Long-term follow-up data of MonarchE confirm adjuvant abemaciclib plus endocrine therapy as standard of care for patients with high-risk, HR+/HER2- early breast cancer^1,2

MINIMAL INFORMATIONS OF THE SPC    1. NAME OF THE MEDICINAL PRODUCT   Verzenios 50 mg film-coated tablets Verzenios 100 mg film-coated tablets Verzenios 150 mg film-coated tablets   2. QUALITATIVE AND QUANTITATIVE COMPOSITION   Verzenios 50 mg film-coated tablets  Each film-coated tablet contains 50 mg abemaciclib.  Excipients with known effect Each film-coated tablet contains 14 mg of lactose monohydrate.  Verzenios 100 mg film-coated tablets  Each film-coated tablet contains 100 mg abemaciclib.  Excipients with known effect Each film-coated tablet contains 28 mg of lactose monohydrate.  Verzenios 150 mg film-coated tablets  Each film-coated tablet contains 150 mg abemaciclib.  Excipients with known effect Each film-coated tablet contains 42 mg of lactose monohydrate.  For the full list of excipients, see section 6.1.   3. PHARMACEUTICAL FORM   Film-coated tablet (tablet).  Verzenios 50 mg film-coated tablets  Beige, oval tablet of 5.2 x 9.5 mm, debossed with “Lilly” on one side and “50” on the other.  Verzenios 100 mg film-coated tablets  White, oval tablet of 6.6 x 12.0 mm, debossed with “Lilly” on one side and “100” on the other.  Verzenios 150 mg film-coated tablets  Yellow, oval tablet of 7.5 x 13.7 mm, debossed with “Lilly” on one side and “150” on the other.   4. CLINICAL PARTICULARS   4.1 Therapeutic indications   Early breast cancer  Verzenios in combination with endocrine therapy is indicated for the adjuvant treatment of adult patients with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative, node‑positive early breast cancer at high risk of recurrence (see section 5.1).  In pre‑ or perimenopausal women, aromatase inhibitor endocrine therapy should be combined with a luteinising hormone‑releasing hormone (LHRH) agonist.  Advanced or metastatic breast cancer  Verzenios is indicated for the treatment of women with hormone receptor (HR)‑positive, human epidermal growth factor receptor 2 (HER2)‑negative locally advanced or metastatic breast cancer in combination with an aromatase inhibitor or fulvestrant as initial endocrine-based therapy, or in women who have received prior endocrine therapy.  In pre- or perimenopausal women, the endocrine therapy should be combined with a LHRH agonist.  4.2 Posology and method of administration   Verzenios therapy should be initiated and supervised by physicians experienced in the use of anti‑cancer therapies.  Posology  The recommended dose of abemaciclib is 150 mg twice daily when used in combination with endocrine therapy. Please refer to the summary of product characteristics of the endocrine therapy combination partner for the recommended posology.   Duration of treatment  Early breast cancer Verzenios should be taken continuously for two years, or until disease recurrence or unacceptable toxicity occurs.  Advanced or metastatic breast cancer Verzenios should be taken continuously as long as the patient is deriving clinical benefit from therapy or until unacceptable toxicity occurs.  If a patient vomits or misses a dose of Verzenios, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.  Dose adjustments  Management of some adverse reactions may require dose interruption and/or dose reduction as shown in Tables 1-7.   Table 1. Dose adjustment recommendations for adverse reactions

 Table 2. Management recommendations for haematologic toxicities  Complete blood counts should be monitored prior to the start of Verzenios therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated. Before treatment initiation, absolute neutrophil counts (ANC) ≥ 1 500 / mm³, platelets ≥ 1 00 000 / mm³, and haemoglobin ≥ 8 g/dL are recommended.   

^a NCI Common Terminology Criteria for Adverse Events (CTCAE) ^b ANC: Grade 1: ANC < LLN – 1 500 / mm³; Grade 2: ANC 1 000 – < 1 500 / mm³;
 Grade 3: ANC 500 – < 1 000 / mm³; Grade 4: ANC < 500 / mm³  LLN = lower limit of normal  Table 3. Management recommendations for diarrhoea  Treatment with antidiarrhoeal agents, such as loperamide, should be started at the first sign of loose stools.

