Addressing EGFR-mutated and RET fusion-positive non-small cell lung cancer

MINIMAL INFORMATIONS OF THE SPC 1. NAME OF THE MEDICINAL PRODUCT  Cyramza 10 mg/ml concentrate for solution for infusion    2. QUALITATIVE AND QUANTITATIVE COMPOSITION  One ml of concentrate for solution for infusion contains 10 mg ramucirumab.  Each 10 ml vial contains 100 mg of ramucirumab. Each 50 ml vial contains 500 mg of ramucirumab.   Ramucirumab is a human IgG1 monoclonal antibody produced in murine (NS0) cells by recombinant DNA technology.  Excipient with known effect  Each 10 ml vial contains approximately 17 mg sodium. Each 50 ml vial contains approximately 85 mg sodium. For the full list of excipients, see section 6.1.   3. PHARMACEUTICAL FORM  Concentrate for solution for infusion (sterile concentrate).  The concentrate is a clear to slightly opalescent and colourless to slightly yellow solution, pH 6.0.    4. CLINICAL PARTICULARS  4.1 Therapeutic indications  Gastric cancer  Cyramza in combination with paclitaxel is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum and fluoropyrimidine chemotherapy (see section 5.1).   Cyramza monotherapy is indicated for the treatment of adult patients with advanced gastric cancer or gastro-oesophageal junction adenocarcinoma with disease progression after prior platinum or fluoropyrimidine chemotherapy, for whom treatment in combination with paclitaxel is not appropriate (see section 5.1).  Colorectal cancer  Cyramza, in combination with FOLFIRI (irinotecan, folinic acid, and 5‑fluorouracil), is indicated for the treatment of adult patients with metastatic colorectal cancer (mCRC) with disease progression on or after prior therapy with bevacizumab, oxaliplatin and a fluoropyrimidine.  Non-small cell lung cancer  Cyramza in combination with erlotinib is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer with activating epidermal growth factor receptor (EGFR) mutations (see section 5.1).  Cyramza in combination with docetaxel is indicated for the treatment of adult patients with locally advanced or metastatic non-small cell lung cancer with disease progression after platinum-based chemotherapy.  Hepatocellular carcinoma  Cyramza monotherapy is indicated for the treatment of adult patients with advanced or unresectable hepatocellular carcinoma who have a serum alpha fetoprotein (AFP) of ≥ 400 ng/ml and who have been previously treated with sorafenib.  4.2 Posology and method of administration  Ramucirumab therapy must be initiated and supervised by physicians experienced in oncology.  Posology  Gastric cancer and gastro-oesophageal junction (GEJ) adenocarcinoma  Cyramza in combination with paclitaxel The recommended dose of ramucirumab is 8 mg/kg on days 1 and 15 of a 28 day cycle, prior to paclitaxel infusion. The recommended dose of paclitaxel is 80 mg/m² administered by intravenous infusion over approximately 60 minutes on days 1, 8 and 15 of a 28 day cycle. Prior to each paclitaxel infusion, patients should have a complete blood count and blood chemistry performed to evaluate hepatic function. Criteria to be met prior to each paclitaxel infusion are provided in Table 1.   Table 1: Criteria to be met prior to each paclitaxel administration

	Criteria
Neutrophils	Day 1: ≥1.5 x 109/L Days 8 and 15: ≥1.0 x 109/L
Platelets	Day 1: ≥100 x 109/L Days 8 and 15: ≥75 x 109/L
Bilirubin	<1.5 x upper limit of normal value (ULN)
Aspartate aminotransferase (AST) /Alanine aminotransferase (ALT)	No liver metastases: ALT/AST ≤3 x ULN Liver metastases: ALT/AST ≤5 x ULN

 Cyramza as a single agent The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks.  Colorectal cancer  The recommended dose of ramucirumab is 8 mg/kg every 2 weeks administered by intravenous infusion, prior to FOLFIRI administration. Prior to chemotherapy, patients should have a complete blood count. Criteria to be met prior to FOLFIRI are provided in Table 2.  Table 2: Criteria to be met prior to FOLFIRI administration

	Criteria
Neutrophils	≥1.5 x 109/L
Platelets	≥100 x 109/L
Chemotherapy-related gastro-intestinal toxicity	≤ Grade 1 (National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE])

