Lonsurf

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ANNEX I 

 
SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Lonsurf 15 mg/6.14 mg film-coated tablets 
Lonsurf 20 mg/8.19 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Lonsurf 15 mg/6.14 mg film-coated tablets 
Each film-coated tablet contains 15 mg trifluridine and 6.14 mg tipiracil (as hydrochloride). 
 
Excipient with known effect 
Each 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). 
 
Excipient with known effect 
Each film-coated tablet contains 120.980 mg of lactose monohydrate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
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 thickness 
of 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 thickness 
of 3.2 mm, imprinted with ‘20’ on one side, and ‘102’ and ‘20 mg’ on the other side, in grey ink. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Colorectal cancer 
 
Lonsurf is indicated as monotherapy for the treatment of adult patients with metastatic colorectal 
cancer (CRC) who have been previously treated with, or are not considered candidates for, available 
therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF 
agents, and anti-EGFR agents. 
 
Gastric cancer 
 
Lonsurf is indicated as monotherapy for the treatment of adult patients with metastatic gastric cancer 
including adenocarcinoma of the gastroesophageal junction, who have been previously treated with at 
least two prior systemic treatment regimens for advanced disease (see section 5.1). 
 
4.2 Posology and method of administration 
 
Lonsurf should be prescribed by physicians experienced in the administration of anticancer therapy. 
 



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Posology 
 
The recommended starting dose of Lonsurf in adults is 35 mg/m2/dose administered orally twice daily 
on Days 1 to 5 and Days 8 to 12 of each 28-day cycle as long as benefit is observed or until 
unacceptable toxicity occurs (see section 4.4). 
 
The dose is calculated according to body surface area (BSA) (see Table 1). The dose must not exceed 
80 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 
 

Starting dose BSA 
(m2) 

Dose in mg 
(2x daily) 

Tablets per dose 
(2x daily) 

Total 
daily 
dose 
(mg) 15 mg/6.14 mg 20 mg/8.19 mg 

35 mg/m2 < 1.07 35 1 1 70 
1.07 - 1.22 40 0 2 80 
1.23 - 1.37 45 3 0 90 
1.38 - 1.52 50 2 1 100 
1.53 - 1.68 55 1 2 110 
1.69 - 1.83 60 0 3 120 
1.84 - 1.98 65 3 1 130 
1.99 - 2.14 70 2 2 140 
2.15 - 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. Dose 
escalation is not permitted after it has been reduced. 
 
In the event of haematological and/or non-haematological toxicities patients should follow the dose 
interruption, resumption and reduction criteria stated in Table 2, Table 3 and Table 4. 

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

 

Parameter Interruption criteria Resumption criteriaa 

Neutrophils < 0.5 × 109/L ≥ 1.5 × 109/L 

Platelets < 50 × 109/L ≥ 75 × 109/L 
a Resumption criteria applied to the start of the next cycle for all patients regardless of whether or not 

the interruption criteria were met. 
 



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

 
Adverse reaction Recommended dose modifications 

• Febrile neutropenia 
• CTCAE* Grade 4 neutropenia 

(< 0.5 x 109/L) or thrombocytopenia 
(< 25 × 109/L) that results in more than 1 
week’s delay in start of next cycle 

• CTCAE* non-haematologic Grade 3 or 
Grade 4 adverse reaction; except for 
Grade 3 nausea and/or vomiting 
controlled by antiemetic therapy or 
diarrhoea responsive to antidiarrhoeal 
medicinal products 

• Interrupt dosing until toxicity resolves to 
Grade 1 or baseline. 

• When resuming dosing, decrease the dose 
level by 5 mg/m2/dose from the previous 
dose level (Table 4). 

• Dose reductions are permitted to a 
minimum dose of 20 mg/m2/dose twice 
daily (or 15 mg/m2/dose twice daily in 
severe renal impairment).  

• Do not increase dose after it has been 
reduced. 

 
* Common terminology criteria for adverse events 

 



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Table 4 - Dose reductions according to BSA 
 

Reduced dose BSA 
(m2) 

Dose in 
mg 

(2x daily) 

Tablets per dose 
(2x daily) 

Total 
daily 
dose 
(mg) 15 mg/6.14 mg 20 mg/8.19 mg 

Level 1 dose reduction: From 35 mg/m2 to 30 mg/m2 
30 mg/m2 < 1.09 30 2 0 60 

1.09 - 1.24 35 1 1 70 
1.25 - 1.39 40 0 2 80 
1.40 - 1.54 45 3 0 90 
1.55 - 1.69 50 2 1 100 
1.70 - 1.94 55 1 2 110 
1.95 - 2.09 60 0 3 120 
2.10 - 2.28 65 3 1 130 

≥ 2.29 70 2 2 140 
Level 2 dose reduction: From 30 mg/m2 to 25 mg/m2 

25 mg/m2 < 1.10 25a 2a 1a 50a 
1.10 - 1.29 30 2 0 60 
1.30 - 1.49 35 1 1 70 
1.50 - 1.69 40 0 2 80 
1.70 - 1.89 45 3 0 90 
1.90 - 2.09 50 2 1 100 
2.10 - 2.29 55 1 2 110 

≥ 2.30 60 0 3 120 
Level 3 dose reduction: From 25 mg/m2 to 20 mg/m2 

20 mg/m2 < 1.14 20 0 1 40 
1.14 – 1.34 25a 2a 1a 50a 
1.35 – 1.59 30 2 0 60 
1.60 – 1.94 35 1 1 70 
1.95 – 2.09 40 0 2 80 
2.10 – 2.34 45 3 0 90 

≥ 2.35 50 2 1 100 
a At a total daily dose of 50 mg, patients should take 1 x 20 mg/8.19 mg tablet in the morning and 

2 x 15 mg/6.14 mg tablets in the evening. 

 

Special populations 
 
Renal impairment 
 
• Mild renal impairment (CrCl 60 to 89 mL/min) or moderate renal impairment (CrCl 30 to 

59 mL/min) 
No adjustment of the starting dose is recommended in patients with mild or moderate renal 
impairment (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 permitted 



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based on individual safety and tolerability (see Table 5). Dose escalation is not permitted after it has 
been reduced. 
In the event of haematological and/or non-haematological toxicities patients should follow the dose 
interruption, 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 according 

to BSA 
 

Reduced dose BSA 
(m2) 

Dose in 
mg 

(2x daily) 

Tablets per dose 
(2x daily) 

Total 
daily 
dose 
(mg) 15 mg/6.14 mg 20 mg/8.19 mg 

Starting dose 
20 mg/m2 < 1.14 20 0 1 40 

1.14 – 1.34 25a 2a 1a 50a 
1.35 – 1.59 30 2 0 60 
1.60 – 1.94 35 1 1 70 
1.95 – 2.09 40 0 2 80 
2.10 – 2.34 45 3 0 90 

≥ 2.35 50 2 1 100 
Dose reduction: From 20 mg/m2 to 15 mg/m2 

15 mg/m2 < 1.15 15 1 0 30 
1.15 – 1.49 20 0 1 40 
1.50 – 1.84 25a 2a 1a 50a 
1.85 – 2.09 30 2 0 60 
2.10 – 2.34 35 1 1 70 

≥ 2.35 40 0 2 80 
a At a total daily dose of 50 mg, patients should take 1 x 20 mg/8.19 mg tablet in the morning and 
2 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 data 
available for these patients (see section 4.4). 
 
