LONSURF 15mg / 6.14mg tablets medication leaflet

Lonsurf 15 mg/6.14 mg film-coated tablets

Lonsurf 20 mg/8.19 mg film-coated tablets

Lonsurf 15 mg/6.14 mg film-coated tablets

Each film-coated tablet contains 15 mg trifluridine and 6.14 mg tipiracil (as hydrochloride).

Eac`h film-coated tablet contains 90.735 mg of lactose monohydrate.

Lonsurf 20 mg/8.19 mg film-coated tablets

Each film-coated tablet contains 20 mg trifluridine and 8.19 mg tipiracil (as hydrochloride).

Each film-coated tablet contains 120.980 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Lonsurf 15 mg/6.14 mg film-coated tablets

The tablet is a white, biconvex, round, film-coated tablet, with a diameter of 7.1 mm and a thicknessof 2.7 mm, imprinted with ‘15’ on one side, and ‘102’ and ’15 mg’ on the other side, in grey ink.

Lonsurf 20 mg/8.19 mg film-coated tablets

The tablet is a pale red, biconvex, round, film-coated tablet, with a diameter of 7.6 mm and a thicknessof 3.2 mm, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in grey ink.

Lonsurf is indicated in combination with bevacizumab for the treatment of adult patients withmetastatic colorectal cancer (CRC) who have received two prior anticancer treatment regimensincluding fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents,and/or anti-EGFR agents.

Lonsurf is indicated as monotherapy for the treatment of adult patients with metastatic colorectalcancer who have been previously treated with, or are not considered candidates for, available therapiesincluding fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents, andanti-EGFR agents.

Gastric cancer

Lonsurf is indicated as monotherapy for the treatment of adult patients with metastatic gastric cancerincluding adenocarcinoma of the gastroesophageal junction, who have been previously treated with atleast two prior systemic treatment regimens for advanced disease (see section 5.1).

Lonsurf should be prescribed by physicians experienced in the administration of anticancer therapy.

The recommended starting dose of Lonsurf in adults, as monotherapy or in combination withbevacizumab, is 35 mg/m2/dose administered orally twice daily on Days 1 to 5 and Days 8 to 12 ofeach 28-day cycle until disease progression or unacceptable toxicity (see section 4.4).

When Lonsurf is used in combination with bevacizumab for the treatment of metastatic CRC, the doseof bevacizumab is 5 mg/kg of body weight given once every 2 weeks. Please refer to the full productinformation for bevacizumab.

The dose is calculated according to body surface area (BSA) (see Table 1). The dose must not exceed80 mg/dose.

If doses were missed or held, the patient must not make up for missed doses.

Table 1 - Starting dose calculation according to BSA

Tablets per dose Total

BSA Dose in mg (2x daily) daily

Starting dose(m2) (2x daily) dose15 mg/6.14 mg 20 mg/8.19 mg (mg)35 mg/m2 < 1.07 35 1 1 701.07 - 1.22 40 0 2 801.23 - 1.37 45 3 0 901.38 - 1.52 50 2 1 1001.53 - 1.68 55 1 2 1101.69 - 1.83 60 0 3 1201.84 - 1.98 65 3 1 1301.99 - 2.14 70 2 2 1402.15 - 2.29 75 1 3 150≥ 2.30 80 0 4 160

Recommended dose adjustments

Dosing adjustments may be required based on individual safety and tolerability.

A maximum of 3 dose reductions are permitted to a minimum dose of 20 mg/m2 twice daily. Doseescalation is not permitted after it has been reduced.

In the event of haematological and/or non-haematological toxicities patients should follow the doseinterruption, resumption and reduction criteria stated in Table 2, Table 3 and Table 4.

Table 2 - Dose interruption and resumption criteria forhaematological toxicities related to myelosuppression

Parameter Interruption criteria Resumption criteriaa

Neutrophils < 0.5  109/L  1.5  109/L

Platelets < 50  109/L  75  109/La Resumption criteria applied to the start of the next cycle for all patients regardless of whether or notthe interruption criteria were met.

Table 3 - Recommended dose modifications for Lonsurf in case ofhaematological and non-haematological adverse reactions

Adverse reaction Recommended dose modifications

* Febrile neutropenia * Interrupt dosing until toxicity resolves to

* CTCAE* Grade 4 neutropenia Grade 1 or baseline.

(< 0.5 x 109/L) or thrombocytopenia * When resuming dosing, decrease the dose(< 25  109/L) that results in more than 1 level by 5 mg/m2/dose from the previousweek’s delay in start of next cycle dose level (Table 4).

* CTCAE* non-haematologic Grade 3 or * Dose reductions are permitted to a

Grade 4 adverse reaction; except for minimum dose of 20 mg/m2/dose twice

Grade 3 nausea and/or vomiting daily (or 15 mg/m2/dose twice daily incontrolled by antiemetic therapy or severe renal impairment).

diarrhoea responsive to antidiarrhoeal * Do not increase dose after it has beenmedicinal products reduced.

* Common terminology criteria for adverse events

Table 4 - Dose reductions according to BSA

Tablets per dose Total

Dose in

BSA

Reduced dose mg (2x daily) daily(m2) dose(2x daily)15 mg/6.14 mg 20 mg/8.19 mg (mg)

Level 1 dose reduction: From 35 mg/m2 to 30 mg/m230 mg/m2 < 1.09 30 2 0 601.09 - 1.24 35 1 1 701.25 - 1.39 40 0 2 801.40 - 1.54 45 3 0 901.55 - 1.69 50 2 1 1001.70 - 1.94 55 1 2 1101.95 - 2.09 60 0 3 1202.10 - 2.28 65 3 1 130≥ 2.29 70 2 2 140

Level 2 dose reduction: From 30 mg/m2 to 25 mg/m225 mg/m2 < 1.10 25a 2a 1a 50a1.10 - 1.29 30 2 0 601.30 - 1.49 35 1 1 701.50 - 1.69 40 0 2 801.70 - 1.89 45 3 0 901.90 - 2.09 50 2 1 1002.10 - 2.29 55 1 2 110≥ 2.30 60 0 3 120

Level 3 dose reduction: From 25 mg/m2 to 20 mg/m220 mg/m2 < 1.14 20 0 1 401.14 - 1.34 25a 2a 1a 50a1.35 - 1.59 30 2 0 601.60 - 1.94 35 1 1 701.95 - 2.09 40 0 2 802.10 - 2.34 45 3 0 90≥ 2.35 50 2 1 100a At a total daily dose of 50 mg, patients should take 1 x 20 mg/8.19 mg tablet in the morning and2 x 15 mg/6.14 mg tablets in the evening.

* Mild renal impairment (CrCl 60 to 89 mL/min) or moderate renal impairment (CrCl 30 to59 mL/min)

No adjustment of the starting dose is recommended in patients with mild or moderate renalimpairment (see sections 4.4 and 5.2).

* Severe renal impairment (CrCl 15 to 29 mL/min)

For patients with severe renal impairment a starting dose of 20 mg/m2 twice daily is recommended(see sections 4.4 and 5.2). One dose reduction to a minimum dose of 15 mg/m2 twice daily is permittedbased on individual safety and tolerability (see Table 5). Dose escalation is not permitted after it hasbeen reduced.

In the event of haematological and/or non-haematological toxicities patients should follow the doseinterruption, resumption and reduction criteria stated in Table 2, Table 3 and Table 5.