 Non-small cell lung cancer (NSCLC)  Cyramza in combination with erlotinib for the treatment of NSCLC with activating EGFR mutations The recommended dose of ramucirumab in combination with erlotinib is 10 mg/kg every two weeks.  EGFR mutation status should be determined prior to initiation of treatment with ramucirumab and erlotinib using a validated test method. See erlotinib prescribing information for the posology and method of administration of erlotinib.  Cyramza in combination with docetaxel for the treatment of NSCLC after platinum-based chemotherapy The recommended dose of ramucirumab is 10 mg/kg on day 1 of a 21 day cycle, prior to docetaxel infusion. The recommended dose of docetaxel is 75 mg/m² administered by intravenous infusion over approximately 60 minutes on day 1 of a 21 day cycle. For East Asian patients, a reduced docetaxel starting dose of 60 mg/m² on day 1 of a 21 day cycle should be considered. See docetaxel prescribing information for specific dosing advice.  Hepatocellular carcinoma (HCC)  The recommended dose of ramucirumab as a single agent is 8 mg/kg every 2 weeks.  Alpha fetoprotein (AFP) testing in HCC  Patients with HCC should be selected based on a serum AFP concentration of ≥ 400 ng/ml with a validated AFP test prior to ramucirumab treatment (see section 5.1).  Duration of treatment  It is recommended that treatment be continued until disease progression or until unacceptable toxicity has occurred.  Premedication  Premedication is recommended with a histamine H1 antagonist (for example diphenhydramine) prior to infusion of ramucirumab. If a patient experiences a Grade 1 or 2 infusion-related reaction premedication must be given for all subsequent infusions. If a patient experiences a second Grade 1 or 2 infusion-related reaction (IRR) administer dexamethasone (or equivalent); then, for subsequent infusions, premedicate with the following or equivalent medicinal products: an intravenous histamine H1 antagonist (for example diphenhydramine hydrochloride), paracetamol and dexamethasone.  See prescribing information for paclitaxel, for components of FOLFIRI and for docetaxel, as applicable, for premedication requirements and additional information.  Posology adjustments for ramucirumab  Infusion-related reactions The infusion rate of ramucirumab should be reduced by 50% for the duration of the infusion and all subsequent infusions if the patient experiences a grade 1 or 2 IRR. Ramucirumab should be immediately and permanently discontinued in the event of a grade 3 or 4 IRR (see section 4.4).  Hypertension The blood pressure of patients should be monitored prior to each ramucirumab administration and treated as clinically indicated. Ramucirumab therapy should be temporarily discontinued in the event of severe hypertension, until controlled with medical management. If there is medically significant hypertension that cannot be controlled safely with antihypertensive therapy, ramucirumab therapy should be permanently discontinued (see section 4.4).  Proteinuria Patients should be monitored for the development or worsening of proteinuria during ramucirumab therapy. If the urine protein is ≥2+ on a dipstick, a 24 hour urine collection should be performed. Ramucirumab therapy should be temporarily discontinued if the urine protein level is ≥2 g/24 hours. Once the urine protein level returns to <2 g/24 hours, treatment should be resumed at a reduced dose level (see Table 3). A second dose reduction (see Table 3) is recommended if a urine protein level ≥2 g/24 hours reoccurs.  Ramucirumab therapy should be permanently discontinued if the urine protein level is >3 g/24 hours or in the event of nephrotic syndrome.   Table 3: Ramucirumab dose reductions for proteinuria

Initial ramucirumab dose	First dose reduction to	Second dose reduction to
8 mg/kg	6 mg/kg	5 mg/kg
10 mg/kg	8 mg/kg	6 mg/kg

 Elective surgery or impaired wound healing Ramucirumab therapy should be temporarily discontinued for at least 4 weeks prior to elective surgery. Ramucirumab therapy should be temporarily discontinued if there are wound healing complications, until the wound is fully healed (see section 4.4).  Permanent discontinuation  Ramucirumab therapy should be permanently discontinued in the event of: Severe arterial thromboembolic events (see section 4.4). Gastrointestinal perforations (see section 4.4). Severe bleeding: NCI CTCAE Grade 3 or 4 bleeding (see section 4.4). Spontaneous development of fistula (see section 4.4). Hepatic encephalopathy or hepatorenal syndrome (see section 4.4).  Paclitaxel dose adjustments  Paclitaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. For NCI CTCAE Grade 4 haematological toxicity or Grade 3 paclitaxel-related non-haematological toxicity, it is recommended to reduce the paclitaxel dose by 10 mg/m² for all following cycles. A second reduction of 10 mg/m² is recommended if these toxicities persist or reoccur.   FOLFIRI dose adjustments  Dose reductions for individual components of FOLFIRI may be made for specific toxicities. Dose modifications of each component of FOLFIRI should be made independently and are provided in Table 4. Table 5 provides details of dose delays or dose reductions of components of FOLFIRI at the next cycle based on maximum grade of specific adverse drug reactions.  Table 4: FOLFIRI dose reductions