^a NCI CTCAE Table 4. Management recommendations for increased aminotransferases  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) should be monitored prior to the start of Verzenios therapy, every two weeks for the first two months, monthly for the next two months, and as clinically indicated.

^a NCI CTCAEULN = upper limit of normal Table 5. Management recommendations for interstitial lung disease (ILD)/pneumonitis

^a NCI CTCAE  Table 6. Management recommendations for venous thromboembolic events (VTEs)

^a NCI CTCAE  Table 7. Management recommendations for non-haematologic toxicities (excluding diarrhoea, increased aminotransferases, and ILD/pneumonitis and VTEs)

^a NCI CTCAE  CYP3A4 inhibitors Concomitant use of strong CYP3A4 inhibitors should be avoided. If strong CYP3A4 inhibitors cannot be avoided, the abemaciclib dose should be reduced to 100 mg twice daily.  In patients who have had their dose reduced to 100 mg abemaciclib twice daily and in whom co‑administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose should be further reduced to 50 mg twice daily.  In patients who have had their dose reduced to 50 mg abemaciclib twice daily and in whom co‑administration of a strong CYP3A4 inhibitor cannot be avoided, the abemaciclib dose may be continued with close monitoring of signs of toxicity. Alternatively, the abemaciclib dose may be reduced to 50 mg once daily or discontinued.  If the CYP3A4 inhibitor is discontinued, the abemaciclib dose should be increased to the dose used prior to the initiation of the CYP3A4 inhibitor (after 3 to 5 half-lives of the CYP3A4 inhibitor).  Special populations  Elderly No dose adjustment is required based on age (see section 5.2).  Renal impairment No dose adjustments are necessary in patients with mild or moderate renal impairment. There are no data regarding abemaciclib administration in patients with severe renal impairment, end stage renal disease, or in patients on dialysis (see section 5.2). Abemaciclib should be administered with caution in patients with severe renal impairment, with close monitoring for signs of toxicity.  Hepatic impairment No dose adjustments are necessary in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment. In patients with severe (Child Pugh C) hepatic impairment, a decrease in dosing frequency to once daily is recommended (see section 5.2).  Paediatric population The safety and efficacy of abemaciclib in children and adolescents aged less than 18 years has not been established. No data are available.  Method of administration   Verzenios is for oral use.  The dose can be taken with or without food. It should not be taken with grapefruit or grapefruit juice (see section 4.5).  Patients should take the doses at approximately the same times every day.  The tablet should be swallowed whole (patients should not chew, crush, or split tablets before swallowing).  4.3 Contraindications   Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  4.8 Undesirable effects   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 (³1 / 10), common (³1 / 100 to < 1 / 10), uncommon (³1 / 1 000 to < 1 / 100), rare (³1 / 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)  

^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 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: Belgium : Agence fédérale des médicaments et des produits de santé, Division Vigilance, Boîte Postale 97, B- 1000 Bruxelles Madou, Site internet: www.notifieruneffetindesirable.be, e-mail: adr@afmps.be. Luxembourg : Centre Régional de Pharmacovigilance de Nancy ou Division de la pharmacie et des médicaments de la Direction de la santé Site internet : www.guichet.lu/pharmacovigilance   7. MARKETING AUTHORISATION HOLDER   Eli Lilly Nederland B.V., Papendorpseweg 83, 3528BJ Utrecht, The Netherlands.   8. MARKETING AUTHORISATION NUMBER(S)   EU/1/18/1307/001 EU/1/18/1307/002 EU/1/18/1307/003 EU/1/18/1307/004 EU/1/18/1307/005 EU/1/18/1307/006 EU/1/18/1307/007 EU/1/18/1307/008 EU/1/18/1307/009 EU/1/18/1307/010 EU/1/18/1307/011 EU/1/18/1307/012 EU/1/18/1307/013 EU/1/18/1307/014 EU/1/18/1307/015 EU/1/18/1307/016 EU/1/18/1307/017 EU/1/18/1307/018 EU/1/18/1307/019 EU/1/18/1307/020 EU/1/18/1307/021   9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION   Date of first authorisation:  27 September 2018 Date of latest renewal: 23 June 2023   10. DATE OF REVISION OF THE TEXT   23 June 2023.  Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu  METHOD OF DELIVERY Medicinal product subject to restricted medical prescription.