The last decades saw a dramatic evolution in the way physicians try to prolong the survival of patients early-stage hormone-receptor positive breast cancer (HR+ BC) and mitigate the characteristic late recurrence risk in these patients. This evolution is characterized by a continuous de-escalation of local therapies paralleled by an optimization of systemic adjuvant treatment strategies, tailored to the individual relapse risk of patients. In a report, developed by Eli Lilly, Prof. Martine Piccart and Prof. Ahmad Awada from the Institut Jules Bordet in Brussels, Prof. Patrick Neven and Prof. Hans Wildiers from the University Hospitals Leuven, Prof. Hannelore Denys from the Ghent University Hospital and Prof. Guy Jerusalem from the CHU Sart Tilman in Liège talk us through the major milestones in the adjuvant therapy journey for HR+/HER- EBC (http://bit.ly/20yearsofevolutionEBC)
Hormone-receptor positive breast cancer (HR+ BC) is the most common subtype of BC. For patients with early-stage HR+ BC, late recurrences are a key challenge, with a continued risk for disease relapse that extends beyond 20 years after diagnosis.1,2 According to the physicians consulted for this project, one of the main objectives in the treatment of patients with HR+ early BC (EBC) is therefore to mitigate this relapse risk.
With respect to the locoregional management of patients with EBC, surgery has evolved from aggressive surgical procedures such as mastectomy towards less invasive, breast conserving strategies.3,4 This transition was accompanied by a continuous optimisation of radiation therapy (RT) for these patients (i.e., partial breast irradiation, hypofractionation).5-9
Endocrine therapy forms the historical backbone of the systemic treatment for HR+/HER2- EBC. Nowadays, tamoxifen monotherapy is still used in pre-menopausal patients with a low recurrence risk. For patients with a higher recurrence risk, the combination of an AI or tamoxifen with OFS is preferred. Importantly, while the AI + OFS combination is most effective in this setting, this combination does come with troublesome adverse events, making prolonged treatment compliance challenging. In this light, physicians often start with a combination of an AI with OFS but keep a relatively low threshold to de-escalate to tamoxifen plus OFS or even tamoxifen alone in case of tolerability issues.10,11 For post-menopausal women with HR+ EBC, multiple studies have shown that an AI instead or in sequence with tamoxifen is superior to adjuvant tamoxifen. However, this better efficacy is accompanied by more adverse events.12-15 The consensus among the experts is therefore that an AI should always be part of the adjuvant treatment for post-menopausal patients with HR+ EBC. Only for patients with very small, low grade tumors tamoxifen alone is still an option. For all other post-menopausal patients, the rule of thumb is to start with an AI and try to stay on it for as long as possible. In case of tolerability issues, it is safe to switch to tamoxifen after 2 to 3 years, although physicians try to avoid this in high-risk patients.
The observation of late relapses in HR+ EBC patients despite 5 years of adjuvant ET has spurred the medical community to evaluate the benefit of extending adjuvant ET beyond 5 years.2 When opting for an ET extension, there seems to be a consensus that the choice of the agent (AI or tamoxifen) is of lesser importance and that patients should be treated with an agent that they can tolerate. Based on the results of the ABCSG-16 trial, 7 years of ET has become the general standard of care for patients in whom extended ET is warranted.16 Only for patients with a (very) high recurrence risk after 5 years of therapy, the expert panel would consider 10 years of ET. Given the impact of ET on the QoL of patients and the associated compliance issues, they consider it very important to involve the patient in the adjuvant treatment choices, discussing the pros and cons of the different options.