FOLFIRI componenta	Dose level
Initial dose	-1	-2	-3
Irinotecan	180 mg/m2	150 mg/m2	120 mg/m2	100 mg/m2
5‑FU bolus	400 mg/m2	200 mg/m2	0 mg/m2	0 mg/m2
5‑FU infusion	2,400 mg/m2 over 46‑48 hours	2,000 mg/m2 over 46‑48 hours	1,600 mg/m2 over 46‑48 hours	1,200 mg/m2 over 46‑48 hours

^a 5-FU = 5-fluorouracil.  Table 5: Dose modification of FOLFIRI components due to specific ADRs

ADR	NCI CTCAE grade	Dose modification at day 1 of cycle subsequent to ADR
Diarrhoea	2	If diarrhoea has recovered to Grade ≤1, reduce by 1 dose level for 5‑FU. For recurrent Grade 2 diarrhoea, reduce by 1 dose level for 5‑FU and irinotecan.
	3	If diarrhoea has recovered to Grade ≤1, reduce by 1 dose level for 5‑FU and irinotecan.
	4	If diarrhoea has recovered to Grade ≤1, reduce by 2 dose levels for 5‑FU and irinotecan. If Grade 4 diarrhoea does not resolve to Grade ≤1, withhold 5‑FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1.
Neutropenia or Thrombocytopenia		Haematological criteria in Table 2 are met	Haematological criteria in Table 2 are not met
	2	No dose modification.	Reduce by 1 dose level for  5‑FU and irinotecan.
	3	Reduce by 1 dose level for 5‑FU and irinotecan.	Delay 5‑FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 1 level for 5‑FU and irinotecan.
	4	Reduce by 2 dose levels for 5‑FU and irinotecan.	Delay 5‑FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 levels for 5‑FU and irinotecan.
Stomatitis/Mucositis	2	If stomatitis/mucositis has recovered to Grade ≤1, reduce by 1 dose level for 5‑FU. For recurrent Grade 2 stomatitis, reduce by 2 dose levels for 5‑FU.
	3	If stomatitis/mucositis has recovered to Grade ≤1, reduce by 1 dose level for 5‑FU. If Grade 3 mucositis/stomatitis does not resolve to Grade ≤1, delay 5‑FU for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 levels for 5‑FU.
	4	Withhold 5‑FU for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 dose levels for 5‑FU.
Febrile neutropenia		Haematological criteria in Table 2 are met and fever resolved	Haematological criteria in Table 2 are not met and fever resolved
		Reduce by 2 dose levels for 5‑FU and irinotecan.	Delay 5‑FU and irinotecan for a maximum of 28* days until resolution to Grade ≤1, then dose reduce by 2 levels for 5‑FU and irinotecan. Consider use of colony-stimulating factor prior to next cycle.