Table 5 - Starting dose and dose reduction in patients with severe renal impairment accordingto BSA

Tablets per dose Total

Dose in

BSA daily

Reduced dose mg (2x daily)(m2) dose(2x daily)15 mg/6.14 mg 20 mg/8.19 mg (mg)

Starting dose20 mg/m2 < 1.14 20 0 1 401.14 - 1.34 25a 2a 1a 50a1.35 - 1.59 30 2 0 601.60 - 1.94 35 1 1 701.95 - 2.09 40 0 2 802.10 - 2.34 45 3 0 90≥ 2.35 50 2 1 100

Dose reduction: From 20 mg/m2 to 15 mg/m215 mg/m2 < 1.15 15 1 0 301.15 - 1.49 20 0 1 401.50 - 1.84 25a 2a 1a 50a1.85 - 2.09 30 2 0 602.10 - 2.34 35 1 1 70≥ 2.35 40 0 2 80a At a total daily dose of 50 mg, patients should take 1 x 20 mg/8.19 mg tablet in the morning and2 x 15 mg/6.14 mg tablets in the evening.

* End stage renal disease (CrCl below 15 mL/min or requiring dialysis)

Administration is not recommended in patients with end stage renal disease as there are no dataavailable for these patients (see section 4.4).

* Mild hepatic impairment

No adjustment of the starting dose is recommended in patients with mild hepatic impairment (seesection 5.2).

* Moderate or severe hepatic impairment

Administration is not recommended in patients with baseline moderate or severe hepatic impairment(National Cancer Institute [NCI] Criteria Group C and D defined by total bilirubin > 1.5 x ULN) as, ahigher incidence of Grade 3 or 4 hyperbilirubinaemia is observed in patients with baseline moderatehepatic impairment, although this is based on very limited data (see sections 4.4 and 5.2).

No adjustment of the starting dose is required in patients ≥ 65 years old (see sections 4.8, 5.1 and 5.2).

Efficacy and safety data in patients over 75 years old is limited.

There is no relevant use of Lonsurf in the paediatric population for the indications of metastaticcolorectal cancer and metastatic gastric cancer.

No adjustment of the starting dose is required on the basis of patient’s race (see sections 5.1 and 5.2).

There is limited data on Lonsurf in Black/African American patients but there is no biologicalrationale to expect any difference between this subgroup and the overall population.

Lonsurf is for oral use. The tablets must be taken with a glass of water within 1 hour after completionof the morning and evening meals.

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Bone marrow suppression

Lonsurf caused an increase in the incidence of myelosuppression including anaemia, neutropenia,leukopenia, and thrombocytopenia.

Complete blood cell counts must be obtained prior to initiation of therapy and as needed to monitortoxicity, but at a minimum, prior to each treatment cycle.

Treatment must not be started if the absolute neutrophil count is < 1.5 109/L, if the platelet counts are< 75  109/L, or if the patient has an unresolved Grade 3 or 4 non-haematological clinically relevanttoxicity from prior therapies.

Serious infections have been reported following treatment with Lonsurf (see section 4.8). Given thatthe majority were reported in the context of bone marrow suppression, the patient’s condition shouldbe monitored closely, and appropriate measures, such as antimicrobial agents and granulocyte-colonystimulating factor (G-CSF), should be administered as clinically indicated. In RECOURSE, TAGS and

SUNLIGHT studies, 9.4%, 17.3% and 19.5% of patients in the Lonsurf group respectively received G-

CSF mainly for therapeutic use. In the SUNLIGHT study, 29.3% of patients in the Lonsurf withbevacizumab group received G-CSF including 16.3% for therapeutic use.

Gastrointestinal toxicity

Lonsurf caused an increase in the incidence of gastrointestinal toxicities including nausea, vomitingand diarrhoea.

Patients with nausea, vomiting, diarrhoea and other gastrointestinal toxicities should be carefullymonitored, and anti-emetic, anti-diarrhoeal and other measures, such as fluid/electrolyte replacementtherapy, should be administered as clinically indicated. Dose modifications (delay and/or reduction)should be applied as necessary (see section 4.2).

Lonsurf is not recommended for use in patients with end-stage renal disease (creatinine clearance[CrCl] < 15 mL/min or requiring dialysis), as Lonsurf has not been studied in these patients (seesection 5.2).

The global incidence of adverse events (AEs) is similar in normal renal function (CrCl ≥ 90 mL/min),mild (CrCl = 60 to 89 mL/min) or moderate (CrCl = 30 to 59 mL/min) renal impairment subgroups.

However, the incidence of serious, severe AEs and AEs leading to dose modification tends to increasewith advancing levels of renal impairment. In addition, a higher exposure of trifluridine and tipiracilhydrochloride was observed in patients with moderate renal impairment, compared with patients withnormal renal function or patients with mild renal impairment (see section 5.2).

Patients with severe renal impairment (CrCl = 15 to 29 mL/min) and adjusted starting dose of20 mg/m2 twice daily had a safety profile consistent with the safety profile of Lonsurf in patients withnormal renal function or mild renal impairment. Their exposure to trifluridine was similar to that ofpatients with normal renal function and their exposure to tipiracil hydrochloride was increasedcompared to patients with normal renal function, mild and moderate renal impairment (see sections 4.2and 5.2).

Patients with renal impairment should be monitored closely when being treated with Lonsurf; patientswith moderate or severe renal impairment should be more frequently monitored for haematologicaltoxicities.

Lonsurf is not recommended for use in patients with baseline moderate or severe hepatic impairment(National Cancer Institute [NCI] Criteria Group C and D defined by total bilirubin > 1.5 x ULN), as ahigher incidence of Grade 3 or 4 hyperbilirubinaemia is observed in patients with baseline moderatehepatic impairment, although this is based on very limited data (see section 5.2).

Proteinuria

Monitoring of proteinuria by dipstick urinalysis is recommended prior to starting and during therapy(see section 4.8).

Lonsurf contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactasedeficiency or glucose-galactose malabsorption should not take this medicinal product.

In vitro studies indicated that trifluridine, tipiracil hydrochloride and 5-[trifluoromethyl] uracil (FTY)did not inhibit the activity of human cytochrome P450 (CYP) isoforms. In vitro evaluation indicatedthat trifluridine, tipiracil hydrochloride and FTY had no inductive effect on human CYP isoforms (seesection 5.2).

In vitro studies indicated that trifluridine is a substrate for the nucleoside transporters CNT1, ENT1and ENT2. Therefore, caution is required when using medicinal products that interact with thesetransporters. Tipiracil hydrochloride was a substrate for OCT2 and MATE1, therefore, theconcentration might be increased when Lonsurf is administered concomitantly with inhibitors of

OCT2 or MATE1.

Caution is required when using medicinal products that are human thymidine kinase substrates, e.g.,zidovudine. Such medicinal products, if used concomitantly with Lonsurf, may compete with theeffector, trifluridine, for activation via thymidine kinases. Therefore, when using antiviral medicinalproducts that are human thymidine kinase substrates, monitor for possible decreased efficacy of theantiviral medicinal product, and consider switching to an alternative antiviral medicinal product that isnot a human thymidine kinase substrate, such as lamivudine, didanosine and abacavir (see section 5.1).

It is unknown whether Lonsurf may reduce the effectiveness of hormonal contraceptives. Therefore,women using hormonal contraceptive must also use a barrier contraceptive method.

Based on findings in animals, trifluridine may cause foetal harm when administered to pregnantwomen. Women should avoid becoming pregnant while taking Lonsurf and for up to 6 months afterending treatment. Therefore, women of child-bearing potential must use highly effective contraceptivemeasures while taking Lonsurf and for 6 months after stopping treatment. It is currently unknownwhether Lonsurf may reduce the effectiveness of hormonal contraceptives, and therefore women usinghormonal contraceptives should add a barrier contraceptive method.