Hepatic impairment 
 
• Mild hepatic impairment 
No adjustment of the starting dose is recommended in patients with mild hepatic impairment (see 
section 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, a 
higher incidence of Grade 3 or 4 hyperbilirubinaemia is observed in patients with baseline moderate 
hepatic impairment, although this is based on very limited data (see sections 4.4 and 5.2). 
 
Elderly  
 
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. 
 



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Paediatric population 
 
There is no relevant use of Lonsurf in the paediatric population for the indications of metastatic 
colorectal cancer and metastatic gastric cancer. 
 
Race  
 
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 biological 
rationale to expect any difference between this subgroup and the overall population.   
 
Method of administration  
 
Lonsurf is for oral use. The tablets must be taken with a glass of water within 1 hour after completion 
of the morning and evening meals. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
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 monitor 
toxicity, 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 relevant 
toxicity from prior therapies.  
 
Serious infections have been reported following treatment with Lonsurf (see section 4.8). Given that 
the majority were reported in the context of bone marrow suppression, the patient’s condition should 
be monitored closely, and appropriate measures, such as antimicrobial agents and granulocyte-colony 
stimulating factor (G-CSF), should be administered as clinically indicated. In RECOURSE and TAGS 
studies, 9.4% and 17.3% of patients in the Lonsurf group respectively received G-CSF mainly for 
therapeutic use. 
 
Gastrointestinal toxicity 
 
Lonsurf caused an increase in the incidence of gastrointestinal toxicities including nausea, vomiting 
and diarrhoea. 
 
Patients with nausea, vomiting, diarrhoea and other gastrointestinal toxicities should be carefully 
monitored, and anti-emetic, anti-diarrhoeal and other measures, such as fluid/electrolyte replacement 
therapy, should be administered as clinically indicated. Dose modifications (delay and/or reduction) 
should be applied as necessary (see section 4.2).  
 
Renal impairment 
 
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 (see 
section 5.2). 



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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 increase 
with advancing levels of renal impairment. In addition, a higher exposure of trifluridine and tipiracil 
hydrochloride was observed in patients with moderate renal impairment, compared with patients with 
normal 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 of 
20 mg/m2 twice daily had a safety profile consistent with the safety profile of Lonsurf in patients with 
normal renal function or mild renal impairment. Their exposure to trifluridine was similar to that of 
patients with normal renal function and their exposure to tipiracil hydrochloride was increased 
compared to patients with normal renal function, mild and moderate renal impairment (see sections 4.2 
and 5.2). 
Patients with renal impairment should be monitored closely when being treated with Lonsurf; patients 
with moderate or severe renal impairment should be more frequently monitored for haematological 
toxicities. 
 
Hepatic impairment 
 
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 a 
higher incidence of Grade 3 or 4 hyperbilirubinaemia is observed in patients with baseline moderate 
hepatic 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). 
 
Lactose intolerance 
 
Lonsurf contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase 
deficiency or glucose-galactose malabsorption should not take this medicinal product. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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 indicated 
that trifluridine, tipiracil hydrochloride and FTY had no inductive effect on human CYP isoforms (see 
section 5.2). 
 
In vitro studies indicated that trifluridine is a substrate for the nucleoside transporters CNT1, ENT1 
and ENT2. Therefore, caution is required when using medicinal products that interact with these 
transporters. Tipiracil hydrochloride was a substrate for OCT2 and MATE1, therefore, the 
concentration 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 the 
effector, trifluridine, for activation via thymidine kinases. Therefore, when using antiviral medicinal 
products that are human thymidine kinase substrates, monitor for possible decreased efficacy of the 
antiviral medicinal product, and consider switching to an alternative antiviral medicinal product that is 
not 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. 
 



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4.6 Fertility, pregnancy and lactation 
 
Women of childbearing potential / Contraception in males and females 
 
Based on findings in animals, trifluridine may cause foetal harm when administered to pregnant 
women. Women should avoid becoming pregnant while taking Lonsurf and for up to 6 months after 
ending treatment. Therefore, women of child-bearing potential must use highly effective contraceptive 
measures while taking Lonsurf and for 6 months after stopping treatment. It is currently unknown 
whether Lonsurf may reduce the effectiveness of hormonal contraceptives, and therefore women using 
hormonal contraceptives should add a barrier contraceptive method. 
Men with a partner of child-bearing potential must use effective contraception during treatment and 
for up to 6 months after discontinuation of treatment. 
 
Pregnancy 
 
There are no available data from the use of Lonsurf in pregnant women. Based on the mechanism of 
action, trifluridine is suspected to cause congenital malformations when administered during 
pregnancy. Studies in animals have shown reproductive toxicity (see section 5.3). Lonsurf should not 
be used during pregnancy unless the clinical condition of the woman requires treatment with Lonsurf. 
 
Breast-feeding  
 
It is unknown whether Lonsurf or its metabolites are excreted in human milk. Studies in animals have 
shown excretion of trifluridine, tipiracil hydrochloride and/or their metabolites in milk (see 
section 5.3). A risk to the suckling child cannot be excluded. Breast-feeding should be discontinued 
during treatment with Lonsurf. 
 
Fertility 
 
There are no data available on the effects of Lonsurf on human fertility. Results of animal studies did 
not indicate an effect of Lonsurf on male or female fertility (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Lonsurf has minor influence on the ability to drive and use machines. Fatigue, dizziness or malaise 
may occur during treatment (see section 4.8).  
 
4.8 Undesirable effects 
 
Summary of safety profile 
 
The most serious observed adverse drug reactions in patients receiving Lonsurf are bone marrow 
suppression and gastrointestinal toxicity (see section 4.4). 
 
The most frequently observed adverse drug reactions (≥ 30%) in patients receiving Lonsurf are 
neutropenia (53% [34% ≥ Grade 3]), nausea (34% [1% ≥ Grade 3]), fatigue (32% [4% ≥ Grade 3]), 
anaemia (32% [12% ≥ Grade 3]). 
 
The most common adverse drug reactions (≥ 2%) in patients receiving Lonsurf that resulted in 
treatment discontinuation, dose reduction, dose delay, or dose interruption were neutropenia, 
anaemia, leukopenia, fatigue, thrombocytopenia, nausea and diarrhoea. 
 
Tabulated list of adverse drug reactions 
 
The adverse drug reactions observed from the 533 treated patients with metastatic colorectal cancer in 
the placebo-controlled Phase III (RECOURSE) clinical study and the 335 treated patients with 
metastatic gastric cancer in the placebo-controlled Phase III (TAGS) clinical study, are shown in 



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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 its 
synonyms and related conditions. 
 
Adverse drug reactions are grouped according to their frequencies. Frequency groups are defined by 
the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); and uncommon 
(≥1/1,000 to < 1/100).  
 
