4.1. Therapeutic indications

Colorectal cancer

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

Trifluridine/ Tipiracil is indicated as monotherapy for the treatment of adult patients with metastatic colorectal cancer 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

Trifluridine/ Tipiracil 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

Trifluridine/ Tipiracil should be prescribed by physicians experienced in the administration of anticancer therapy.

Posology

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

When Trifluridine/ Tipiracil is used in combination with bevacizumab for the treatment of metastatic CRC, the dose of bevacizumab is 5 mg/kg of body weight given once every 2 weeks. Please refer to the full product information for bevacizumab.

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 criterion applied to the start of the next cycle for all patients regardless of whether or not the interruption criteria were met.

Table 3 - Recommended dose modifications for Trifluridine/ Tipiracilin 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

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 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.

Paediatric population

There is no relevant use of trifluridine/ tipiracil 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 trifluridine/ tipiracil 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

Trifluridine/ Tipiracil 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

Trifluridine/ Tipiracil 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 trifluridine/ tipiracil (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, TAGS and SUNLIGHT studies, 9.4%, 17.3% and 19.5% of patients in the trifluridine/ tipiracil group respectively received G-CSF mainly for therapeutic use. In the SUNLIGHT study, 29.3% of patients in the trifluridine/ tipiracil with bevacizumab group received G-CSF including 16.3% for therapeutic use.

Gastrointestinal toxicity

Trifluridine/ Tipiracil 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

Trifluridine/ Tipiracil is not recommended for use in patients with end-stage renal disease (creatinine clearance [CrCl] < 15 mL/min or requiring dialysis), as trifluridine/ tipiracil has not been studied in these patients (see section 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 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 trifluridine/ tipiracil 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 trifluridine/ tipiracil; patients with moderate or severe renal impairment should be more frequently monitored for haematological toxicities.

Hepatic impairment

Trifluridine/ Tipiracil 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

Trifluridine/ Tipiracil 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 trifluridine/ tipiracil 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 trifluridine/ tipiracil, 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 trifluridine/ tipiracil may reduce the effectiveness of hormonal contraceptives. Therefore, women using hormonal contraceptive must also use a barrier contraceptive method.

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 trifluridine/ tipiracil and for up to 6 months after ending treatment. Therefore, women of child-bearing potential must use highly effective contraceptive measures while taking trifluridine/ tipiracil and for 6 months after stopping treatment. It is currently unknown whether trifluridine/ tipiracil 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 trifluridine/ tipiracil 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). Trifluridine/ Tipiracil should not be used during pregnancy unless the clinical condition of the woman requires treatment with trifluridine/ tipiracil.

Breast-feeding

It is unknown whether trifluridine/ tipiracil 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 trifluridine/ tipiracil.

Fertility

There are no data available on the effects of trifluridine/ tipiracil on human fertility. Results of animal studies did not indicate an effect of trifluridine/ tipiracil on male or female fertility (see section 5.3). Patients who wish to conceive a child should be advised to seek reproductive counselling and cryo-conservation of either the ovum or sperm prior to starting trifluridine/ tipiracil treatment.

4.7. Effects on ability to drive and use machines

Trifluridine/ Tipiracil 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 reactions in patients receiving trifluridine/ tipiracil are bone marrow suppression and gastrointestinal toxicity (see section 4.4).

Trifluridine/ Tipiracil as monotherapy

The safety profile of trifluridine/ tipiracil as monotherapy is based on the pooled data from 1114 patients with metastatic 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 most common adverse reactions (≥ 2%) that resulted in treatment discontinuation, dose reduction, dose delay, or dose interruption were neutropenia, anaemia, fatigue, leukopenia, thrombocytopenia, diarrhoea, and nausea.

Trifluridine/ Tipiracil in combination with bevacizumab

The safety profile of trifluridine/ tipiracil in combination with bevacizumab is based on the data from 246 patients with 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 trifluridine/ tipiracil when used in combination with bevacizumab were neutropenia, fatigue, thrombocytopenia, nausea and anaemia.

When trifluridine/ tipiracil is used in combination with bevacizumab, the frequency of the following adverse reactions was increased compared to trifluridine/ tipiracil as monotherapy: neutropenia (69% vs 53%), severe neutropenia (48% vs 34%), thrombocytopenia (24% vs 16%), stomatitis (11% vs 6%).

Tabulated list of adverse reactions

The adverse reactions observed from the 533 treated patients with metastatic colorectal cancer in the placebo-controlled Phase III (RECOURSE) clinical study, the 335 treated patients with metastatic gastric cancer in the placebo-controlled Phase III (TAGS) clinical study, the 246 patients treated with trifluridine/ tipiracil in monotherapy and the 246 patients treated with trifluridine/ tipiracil in combination with bevacizumab for 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 its synonyms and related conditions.