*The 28 day time period begins on day 1 of the cycle subsequent to the ADR.  Docetaxel dose adjustments  Docetaxel dose reductions may be applied based upon the grade of toxicity experienced by the patient. Patients who experience either febrile neutropenia, neutrophils <500 cells/mm³ for more than 1 week, severe or cumulative cutaneous reactions, or other Grade 3 or 4 non-haematological toxicities during docetaxel treatment should have treatment withheld until resolution of the toxicity. It is recommended to reduce the docetaxel dose by 10 mg/m² for all following cycles. A second reduction of 15 mg/m² is recommended if these toxicities persist or reoccur. In this case, East Asian patients with a starting dose of 60 mg/m² should have docetaxel treatment discontinued (see Posology).  Special populations  Elderly In the pivotal studies there is limited evidence that patients 65 years of age or older are at increased risk of adverse events compared to patients younger than 65 years old. No dose reductions are recommended (see sections 4.4 and 5.1).  Renal impairment There have been no formal studies with Cyramza in patients with renal impairment. Clinical data suggest that no dose adjustments are required in patients with mild, moderate or severe renal impairment (see sections 4.4 and 5.2). No dose reductions are recommended.    Hepatic impairment There have been no formal studies with Cyramza in patients with hepatic impairment. Clinical data suggest that no dose adjustments are required in patients with mild or moderate hepatic impairment. There are no data regarding ramucirumab administration in patients with severe hepatic impairment (see sections 4.4 and 5.2). No dose reductions are recommended.  Paediatric population The safety and efficacy of Cyramza in children and adolescents (<18 years) has not been established.  Currently available data are described in section 4.8, 5.1 and 5.2. Due to limited data no recommendation on posology can be made.   There is no relevant use of ramucirumab in the paediatric population for the indications of advanced gastric cancer or gastro-oesophageal adenocarcinoma, adenocarcinoma of the colon and rectum, lung carcinoma, and hepatocellular carcinoma.  Method of administration   Cyramza is for intravenous use. After dilution, Cyramza is administered as an intravenous infusion over approximately 60 minutes. It should not be administered as an intravenous bolus or push. To achieve the required infusion duration of approximately 60 minutes, the maximum infusion rate of 25 mg/minute should not be exceeded, instead the infusion duration should be increased. The patient should be monitored during infusion for signs of infusion-related reactions (see section 4.4) and the availability of appropriate resuscitation equipment should be ensured.   For instructions on dilution of the medicinal product before administration, see section 6.6.   4.3 Contraindications  Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.  For patients with NSCLC, ramucirumab is contraindicated where there is tumour cavitation or tumour involvement of major vessels (see section 4.4).  4.8 Undesirable effects  Summary of the safety profile  The most serious adverse reactions associated with ramucirumab treatment (as a single agent or in combination with cytotoxic chemotherapy) were: Gastrointestinal perforation (see section 4.4) Severe gastrointestinal haemorrhage (see section 4.4) Arterial thromboembolic events (see section 4.4) Posterior reversible encephalopathy syndrome (see section 4.4) The most common adverse reactions observed in patients treated with ramucirumab as monotherapy are: peripheral oedema, hypertension, diarrhoea, abdominal pain, headache, proteinuria and thrombocytopenia.  The most common adverse reactions observed in patients treated with ramucirumab in combination with chemotherapy are: fatigue/asthenia, neutropenia, diarrhoea, epistaxis and stomatitis.  The most common adverse reactions observed in patients treated with ramucirumab in combination with erlotinib are: infections, diarrhoea, hypertension, stomatitis, proteinuria, alopecia and epistaxis.  Tabulated list of adverse reactions  Tables 6 and 7 below list the adverse drug reactions (ADRs) from placebo controlled phase III clinical trials associated with ramucirumab used either as a monotherapy treatment for gastric cancer and HCC or in combination with different chemotherapy regimens or erlotinib for the treatment of gastric cancer, mCRC and NSCLC. ADRs are listed below by MedDRA body system organ class.  The following convention has been used for classification of frequency for ADR tables:  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) Not known (cannot be estimated from the available data)  Within each frequency grouping, ADRs are presented in order of decreasing seriousness.  Table 6: ADRs reported in patients treated with ramucirumab as monotherapy in phase 3 clinical trials (REGARD, REACH-2 and REACH patients with alpha fetoprotein ≥ 400 ng/ml)  

System Organ Class (MedDRA)	Very Common	Common	Uncommon
Blood and lymphatic system disorders	Thrombocytopeniaa	Neutropeniaa
Metabolism and nutrition disorders		Hypokalaemiaa,b Hyponatraemiaa Hypoalbuminaemiaa
Nervous system disorders	Headache	Hepatic encephalopathyc
Vascular disorders	Hypertensiona,d	Arterial thromboembolic eventsa
Respiratory, thoracic, and mediastinal disorders		Epistaxis
Gastrointestinal disorders	Abdominal paina,e Diarrhoea	Intestinal obstructiona	Gastrointestinal perforationa
Skin and subcutaneous tissue disorders		Rasha
Renal and urinary disorders	Proteinuriaa,f
General disorders and administration site disorders	Peripheral oedema	Infusion-related reactionsa

^a Terms represent a group of events that describe a medical concept rather than a single event or preferred term. ^b Includes: hypokalaemia and blood potassium decreased. ^c Based on study REACH-2 and REACH (single-agent ramucirumab in HCC). Includes hepatic encephalopathy and hepatic coma. ^d Includes: blood pressure increased and hypertension. ^e Includes: abdominal pain, abdominal pain lower, abdominal pain upper, and hepatic pain. ^f Includes one case of nephrotic syndrome  Table 7: ADRs reported in patients treated with ramucirumab in combination with chemotherapy or erlotinib in phase 3 clinical trials (RAINBOW, REVEL, RAISE and RELAY)

System Organ Class (MedDRA)	Very Common	Common
Infections and infestations	Infectionsj,k	Sepsisa,b
Blood and lymphatic system disorders	Neutropeniaa Leukopeniaa,c Thrombocytopeniaa Anaemiaj	Febrile neutropeniad
Metabolism and nutrition disorders		Hypoalbuminaemiaa Hyponatraemiaa
Nervous system disorders	Headachej
Vascular disorders	Hypertensiona,e
Respiratory, thoracic, and mediastinal disorders	Epistaxis	Pulmonary haemorrhagej,l
Gastrointestinal disorders	Stomatitis Diarrhoea	Gastrointestinal haemorrhage eventsa,f Gastrointestinal perforationa  Gingival bleedingj
Skin and subcutaneous tissue disorders	Alopeciaj	Palmar-plantar erthyrodysaesthesia syndromeg
Renal and urinary disorders	Proteinuriaa,h
General disorders and administration site disorders	Fatiguea,i Mucosal inflammationd Peripheral oedema