Within each frequency group, adverse drug reactions are presented in order of decreasing seriousness. 
 

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

System Organ Class 

(MedDRA)a 
Very common Common Uncommon 

Infections and 
infestations 

 Lower respiratory tract 
infection 
 
 

Septic shockb 

Enteritis infectious 
Lung infection 
Biliary tract infection 
Influenza 
Urinary tract infection 
Gingivitis 
Herpes zoster 
Tinea pedis 
Candida infection 
Bacterial infection 
Infection 
Neutropenic sepsis 
Upper respiratory tract infection 
Conjunctivitis 

Neoplasms benign, 
malignant and 
unspecified (incl. 
cysts and polyps) 

  Cancer pain 

Blood and lymphatic 
system disorders 

Neutropenia 
Leukopenia 
Anaemia 
Thrombocytopenia 

Febrile neutropenia 
Lymphopenia 
 

Pancytopenia 
Granulocytopenia 
Monocytopenia 
Erythropenia 
Leukocytosis 
Monocytosis 

Metabolism and 
nutrition disorders 

Decreased appetite Hypoalbuminaemia 
 

Dehydration 
Hyperglycaemia 
Hyperkalaemia 
Hypokalaemia 
Hypophosphataemia 
Hypernatraemia 
Hyponatraemia 
Hypocalcaemia 
Gout 

Psychiatric disorders   Anxiety 
Insomnia 



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System Organ Class 

(MedDRA)a 
Very common Common Uncommon 

Nervous system 
disorders 

 Dysgeusia 
Neuropathy peripheral 
 

Neurotoxicity 
Dysaesthesia 
Hyperaesthesia 
Hypoaesthesia 
Syncope 
Paraesthesia 
Burning sensation 
Lethargy 
Dizziness 
Headache 

Eye disorders   Visual acuity reduced 
Vision blurred 
Diplopia 
Cataract 
Dry eye 

Ear and labyrinth 
disorders 

  Vertigo 
Ear discomfort 

Cardiac disorders   Angina pectoris 
Arrhythmia  
Palpitations 

Vascular disorders   Embolism 
Hypertension 
Hypotension 
Flushing 

Respiratory, thoracic 
and mediastinal 
disorders 

 Dyspnoea 
 

Pulmonary embolismb 
Pleural effusion 
Rhinorrhoea 
Dysphonia 
Oropharyngeal pain 
Epistaxis 
Cough 



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System Organ Class 

(MedDRA)a 
Very common Common Uncommon 

Gastrointestinal 
disorders 

Diarrhoea 
Nausea 
Vomiting 

Abdominal pain 
Constipation 
Stomatitis 
Oral disorder 

Enterocolitis haemorrhagic 
Gastrointestinal haemorrhage 
Pancreatitis acute 
Ascites 
Ileus 
Subileus 
Colitis 
Gastritis 
Reflux gastritis 
Oesophagitis 
Impaired gastric emptying 
Abdominal distension 
Anal inflammation 
Mouth ulceration 
Dyspepsia 
Gastrooesophageal reflux disease 
Proctalgia 
Buccal polyp 
Gingival bleeding 
Glossitis 
Periodontal disease 
Tooth disorder 
Retching 
Flatulence 
Breath odour 

Hepatobiliary 
disorders 

 Hyperbilirubinaemia Hepatotoxicity 
Biliary dilatation 

Skin and 
subcutaneous tissue 
disorders 

 Palmar-plantar 
erythrodysaesthesia 
syndromec 

Rash 
Alopecia 
Pruritus 
Dry skin 

Skin exfoliation 
Urticaria 
Photosensitivity reaction 
Erythema 
Acne 
Hyperhidrosis 
Blister 
Nail Disorder 

Musculoskeletal and 
connective tissue 
disorders 

  Joint swelling 
Arthralgia 
Bone pain 
Myalgia 
Musculoskeletal pain 
Muscular weakness 
Muscle spasms 
Pain in extremity 

Renal and urinary 
disorders 

 Proteinuria Renal failure 
Cystitis noninfective 
Micturition disorder 
Haematuria 
Leukocyturia 

Reproductive system 
and breast disorders 

  Menstrual disorder 



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System Organ Class 

(MedDRA)a 
Very common Common Uncommon 

General disorders and 
administration site 
conditions 

Fatigue Pyrexia 
Oedema 
Mucosal inflammation 
Malaise 

General physical health 
deterioration 
Pain 
Feeling of body temperature change 
Xerosis 
Discomfort 

Investigations  Hepatic enzyme 
increased 
Blood alkaline 
phosphatase increased 
Weight decreased 

Blood creatinine increased 
Electrocardiogram QT prolonged 
International normalised ratio 
increased 
Activated partial thromboplastin 
time prolonged 
Blood urea increased 
Blood lactate dehydrogenase 
increased 
Protein total decreased 
C-reactive protein increased 
Haematocrit decreased 

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

b. Fatal cases have been reported. 
c. Hand-foot skin reaction. 

 
Elderly 
 
Patients 65 years of age or older who received Lonsurf had a higher incidence of the following events 
compared to patients younger than 65 years: 
- metastatic colorectal cancer (RECOURSE): Grade 3 or 4 neutropenia (48% vs 30%), Grade 3 
anaemia (26% vs 12%), Grade 3 or 4 leukopenia (26% vs 18%) and Grade 3 or 4 thrombocytopenia 
(9% vs 2%), 
- metastatic gastric cancer (TAGS): Grade 3 or 4 neutrophil count decrease (17.0% vs 6.6%), 
decreased appetite (37.3% vs 31.9%), asthenia (22.2% vs 17.0%) and stomatitis (7.2% vs 2.2%). 
 
Infections 
 
In the Phase III clinical studies, treatment-related infections occurred more frequently in Lonsurf-
treated patients (5.8%) compared to those receiving placebo (1.8%). 
 
Proteinuria 
 
Treatment-related proteinuria occurred more frequently in Lonsurf-treated patients (1.8%) compared 
to those receiving placebo (0.9%), all of which were Grade 1 or 2 in severity (see section 4.4). 
 
Radiotherapy 
 
There was a slightly higher incidence of overall haematological and myelosuppression-related adverse 
reactions for patients who received prior radiotherapy compared to patients without prior radiotherapy 
in 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. 
 
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.  
 



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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 the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
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 established 
safety 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 medical 
intervention aimed at correcting the presenting clinical manifestations and preventing their possible 
complications. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
Pharmacotherapeutic group: antineoplastic agents, antimetabolites, ATC code: L01BC59 
 
Mechanism of action 
 
Lonsurf is comprised of an antineoplastic thymidine-based nucleoside analogue, trifluridine, and the 
thymidine 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, further 
metabolised 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 effect 
following oral administration, hence the inclusion of the TPase inhibitor, tipiracil hydrochloride.  
 
In nonclinical studies, trifluridine/tipiracil hydrochloride demonstrated antitumour activity against 
both 5-fluorouracil (5-FU) sensitive and resistant colorectal cancer cell lines. 
 