Adverse reactions known to occur with trifluridine/ tipiracil given alone or with bevacizumab may occur during treatment with these medicinal products in combination, even if these reactions were not reported in clinical trials with combination therapy.

Adverse 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); uncommon (≥1/1,000 to < 1/100); and rare (≥ 1/10 000 to < 1/1 000).

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

Table 6 – Adverse reactions reported in clinical studies in patients treated with Trifluridine/ Tipiracil

System Organ Class (MedDRA)a

Adverse reactions

Frequency

Monotherapy

Combination with bevacizumab

Infections and infestations

Lower respiratory tract infection

Common

-

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 infection

Uncommon

-

Enteritis infectious

Rare

-

Septic shockb

Rare

-

Gingivitis

Rare

Uncommon

Tinea pedis

Rare

-

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

Cancer pain

Uncommon

-

Blood and lymphatic system disorders

Anaemia

Very common

Very common

Neutropenia

Very common

Very common

Leukopenia

Very common

Common

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 disorders

Decreased appetite

Very common

Very common

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 mediastinal disorders

Dyspnoea

Common

Common

Pulmonary embolismb

Uncommon

-

Dysphonia

Uncommon

Uncommon

Cough

Uncommon

-

Epistaxis

Uncommon

-

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 disease

Uncommon

-

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 disorders

Alopecia

Common

Common

Dry skin

Common

Common

Pruritus

Common

Uncommon

Rash

Common

Uncommon

Nail disorder

Uncommon

Uncommon

Palmar-plantar erythrodysaesthesia syndromec

Uncommon

Uncommon

Acne

Uncommon

-

Hyperhidrosis

Uncommon

-

Urticaria

Uncommon

-

Blister

Rare

-

Erythema

Rare

-

Photosensitivity reaction

Rare

-

Skin exfoliation

Rare

-

Musculoskeletal and connective tissue disorders

Arthralgia

Uncommon

Common

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 breast disorders

Menstrual disorder

Rare

Uncommon

General disorders and administration site conditions

Fatigue

Very common

Very common

Pyrexia

Common

Uncommon

Mucosal inflammation

Common

Uncommon

Malaise

Common

-

Oedema

Common

-

General physical health deterioration

Uncommon

-

Pain

Uncommon

Uncommon

Feeling of body temperature change

Uncommon

-

Xerosis

Rare

-

Investigations

Weight decreased

Common

Common

Hepatic enzyme increased

Common

Common

Blood alkaline phosphatase increased

Common

Uncommon

Blood lactate dehydrogenase increased

Uncommon

-

C-reactive protein increased

Uncommon

-

Blood creatinine increased

Uncommon

-

Blood urea increased

Uncommon

-

Haematocrit decreased

Uncommon

-

International normalised ratio increased

Uncommon

-

Activated partial thromboplastin time prolonged

Rare

-

Electrocardiogram QT prolonged

Rare

-

Protein total decreased

Rare

-

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 trifluridine/ tipiracil 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 trifluridine/ tipiracil is used in combination with bevacizumab, patients 65 years of age or older had a higher incidence (≥ 5%) of the following treatment-related adverse events compared to patients younger 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%).

Infections

In the Phase III placebo-controlled clinical studies, treatment-related infections occurred more frequently in trifluridine/ tipiracil - treated patients (5.8%) compared to those receiving placebo (1.8%). In the clinical study in combination with bevacizumab, treatment-related infections occurred similarly in patients who received trifluridine/ tipiracil with bevacizumab (2.8%) compared to trifluridine/ tipiracil -treated patients (2.4%).

Proteinuria

In the Phase III placebo-controlled clinical studies, treatment-related proteinuria occurred more frequently in trifluridine/ tipiracil -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).

In the clinical study in combination with bevacizumab, one patient who received trifluridine/ tipiracil with bevacizumab (0.4%) reported a treatment-related proteinuria which was Grade 2 and none among the trifluridine/ tipiracil -treated patients (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 trifluridine/ tipiracil -treated patients who received prior radiotherapy vs. those that did not.

In the clinical study in combination with bevacizumab, no increase of incidence of overall haematological and myelosuppression-related adverse reactions was observed for patients who received prior radiotherapy compared to patients without prior radiotherapy in both arms in SUNLIGHT: trifluridine/ tipiracil with bevacizumab (73.7% versus 77.4%) and in trifluridine/ tipiracil-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 trifluridine/ tipiracil post approval.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

The highest dose of trifluridine/ tipiracil 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 trifluridine/ tipiracil.

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.