib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Verzenios is not recommended during pregnancy and in women of child-bearing potential not using contraception.

Breast-feeding

It is unknown whether abemaciclib is excreted in human milk. A risk to breast-feeding children cannot be excluded. Patients receiving abemaciclib should not breast-feed.

Fertility

The effect of abemaciclib on fertility in humans is unknown. While in rats no effects on male fertility were noted, cytotoxic effects to the male reproductive tract in mice, rats, and dogs indicate that abemaciclib may impair fertility in males. No adverse effects on female reproductive organs in mice, rats, or dogs, nor effects on female fertility and early embryonic development in rats were observed (see section 5.3).

Verzenios has minor influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines in case they experience fatigue or dizziness during treatment with Verzenios (see section 4.8).

Summary of the safety profile

The most commonly occurring adverse reactions are diarrhoea, infections, neutropenia, leukopenia, anaemia, fatigue, nausea, vomiting, alopecia and decreased appetite.

Of the most common adverse reactions, Grade ≥ 3 events were less than 5% with the exception of neutropenia, leukopenia, and diarrhoea.

Tabulated list of adverse reactions

In the following table, adverse reactions are listed in order of MedDRA body system organ class and frequency. Frequency gradings are: 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 the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 8. Adverse reactions reported in the phase 3 studies of abemaciclib in combination with endocrine therapy^a (N=3 559) and during post-marketing experience:

^a Abemaciclib in combination with anastrozole, letrozole, exemestane, tamoxifen, or fulvestrant.
^b Infections include all reported preferred terms that are part of the system organ class infections and infestations.
^c Venous thromboembolic events include deep vein thrombosis (DVT), pulmonary embolism, cerebral venous sinus thrombosis, subclavian, axillary vein thrombosis, DVT inferior vena cava and pelvic venous thrombosis.
^d ILD/pneumonitis for early breast cancer (EBC) include all reported preferred terms that are part of the MedDRA SMQ interstitial lung disease. For metastatic breast cancer (mBC) preferred terms include interstitial lung disease, pneumonitis, organising pneumonia, pulmonary fibrosis and bronchiolitis obliterans.
^e Considered ADRs in the mBC setting only (MONARCH 2 and MONARCH 3).
^f Considered ADRs in the EBC setting only (monarchE).
^g Common frequency in the EBC setting (monarchE), very common in the mBC setting
(MONARCH 2 and MONARCH 3).
^h Common frequency in mBC setting (MONARCH 2 and MONARCH 3), very common in the EBC setting (monarchE).

Description of selected adverse reactions

Neutropenia

Neutropenia was reported frequently across studies. In the monarchE study, neutropenia was reported in 45.8% of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 19.1% of patients receiving abemaciclib in combination with endocrine therapy with a median time to onset of 30 days, and median time to resolution of 16 days. Febrile neutropenia was reported in 0.3% patients. In MONARCH 2 and MONARCH 3 studies, neutropenia was reported in 45.1% of patients. Grade 3 or 4 decrease in neutrophil counts (based on laboratory findings) was reported in 28.2% of patients receiving abemaciclib in combination with aromatase inhibitors or fulvestrant. The median time to onset of Grade 3 or 4 neutropenia was 29 to 33 days, and median time to resolution was 11 to 15 days. Febrile neutropenia was reported in 0.9% patients. Dose modification is recommended for patients who develop Grade 3 or 4 neutropenia (see section 4.2).

Diarrhoea

Diarrhoea was the most commonly reported adverse reaction (see Table 8). Incidence was greatest during the first month of abemaciclib treatment and was lower subsequently. In the monarchE study, the median time to onset of the first diarrhoea event of any grade was 8 days. The median duration of diarrhoea was 7 days for Grade 2 and 5 days for Grade 3. In MONARCH 2 and MONARCH 3 studies, the median time to onset of the first diarrhoea event of any grade was approximately 6 to 8 days. The median duration of diarrhoea was 9 to 12 days for Grade 2 and 6 to 8 days for Grade 3. Diarrhoea returned to baseline or lesser grade with supportive treatment such as loperamide and/or dose adjustment (see section 4.2).

Increased aminotransferases

In the monarchE study, ALT and AST elevations were reported frequently (12.3% and 11.8%, respectively) in patients receiving abemaciclib in combination with endocrine therapy. Grade 3 or 4 ALT or AST elevations (based on laboratory findings) were reported in 2.6% and 1.6% patients. The median time to onset of Grade 3 or 4 ALT elevation was 118 days, and median time to resolution was 14.5 days. The median time to onset of Grade 3 or 4 AST elevation was 90.5 days, and median time to resolution was 11 days. In MONARCH 2 and MONARCH 3 studies, ALT and AST elevations were reported frequently (15.1% and 14.2%, respectively) in patients receiving abemaciclib in combination with aromatase inhibitors or fulvestrant. Grade 3 or 4 ALT or AST elevations (based on laboratory findings) were reported in 6.1% and 4.2% patients. The median time to onset of Grade 3 12 or 4 ALT elevation was 57 to 61 days, and median time to resolution was 14 days. The median time to onset of Grade 3 or 4 AST elevation was 71 to 185 days, and median time to resolution was 13 to 15 days. Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase (see section 4.2).

Creatinine

Although not an adverse reaction, abemaciclib has been shown to increase serum creatinine. In the monarchE study, 99.3% of patients had serum creatinine elevations (based on laboratory findings), and of these, 0.5% of patients had Grade 3 or 4 elevations. In patients receiving endocrine therapy alone, 91.0% reported an increase in serum creatinine (all laboratory grades). In MONARCH 2 and MONARCH 3 studies, 98.3% of patients had serum creatinine elevations (based on laboratory findings), and of these, 1.9% of patients had Grade 3 or 4 elevations. In patients receiving an aromatase inhibitor or fulvestrant alone, 78.4% reported an increase in serum creatinine (all laboratory grades). Abemaciclib has been shown to increase serum creatinine due to inhibition of renal tubular secretion transporters without affecting glomerular function (as measured by iohexol clearance) (see section 4.5). In clinical studies, increases in serum creatinine occurred within the first month of abemaciclib dosing, remained elevated but stable through the treatment period, were reversible upon treatment discontinuation, and were not accompanied by changes in markers of renal function, such as blood urea nitrogen (BUN), cystatin C, or calculated glomerular filtration rate based on cystatin C.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.