The cytotoxic activity of trifluridine/tipiracil hydrochloride against several human tumour xenografts 
correlated highly with the amount of trifluridine incorporated into DNA, suggesting this as the primary 
mechanism of action. 
 
Pharmacodynamic effects 
 
Lonsurf had no clinically relevant effect on QT/QTc prolongation compared with placebo in an open 
label study in patients with advanced solid tumours. 
  
Clinical efficacy and safety 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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Metastatic colorectal cancer 
 
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 metastatic 
colorectal cancer. The primary efficacy endpoint was overall survival (OS), and supportive efficacy 
endpoints 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 starting 
dose of 35 mg/m2/dose. Study treatment was administered orally twice daily after morning and 
evening meals for 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 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 patients 
had baseline Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. The 
primary 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. All 
patients received prior treatment with fluoropyrimidine-, oxaliplatin-, and irinotecan-based 
chemotherapy. All but 1 patient received bevacizumab, and all but 2 patients with KRAS wild type 
tumours received panitumumab or cetuximab. The 2 treatment groups were comparable with respect to 
demographic and baseline disease characteristics. 
 
An OS analysis of the study, carried out as planned at 72% (N = 574) of events, demonstrated a 
clinically meaningful and statistically significant survival benefit of Lonsurf plus BSC compared to 
placebo plus BSC (hazard ratio: 0.68; 95% confidence interval [CI] [0.58 to 0.81]; p < 0.0001) and a 
median 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 with 
metastatic colorectal cancer  

 

 
Lonsurf plus BSC 

(N=534) 
Placebo plus BSC 

(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 estimates 
b Methodology of Brookmeyer and Crowley 
c Stratified log-rank test (strata: KRAS status, time since diagnosis of first metastasis, region) 
 



16 

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

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Figure 2 - Kaplan-Meier curves of progression-free survival in patients with metastatic 
colorectal cancer 

 

 

 

 

 

 

 

 

 

 

 

 

 

 
An updated OS analysis, carried out at 89% (N = 712) of events, confirmed the clinically meaningful 
and statistically significant survival benefit of Lonsurf plus BSC compared to placebo plus BSC 
(hazard ratio: 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, including 
race, geographic region, age (< 65; ≥ 65), sex, ECOG PS, KRAS status, time since diagnosis of first 
metastasis, number of metastatic sites, and primary tumour site. The Lonsurf survival benefit was 
maintained after adjusting for all significant prognostic factors, namely, time since diagnosis of first 
metastasis, ECOG PS and number of metastatic sites (hazard ratio: 0.69; 95% CI [0.58 to 0.81]). 
 

Hazard ratio for progression or death, 0.48 (95% CI, 0.41-0.57) 
P<0.0001 by log-rank test 

Lonsurf 
Placebo 

Months from Randomisation 

Placebo 
Lonsurf 

No. at Risk: 

Pr
og

re
ss

io
n-

fr
ee

 S
ur

vi
va

l P
ro

ba
bi

lit
y 

(%
) 

Months from Randomisation 

Placebo 

Hazard ratio for death, 0.68 (95% CI, 0.58-0.81) 
P<0.0001 

Placebo 

Su
rv

iv
al

 P
ro

ba
bi

lit
y 

(%
) 

Lonsurf 

Lonsurf 
No. at Risk: 



17 

Sixty one percent (61%, N = 485) of all randomised patients received a fluoropyrimidine as part of 
their last treatment regimen prior to randomisation, of which 455 (94%) were refractory to the 
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 to 
randomisation. 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 patients 
treated with Lonsurf (44% vs 16%, p < 0.0001). 
 
Treatment with Lonsurf plus BSC resulted in a statistically significant prolongation of PS <2 in 
comparison to placebo plus BSC. The median time to PS ≥ 2 for the Lonsurf group and placebo group 
was 5.7 months and 4.0 months, respectively, with a hazard ratio of 0.66 (95% CI: [0.56, 0.78]), 
p < 0.0001. 
 
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 gastric 
cancer (including adenocarcinoma of the gastroesophageal junction), who had been previously treated 
with at least two prior systemic treatment regimens for advanced disease, including fluoropyrimidine-, 
platinum-, and either taxane- or irinotecan-based chemotherapy, plus if appropriate human epidermal 
growth 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 quality 
of 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 of 
35 mg/m2/dose. Study treatment was administered orally twice daily after morning and evening meals 
for 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%) or 
gastroesophageal junction cancer (28.6%) or both (0.4%). The median number of prior regimens of 
therapy 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 
prior HER2-targeted therapy. The 2 treatment groups were comparable with respect to demographic 
and 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 and 
0.0006, respectively) corresponding to a 31% reduction in the risk of death in the Lonsurf group. The 
median 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 8, Figure 3 and Figure 4). 
 



18 

Table 8 - Efficacy results from the Phase III (TAGS) clinical study in patients with metastatic 
gastric cancer 

 

 
Lonsurf plus BSC 

(N=337) 
Placebo plus BSC 

(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, 
N (%) 

287 (85.2) 
 

156 (91.8) 

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 estimates 
b Methodology of Brookmeyer and Crowley 
c Stratified log-rank test (strata: region, ECOG status at baseline, prior ramucirumab treatment) 
 
Figure 3- Kaplan-Meier curves of overall survival in patients with metastatic gastric cancer 
 

 
 

Months from Randomisation 

Placebo 

Hazard ratio for death, 0.69 (95% CI, 0.56-0.85) 
P=0.0003 (1-sided) ; p =0.0006 (2-sided) 

Placebo 

Su
rv

iv
al

 P
ro

ba
bi

lit
y 

(%
) 

Lonsurf 

Lonsurf 
No. at Risk: 



19 

Figure 4 - Kaplan-Meier curves of progression-free survival in patients with metastatic gastric 
cancer 

 

 
 
The OS and PFS benefit was observed consistently, in all randomization strata and across most 
pre-specified subgroups, including sex, age (< 65; ≥ 65 years), ethnic origin, ECOG PS, prior 
ramucirumab treatment, prior irinotecan treatment, number of prior regimens (2; 3; ≥ 4), previous 
gastrectomy, 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 or 
stable 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 Lonsurf 
group versus 2.3 months for the placebo group with HR of 0.69 (95% CI: 0.562, 0.854), 
p-value = 0.0005.  
 
Paediatric population 
 
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 in 
refractory metastatic gastric cancer (see section 4.2 for information on paediatric use). 
 
Elderly 
 
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 85 years or older). The effect of 
Lonsurf on overall survival was similar in patients <65 years and ≥65 years of age. 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
After oral administration of Lonsurf with [14C]-trifluridine, at least 57% of the administered 
trifluridine was absorbed and only 3% of the dose was excreted into faeces. After oral administration 
of Lonsurf with [14C]-tipiracil hydrochloride, at least 27% of the administered tipiracil hydrochloride 
was absorbed and 50% of the total radioactivity dose measured into faeces, suggestive of moderate 
gastrointestinal absorption of tipiracil hydrochloride. 
Following a single dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the mean 
times to peak plasma concentrations (tmax) of trifluridine and tipiracil hydrochloride were around 2 
hours and 3 hours, respectively. 
 