Men with a partner of child-bearing potential must use effective contraception during treatment andfor up to 6 months after discontinuation of treatment.

There are no available data from the use of Lonsurf in pregnant women. Based on the mechanism ofaction, trifluridine is suspected to cause congenital malformations when administered duringpregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). Lonsurf should notbe used during pregnancy unless the clinical condition of the woman requires treatment with Lonsurf.

It is unknown whether Lonsurf or its metabolites are excreted in human milk. Studies in animals haveshown excretion of trifluridine, tipiracil hydrochloride and/or their metabolites in milk (seesection 5.3). A risk to the suckling child cannot be excluded. Breast-feeding should be discontinuedduring treatment with Lonsurf.

There are no data available on the effects of Lonsurf on human fertility. Results of animal studies didnot indicate an effect of Lonsurf on male or female fertility (see section 5.3). Patients who wish toconceive a child should be advised to seek reproductive counselling and cryo-conservation of eitherthe ovum or sperm prior to starting Lonsurf treatment.

Lonsurf has minor influence on the ability to drive and use machines. Fatigue, dizziness or malaisemay occur during treatment (see section 4.8).

The most serious observed adverse reactions in patients receiving Lonsurf are bone marrowsuppression and gastrointestinal toxicity (see section 4.4).

Lonsurf as monotherapy

The safety profile of Lonsurf as monotherapy is based on the pooled data from 1114 patients withmetastatic colorectal or gastric cancer in controlled phase III clinical studies.

The most common adverse reactions (≥ 30%) are neutropenia (53% [34% ≥ Grade 3]), nausea (31%[1% ≥ Grade 3]), fatigue (31% [4% ≥ Grade 3]), and anaemia (30% [11% ≥ Grade 3]).The mostcommon adverse reactions (≥ 2%) that resulted in treatment discontinuation, dose reduction, dosedelay, or dose interruption were neutropenia, anaemia, fatigue, leukopenia, thrombocytopenia,diarrhoea, and nausea.

Lonsurf in combination with bevacizumab

The safety profile of Lonsurf in combination with bevacizumab is based on the data from 246 patientswith metastatic colorectal cancer in the controlled phase III clinical study (SUNLIGHT).

The most common adverse reactions (≥ 30%) are neutropenia (69% [48% ≥ Grade 3]), fatigue (35%[3% ≥ Grade 3]), and nausea (33% [1% ≥ Grade 3]).

The most common adverse reactions (≥ 2%) that resulted in treatment discontinuation, dose reduction,dose delay, or dose interruption of Lonsurf when used in combination with bevacizumab wereneutropenia, fatigue, thrombocytopenia, nausea and anaemia.

When Lonsurf is used in combination with bevacizumab, the frequency of the following adversereactions was increased compared to Lonsurf as monotherapy: neutropenia (69% vs 53%), severeneutropenia (48% vs 34%), thrombocytopenia (24% vs 16%), stomatitis (11% vs 6%).

The adverse reactions observed from the 533 treated patients with metastatic colorectal cancer in theplacebo-controlled Phase III (RECOURSE) clinical study, the 335 treated patients with metastaticgastric cancer in the placebo-controlled Phase III (TAGS) clinical study, the 246 patients treated with

Lonsurf in monotherapy and the 246 patients treated with Lonsurf in combination with bevacizumabfor metastatic colorectal cancer in the controlled Phase III (SUNLIGHT) clinical study are shown in

Table 6. They are classified according to System Organ Class (SOC) and the appropriate Medical

Dictionary for Regulatory (MedDRA) term is used to describe a certain drug reaction and itssynonyms and related conditions.

Adverse reactions known to occur with Lonsurf given alone or with bevacizumab may occur duringtreatment with these medicinal products in combination, even if these reactions were not reported inclinical trials with combination therapy.

Adverse reactions are grouped according to their frequencies. Frequency groups are defined by thefollowing convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥1/1 000 to <1/100); and rare (≥ 1/10 000 to < 1/1 000).

Within each frequency group, adverse reactions are presented in order of decreasing seriousness.

Table 6 - Adverse reactions reported in clinical studies in patients treated with Lonsurf

System Organ Class(MedDRA)a Adverse reactions Frequency

Monotherapy Combination withbevacizumab

Infections and infestations Lower respiratory tract Common -infection

Neutropenic sepsis Uncommon -

Biliary tract infection Uncommon -

Infection Uncommon Common

Urinary tract infection Uncommon Uncommon

Bacterial infection Uncommon -

Candida infection Uncommon -

Conjunctivitis Uncommon -

Herpes zoster Uncommon -

Influenza Uncommon -

Upper respiratory tract Uncommon -infection

Enteritis infectious Rare -

Septic shockb Rare -

Gingivitis Rare Uncommon

Tinea pedis Rare -

Neoplasms benign, malignant Cancer pain Uncommon -and unspecified (incl cysts andpolyps)

Blood and lymphatic system Anaemia Very common Very commondisorders Neutropenia Very common Very common

Leukopenia Very common Common

System Organ Class(MedDRA)a Adverse reactions Frequency

Monotherapy Combination withbevacizumab

Thrombocytopenia Very common Very common

Febrile neutropenia Common Uncommon

Lymphopenia Common Common

Pancytopenia Uncommon Uncommon

Erythropenia Uncommon -

Leukocytosis Uncommon -

Monocytopenia Uncommon -

Monocytosis Uncommon -

Granulocytopenia Rare -

Metabolism and nutrition Decreased appetite Very common Very commondisorders Hypoalbuminaemia Common Uncommon

Dehydration Uncommon -

Hyperglycaemia Uncommon Uncommon

Hyperkalaemia Uncommon -

Hypocalcaemia Uncommon -

Hypokalaemia Uncommon -

Hyponatraemia Uncommon -

Hypophosphataemia Uncommon -

Gout Rare -

Hypernatraemia Rare -

Psychiatric disorders Anxiety Uncommon -

Insomnia Uncommon -

Nervous system disorders Dysgeusia Common Common

Dizziness Uncommon Common

Headache Uncommon Common

Neuropathy peripheral Uncommon Uncommon

Paraesthesia Uncommon Uncommon

Lethargy Uncommon -

Neurotoxicity Uncommon -

Burning sensation Rare -

Dysaesthesia Rare -

Hyperaesthesia Rare -

Hypoaesthesia Rare -

Syncope Rare -

Eye disorders Cataract Rare -

Diplopia Rare -

Dry eye Rare -

Vision blurred Rare -

Visual acuity reduced Rare -

Ear and labyrinth disorders Vertigo Uncommon -

Ear discomfort Rare -

Cardiac disorders Angina pectoris Uncommon -

Arrhythmia Uncommon -

Palpitations Uncommon -

Vascular disorders Hypertension Uncommon Common

Flushing Uncommon -

Hypotension Uncommon -

Embolism Rare -

Respiratory, thoracic and Dyspnoea Common Commonmediastinal disorders Pulmonary embolismb Uncommon -

