THE PLACE OF CDK4/6 INHIBITORS IN THE HR+/HER2- BREAST CANCER SPECTRUM

October 2022 Pharma News Jolien Blokken

In recent years, cyclin-dependant kinase 4/6 (CDK4/6) inhibitors have abundantly proven their worth in the treatment of patients with advanced hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and they are now also being explored in the treatment of patients with early breast cancer (EBC). As metastatic breast cancer (MBC) remains to be incurable, research continues to focus on the development of alternative treatment strategies, including combinations of traditional endocrine therapy (ET) with targeted agents.1

Therapeutic approaches to tackle or delay endocrine resistance in HR+/HER2- MBC

The first-line standard-of-care for patients with HR+/HER2- MBC consists of ET in combination with a CDK4/6 inhibitor.2 For the three CDK4/6 inhibitors available in this setting (palbociclib, ribociclib and abemaciclib), fairly similar progression-free survival (PFS) hazard ratios were reported across their respective pivotal clinical trials. However, some important differences have been noted in their effect on overall survival (OS). In first-line, ribociclib has shown to improve OS, both in pre- and postmenopausal patients.3,4 In contrast however, no OS benefit was seen with the addition of palbociclib to ET in the PALOMA-2 study. Despite a significant improvement in the primary endpoint of PFS, in the final OS analysis presented at ASCO 2022, no significant differences were observed between palbociclib + letrozole vs. placebo + letrozole (53.9 vs. 51.2 months; HR[95%CI]: 0.956[0.777-1.777], p= 0.3378).6 These negative OS results in first-line indicate that this drug is perhaps not suitable for all patients with HR+/HER2- MBC and underscore the importance of careful decision-making. Finally, in MONARCH-3, the use of abemaciclib significantly improved PFS (28.2 vs. 14.8 months, HR= 0.525), but OS data are still awaited.7 However, in the MONARCH-2 trial in patients with HR+/HER2- advanced breast cancer that progressed on endocrine therapy, abemaciclib plus fulvestrant significantly improved median OS to 46.7 months, compared with 37.3 months for patients receiving placebo plus fulvestrant (HR[95%CI]: 0.757[0.606-0.945], p= 0.01).8

Treatment escalation in high-risk HR+/HER2- early breast cancer

In the adjuvant setting, ET is an effective treatment option for patients with endocrine-sensitive EBC. Still, especially for patients with high risk of recurrence, new treatment combinations are needed. In this light, the positive results observed with CDK4/6 inhibitors in the treatment of advanced HR+/HER2- breast cancer triggered the evaluation of these agents in the early-stage setting.9 To date, four clinical trials have assessed CDK4/6 inhibitors in combination with ET in the adjuvant setting. While the results with palbociclib in the Penelope-B and PALLAS trials are negative, the MonarchE trial assessing adjuvant abemaciclib did meet its primary endpoint. The results with adjuvant ribociclib in the NATALEE trial are awaited.10-13 To date, abemaciclib (in combination with ET) is the only CDK4/6 inhibitor that is EMA-approved for the adjuvant treatment of adult patients with HR+/HER2-, node-positive EBC at a high risk of recurrence and is thus the treatment of choice in this setting.14

Patient management strategies

In order to maximise treatment efficacy, potential comorbidities of the patients have to be taken into account and patients should be involved in the treatment decisions. In this shared decision-making process, an optimal and appropriate treatment dose should be chosen and side effects should be managed in a pro-active manner with close monitoring of the patient. In general, however, the toxicity profile of all three drugs is well described and adverse events can usually be managed with dose reductions.15 In this respect, it is important to note that for all three agents, the efficacy does not seem to be compromised in patients who required a dose reduction.16-18

Conclusion

For patients with HR+/HER2- MBC, endocrine-based treatment in combination with a CDK4/6 inhibitor results in superior PFS, with highly comparable hazard ratios for all three agents. However, OS results are less consistent, with palbociclib failing to demonstrate a significant OS benefit in contrast to ribociclib (OS data for abemaciclib are eagerly awaited). For patients with high-risk HR+/HER2- EBC, abemaciclib is currently the first and only CDK4/6 inhibitor to demonstrate efficacy in the adjuvant setting. Finally, throughout the disease course, a patient-centred and multidisciplinary approach should be kept in mind.