Months from Randomisation 

Hazard ratio for progression or death, 0.57 (95% CI, 0.47-0.70) 
P<0.0001 (1-sided and 2-sided) 

Lonsurf 
Placebo 

Placebo 

Pr
og

re
ss

io
n-

fr
ee

 S
ur

vi
va

l P
ro

ba
bi

lit
y 

(%
) 

Lonsurf 
No. at Risk: 



20 

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 4 
weeks), trifluridine area under the concentration-time curve from time 0 to the last measurable 
concentration (AUC0-last) was approximately 3-fold higher and maximum concentration (Cmax) was 
approximately 2-fold higher after multiple dose administration (Day 12 of Cycle 1) of Lonsurf than 
after single-dose (Day 1 of Cycle 1). 
 
However, there was no accumulation for tipiracil hydrochloride, and no further accumulation of 
trifluridine with successive cycles (Day 12 of Cycles 2 and 3) of administration of Lonsurf. Following 
multiple doses of Lonsurf (35 mg/m2/dose twice daily) in patients with advanced solid tumours, the 
mean times to peak plasma concentrations (tmax) of trifluridine and tipiracil hydrochloride were around 
2 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 by 
37-fold and Cmax by 22-fold with reduced variability compared to trifluridine alone (35 mg/m2/dose). 
 
Effect of food 
 
When Lonsurf at a single dose of 35 mg/m2 was administered to 14 patients with solid tumours after a 
standardised 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 by 
approximately 40% compared to those in a fasting state. In clinical studies Lonsurf was administered 
within 1 hour after completion of the morning and evening meals (see section 4.2). 
 
Distribution 
 
The protein binding of trifluridine in human plasma was over 96% and trifluridine bound mainly to 
human serum albumin. Plasma protein binding of tipiracil hydrochloride was below 8%. Following a 
single dose of Lonsurf (35 mg/m2) in patients with advanced solid tumours, the apparent volume of 
distribution (Vd/F) for trifluridine and tipiracil hydrochloride was 21 L and 333 L, respectively.  
 
Biotransformation 
 
Trifluridine was mainly eliminated by metabolism via TPase to form an inactive metabolite, FTY. The 
absorbed trifluridine was metabolised, and excreted into urine as FTY and trifluridine glucuronide 
isomers. Other minor metabolites, 5-carboxyuracil and 5-carboxy-2’-deoxyuridine, were detected, but 
those levels in plasma and urine were at low or trace levels. 
 
Tipiracil hydrochloride was not metabolised in human liver S9 or in cryopreserved human 
hepatocytes. Tipiracil hydrochloride was the major component and 6-hydroxymethyluracil was the 
major metabolite consistently in human plasma, urine, and faeces. 
 
Elimination 
 
Following the multiple-dose administration of Lonsurf at the recommended dose and regimen, the 
mean elimination half-life (t1/2) for trifluridine on Day 1 of Cycle 1 and on Day 12 of Cycle 1 were 1.4 
hours and 2.1 hours, respectively. The mean t1/2 values for tipiracil hydrochloride on Day 1 of Cycle 1 
and 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 oral 
clearance (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 of 
radioactivity was 60% of the administered dose. The majority of recovered radioactivity was 
eliminated into urine (55% of the dose) within 24 hours, and the excretion into faeces and expired air 
was less than 3% for both. After single oral administration of Lonsurf with [14C]-tipiracil 



21 

hydrochloride, recovered radioactivity was 77% of the dose, which consisted of 27% urinary excretion 
and 50% faecal excretion. 
 
Linearity/non-linearity 
 
In a dose finding study (15 to 35 mg/m2 twice daily), the AUC from time 0 to 10 hours (AUC0-10) of 
trifluridine tended to increase more than expected based on the increase in dose; however, oral 
clearance (CL/F) and apparent volume of distribution (Vd/F) of trifluridine were generally constant at 
the dose range of 20 to 35 mg/m2. As for the other exposure parameters of trifluridine and tipiracil 
hydrochloride, those appeared to be dose proportional. 
 
Pharmacokinetics in special populations 
 
Age, gender and race 
 
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. 
 
Renal impairment 
 
Of the 533 patients in the RECOURSE study who received Lonsurf, 306 (57%) patients had normal 
renal function (CrCl ≥ 90 mL/min), 178 (33%) patients had mild renal impairment (CrCl 60 to 
89 mL/min), and 47 (9%) had moderate renal impairment (CrCl 30 to 59 mL/min), with data missing 
for 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 of 
trifluridine 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) were 
1.31 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 in 
cancer 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 severe 
renal impairment (CrCl =15 to 29 mL/min, N=8). Patients with severe renal impairment received an 
adjusted starting dose of 20 mg/m2 twice daily (reduced to 15 mg/m2 twice daily based on individual 
safety and tolerability). The effect of renal impairment after repeated administration was a 1.6- and 
1.4-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 total 
exposure of tipiracil hydrochloride in patients with moderate and severe renal impairment after 
repeated administration was 2.3- and 4.1-fold higher, respectively, compared to patients with normal 
renal 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 renal 
disease (CrCl < 15 mL/min or requiring dialysis) (see sections 4.2 and 4.4). 
 
Hepatic impairment 
 
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 parameters 
of either trifluridine or tipiracil hydrochloride. Serum albumin was found to significantly affect 
trifluridine clearance, with a negative correlation. For low albumin values ranging from 2.2 to 
3.5 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 patients 
with 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 a 



22 

considerable variability, no statistically significant differences were observed in the pharmacokinetics 
in patients with normal hepatic function versus patients with mild or moderate hepatic impairment. No 
correlation was seen for trifluridine nor tipiracil hydrochloride between PK parameters and AST 
or/and total blood bilirubin. Half-life time (t1/2) and the accumulation ratio of trifluridine and tipiracil 
hydrochloride 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 section 
4.2). 
 
Gastrectomy 
 
The influence of gastrectomy on PK parameters was not able to be examined in the population PK 
analysis 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). Tipiracil 
hydrochloride is not metabolised in either human liver S9 or cryopreserved hepatocytes. 
 
In vitro studies indicated that trifluridine, tipiracil hydrochloride and FTY (inactive metabolite of 
trifluridine) did not inhibit the CYP isoforms tested (CYP1A2, CYP2A6, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5). In vitro evaluation indicated that 
trifluridine, 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 a 
significant medicinal product interaction mediated by CYP. 
 
In vitro evaluation of trifluridine and tipiracil hydrochloride was conducted using human uptake and 
efflux transporters (trifluridine with MDR1, OATP1B1, OATP1B3 and BCRP; tipiracil hydrochloride 
with OAT1, OAT3, OCT2, MATE1, MDR1 and BCRP). Neither trifluridine nor tipiracil 
hydrochloride was an inhibitor of or substrate for human uptake and efflux transporters based on in 
vitro 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, due 
to inhibition of OCT2 and MATE1. Transport of tipiracil hydrochloride by OCT2 and MATE1 might 
be affected when Lonsurf is administered concomitantly with inhibitors of OCT2 and MATE1. 
 