Dysphonia Uncommon Uncommon

Cough Uncommon -

Epistaxis Uncommon -

System Organ Class(MedDRA)a Adverse reactions Frequency

Monotherapy Combination withbevacizumab

Rhinorrhoea Rare Uncommon

Oropharyngeal pain Rare -

Pleural effusion Rare -

Gastrointestinal disorders Diarrhoea Very common Very common

Vomiting Very common Very common

Nausea Very common Very common

Abdominal pain Common Common

Stomatitis Common Very common

Constipation Common Common

Ileus Uncommon -

Gastrointestinal haemorrhage Uncommon -

Colitis Uncommon Uncommon

Mouth ulceration Uncommon Common

Oral disorder Uncommon Common

Abdominal distension Uncommon Uncommon

Anal inflammation Uncommon Uncommon

Dyspepsia Uncommon Uncommon

Flatulence Uncommon Uncommon

Gastritis Uncommon -

Gastrooesophageal reflux Uncommon -disease

Glossitis Uncommon -

Impaired gastric emptying Uncommon -

Retching Uncommon -

Tooth disorder Uncommon -

Ascites Rare -

Pancreatitis acute Rare -

Subileus Rare -

Breath odour Rare -

Buccal polyp Rare -

Enterocolitis haemorrhagic Rare -

Gingival bleeding Rare -

Oesophagitis Rare -

Periodontal disease Rare -

Proctalgia Rare -

Reflux gastritis Rare -

Hepatobiliary disorders Hyperbilirubinaemia Common Common

Hepatotoxicity Uncommon -

Biliary dilatation Rare -

Skin and subcutaneous tissue Alopecia Common Commondisorders Dry skin Common Common

Pruritus Common Uncommon

Rash Common Uncommon

Nail disorder Uncommon Uncommon

Palmar-plantar Uncommon Uncommonerythrodysaesthesia syndromec

Acne Uncommon -

Hyperhidrosis Uncommon -

Urticaria Uncommon -

Blister Rare -

Erythema Rare -

Photosensitivity reaction Rare -

Skin exfoliation Rare -

System Organ Class(MedDRA)a Adverse reactions Frequency

Monotherapy Combination withbevacizumab

Musculoskeletal and Arthralgia Uncommon Commonconnective tissue disorders Myalgia Uncommon Common

Muscular weakness Uncommon Uncommon

Pain in extremity Uncommon Uncommon

Bone pain Uncommon -

Limb discomfort Uncommon -

Muscle spasms Uncommon -

Joint swelling Rare -

Renal and urinary disorders Proteinuria Common Uncommon

Renal failure Uncommon -

Haematuria Uncommon -

Micturition disorder Uncommon -

Cystitis noninfective Rare -

Leukocyturia Rare -

Reproductive system and Menstrual disorder Rare Uncommonbreast disorders

General disorders and Fatigue Very common Very commonadministration site conditions Pyrexia Common Uncommon

Mucosal inflammation Common Uncommon

Malaise Common -

Oedema Common -

General physical health Uncommon -deterioration

Pain Uncommon Uncommon

Feeling of body temperature Uncommon -change

Xerosis Rare -

Investigations Weight decreased Common Common

Hepatic enzyme increased Common Common

Blood alkaline phosphatase Common Uncommonincreased

Blood lactate dehydrogenase Uncommon -increased

C-reactive protein increased Uncommon -

Blood creatinine increased Uncommon -

Blood urea increased Uncommon -

Haematocrit decreased Uncommon -

International normalised ratio Uncommon -increased

Activated partial Rare -thromboplastin time prolonged

Electrocardiogram QT Rare -prolonged

Protein total decreased Rare -

a. Different MedDRA preferred terms that were considered clinically similar have been grouped intoa single term.

b. Fatal cases have been reported.

c. Hand-foot skin reaction.

Patients 65 years of age or older who received Lonsurf as monotherapy had a higher incidence (≥ 5%)of the following treatment-related adverse events compared to patients younger than 65 years:

neutropenia (58.9% vs 48.2%), severe neutropenia (41.3% vs 27.9%), anaemia (36.5% vs 25.2%),severe anaemia (14.1% vs 8.9%), decreased appetite (22.6% vs 17.4%), and thrombocytopenia (21.4%vs 12.1%).When Lonsurf is used in combination with bevacizumab, patients 65 years of age or olderhad a higher incidence (≥ 5%) of the following treatment-related adverse events compared to patientsyounger than 65 years: neutropenia (75.0% vs 65.1%), severe neutropenia (57.0% vs 41.8%), fatigue(39.0% vs 32.2%), thrombocytopenia (28.0% vs 20.5%), and stomatitis (14.0% vs 8.9%).

In the Phase III placebo-controlled clinical studies, treatment-related infections occurred morefrequently in Lonsurf-treated patients (5.8%) compared to those receiving placebo (1.8%).

In the clinical study in combination with bevacizumab, treatment-related infections occurred similarlyin patients who received Lonsurf with bevacizumab (2.8%) compared to Lonsurf-treated patients(2.4%).

Proteinuria

In the Phase III placebo-controlled clinical studies, treatment-related proteinuria occurred morefrequently in Lonsurf-treated patients (1.8%) compared to those receiving placebo (0.9%), all of whichwere Grade 1 or 2 in severity (see section 4.4).

In the clinical study in combination with bevacizumab, one patient who received Lonsurf withbevacizumab (0.4%) reported a treatment-related proteinuria which was Grade 2 and none among the

Lonsurf-treated patients (see section 4.4).

Radiotherapy

There was a slightly higher incidence of overall haematological and myelosuppression-related adversereactions for patients who received prior radiotherapy compared to patients without prior radiotherapyin RECOURSE (54.6% versus 49.2%, respectively), of note febrile neutropenia was higher in

Lonsurf-treated patients who received prior radiotherapy vs. those that did not.

In the clinical study in combination with bevacizumab, no increase of incidence of overallhaematological and myelosuppression-related adverse reactions was observed for patients whoreceived prior radiotherapy compared to patients without prior radiotherapy in both arms in

SUNLIGHT: Lonsurf with bevacizumab (73.7% versus 77.4%) and in Lonsurf-treated patients (64.7%versus 67.7%).

Post-marketing experience in patients with unresectable advanced or recurrent colorectal cancer

There have been reports of interstitial lung disease in patients receiving Lonsurf post approval.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest dose of Lonsurf administered in clinical studies was 180 mg/m2 per day.

The adverse drug reactions reported in association with overdoses were consistent with the establishedsafety profile.

The primary anticipated complication of an overdose is bone marrow suppression.

There is no known antidote for an overdose of Lonsurf.

Medical management of an overdose should include customary therapeutic and supportive medicalintervention aimed at correcting the presenting clinical manifestations and preventing their possiblecomplications.

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, ATC code: L01BC59

Lonsurf is comprised of an antineoplastic thymidine-based nucleoside analogue, trifluridine, and thethymidine phosphorylase (TPase) inhibitor, tipiracil hydrochloride, at a molar ratio 1:0.5 (weight ratio,1:0.471).

Following uptake into cancer cells, trifluridine is phosphorylated by thymidine kinase, furthermetabolised in cells to a deoxyribonucleic acid (DNA) substrate, and incorporated directly into DNA,thereby interfering with DNA function to prevent cell proliferation.

However, trifluridine is rapidly degraded by TPase and readily metabolised by a first-pass effectfollowing oral administration, hence the inclusion of the TPase inhibitor, tipiracil hydrochloride.

In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity againstboth 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines.

The cytotoxic activity of trifluridine/tipiracil hydrochloride against several human tumour xenograftscorrelated highly with the amount of trifluridine incorporated into DNA, suggesting this as the primarymechanism of action.

Lonsurf had no clinically relevant effect on QT/QTc prolongation compared with placebo in an openlabel study in patients with advanced solid tumours.

Metastatic colorectal cancer

Randomised phase III study of Lonsurf as monotherapy versus placebo

The clinical efficacy and safety of Lonsurf were evaluated in an international, randomised, double-blind, placebo-controlled Phase III study (RECOURSE) in patients with previously treated metastaticcolorectal cancer. The primary efficacy endpoint was overall survival (OS), and supportive efficacyendpoints were progression-free survival (PFS), overall response rate (ORR) and disease control rate(DCR).

In total, 800 patients were randomised 2:1 to receive Lonsurf (N = 534) plus best supportive care(BSC) or matching placebo (N = 266) plus BSC. Lonsurf dosing was based on BSA with a startingdose of 35 mg/m2/dose. Study treatment was administered orally twice daily after morning andevening meals for 5 days a week with 2-day rest for 2 weeks, followed by 14-day rest, repeated every4 weeks. Patients continued therapy until disease progression or unacceptable toxicity (see section4.2).

Of the 800 randomised patients, the median age was 63 years, 61% were male, 58% were

Caucasian/White, 35% were Asian/Oriental, and 1% were Black/African American, and all patientshad baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Theprimary site of disease was colon (62%) or rectum (38%). KRAS status was wild (49%) or mutant(51%) at study entry. The median number of prior lines of therapy for metastatic disease was 3. Allpatients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-basedchemotherapy. All but 1 patient received bevacizumab, and all but 2 patients with KRAS wild typetumours received panitumumab or cetuximab. The 2 treatment groups were comparable with respect todemographic and baseline disease characteristics.

An OS analysis of the study, carried out as planned at 72% (N = 574) of events, demonstrated aclinically meaningful and statistically significant survival benefit of Lonsurf plus BSC compared toplacebo plus BSC (hazard ratio: 0.68; 95% confidence interval [CI] [0.58 to 0.81]; p < 0.0001) and amedian OS of 7.1 months vs 5.3 months, respectively; with 1-year survival rates of 26.6% and 17.6%,respectively. PFS was significantly improved in patients receiving Lonsurf plus BSC (hazard ratio:

0.48; 95% CI [0.41 to 0.57]; p < 0.0001 (see Table 7, Figure 1 and Figure 2).

Table 7 - Efficacy results from the Phase III (RECOURSE) clinical study in patients withmetastatic colorectal cancer

Lonsurf plus BSC Placebo plus BSC(N=534) (N=266)

Overall survival

Number of deaths, N (%) 364 (68.2) 210 (78.9)

Median OS (months)a [95% CI]b 7.1 [6.5, 7.8] 5.3 [4.6, 6.0]

Hazard ratio [95% CI] 0.68 [0.58, 0.81]

P-valuec < 0.0001 (1-sided and 2-sided)

Progression-Free Survival

Number of progression or death,

N (%) 472 (88.4) 251 (94.4)

Median PFS (months)a [95% CI]b 2.0 [1.9, 2.1] 1.7 [1.7, 1.8]

Hazard ratio [95% CI] 0.48 [0.41, 0.57]

P-valuec <0.0001 (1-sided and 2-sided)a Kaplan-Meier estimatesb Methodology of Brookmeyer and Crowleyc Stratified log-rank test (strata: KRAS status, time since diagnosis of first metastasis, region)

Figure 1- Kaplan-Meier curves of overall survival in patients with metastatic colorectal cancer(RECOURSE)

Lonsurf

Placebo

Hazard ratio f or death, 0.68 (95% CI, 0.58-0.81)

P<0.0001

Months from Randomisation

No. at Risk:

Lonsurf

Placebo

Figure 2 - Kaplan-Meier curves of progression-free survival in patients with metastaticcolorectal cancer (RECOURSE)

Lonsurf

Placebo

Hazard ratio for progression or death, 0.48 (95% CI, 0.41-0.57)

P<0.0001 by log-rank te st

Months from Randomisation

No. at Risk:

Lonsurf

Placebo

An updated OS analysis, carried out at 89% (N = 712) of events, confirmed the clinically meaningfuland statistically significant survival benefit of Lonsurf plus BSC compared to placebo plus BSC (hazardratio: 0.69; 95% CI [0.59 to 0.81]; p < 0.0001) and a median OS of 7.2 months vs 5.2 months; with 1-year survival rates of 27.1% and 16.6%, respectively.

The OS and PFS benefit was observed consistently, in all relevant pre-specified subgroups, includingrace, geographic region, age (< 65; ≥ 65), sex, ECOG PS, KRAS status, time since diagnosis of firstmetastasis, number of metastatic sites, and primary tumour site. The Lonsurf survival benefit wasmaintained after adjusting for all significant prognostic factors, namely, time since diagnosis of firstmetastasis, ECOG PS and number of metastatic sites (hazard ratio: 0.69; 95% CI [0.58 to 0.81]).

Sixty one percent (61%, N = 485) of all randomised patients received a fluoropyrimidine as part oftheir last treatment regimen prior to randomisation, of which 455 (94%) were refractory to the

Survival Probability (%)

Progression-free Survival Probability (%)fluoropyrimidine at that time. Among these patients, the OS benefit with Lonsurf was maintained(hazard ratio: 0.75, 95% CI [0.59 to 0.94]).

Eighteen percent (18%, N = 144) of all randomised patients received regorafenib prior torandomisation. Among these patients, the OS benefit with Lonsurf was maintained (hazard ratio: 0.69,95% CI [0.45 to 1.05]). The effect was also maintained in regorafenib-naive patients (hazard ratio:

0.69, 95% CI [0.57 to 0.83]).

The DCR (complete response or partial response or stable disease) was significantly higher in patientstreated with Lonsurf (44% vs 16%, p < 0.0001).

Treatment with Lonsurf plus BSC resulted in a statistically significant prolongation of PS <2 incomparison to placebo plus BSC. The median time to PS ≥ 2 for the Lonsurf group and placebo groupwas 5.7 months and 4.0 months, respectively, with a hazard ratio of 0.66 (95% CI: [0.56, 0.78]),p < 0.0001.

Randomised phase III study of Lonsurf in combination with bevacizumab versus Lonsurf

The clinical efficacy and safety of Lonsurf in combination with bevacizumab, versus Lonsurfmonotherapy, were evaluated in an international, randomised, open-label, phase III study(SUNLIGHT) in patients with metastatic colorectal cancer who had been previously treated with amaximum of two prior systemic treatment regimens for advanced disease, including afluoropyrimidine, irinotecan, oxaliplatin, an anti-VEGF monoclonal antibody and/or an anti-EGFRmonoclonal antibody for patients with a RAS wild type tumour. The primary efficacy endpoint wasoverall survival (OS) and the key secondary efficacy endpoint was progression-free survival (PFS).

In total, 492 patients were randomised (1:1) to receive Lonsurf with bevacizumab (N = 246) or

Lonsurf monotherapy (N = 246).

Patients received Lonsurf (starting dose of 35 mg/m2) administered orally twice daily on Days 1 to 5and Days 8 to 12 of each 28-day cycle alone or combined with bevacizumab (5 mg/kg) administeredintravenously every 2 weeks (on days 1 and 15) of each 4-week cycle. Patients continued therapy untildisease progression or unacceptable toxicity (see section 4.2). Bevacizumab monotherapy was notallowed. Baseline characteristics were generally balanced between the two groups. The median agewas 63 years (range: 20-90), with 44% ≥ 65 years of age and 12% ≥ 75 years of age, 52% of patientswere male and 95% were white, 46% had ECOG PS 0 and 54% had ECOG PS 1. The primary site ofdisease was colon (73%) or rectum (27%). Overall, 71% of the patients had a RAS mutant tumour.

The median duration of treatment was 5 months in the Lonsurf-bevacizumab group and 2 months inthe Lonsurf group. A total of 92% of patients received two prior anticancer treatment regimens foradvanced CRC, 5% received one and 3% received more than two. All patients received priorfluoropyrimidine, irinotecan and oxaliplatin, 72% received prior anti-VEGF monoclonal antibody,94%of patients with a RAS wild type tumour received prior anti-EGFR monoclonal antibody.

Lonsurf in combination with bevacizumab resulted in a statistically significant improvement in OSand PFS compared to Lonsurf monotherapy (see Table 8 and Figures 3 and 4).

Table 8 - Efficacy results from the Phase III (SUNLIGHT) clinical study in patients withmetastatic colorectal cancer

Lonsurf plus bevacizumab Lonsurf(N=246) (N=246)

Overall survival

Number of deaths, N (%) 148 (60.2) 183 (74.4)

Median OS (months)a [95% CI]b 10.8 [9.4, 11.8] 7.5 [6.3, 8.6]

Hazard ratio [95% CI] 0.61 [0.49, 0.77]

P-valuec < 0.001 (1-sided)

Progression-free survival (per investigator)

Number of progression or death,

N (%) 206 (83.7) 236 (95.9)

Median PFS (months)a [95% CI]b 5.6 [4.5, 5.9] 2.4 [2.1, 3.2]

Hazard ratio [95% CI] 0.44 [0.36, 0.54]

P-valuec < 0.001 (1-sided)a Kaplan-Meier estimatesb Methodology of Brookmeyer and Crowleyc Stratified log-rank test (strata: region, time since first metastasis diagnosis, RAS status)

Figure 3- Kaplan-Meier curves of overall survival in patients with metastatic colorectal cancer(SUNLIGHT)

Lonsurf+bevacizumab

Lonsurf

Hazard ratio for death, 0.61 (95% CI, 0.49-0.77)

P<0.001 (1-sided)

OS (months from randomization)

Number of patients at risk

Lonsurf+bevacizumab

Lonsurf

Figure 4 - Kaplan-Meier curves of progression-free survival in patients with metastaticcolorectal cancer (SUNLIGHT)

Survival probability (%)

Lonsurf+bevacizumab

Lonsurf

Hazard ratio for progression or death, 0.44 (95% CI, 0.36-0.54)

P<0.001 (1-sided)

PFS (months from randomization)

Number of patients at risk

Lonsurf+bevacizumab

Lonsurf

The OS and PFS benefit was observed consistently, in all randomization strata and pre specifiedsubgroups, including gender, age (< 65, ≥ 65 years), location of primary disease (right, left), ECOGperformance status (0, ≥1), prior surgical resection, number of metastatic sites (1-2, ≥ 3), neutrophilsto lymphocytes ratio (NLR < 3, NLR ≥ 3), number of prior metastatic drug regimens (1, ≥ 2), BRAFstatus, MSI status, prior bevacizumab and subsequent regorafenib.

Metastatic gastric cancer

The clinical efficacy and safety of Lonsurf were evaluated in an international, randomised, double-blind, placebo-controlled Phase III study (TAGS) in patients with previously treated metastatic gastriccancer (including adenocarcinoma of the gastroesophageal junction), who had been previously treatedwith at least two prior systemic treatment regimens for advanced disease, including fluoropyrimidine-,platinum-, and either taxane- or irinotecan-based chemotherapy, plus if appropriate human epidermalgrowth factor receptor 2 (HER2) -targeted therapy. The primary efficacy endpoint was overall survival(OS), and supportive efficacy endpoints were progression-free survival (PFS), overall response rate(ORR), disease control rate (DCR), time to deterioration of ECOG performance status ≥2 and qualityof life (QoL). Tumour assessments, according to the Response Evaluation Criteria in Solid Tumours(RECIST), version 1.1, were performed by the investigator/local radiologist every 8 weeks.

In total, 507 patients were randomised 2:1 to receive Lonsurf (N = 337) plus best supportive care(BSC) or placebo (N = 170) plus BSC. Lonsurf dosing was based on BSA with a starting dose of35 mg/m2/dose. Study treatment was administered orally twice daily after morning and evening mealsfor 5 days a week with 2-day rest for 2 weeks, followed by 14-day rest, repeated every 4 weeks.

Patients continued therapy until disease progression or unacceptable toxicity (see section 4.2).

Of the 507 randomised patients, the median age was 63 years, 73% were male, 70% were White, 16%were Asian, and <1% were Black/African American, and all patients had baseline Eastern Cooperative

Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Primary cancer was gastric (71.0%) orgastroesophageal junction cancer (28.6%) or both (0.4%). The median number of prior regimens oftherapy for metastatic disease was 3. Nearly all (99.8%) patients received prior fluoropyrimidine,100% received prior platinum therapy and 90.5% received prior taxane therapy. Approximately half(55.4%) of patients received prior irinotecan, 33.3% received prior ramucirumab, and 16.6% received

Progression-free Survival probability (%)prior HER2-targeted therapy. The 2 treatment groups were comparable with respect to demographicand baseline disease characteristics.

An OS analysis of the study, carried out as planned at 76% (N = 384) of events, demonstrated that

Lonsurf plus BSC resulted in a statistically significant improvement in OS compared to placebo plus

BSC with an hazard ratio (HR) of 0.69 (95% CI: 0.56, 0.85; 1- and 2-sided p-values were 0.0003 and0.0006, respectively) corresponding to a 31% reduction in the risk of death in the Lonsurf group. Themedian OS was 5.7 months (95% CI: 4.8, 6.2) for the Lonsurf group versus 3.6 months (95% CI: 3.1,4.1) for the placebo group; with 1-year survival rates of 21.2% and 13.0%, respectively.

PFS was significantly improved in patients receiving Lonsurf plus BSC compared to placebo plus

BSC (HR of 0.57; 95% CI [0.47 to 0.70]; p < 0.0001 (see Table 9, Figure 5 and Figure 6).

Table 9 - Efficacy results from the Phase III (TAGS) clinical study in patients with metastaticgastric cancer

Lonsurf plus BSC Placebo plus BSC(N=337) (N=170)

Overall survival

Number of deaths, N (%) 244 (72.4) 140 (82.4)

Median OS (months)a [95% CI]b 5.7 [4.8, 6.2] 3.6 [3.1, 4.1]

Hazard ratio [95% CI] 0.69 [0.56, 0.85]

P-valuec 0.0003 (1-sided), 0.0006 (2-sided)

Progression-Free Survival

Number of progression or death, 287 (85.2) 156 (91.8)

N (%)

Median PFS (months)a [95% CI]b 2.0 [1.9, 2.3] 1.8 [1.7, 1.9]

Hazard ratio [95% CI] 0.57 [0.47, 0.70]

P-valuec < 0.0001 (1-sided and 2-sided)a Kaplan-Meier estimatesb Methodology of Brookmeyer and Crowleyc Stratified log-rank test (strata: region, ECOG status at baseline, prior ramucirumab treatment)

Figure 5- Kaplan-Meier curves of overall survival in patients with metastatic gastric cancer(TAGS)

Lonsurf

Placebo

Hazard ratio for death, 0.69 (95% CI, 0.56-0.85)

P=0.0003 (1-sided) ; p =0.0006 (2-sided)

Months from Randomisation

No. at Risk:

Lonsurf

Placebo

Survival Probability (%)

Figure 6 - Kaplan-Meier curves of progression-free survival in patients with metastatic gastriccancer (TAGS)

Lonsurf

Placebo

Hazard ratio for progression or death, 0.57 (95% CI, 0.47-0.70)

P<0.0001 (1-sided and 2-sided)

Months from Randomisation

No. at Risk:

Lonsurf

Placebo

The OS and PFS benefit was observed consistently, in all randomization strata and across mostpre-specified subgroups, including sex, age (< 65; ≥ 65 years), ethnic origin, ECOG PS, priorramucirumab treatment, prior irinotecan treatment, number of prior regimens (2; 3; ≥ 4), previousgastrectomy, primary tumour site (gastric; gastroesophageal junction) and HER2 status.