References

  1. Elfgen C, et al. Cancers (Basel). 2021;13(23):5994.
  2. Gennari A, et al. Ann Oncol. 2021;32(12): 1475-95.
  3. Lu Y, et al. Clin Cancer Res. 2022;28(5):851-9.
  4. Hortobagyi G, et al. N Engl J Med. 2022;386:942-50.
  5. Rugo HS, et al. Breast Cancer Res Treat. 2019;174(3):719-29.  
  6. Finn RS, et al. Presented at ASCO 2022; Abstract LBA1003.
  7. Johnston S, et al. NPJ Breast Cancer. 2021;7(1):80.
  8. Sledge GW, et al. JAMA Oncol. 2020;6(1):116-124.
  9. Kraus K and Stickeler E. Breast Care (Base). 2020;15(4):337-46.
  10. Mayer E, et al. Lancet. 2021;22(2):212-22.
  11. Gnant M, et al. J Clin Oncol. 2021;40(3):282-93.
  12. Loibl S, et al. J Clin Oncol. 2021;39(14):1518-30.
  13. O’Shaughnessy J, et al. Presented at ESMO Virtual Plenary 2021; Abstract VP8-2021
  14. https://www.ema.europa.eu/en/documents/product-information/verzenios-epar-product-information_en.pdf.
  15. Spring L, et al. Lancet. 2020; 95:817–27.
  16. Hart L, et al. Presented at ASCO 2022; Abstract 1017.
  17. Rugo HS, et al Presented at ASCO 2018; Abstract 1058.
  18. Verma S, et al. Oncologist. 2016;21(10):1165-75.

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.

  • ▼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.
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PP-AL-BE-0261 SEPTEMBER 2022.


Hospital pricePatient price
MBC
Verzenios® 150 mg€ 3.820,11€ 0
Verzenios® 100 mg€ 3.820,11€ 0
Verzenios® 50 mg€ 3.820,11€ 0
EBC
In requestIn 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 dose150 mg twice daily
First dose adjustment100 mg twice daily
Second dose adjustment50 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, bManagement recommendations
Grade 1 or 2No dose adjustment required.
Grade 3Suspend dose until toxicity resolves to Grade 2 or less.  Dose reduction is not required.
Grade 3, recurrent; or Grade 4Suspend dose until toxicity resolves to Grade 2 or less.  Resume at next lower dose.
Patient requires administration of blood cell growth factorsSuspend 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 aManagement recommendations
Grade 1No dose adjustment required.
Grade 2If 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 measuresSuspend 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.

ToxicityaManagement recommendations
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 cholestasisDiscontinue 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

ToxicityaManagement recommendations
Grade 1 or 2No dose adjustment required.
Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures within 7 days to baseline or Grade 1Suspend dose until toxicity resolves to baseline or Grade 1. Resume at next lower dose.
Grade 3 or 4Discontinue abemaciclib.

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

ToxicityaManagement recommendations
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 2No dose modification is required.
Grade 3 or 4Suspend 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 aManagement recommendations
Grade 1 or 2No dose adjustment required.
Persistent or recurrent Grade 2 toxicity that does not resolve with maximal supportive measures to baseline or Grade 1 within 7 daysSuspend 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 ClassVery CommonCommonUncommon
Infections and infestationsInfections b  
Blood and lymphatic system disorders   Neutropenia Leukopenia Anaemia Thrombocytopenia Lymphopenia h Febrile neutropenia e 
Metabolism and nutrition disordersDecreased appetite  
Nervous system disordersHeadache f Dysgeusia g Dizziness g  
Eye disorders Lacrimation increased 
Vascular disorders Venous thromboembolism c 
Respiratory, thoracic and mediastinal disorders ILD/pneumonitis d 
Gastrointestinal disordersDiarrhoeaVomiting  Nausea Stomatitis fDyspepsia f 
Skin and subcutaneous tissue disordersAlopecia g Pruritus g Rash gNail disorder f   Dry skin e 
Musculoskeletal and connective tissue disorders Muscular weakness e 
General disorders and administration site conditionsPyrexia e Fatigue  
InvestigationsAlanine 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: adr@afmps.be. 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 : crpv@chru-nancy.fr 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 : pharmacovigilance@ms.etat.lu. 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.

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