Pharmacokinetic/pharmacodynamic relationship 
 
The efficacy and safety of Lonsurf in metastatic colorectal cancer was compared between a 
high-exposure group (>median) and a low-exposure group (≤median) based on the median AUC value 
of 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 placebo 
throughout the follow-up period. The incidences of Grade ≥3 neutropenia were higher in the 
high-trifluridine AUC group (47.8%) compared with the low-trifluridine AUC group (30.4%). 
 
5.3 Preclinical safety data 
 
Repeat-dose toxicity 
 
Toxicology assessment of trifluridine/tipiracil hydrochloride was performed in rats, dogs and 
monkeys. The target organs identified were the lymphatic and haematopoietic systems and the 
gastrointestinal tract. All changes, i.e., leukopenia, anaemia, bone marrow hypoplasia, atrophic 
changes in the lymphatic and haematopoietic tissues and the gastrointestinal tract, were reversible 
within 9 weeks of drug withdrawal. Whitening, breakage, and malocclusion were observed in teeth of 
rats treated with trifluridine/tipiracil hydrochloride, which are considered rodent specific and not 
relevant for human.  
 



23 

Carcinogenesis and mutagenesis 
 
No long term studies evaluating the carcinogenic potential of trifluridine/tipiracil hydrochloride in 
animals have been performed. Trifluridine was shown to be genotoxic in a reverse mutation test in 
bacteria, a chromosomal aberration test in mammal-cultured cells, and a micronucleus test in mice. 
Therefore, Lonsurf should be treated as a potential carcinogen. 
 
Reproductive toxicity 
 
Results of animal studies did not indicate an effect of trifluridine and tipiracil hydrochloride on male 
and female fertility in rats. The increases in the corpus luteum count and implanting embryo count 
observed in female rats at high doses were not considered adverse (see section 4.6). Lonsurf has been 
shown to cause embryo-foetal lethality and embryo-foetal toxicity in pregnant rats when given at dose 
levels lower than the clinical exposure. No peri/post-natal developmental toxicity studies have been 
performed. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core 
 
Lactose monohydrate 
Starch, pregelatinised (maize) 
Stearic acid 
 
Film coating 
 
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 
 
Printing ink 
 
Shellac 
Iron oxide red (E172) 
Iron oxide yellow (E172) 
Titanium dioxide (E171) 
Indigo carmine aluminium lake (E132) 
Carnauba wax  
Talc 
 
6.2 Incompatibilities 
 
Not applicable. 
 



24 

6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container  
 
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. 
 
6.6 Special precautions for disposal and other handling 
 
Hands should be washed after handling the tablets.  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier  
50 rue Carnot 
92284 Suresnes Cedex 
France 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1096/001-006 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 25 April 2016 
Date of latest renewal:  
 
10. DATE OF REVISION OF THE TEXT 
 
 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu.

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


25 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 
AND USE 

 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



26 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer responsible for batch release 

Les Laboratoires Servier Industrie 
905, route de Saran 
45520 Gidy 
France 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 
Characteristics, section 4.2). 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION  

• Periodic safety update reports (PSURs)  
 
The requirements for submission of PSURs for this medicinal product are set out in the list of 
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and 
any subsequent updates published on the European medicines web-portal. 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT 

• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing 
authorisation and any agreed subsequent updates of the RMP. 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new 
information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  



27 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



28 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 

A. LABELLING 



29 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Lonsurf 15 mg/6.14 mg film-coated tablets 
trifluridine/tipiracil  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 15 mg trifluridine and 6.14 mg of tipiracil (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate, see leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
20 film-coated tablets 
40 film-coated tablets 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 



30 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier  
50 rue Carnot 
92284 Suresnes Cedex 
France  
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1096/001 20 film-coated tablets 
EU/1/16/1096/002 40 film-coated tablets 
EU/1/16/1096/003 60 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Lonsurf 15 mg/6.14 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



31 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Lonsurf 15 mg/6.14 mg tablets 
trifluridine/tipiracil  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
 
 
 
 
 
 



32 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Lonsurf 20 mg/8.19 mg film-coated tablets 
trifluridine/tipiracil  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 20 mg trifluridine and 8.19 mg of tipiracil (as hydrochloride). 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose monohydrate, see leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
20 film-coated tablets 
40 film-coated tablets 
60 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use. 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
Cytotoxic. 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
 



33 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier  
50 rue Carnot 
92284 Suresnes Cedex 
France  
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/16/1096/004 20 film-coated tablets 
EU/1/16/1096/005 40 film-coated tablets 
EU/1/16/1096/006 60 film-coated tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
 
16. INFORMATION IN BRAILLE 
 
Lonsurf 20 mg/8.19 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



34 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Lonsurf 20 mg/8.19 mg tablets 
trifluridine/tipiracil  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Les Laboratoires Servier  
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
 
 
 
 
 
 



35 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

B. PACKAGE LEAFLET 



36 

Package leaflet: Information for the patient 
 

Lonsurf 15 mg/6.14 mg film-coated tablets 
Lonsurf 20 mg/8.19 mg film-coated tablets 

trifluridine/tipiracil 
 

Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist.  
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you experience any side effects, talk to your doctor or pharmacist. This includes any possible 

side effects not listed in this leaflet. See Section 4. 
 

What is in this leaflet  
1. What Lonsurf is and what it is used for 
2. What you need to know before you take Lonsurf  
3. How to take Lonsurf 
4. Possible side effects 
5. How to store Lonsurf 
6. Contents of the pack and other information 

 
 

1. What Lonsurf is and what it is used for  
 
Lonsurf is a type of cancer chemotherapy which belongs to the group of medicines called "cytostatic 
antimetabolite medicines". 
 
Lonsurf contains two different active substances: trifluridine and tipiracil. 
• Trifluridine stops the growth of cancer cells. 
• Tipiracil stops the trifluridine from being broken down by the body, helping trifluridine to work 

longer. 
 
Lonsurf is used to treat adults with colon or rectal cancer - sometimes called ‘colorectal’ cancer and 
stomach cancer (including cancer of the junction between the oesophagus and the stomach).  
• It is used when the cancer has spread to other parts of the body (metastases).  
• It is used when other treatments have not worked - or when other treatments are not suitable for 

you. 
 
 
2. What you need to know before you take Lonsurf 
 
Do not take Lonsurf  
• if you are allergic to trifluridine or tipiracil or any of the other ingredients of this medicine (listed in 

section 6). 
Do not take Lonsurf if the above applies to you. If you are not sure, talk to your doctor before taking 
Lonsurf. 

  
Warnings and precautions 
Talk to your doctor or pharmacist before taking Lonsurf if: 
• you have kidney problems 
• you have liver problems 
If you are not sure, talk to your doctor or pharmacist before taking Lonsurf.  
 



37 

Treatment may lead to the following side effects (see section 4): 
•  a reduced number of certain types of white blood cells (neutropenia) which are important for 

protecting the body against bacterial or fungal infections. As a consequence of neutropenia, fever 
(febrile neutropenia) and blood infection (septic shock) may occur  

• a reduced number of red blood cells (anaemia)  
• a reduced number of platelets in the blood (thrombocytopenia) which are important to stop 

bleeding and work by clumping and clotting blood vessel injuries  
• gastrointestinal problems. 