The ORR (complete response + partial response) was not significantly higher in patients treated with

Lonsurf (4.5% vs 2.1 %, p-value = 0.2833) but the DCR (complete response or partial response orstable disease) was significantly higher in patients treated with Lonsurf (44.1% vs 14.5%, p < 0.0001).

The median time to deterioration of ECOG performance status to ≥2 was 4.3 months for the Lonsurfgroup versus 2.3 months for the placebo group with HR of 0.69 (95% CI: 0.562, 0.854),p-value = 0.0005.

The European Medicines Agency has waived the obligation to submit the results of studies with

Lonsurf in all subsets of the paediatric population in refractory metastatic colorectal cancer and inrefractory metastatic gastric cancer (see section 4.2 for information on paediatric use).

There is limited data in Lonsurf treated patients aged 75 years and above:

- 87 patients (10%) in pooled data of the RECOURSE and TAGS studies, of which 2 patients were 85years or older. The effect of Lonsurf on overall survival was similar in patients <65 years and ≥65years of age.

- 58 patients (12%) were aged 75 years and above, of which 1 patient was 85 years or older in the

SUNLIGHT study. The effect of Lonsurf in combination with bevacizumab on overall survival wassimilar in patients < 65 years and ≥ 65 years of age.

After oral administration of Lonsurf with [14C]-trifluridine, at least 57% of the administeredtrifluridine was absorbed and only 3% of the dose was excreted into faeces. After oral administrationof Lonsurf with [14C]-tipiracil hydrochloride, at least 27% of the administered tipiracil hydrochloridewas absorbed and 50% of the total radioactivity dose measured into faeces, suggestive of moderategastrointestinal absorption of tipiracil hydrochloride.

Progression-free Survival Probability (%)

Following a single dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the meantimes to peak plasma concentrations (tmax) of trifluridine and tipiracil hydrochloride were around 2hours and 3 hours, respectively.

In the pharmacokinetic (PK) analyses of the multiple dose administration of Lonsurf (35 mg/m2/dose,twice daily for 5 days a week with 2-day rest for 2 weeks followed by a 14-day rest, repeated every 4weeks), trifluridine area under the concentration-time curve from time 0 to the last measurableconcentration (AUC0-last) was approximately 3-fold higher and maximum concentration (Cmax) wasapproximately 2-fold higher after multiple dose administration (Day 12 of Cycle 1) of Lonsurf thanafter single-dose (Day 1 of Cycle 1).

However, there was no accumulation for tipiracil hydrochloride, and no further accumulation oftrifluridine with successive cycles (Day 12 of Cycles 2 and 3) of administration of Lonsurf. Followingmultiple doses of Lonsurf (35 mg/m2/dose twice daily) in patients with advanced solid tumours, themean times to peak plasma concentrations (tmax) of trifluridine and tipiracil hydrochloride were around2 hours and 3 hours, respectively.

Contribution of tipiracil hydrochloride

Single-dose administration of Lonsurf (35 mg/m2/dose) increased the mean AUC0-last of trifluridine by37-fold and Cmax by 22-fold with reduced variability compared to trifluridine alone (35 mg/m2/dose).

When Lonsurf at a single dose of 35 mg/m2 was administered to 14 patients with solid tumours after astandardised high-fat, high-calorie meal, trifluridine area under the concentration-time curve (AUC)did not change, but trifluridine Cmax, tipiracil hydrochloride Cmax and AUC decreased byapproximately 40% compared to those in a fasting state. In clinical studies Lonsurf was administeredwithin 1 hour after completion of the morning and evening meals (see section 4.2).

The protein binding of trifluridine in human plasma was over 96% and trifluridine bound mainly tohuman serum albumin. Plasma protein binding of tipiracil hydrochloride was below 8%. Following asingle dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the apparent volume ofdistribution (Vd/F) for trifluridine and tipiracil hydrochloride was 21 L and 333 L, respectively.

Trifluridine was mainly eliminated by metabolism via TPase to form an inactive metabolite, FTY. Theabsorbed trifluridine was metabolised, and excreted into urine as FTY and trifluridine glucuronideisomers. Other minor metabolites, 5-carboxyuracil and 5-carboxy-2’-deoxyuridine, were detected, butthose levels in plasma and urine were at low or trace levels.

Tipiracil hydrochloride was not metabolised in human liver S9 or in cryopreserved humanhepatocytes. Tipiracil hydrochloride was the major component and 6-hydroxymethyluracil was themajor metabolite consistently in human plasma, urine, and faeces.

Following the multiple-dose administration of Lonsurf at the recommended dose and regimen, themean elimination half-life (t1/2) for trifluridine on Day 1 of Cycle 1 and on Day 12 of Cycle 1 were 1.4hours and 2.1 hours, respectively. The mean t1/2 values for tipiracil hydrochloride on Day 1 of Cycle 1and on Day 12 of Cycle 1 were 2.1 hours and 2.4 hours, respectively.

Following a single dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the oralclearance (CL/F) for trifluridine and tipiracil hydrochloride were 10.5 L/hr and 109 L/hr, respectively.

After single oral administration of Lonsurf with [14C]-trifluridine, the total cumulative excretion ofradioactivity was 60% of the administered dose. The majority of recovered radioactivity waseliminated into urine (55% of the dose) within 24 hours, and the excretion into faeces and expired airwas less than 3% for both. After single oral administration of Lonsurf with [14C]-tipiracilhydrochloride, recovered radioactivity was 77% of the dose, which consisted of 27% urinary excretionand 50% faecal excretion.

In a dose finding study (15 to 35 mg/m2 twice daily), the AUC from time 0 to 10 hours (AUC0-10) oftrifluridine tended to increase more than expected based on the increase in dose; however, oralclearance (CL/F) and apparent volume of distribution (Vd/F) of trifluridine were generally constant atthe dose range of 20 to 35 mg/m2. As for the other exposure parameters of trifluridine and tipiracilhydrochloride, those appeared to be dose proportional.

Based on the population PK analysis, there is no clinically relevant effect of age, gender or race on the

PK of trifluridine or tipiracil hydrochloride.

Of the 533 patients in the RECOURSE study who received Lonsurf, 306 (57%) patients had normalrenal function (CrCl ≥ 90 mL/min), 178 (33%) patients had mild renal impairment (CrCl 60 to89 mL/min), and 47 (9%) had moderate renal impairment (CrCl 30 to 59 mL/min), with data missingfor 2 patients. Patients with severe renal impairment were not enrolled in the study.

Based on a population PK analysis, the exposure of Lonsurf in patients with mild renal impairment(CrCl = 60 to 89 mL/min) was similar to those in patients with normal renal function(CrCl ≥ 90 mL/min). A higher exposure of Lonsurf was observed in moderate renal impairment (CrCl= 30 to 59 mL/min). Estimated (CrCl) was a significant covariate for CL/F in both final models oftrifluridine and tipiracil hydrochloride. The mean relative ratio of AUC in patients with mild (n=38)and moderate (n=16) renal impairment compared to patients with normal renal function (n=84) were1.31 and 1.43 for trifluridine, respectively, and 1.34 and 1.65 for tipiracil hydrochloride, respectively.

In a dedicated study the pharmacokinetics of trifluridine and tipiracil hydrochloride were evaluated incancer patients with normal renal function (CrCl ≥90 mL/min, N=12), mild renal impairment (CrCl=60 to 89 mL/min, N=12), moderate renal impairment (CrCl =30 to 59 mL/min, N=11), or severerenal impairment (CrCl =15 to 29 mL/min, N=8). Patients with severe renal impairment received anadjusted starting dose of 20 mg/m2 twice daily (reduced to 15 mg/m2 twice daily based on individualsafety and tolerability). The effect of renal impairment after repeated administration was a 1.6- and1.4-fold increase of trifluridine total exposure in patients with moderate and severe renal impairment,respectively, compared to patients with normal renal function; Cmax remained similar. The totalexposure of tipiracil hydrochloride in patients with moderate and severe renal impairment afterrepeated administration was 2.3- and 4.1-fold higher, respectively, compared to patients with normalrenal function; this being linked to a more decreased clearance with increasing renal impairment. The

PK of trifluridine and tipiracil hydrochloride have not been studied in patients with end-stage renaldisease (CrCl < 15 mL/min or requiring dialysis) (see sections 4.2 and 4.4).

Based on the population PK analysis, liver function parameters including alkaline phosphatase (ALP,36-2322 U/L), aspartate aminotransferase (AST, 11-197 U/L), alanine aminotransferase (ALT,5-182 U/L) , and total bilirubin (0.17-3.20 mg/dL) were not significant covariates for PK parametersof either trifluridine or tipiracil hydrochloride. Serum albumin was found to significantly affecttrifluridine clearance, with a negative correlation. For low albumin values ranging from 2.2 to3.5 g/dL, the corresponding clearance values range from 4.2 to 3.1 L/h.

In a dedicated study the PK of trifluridine and tipiracil hydrochloride were evaluated in cancer patientswith mild or moderate hepatic impairment (National Cancer Institute [NCI] Criteria Group B and C,respectively) and in patients with normal hepatic function. Based upon limited data with aconsiderable variability, no statistically significant differences were observed in the pharmacokineticsin patients with normal hepatic function versus patients with mild or moderate hepatic impairment. Nocorrelation was seen for trifluridine nor tipiracil hydrochloride between PK parameters and ASTor/and total blood bilirubin. Half-life time (t1/2) and the accumulation ratio of trifluridine and tipiracilhydrochloride were similar between the moderate, mild and normal hepatic function patients.

There is no need for a starting dose adjustment in patients with mild hepatic impairment (see section4.2).

Gastrectomy

The influence of gastrectomy on PK parameters was not able to be examined in the population PKanalysis because there were few patients who had undergone gastrectomy (1% of overall).

In vitro interaction studies

Trifluridine is a substrate of TPase, but is not metabolised by cytochrome P450 (CYP). Tipiracilhydrochloride is not metabolised in either human liver S9 or cryopreserved hepatocytes.

In vitro studies indicated that trifluridine, tipiracil hydrochloride and FTY (inactive metabolite oftrifluridine) did not inhibit the CYP isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8,

CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5). In vitro evaluation indicated thattrifluridine, tipiracil hydrochloride and FTY had no inductive effect on human CYP1A2, CYP2B6 or

CYP3A4/5. Thus trifluridine and tipiracil hydrochloride are not expected to cause or be subject to asignificant medicinal product interaction mediated by CYP.

In vitro evaluation of trifluridine and tipiracil hydrochloride was conducted using human uptake andefflux transporters (trifluridine with MDR1, OATP1B1, OATP1B3 and BCRP; tipiracil hydrochloridewith OAT1, OAT3, OCT2, MATE1, MDR1 and BCRP). Neither trifluridine nor tipiracilhydrochloride was an inhibitor of or substrate for human uptake and efflux transporters based on invitro studies, except for OCT2 and MATE1. Tipiracil hydrochloride was an inhibitor of OCT2 and

MATE1 in vitro, but at concentrations substantially higher than human plasma Cmax at steady state.

Thus it is unlikely to cause an interaction with other medicinal products, at recommended doses, dueto inhibition of OCT2 and MATE1. Transport of tipiracil hydrochloride by OCT2 and MATE1 mightbe affected when Lonsurf is administered concomitantly with inhibitors of OCT2 and MATE1.

The efficacy and safety of Lonsurf in metastatic colorectal cancer was compared between ahigh-exposure group (>median) and a low-exposure group (≤median) based on the median AUC valueof trifluridine. OS appeared more favourable in the high AUC group compared to the low AUC group(median OS of 9.3 vs. 8.1 months, respectively). All AUC groups performed better than placebothroughout the follow-up period. The incidences of Grade ≥3 neutropenia were higher in thehigh-trifluridine AUC group (47.8%) compared with the low-trifluridine AUC group (30.4%).

Toxicology assessment of trifluridine/tipiracil hydrochloride was performed in rats, dogs andmonkeys. The target organs identified were the lymphatic and haematopoietic systems and thegastrointestinal tract. All changes, i.e., leukopenia, anaemia, bone marrow hypoplasia, atrophicchanges in the lymphatic and haematopoietic tissues and the gastrointestinal tract, were reversiblewithin 9 weeks of drug withdrawal. Whitening, breakage, and malocclusion were observed in teeth ofrats treated with trifluridine/tipiracil hydrochloride, which are considered rodent specific and notrelevant for human.

Carcinogenesis and mutagenesis

No long term studies evaluating the carcinogenic potential of trifluridine/tipiracil hydrochloride inanimals have been performed. Trifluridine was shown to be genotoxic in a reverse mutation test inbacteria, a chromosomal aberration test in mammal-cultured cells, and a micronucleus test in mice.

Therefore, Lonsurf should be treated as a potential carcinogen.

Results of animal studies did not indicate an effect of trifluridine and tipiracil hydrochloride on maleand female fertility in rats. The increases in the corpus luteum count and implanting embryo countobserved in female rats at high doses were not considered adverse (see section 4.6). Lonsurf has beenshown to cause embryo-foetal lethality and embryo-foetal toxicity in pregnant rats when given at doselevels lower than the clinical exposure. No peri/post-natal developmental toxicity studies have beenperformed.

Lactose monohydrate

Starch, pregelatinised (maize)

Stearic acid

Lonsurf 15 mg/6.14 mg film-coated tablets

Hypromellose

Macrogol (8000)

Titanium dioxide (E171)

Magnesium stearate

Lonsurf 20 mg/8.19 mg film-coated tablets

Hypromellose

Macrogol (8000)

Titanium dioxide (E171)

Iron oxide red (E172)

Magnesium stearate

Shellac

Iron oxide red (E172)

Iron oxide yellow (E172)

Titanium dioxide (E171)

Indigo carmine aluminium lake (E132)

Carnauba wax

Talc

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Aluminium/Aluminium blister with laminated desiccant (calcium oxide) containing 10 tablets.

Each pack contains 20, 40 or 60 film-coated tablets.

Not all pack sizes may be marketed.

Hands should be washed after handling the tablets.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Les Laboratoires Servier50 rue Carnot92284 Suresnes Cedex

France

EU/1/16/1096/001-006

Date of first authorisation: 25 April 2016

Date of latest renewal: 14 December 2020

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.