Despite the success of adjuvant ET strategies, about 20% of high-risk HR+ EBC patients experience recurrence metastases in the first 10 years following surgery. More importantly, 50% of these relapses during the first 9 years prove to be metastatic, condemning these patients to a non-curative treatment.17 The MonarchE trial demonstrated that adding abemaciclib to adjuvant ET resulted in a significant 34.6% reduction in the risk for an invasive DFS (IDFS) event (HR: 0.653) in high-risk, node-positive HR+ HER2- EBC patients.18 At the four-year landmark, this translates into an absolute IDFS benefit of 6.9% in favour of abemaciclib. In addition, the abemaciclib-treatment was associated with a 35% reduced risk for a distant relapse. At the time of the most recent analysis, OS data were still immature, but with a numerical benefit in OS events for abemaciclib + ET compared to ET alone (147 vs. 168). Interestingly, the magnitude of the benefit obtained with abemaciclib increased over time, beyond the completion of study treatment, indicating a clear carry-over effect.18
In addition to endocrine therapy, also chemotherapy forms an important element of the adjuvant treatment for (selected) HR+ EBC patients. In clinical practice, the choice whether or not to opt for adjuvant chemotherapy is a multidisciplinary decision and should also consider patient preferences. Across the different experts there is a consensus that this choice should first and foremost be based on clinicopathological factors, such as nodal involvement, lymphovascular invasion, tumor grade and proliferation rate. For patients with a low clinicopathological risk, irrespective of the menopausal status, chemotherapy does not add any clinical benefit and can be safely omitted. For post-menopausal patients in whom this clinicopathological assessment points towards a higher risk for disease recurrence, a genome expression profile (GEP) can be used to steer the decision. For post-menopausal patients with a clinicopathological high but genomic low risk, the added benefit of adjuvant chemotherapy is limited and does not outweigh the negative effects of chemotherapy.19-21 In the pre-menopausal setting, the scientific basis to use GEPs in the decision-making process for adjuvant chemotherapy is more scanty.19-21 Also, the standard chemotherapy regimen that is given in the adjuvant setting has been subject to change over the years. Currently, the standard adjuvant chemotherapy consists of a taxane with cyclophosphamide for the majority of HR+ EBC patients, with the addition of (dose-dense) anthracyclines in patients with high-risk features.15,22-24
In conclusion, it is clear that we have come a long way in the adjuvant treatment of patients with HR+ EBC. Most recently, the MonarchE study has set a new benchmark for future clinical trials in the adjuvant setting. Nevertheless, some patients will still suffer a recurrence and continued efforts are needed to further improve patient outcomes. In this respect, it is important to underscore that it is not easy to perform clinical trials in this setting, given the need for large patient populations and long follow-up periods. Currently, several studies are ongoing that evaluate the potential of selective oestrogen receptor degraders (SERDs). In the future, it is likely that also antibody-drug conjugates will be tested in this setting. However, there is also a need for continued research into better prediction of recurrence risk in HR+ EBC patients, as well as further refinement of patient selection that can potentially benefit from CDK4/6 inhibitors in the adjuvant setting.
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 (defined by clinical and pathological features: either ≥ 4 pALN (positive axillary lymph nodes), or 1-3 pALN and at least one of the following criteria: tumor size ≥ 5 cm or histological grade 3). 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.
▼This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
This material is meant only for individuals allowed by law to prescribe or deliver.
Responsible publisher: ELB-Markiesstraat 1/4B Rue du Marquis – 1000 Brussels
PP-ON-BE-0118 MAY 2023
|Hospital price||Patient price|
|Verzenios® 150 mg|
|Verzenios® 150 mg|
|Verzenios® 150 mg|
|In request||In request|
MINIMAL INFORMATIONS OF THE SPC This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions. 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 Verzenios in combination with endocrine therapy 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
|Verzenios dose combination therapy|
|Recommended dose||150 mg twice daily|
|First dose adjustment||100 mg twice daily|
|Second dose adjustment||50 mg twice daily|
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.
|Toxicitya, b||Management recommendations|
|Grade 1 or 2||No dose adjustment required.|
|Grade 3||Suspend dose until toxicity resolves to Grade 2 or less. Dose reduction is not required.|
|Grade 3, recurrent; or Grade 4||Suspend dose until toxicity resolves to Grade 2 or less. Resume at next lower dose.|
|Patient requires administration of blood cell growth factors||Suspend abemaciclib dose for at least 48 hours after the last dose of blood cell growth factors was administered and until toxicity resolves to Grade 2 or less. Resume at next lower dose unless the dose was already reduced for the toxicity that led to the use of the growth factor.|
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.
|Toxicity a||Management recommendations|
|Grade 1||No dose adjustment required.|
|Grade 2||If toxicity does not resolve within 24 hours to Grade 1 or less, suspend dose until resolution. Dose reduction is not required.|
|Grade 2 that persists or recurs after resuming the same dose despite maximal supportive measures||Suspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose.|
|Grade 3 or 4 or requires hospitalisation|
a NCI CTCAE Table 4. Management recommendations for increased aminotransferases Alanine aminotransferase (ALT) and aspartate aminostransferase (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.
|Grade 1 (> ULN – 3.0 x ULN) Grade 2 (> 3.0 – 5.0 x ULN)||No dose adjustment required.|
|Persistent or Recurrent Grade 2, or Grade 3 (> 5.0 – 20.0 x ULN)||Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.|
|Elevation in AST and/or ALT > 3 x ULN WITH total bilirubin > 2 x ULN, in the absence of cholestasis||Discontinue abemaciclib.|
|Grade 4 (> 20.0 x ULN)||Discontinue abemaciclib.|
a NCI CTCAEULN = upper limit of normal Table 5. Management recommendations for interstitial lung disease (ILD)/pneumonitis
|Grade 1 or 2||No dose adjustment required.|
|Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1||Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.|
|Grade 3 or 4||Discontinue abemaciclib.|
a NCI CTCAE Table 6. Management recommendations for venous thromboembolic events (VTEs)
|Early Breast Cancer|
|All Grades (1, 2, 3, or 4)||Suspend dose and treat as clinically indicated. Abemaciclib may be resumed when the patient is clinically stable.|
|Advanced or metastatic breast cancer|
|Grade 1 or 2||No dose modification is required.|
|Grade 3 or 4||Suspend dose and treat as clinically indicated. Abemaciclib may be resumed when the patient is clinically stable.|
a NCI CTCAE Table 7. Management recommendations for non-haematologic toxicities (excluding diarrhoea, increased aminotransferases, and ILD/pneumonitis and VTEs)
|Toxicity a||Management recommendations|
|Grade 1 or 2||No dose adjustment required.|
|Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures to baseline or Grade 1 within 7 days||Suspend dose until toxicity resolves to Grade 1 or less. Resume at next lower dose.|
|Grade 3 or 4|
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 (³ 1 / 10), common (³ 1 / 100 to < 1 / 10), uncommon (³ 1 / 1 000 to < 1 / 100), rare (³ 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 therapya (N = 3 559)
|System Organ Class||Very Common||Common||Uncommon|
|Infections and infestations||Infections b|
|Blood and lymphatic system disorders||Neutropenia Leukopenia Anaemia Thrombocytopenia Lymphopenia h||Febrile neutropenia e|
|Metabolism and nutrition disorders||Decreased appetite|
|Nervous system disorders||Headache f Dysgeusia g Dizziness g|
|Eye disorders||Lacrimation increased|
|Vascular disorders||Venous thromboembolism c|
|Respiratory, thoracic and mediastinal disorders||ILD/pneumonitis d|
|Gastrointestinal disorders||DiarrhoeaVomiting Nausea Stomatitis f||Dyspepsia f|
|Skin and subcutaneous tissue disorders||Alopecia g Pruritus g Rash g||Nail disorder f Dry skin e|
|Musculoskeletal and connective tissue disorders||Muscular weakness e|
|General disorders and administration site conditions||Pyrexia e Fatigue|
|Investigations||Alanine aminotransferase increased g Aspartate aminotransferase increased g|
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 Interstitial lung disease (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: firstname.lastname@example.org. Luxembourg :Centre Régional de Pharmacovigilance de Nancy, Bâtiment de Biologie Moléculaire et de Biopathologie (BBB), CHRU de Nancy – Hôpitaux de Brabois, Rue du Morvan, 54 511 VANDOEUVRE LES NANCY CEDEX, Tél : (+33) 3 83 65 60 85 / 87, E-mail : email@example.com ou Direction de la Santé, Division de la Pharmacie et des Médicaments, 20, rue de Bitbourg, L-1273 Luxembourg-Hamm, Tél. : (+352) 2478 5592, E-mail : firstname.lastname@example.org. Link pour le formulaire : https://guichet.public.lu/fr/entreprises/sectoriel/sante/medecins/notification-effets-indesirables-medicaments.html. 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 10. DATE OF REVISION OF THE TEXT 1 April 2022. 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.