Tests and checks 
Your doctor will do blood tests before each cycle of Lonsurf. You start a new cycle every 4 weeks. 
The tests are needed because Lonsurf can sometimes affect your blood cells. 
 
Children and adolescents 
This medicine is not indicated for use in children and adolescents below the age of 18 years. This is 
because it may not work or be safe. 

Other medicines and Lonsurf 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This includes medicines obtained without a prescription and herbal medicines. This is 
because Lonsurf can affect the way some other medicines work. Also some other medicines can affect 
the way Lonsurf works. 
In particular tell your doctor or pharmacist if you are taking medicines used for treatment of HIV, such 
as zidovudine. This is because zidovudine may not work as well if you are taking Lonsurf. Talk to 
your doctor about whether to switch to a different HIV medicine. 
If the above applies to you (or you are not sure), talk to your doctor or pharmacist before taking 
Lonsurf. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, or if you think you might be pregnant or are planning to have a 
baby, ask your doctor or pharmacist for advice before taking this medicine. Lonsurf may harm your 
unborn baby.  
If you become pregnant, you and your doctor will have to decide if the benefits of Lonsurf are greater 
than the risk of harm to the baby.  
Do not breast-feed if you are taking Lonsurf as it is not known whether Lonsurf passes into the 
mother’s milk. 
 
Contraception 
You must not become pregnant while taking this medicine. This is because it may harm your unborn 
baby.  
You and your partner should use effective methods of contraception while taking this medicine. You 
should also do this for 6 months after you stop taking the medicine. If you or your partner become 
pregnant during this time, you must talk to your doctor or pharmacist straight away. 
 
Driving and using machines 
It is not known whether Lonsurf changes your ability to drive or use machines. Do not drive or use any 
tools or machines if you experience symptoms that affect your ability to concentrate and react.  
 
Lonsurf contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
 
3. How to take Lonsurf 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure.  



38 

 
How much to take 
• Your doctor will decide the right dose for you - the dose depends on your weight and height and if 

you have kidney problems.  
• Lonsurf comes in two strengths. Your doctor may prescribe both strengths for your prescribed 

dose. 
• Your doctor will tell you how many tablets to take each time. 
• You will take a dose 2 times a day.  

 
When to take Lonsurf 
You will take Lonsurf for 10 days during the first 2 weeks, and then have 2 weeks off. This 4-week 
period is called a ‘cycle.’ The specific dosing schedule is as follows: 
• Week 1  

- take the dose 2 times a day for 5 days  
- then have 2 days off - no medicine 

• Week 2  
- take the dose 2 times a day for 5 days  
- then have 2 days off - no medicine 

• Week 3 
- No medicine 

• Week 4 
- No medicine 

You will then start again with another cycle of 4 weeks following the above pattern. 
 
How to take 
• Take this medicine by mouth. 
• Swallow the tablets whole with a glass of water. 
• Take within 1 hour after your morning and evening meals. 
• Wash your hands after handling this medicine. 

 
If you take more Lonsurf than you should 
If you take more Lonsurf than you should, talk to a doctor or go to a hospital straight away. Take your 
pack(s) of medicine with you.  
 
If you forget to take Lonsurf 
• If you forget a dose, talk to your doctor or pharmacist. 
• Do not take a double dose to make up for a forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
The following side effects may happen with this medicine: 
 
Serious side effects 
Tell your doctor immediately if you notice any of the following serious side effects (many of the side 
effects are shown in laboratory tests - for example those affecting your blood cells): 
• Neutropenia (very common), febrile neutropenia (common) and septic shock (uncommon). The 

signs include chills, fever, sweating or other signs of bacterial or fungal infection (see section 2).  
• Anaemia (very common). The signs include feeling short of breath, tiredness or looking pale (see 

section 2). 
• Vomiting (very common) and diarrhoea (very common), which may lead to a dehydration if severe 

or persistent. 



39 

• Severe gastrointestinal problems: abdominal pain (common), ascites (uncommon), colitis 
(uncommon), acute pancreatitis (uncommon), ileus (uncommon) and subileus (uncommon). The 
signs include intense stomach or abdominal pain that can be associated with vomiting, blocked or 
partly blocked bowel, fever or swelling of the abdomen. 

• Thrombocytopenia (very common). The signs include unusual bruising or bleeding (see section 2).  
• Pulmonary embolism (uncommon): blood clots in lungs. The signs include shortness of breath and 

pain in the chest or in the legs. 
• Interstitial lung disease has been reported in patients receiving the medicine. The signs include 

difficulty in breathing, shortness of breath, with cough or fever. 
Some of these serious side effects may lead to death. 
 
Other side effects 
Tell your doctor if you notice any of the following side effects. Many of the side effects are shown in 
laboratory tests - for example those affecting your blood cells. Your doctor will be looking out for 
these side effects in your test results. 
 
Very common: may affect more than 1 in 10 people: 
• decreased appetite 
• feeling very tired (fatigue) 
• feeling sick (nausea)  
• reduced white blood cells called leucocytes - can increase your risk for infection  

 
Common: may affect up to 1 in 10 people: 
• fever 
• hair loss 
• weight loss 
• changes in taste 
• constipation 
• feeling generally out of sorts (malaise) 
• low level of albumin in the blood 
• increased bilirubin in your blood - can cause yellowing of skin or eyes  
• reduced number of white blood cells called lymphocytes - can increase your risk for infection  
• swelling in your hands or legs or feet 
• redness, swelling, pain on the palms of your hands and soles of your feet (hand-foot syndrome) 
• feeling of numbness or pins and needles in hands or feet 
• mouth pain or problems  
• swelling of mucous membranes - this could be inside the nose, mouth, throat, eyes, vagina, lungs 

or gut 
• increased liver enzymes 
• protein in your urine 
• rash, itchy or dry skin 
• feeling short of breath, airway or lungs, chest infections 

 
Uncommon: may affect up to 1 in 100 people 
• low or high blood pressure 
• blood clots, e.g. in the brain or legs 
• blood test results indicating problems with clotting making you bleed more easily 
• more noticeable heart-beat, chest pain  
• abnormal increase or decrease in heart rate 
• changes in your heart trace (ECG - electrocardiogram) 
• increased white blood cells  
• increased number of white blood cells called monocytes  
• increased lactate dehydrogenase level in your blood 
• low levels of phosphates, sodium, potassium or calcium in your blood 
• reduced white blood cells called granulocytes or monocytes - can increase your risk for infection 