^a Terms represent a group of events that describe a medical concept rather than a single event or preferred term. ^b Based on study RAINBOW (ramucirumab plus paclitaxel). ^c Based on study RAINBOW (ramucirumab plus paclitaxel). Includes: leukopenia and white blood cell count decreased. ^d Based on study REVEL (ramucirumab plus docetaxel). ^e Includes: blood pressure increased, hypertension, and hypertensive cardiomyopathy. ^f Based on study RAINBOW (ramucirumab plus paclitaxel) and study RAISE (ramucirumab plus FOLFIRI). Includes: anal haemorrhage, diarrhoea haemorrhage, gastric haemorrhage, gastrointestinal haemorrhage, haematemesis, haematochezia, haemorrhoidal haemorrhage, Mallory‑Weiss syndrome, melaena, oesophageal haemorrhage, rectal haemorrhage, and upper gastrointestinal haemorrhage. ^g Based on study RAISE (ramucirumab plus FOLFIRI).^h Includes cases of nephrotic syndrome. ⁱ Based on study RAINBOW (ramucirumab plus paclitaxel) and study REVEL (ramucirumab plus docetaxel). Includes: fatigue and asthenia. ^j Based on study RELAY (ramucirumab plus erlotinib). ^k Infections includes all preferred terms that are part of the System Organ Class Infections and infestations. Most common (³1%) Grade ³3 infections include pneumonia, cellulitis, paronychia, skin infection, and urinary tract infection.^l Includes haemoptysis, laryngeal haemorrhage, haemothorax (a fatal event occurred) and pulmonary haemorrhage.  Clinically relevant reactions (including Grade ≥3) associated with antiangiogenic therapy observed in ramucirumab-treated patients across clinical studies were: gastrointestinal perforations, infusion-related reactions and proteinuria (see sections 4.2 and 4.4).   Colorectal cancer  Ramucirumab in combination with FOLFIRI In the RAISE study, in mCRC patients treated with ramucirumab plus FOLFIRI, the most frequent (≥1%) ADR that led to the discontinuation of ramucirumab was proteinuria (1.5%). The most frequent (≥1%) ADRs leading to discontinuation of one or more components of FOLFIRI were: neutropenia(12.5%), thrombocytopenia (4.2%), diarrhoea (2.3%) and stomatitis (2.3%). The most frequent component of FOLFIRI to be discontinued was the 5‑FU bolus.  Adverse reactions from other sources   Table 8: Post-marketing ADRs associated with ramucirumab reported in clinical trials and through post-marketing reporting   

System Organ Class (MedDRA)	Common	Uncommon	Rare	Not known
Neoplasms benign, malignant and unspecified (including cysts and polyps)	Haemangioma
Blood and lymphatic system disorders			Thrombotic microangiopathy
Endocrine disorders	Hypothyroidism
Nervous system disorders			Posterior reversible encephalopathy syndrome
Vascular disorders				Aneurysms and artery dissections
Respiratory, thoracic and mediastinal disorders	Dysphonia

 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.  Paediatric population  No new safety concerns were identified based on the limited number of paediatric patients treated with ramucirumab monotherapy in study I4T‑MC‑JVDA (see section 5.1). One patient in this study had progressive widening of distal femoral growth plate. The impact of this finding on growth is not known.  7. MARKETING AUTHORISATION HOLDER  Eli Lilly Nederland B.V.Papendorpseweg 83  3528 BJ Utrecht  The Netherlands  8. MARKETING AUTHORISATION NUMBER(S)   EU/1/14/957/001-003   9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  Date of first authorisation: 19 December 2014 Date of latest renewal: 26 September 2019   10. DATE OF REVISION OF THE TEXT  21 August 2021.  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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	Hospital Price (€)	Patient Price (€)
CYRAMZA® 100mg	377.74	0
CYRAMZA® 500mg	1888.69	0

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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  Retsevmo 40 mg hard capsules Retsevmo 80 mg hard capsules   2. QUALITATIVE AND QUANTITATIVE COMPOSITION  Retsevmo 40 mg hard capsules  Each hard capsule contains 40 mg selpercatinib.  Retsevmo 80 mg hard capsules  Each hard capsule contains 80 mg selpercatinib.  For the full list of excipients, see section 6.1.   3. PHARMACEUTICAL FORM  Hard capsules.  Retsevmo 40 mg hard capsules  Grey opaque capsule, 6 x 18 mm (size 2), imprinted with “Lilly”, “3977” and “40 mg” in black ink.  Retsevmo 80 mg hard capsules  Blue opaque capsule, 8 x 22 mm (size 0), imprinted with “Lilly”, “2980” and “80 mg” in black ink.   4. CLINICAL PARTICULARS  4.1 Therapeutic indications  Retsevmo as monotherapy is indicated for the treatment of adults with:  advanced RET fusion‑positive non‑small cell lung cancer (NSCLC) who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy advanced RET fusion‑positive thyroid cancer who require systemic therapy following prior treatment with sorafenib and/or lenvatinib Retsevmo as monotherapy is indicated for the treatment of adults and adolescents 12 years and older with advanced RET‑mutant medullary thyroid cancer (MTC) who require systemic therapy following prior treatment with cabozantinib and/or vandetanib. 4.2 Posology and method of administration  Retsevmo therapy should be initiated and supervised by physicians experienced in the use of anti‑cancer therapies.  RET testing  The presence of a RET gene fusion (NSCLC and non‑medullary thyroid cancer) or mutation (MTC) should be confirmed by a validated test prior to initiation of treatment with Retsevmo.  Posology  The recommended dose of Retsevmo based on body weight is:  Less than 50 kg: 120 mg twice daily.  50 kg or greater: 160 mg twice daily.  If a patient vomits or misses a dose, the patient should be instructed to take the next dose at its scheduled time; an additional dose should not be taken.   Treatment should be continued until disease progression or unacceptable toxicity.   The current selpercatinib dose should be reduced by 50% if co‑administering with a strong CYP3A inhibitor. If the CYP3A inhibitor is discontinued, the selpercatinib dose should be increased (after 3‑5 half‑lives of the inhibitor) to the dose that was used before starting the inhibitor.  Dose adjustments Management of some adverse reactions may require dose interruption and/or dose reduction. Retsevmo dose modifications are summarised in Table 1 and Table 2.  Table 1 Recommended dose modifications for Retsevmo for adverse reactions based on body weight

Dose modification	Adults and adolescents ≥50 Kg	Adults and adolescents <50 Kg
Starting dose	160 mg orally twice daily	120 mg orally twice daily
First dose reduction	120 mg orally twice daily	80 mg orally twice daily
Second dose reduction	80 mg orally twice daily	40 mg orally twice daily
Third dose reduction	40 mg orally twice daily	Not applicable

  Table 2 Recommended dose modifications for adverse reactions  

Adverse drug reaction (ADR)		Dose modification
Increased ALT or AST	Grade 3 or Grade 4	Suspend dose until toxicity resolves to baseline (see sections 4.4 and 4.8). Resume at a dose reduced by 2 levels.  If after at least 2 weeks selpercatinib is tolerated without recurrent increased ALT or AST, increase dosing by 1 dose level.  If selpercatinib is tolerated without recurrence for at least 4 weeks, increase to dose taken prior to the onset of Grade 3 or 4 increased AST or ALT. Permanently discontinue selpercatinib if Grade 3 or 4 ALT or AST increases recur despite dose modifications.
Hypersensitivity	All Grades	Suspend dose until toxicity resolves and begin corticosteroids at a dose of 1 mg/kg (see sections 4.4 and 4.8). Resume selpercatinib at 40 mg twice daily while continuing steroid treatment. Discontinue selpercatinib for recurrent hypersensitivity. If after at least 7 days, selpercatinib is tolerated without recurrent hypersensitivity, incrementally increase the selpercatinib dose by 1 dose level each week, until the dose taken prior to the onset of hypersensitivity is reached. Taper steroid dose after selpercatinib has been tolerated for at least 7 days at the final dose.
QT interval prolongation	Grade 3	Suspend dose for QTcF intervals >500 ms until the QTcF returns to <470 ms or baseline (see section 4.4).  Resume selpercatinib treatment at the next lower dose level.
Grade 4	Permanently discontinue selpercatinib if QT prolongation remains uncontrolled after two dose reductions or if the patient has signs or symptoms of serious arrhythmia.
Hypertension	Grade 3	Patient blood pressure should be controlled before starting treatment. Selpercatinib should be suspended temporarily for medically significant hypertension until controlled with antihypertensive therapy. Dosing should be resumed at the next lower dose if clinically indicated (see sections 4.4 and 4.8).
Grade 4	Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled.
Haemorrhagic events	Grade 3 or Grade 4	Selpercatinib should be suspended until recovery to baseline.  Discontinue selpercatinib for severe or life-threatening haemorrhagic events.
Other adverse reactions	Grade 3 or Grade 4	Selpercatinib should be suspended until recovery to baseline.  Discontinue selpercatinib for severe or life-threatening events

 Special populations  Elderly No dose adjustment is required based on age (see section 5.2). No overall differences were observed in the treatment emergent adverse events or effectiveness of selpercatinib between patients who were ≥65 years of age and younger patients. Limited data are available in patients ≥75 years.  Renal impairment Dose adjustment is not necessary in patients with mild, moderate or severe renal impairment. There are no data in patients with end stage renal disease, or in patients on dialysis (section 5.2).  Hepatic impairment Close monitoring of patients with impaired hepatic function is important. No dose adjustment is required for patients with mild (Child‑Pugh class A) or moderate (Child‑Pugh class B) hepatic impairment. Patients with severe (Child‑Pugh class C) hepatic impairment should be dosed with 80 mg selpercatinib twice daily (section 5.2).   Paediatric population Retsevmo should not be used in children aged less than 12 years.  There is no data in children or adolescents with RET fusion‑positive NSCLC or thyroid cancer. Retsevmo is intended to be used from the age of 12 years for the treatment of patients with RET‑mutant MTC (see section 5.1). In RET‑mutant MTC, there are very limited data available in children or adolescents aged less than 18 years. Patients should be dosed according to body weight (see section 4.2).   Method of administration   Retsevmo is for oral use.  The capsules should be swallowed whole (patients should not open, crush, or chew the capsule before swallowing) and can be taken with or without food.  Patients should take the doses at approximately the same time every day.  Retsevmo must be accompanied by a meal if used concomitantly with a proton pump inhibitor (see section 4.5). Retsevmo should be administered 2 hours before or 10 hours after H₂ receptor antagonists (see section 4.5).  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 common serious adverse drug reactions (ADRs) are hypertension (0.9%), increased aspartate aminotransferase (AST) (1.6%) and increased alanine aminotransferase (ALT) (1.6%).  Permanent discontinuation of Retsevmo for treatment emergent adverse events, regardless of attribution occurred in 6.0% of patients. ADRs resulting in permanent discontinuation (2 or more patients) included increased ALT (0.4%), increased AST (0.3%), hypersensitivity (0.4%), and thrombocytopenia (0.3%).   Tabulated list of adverse drug reactions  The ADRs reported in the 746 patients treated with selpercatinib are shown in Table 3.  The ADRs are classified according to MedDRA the system organ class. Frequency groups are defined by the following convention: 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 group, undesirable effects are presented in order of decreasing seriousness. Median time on treatment with selpercatinib was 11.07 months.  Table 3 Adverse drug reactions in patients receiving single agent selpercatinib (LIBRETTO‑001)

System organ class	ADR	Selpercatinib (N=746)
All grades toxicity (%)	Grade 3, 4 toxicity (%)
Immune system disordersa	Common
Hypersensitivityc	5.2	1.7*
Metabolism and nutrition disorders	Very common
Decreased appetite	14.1	0.1*
Nervous system disorders	Very common
Headachec	24	1.5*
Dizzinessc	14.6	0.1*
Cardiac disorders	Very common
Electrocardiogram QT prolongedc	18.1	4.0
Vascular disorders	Very common
Hypertensionc	37.4	19.4
Gastrointestinal disorders	Very common
	Abdominal painc	25.5	1.9*
	Diarrhoeac	39.0	3.5*
	Nausea	23.5	0.7*
	Vomiting	16.2	0.9*
	Constipation	27.1	0.5*
	Dry Mouthc	40.3	0
Skin and subcutaneous tissue disorders	Very common
Rashc	28.7	0.7*
General disorders and administration site conditions	Very common
	Pyrexia	14.3	0.1*
	Fatiguec	38.2	2.3*
	Oedemac	38.7	0.5*
Investigationsb	Very common
	ALT increased	49.5	10.6
	AST increased	55.0	9
	Platelets decreased	34.5	3.0
	LymphocytecCount decreased	46.2	16.1
	Magnesium decreased	25.6	0.5
	Creatinine increased	39.1	1.2
Blood and lymphatic system	Very common Haemorrhaged	16.6	2.4

^a Hypersensitivity reactions were characterised by a maculopapular rash often preceded by a fever with associated arthralgias/myalgias during the patient’s first cycle of treatment (typically between Days 7‑21). ^b Based on laboratory assessments. Only patients with baseline and at least one post-baseline result are included.  ^c Consolidated terms ^d See Description of selected adverse reactions for further characterisation. ^*Only includes a grade 3 adverse reaction.   Description of selected adverse reactions  Aminotransferase elevations (AST / ALT increased) Based on laboratory assessment, ALT and AST elevations were reported in 49.5% and 55% patients, respectively. Grade 3 or 4 ALT or AST elevations were reported in 10.6% and 9.0% patients respectively.  The median time to first onset was: AST increase 4.1 weeks (range: 0.7, 108.1), ALT increase 4.1 weeks (range: 0.9, 111.1).  Dose modification is recommended for patients who develop Grade 3 or 4 ALT or AST increase (see section 4.2).  QT interval prolongation Review of ECG data showed 6.2% of patients had >500 msec maximum post‑baseline QTcF value, and 17.5% of patients had a >60 msec maximum increase from baseline in QTcF intervals. At the time of the last post-baseline measurement, increase in QTc value >60 msec was reported in 2.6% of patients.  There were no reports of Torsade de pointes, sudden death, ventricular tachycardia, ventricular fibrillation, or ventricular flutter. No patient discontinued treatment due to QT prolongation. Retsevmo may require dose interruption or modification (see sections 4.2 and 4.4).  Hypertension In patients receiving selpercatinib, the median maximum increase from baseline systolic pressure was 29 mm Hg (range: –11, +96). Only 13% of patients retained their baseline grade during treatment, 45% had an increasing shift of 1 grade, 32.7% of 2 grades, and 8.3% of 3 grades. Hypertension was reported in 41.9% patients with history of hypertension (26.9% with grade 3) and 34.2% of patients without history of hypertension (14.1% with grade 3, 4). Overall, a total of 19.4% displayed treatment‑emergent Grade 3 hypertension (defined as maximum systolic blood pressure greater than 160 mm Hg). Diastolic blood pressure results were similar, but the increases were of lesser magnitude. No patients were permanently discontinued due to hypertension. Dose modification is recommended in patients who develop hypertension (see section 4.2). Selpercatinib should be discontinued permanently if medically significant hypertension cannot be controlled with antihypertensive therapy (see section 4.4).  Hypersensitivity  Signs and symptoms of hypersensitivity included fever, rash and arthralgias or myalgias with concurrent decreased platelets or increased aminotransferase. In study LIBRETTO‑001, 24.7% (184/746) of patients treated with selpercatinib had previously received anti‑PD‑1/PD‑L1 immunotherapy. Hypersensitivity occurred in a total of 5.2% (39/746) of patients receiving selpercatinib, including Grade 3 hypersensitivity in 1.7% (13/746) of patients.  Of the 39 patients with hypersensitivity, 64.1% (25/39) had NSCLC and had received prior anti‑PD‑1/PD‑L1 immunotherapy. Grade 3 hypersensitivity occurred in 3.8% (7/184) of the patients previously treated with anti‑PD‑1/PD‑L1 immunotherapy.  The median time to onset was 1.9 weeks (range: 0.9 week to 77 weeks): 1.7 weeks in patients with previous anti‑PD‑1/PD‑L1 immunotherapy and 8.9 weeks in patients who were immunotherapy naïve.   Retsevmo may require dose interruption or modification (see section 4.2).   Haemorrhages Grade ≥3 haemorrhagic events occurred in 2.4% of patients treated with selpercatinib, including 3 (0.4%) patients with fatal haemorrhagic events, one case each of cerebral haemorrhage, tracheostomy site haemorrhage, and haemoptysis. The median time to onset was 12.8 weeks (range: 0.1 week to 124.3 weeks). Selpercatinib should be discontinued permanently in patients with severe or life‑threatening haemorrhage (see section 4.2).   Additional information on special populations  Paediatric patients There were 3 patients < 18 years (range: 15‑17) of age in LIBRETTO‑001. The safety of selpercatinib in children aged less than 18 years has not been established.   Elderly In patients receiving selpercatinib, 24.5% were ≥65‑74 years of age, 8.2% were 75‑84 years of age, and 1.07% ≥ 85 years of age. The frequency of serious adverse events reported was higher in patients ≥65‑74 years (43.2%), 75‑84 years (50.8%), and ≥85 years (62.5%), than in patients <65 years (29.8%) of age. The frequency of AE leading to discontinuation of selpercatinib was higher in patients ≥65‑74 years (6.0%), 75‑84 years (13.1%), and ≥85 years (12.5%), than in patients <65 years of age (3.2%).  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/1/20/1527/001 EU/1/20/1527/002 EU/1/20/1527/003 EU/1/20/1527/004 EU/1/20/1527/005 EU/1/20/1527/006 EU/1/20/1527/007 EU/1/20/1527/008 EU/1/20/1527/009 EU/1/20/1527/010 EU/1/20/1527/011   9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION  Date of first authorisation: 11 February 2021   10. DATE OF REVISION OF THE TEXT  22 June 2021  METHOD OF DELIVERY Medicinal product subject to restricted medical prescription.  Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu. 

No price at this moment available. Reimbursement dossier Retsevmo has been filed to the authorities.