40 

• high blood sugar (hyperglycaemia), increased salt, urea, creatinine and potassium in your blood 
• blood test result indicating inflammation (C-Reactive Protein increased) 
• ear pain 
• feeling of spinning (vertigo) 
• feeling dizzy, headache  
• runny or bloody nose, sinus problems 
• sore throat, hoarse voice, problems with your voice  
• redness, itching of the eye, eye infections, watery eyes  
• dry eyes 
• vision troubles as blurred vision, double vision, decreased vision, cataracts 
• dehydration 
• bloating, passing gas, indigestion 
• pain or inflammation in upper or lower part of digestive tract 
• inflammation, swelling or bleeding in your bowel  
• inflammation and infection in your gut 
• inflammation or increased acid in your stomach or gullet, reflux 
• painful tongue, polyps inside your mouth, mouth ulcers, retching 
• bad breath, tooth decay, tooth or gum problems, bleeding gums, gum infections 
• skin flushing 
• swelling or pain in your joints or big toes 
• pain or discomfort in your arms or legs 
• pain, including pain from the cancer   
• bone pain, muscle pain, muscle weakness or spasms, pain in tendons, nerves or ligaments  
• feeling of being cold  
• shingles (pain and vesicular rash on skin over nerve tracts affected by nerve inflammation from 

herpes zoster virus) 
• liver disorder 
• inflammation or infection of bile ducts, increase in the diameter of the bile duct 
• kidney failure 
• viral infection 
• cough, infection of the sinuses, throat infection 
• inflammation or infection in your bladder  
• changes in urine test, blood in urine 
• problems passing water (urine retention), loss of bladder control (incontinence)  
• athlete’s foot - fungal infection of feet, yeast infections 
• accumulation of fluid in the lungs 
• changes in the menstrual cycle 
• anxiety 
• fainting (syncope) 
• burning sensation, unpleasant, increased or loss of sense of touch and other non-severe 

neurological troubles 
• raised itchy rash, red skin, blisters, skin sloughing off, hives, acne  
• sweating more than normal, sensitivity to light, nail problems 
• problem with sleeping or falling asleep 
• low level of total protein in the blood 
 
Reporting of side effects  
If you experience any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


41 

5. How to store Lonsurf 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the outer carton or blister after 
“EXP.” The expiry date refers to the last day of that month.  
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Lonsurf contains 
Lonsurf 15 mg/6.14 mg film-coated tablet 
• The active substances are trifluridine and tipiracil. Each film-coated tablet contains 15 mg 

trifluridine and 6.14 mg tipiracil 
• The other ingredients are:  

- Tablet core: lactose monohydrate, starch pregelatinised (maize) and stearic acid (see section 2 
“Lonsurf contains lactose”). 

- Film coat: hypromellose, macrogol (8000), titanium dioxide (E171), and magnesium stearate. 
- Printing ink: shellac, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide 

(E171), indigo carmine aluminium lake (E132), carnauba wax and talc. 
 
Lonsurf 20 mg/8.19 mg film-coated tablet 
• The active substances are trifluridine and tipiracil. Each film-coated tablet contains 20 mg 

trifluridine and 8.19 mg tipiracil. 
• The other ingredients are:  

- Tablet core: lactose monohydrate, starch pregelatinised (maize) and stearic acid (see section 2 
“Lonsurf contains lactose”). 

- Film coating: hypromellose, macrogol (8000), titanium dioxide (E171), iron oxide red (E172), 
and magnesium stearate. 

- Printing ink: shellac, iron oxide red (E172), iron oxide yellow (E172), titanium dioxide 
(E171), indigo carmine aluminium lake (E132), carnauba wax and talc. 

 
What Lonsurf looks like and contents of the pack 
• Lonsurf 15 mg/6.14 mg is a white, biconvex, round, film-coated tablet, printed with “15” on one 

side and “102” and “15 mg” on the other side in grey ink. 
 
• Lonsurf 20 mg/8.19 mg is a pale red, biconvex, round, film-coated tablet, printed with “20” on one 

side and “102” and “20 mg” on the other side in grey ink. 
 
Each pack contains 20 film-coated tablets (2 blisters of 10 tablets each) or 40 film-coated tablets (4 
blisters of 10 tablets each), or 60 film-coated tablets (6 blisters of 10 tablets each). A desiccant is 
incorporated into each blister foil. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder  
Les Laboratoires Servier  
50 rue Carnot 
92284 Suresnes Cedex 
France  
 



42 

Manufacturer  
Les Laboratoires Servier Industrie 
905, route de Saran 
45520 Gidy 
France 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:  
 
België/Belgique/Belgien 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Lietuva 
UAB “SERVIER PHARMA” 
Tel: +370 (5) 2 63 86 28 

България 
Сервие Медикал ЕООД 
Тел.: +359 2 921 57 00 
 

Luxembourg/Luxemburg 
S.A. Servier Benelux N.V. 
Tel: +32 (0)2 529 43 11 
 

Česká republika 
Servier s.r.o. 
Tel: +420 222 118 111 

Magyarország 
Servier Hungaria Kft. 
Tel: +36 1 238 7799 
 

Danmark 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Malta 
V.J. Salomone Pharma Ltd  
Tel: + 356 21 22 01 74 

Deutschland 
Servier Deutschland GmbH 
Tel: +49 (0)89 57095 01 
 

Nederland 
Servier Nederland Farma B.V. 
Tel: +31 (0)71 5246700 
 

Eesti 
Servier Laboratories OÜ  
Tel:+ 372 664 5040 
 

Norge 
Servier Danmark A/S 
Tlf: +45 36 44 22 60 
 

Eλλάδα 
ΣΕΡΒΙΕ ΕΛΛΑΣ ΦΑΡΜΑΚΕΥΤΙΚΗ ΕΠΕ 
Τηλ: +30 210 939 1000 
 

Österreich 
Servier Austria GmbH 
Tel: +43 (1) 524 39 99 
 

España 
Laboratorios Servier S.L. 
Tel: +34 91 748 96 30 
 

Polska 
Servier Polska Sp. z o.o. 
Tel: +48 (0) 22 594 90 00 

France 
Les Laboratoires Servier 
Tel: +33 (0)1 55 72 60 00 
 

Portugal 
Servier Portugal, Lda 
Tel.: +351 21 312 20 00 

Hrvatska 
Servier Pharma, d. o. o. 
Tel.: +385 (0)1 3016 222 
 

România 
Servier Pharma SRL 
Tel: +4 021 528 52 80 
 

Ireland 
Servier Laboratories (Ireland) Ltd. 
Tel: +353 (0)1 663 8110 
 

Slovenija 
Servier Pharma d. o. o.  
Tel.: +386 (0)1 563 48 11 

Ísland 
Servier Laboratories 
c/o Icepharma hf 
Sími: +354 540 8000 

Slovenská republika 
Servier Slovensko spol. s r.o. 
Tel.:+421 (0) 2 5920 41 11 



43 

 
Italia 
Servier Italia S.p.A. 
Tel: +39 06 669081 

Suomi/Finland 
Servier Finland Oy 
P. /Tel: +358 (0)9 279 80 80 
 

Κύπρος 
C.A. Papaellinas Ltd. 
Τηλ: +357 22741741 
 

Sverige 
Servier Sverige AB 
Tel : +46 (0)8 522 508 00 
 

Latvija 
SIA Servier Latvia 
Tel: +371 67502039 
 

United Kingdom 
Servier Laboratories Ltd 
Tel: +44 (0)1753 666409 

 
 
This leaflet was last revised in  
 
Other sources of information 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 

 
 

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

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET