Trifluridine/ Tipiracil

Registered South African indications:

• Metastatic colorectal cancer
  - 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
• Metastatic gastric cancer
  - 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 advances disease

Contraindications 

Registered contraindications in South Africa & other jurisdictions

• Hypersensitivity to the active ingredient or any of its excipients

Cautions

Recommendations in South Africa & other jurisdictions

• Pregnancy
• Breastfeeding
• Severe renal impairment (CrCl 15-29ml/min)
  - End-stage renal disease (CrCl <15ml/min or haemodialysis)
• Hepatic impairment
  - Moderate to severe hepatic impairment
  - National Cancer Institute [NCI] Criteria Group C and D defined by total bilirubin >1.5 x ULN
• Black patients (See additional prescribing points)
• Bone marrow suppression
• Gastrointestinal toxicity
• Proteinuria
• Coadministration with medicinal products that interact with nucleoside transporters CNT1, ENT1 and ENT2 (See additional prescribing points)
• Coadministration with human thymidine kinase substrates (See additional prescribing points)
• Coadministration with hormonal contraceptives(See additional prescribing points)
• Pre-existing gastrointestinal toxicity
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption 
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Trifluridine/ Tipiracil should only be prescribed by doctors experienced in the administration of anticancer therapy

Used for the treatment of

• Metastatic colorectal cancer
  - 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
• Metastatic gastric cancer
  - 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

Trifluridine/ Tipiracil
15/6.14 (mg)
20/8.19 (mg)

• Oral (fct): Initial: 35mg/m²/dose, twice daily on days 1-5 and days 8-12 of each 28 day cycle as long as benefit is observed or until unacceptable toxicity occurs; The dosage is calculated according to body surface area (BSA) (see table 1 below); The dosage must be rounded to the nearest 5mg increment; Max: Dosage must not exceed 80mg/dose

Table 1: Starting dose calculation according to body surface area (BSA)

Starting dose of trifluridine regardless of BSA is 35mg/m²

BSA (m2)	Dose in mg (2x daily)	Total daily dose
<1.07	35	70
1.07-1.22	40	80
1.23-1.37	45	90
1.38-1.52	50	100
1.53-1.68	55	110
1.69-1.83	60	120
1.84-1.98	65	130
1.99-2.14	70	140
2.15-2.29	75	150
≥2.30	80	160

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Tipiracil is included to inhibit first pass metabolism of the active anti-cancer medicine trifluridine and allow effective plasma concentrations to be achieved. Dosage calculation should be based on the trifluridine content ONLY

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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 20mg/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 as stated in the professional information of the product

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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

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

Not indicated for use in children

Pregnancy

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; not recommended
• 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
• Trifluridine/ tipiracil should not be used during pregnancy unless the clinical condition of the woman requires treatment with trifluridine/ tipiracil
• 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 childbearing 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

Breastfeeding

South African recommendations

• Caution; not recommended
• Studies in animals have shown excretion of trifluridine, tipiracil hydrochloride and/or their metabolites in milk
• Mothers should not breastfeed their infants while taking trifluridine/ tipiracil

Recommendations in other jurisdictions

• Caution; not recommended
• 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. A risk to the breastfeeding child cannot be excluded. Breastfeeding should be discontinued during treatment with trifluridine/ tipiracil

Fertility

South African recommendations

• 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

Recommendations in other jurisdictions

• 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. 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

South African recommendations

• Mild (CrCl 60-89ml/min) to moderate (CrCl 30-59ml/min): No dose adjustment recommended
• Severe renal impairment (CrCl <30ml/min) or end-stage renal disease: Caution; not recommended
  Administration is not recommended in patients with severe renal impairment or end stage renal disease as there are no data available for these patients

Recommendations in other jurisdictions

• Mild (CrCl 60-89ml/min) to moderate (CrCl 30-59ml/min): No dose adjustment recommended
• Severe (CrCl 15-29ml/min): Caution; dose adjustment recommended
  For patients with severe renal impairment, a starting dose of 20mg/m² twice daily is recommended
  One dose reduction to a minimum dose of 15mg/m² twice daily is permitted based on individual safety and tolerability
  Dose escalation is not permitted after it has been reduced
  Consult a specialist for dosages and regimens (dose interruption, resumption and reduction criteria) in the event of haematological and/or non-haematological toxicities in patients with severe impairment
• End-stage renal disease (CrCl <15ml/min or haemodialysis): Caution; not recommended
  There are no data available for patients with end-stage renal disease

Recommendations below are applicable to South Africa and other jurisdictions

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; not recommended for use
  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

Recommendations below are applicable to South Africa and other jurisdictions

• No dose adjustment recommended
  No adjustment of the starting dose is required in patients ≥ 65 years old
  Efficacy and safety data in patients >75 years old is limited

Central Nervous System Disorders

• Anxiety
• Insomnia
• Peripheral neuropathy
• Neurotoxicity
• Dysaesthesia
• Hyperaesthesia
• Hypoaesthesia
• Syncope
• Paraesthesia
• Burning sensation
• Fatigue
• Dizziness
• Headache

Cardiovascular Disorders

• Angina pectoris
• Arrhythmia
• Palpitations
• Embolism
• Hypertension
• Hypotension
• Flushing
• Prolonged QT electrocardiogram

Respiratory Disorders

• Lower respiratory tract infection
• Lung infection
• Influenza
• Upper respiratory tract infection
• Dyspnoea
• Pulmonary embolism
• Pleural effusion
• Rhinorrhoea
• Dysphonia
• Oropharyngeal pain
• Epistaxis
• Cough

Gastrointestinal Disorders

• Infectious enteritis
• Gingivitis
• Diarrhoea
• Nausea and vomiting
• Abdominal pain
• Constipation
• Stomatitis
• Oral disorder
• Haemorrhagic enterocolitis
• Gastrointestinal haemorrhage
• Acute pancreatitis
• 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

• Biliary tract infection
• Hyperbilirubinaemia
• Hepatotoxicity
• Biliary dilatation
• Increased hepatic enzyme
• Increased blood alkaline phosphatase

Genitourinary Disorders

• Urinary tract infection
• Proteinuria
• Renal failure
• Noninfective cystitis
• Micturition disorder
• Haematuria
• Leucocyturia
• Menstrual disorder
• Increased blood creatinine
• Increased blood urea

Endocrine and Metabolic Disorders

• Decreased appetite
• Hypoalbuminaemia
• Dehydration
• Hyperglycaemia
• Hyperkalaemia
• Hypokalaemia
• Hypophosphataemia
• Hypernatraemia
• Hyponatraemia
• Hypocalcaemia
• Gout
• Decreased weight
• Decreased total protein

Musculoskeletal Disorders

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

Skin and Subcutaneous Tissue Disorders

• Tinea pedis
• Candida infection
• Bacterial infection
• Palmar-plantar erythrodysaesthesia syndrome
• Rash
• Alopecia
• Pruritus
• Dry skin
• Xerosis
• Skin exfoliation
• Urticaria
• Photosensitivity reaction
• Erythema
• Acne
• Hyperhidrosis
• Blister
• Nail disorder

Immune, Blood and Lymphatic System Disorders

• Septic shock
• Neutropenic sepsis
• Herpes zoster
• Infections
• Neutropenia
• Leukopenia
• Anaemia
• Thrombocytopenia
• Febrile neutropenia
• Lymphopenia
• Pancytopenia
• Granulocytopenia
• Monocytopenia
• Erythropenia
• Leukocytosis
• Monocytosis
• Oedema
• Fever
• Increased international normalised ratio
• Prolonged activated partial thromboplastin
• Increased c-reactive protein
• Decreased haematocrit
• Increased blood lactate dehydrogenase 

Sensory Disorders

• Conjunctivitis
• Reduced visual acuity
• Blurred vision
• Diplopia
• Cataract
• Dry eye
• Dysgeusia
• Vertigo
• Ear discomfort

Others

• Cancer pain
• Mucosal inflammation
• General physical health deterioration
• Pain
• Feeling of body temperature change
• Discomfort

• OCT2 inhibitors
• MATE1 inhibitors
• Antiviral medicinal agents that are human thymidine kinase substrates
• Zidovudine

• Full blood count
• Proteinuria

Some cases may require

• Pregnancy test
• Renal function
• Hepatitis B screening
  - Hepatitis B surface antigen
  - Hepatitis B core antibody
  - Total Ig or IgG
  - Antibody to hepatitis B surface antigen

Additional observations

• Signs and symptoms of gastrointestinal toxicity

Method of administration

• The tablets must be taken with a glass of water within 1 hour after completion of the morning and evening meals

Use in Black patients

• There is limited data on use in Black/African American patients but there is no biological rationale to expect any difference between this subgroup and the overall population
• No adjustment of the starting dose is required on the basis of patient's race

Coadministration with medicinal products that interact with nucleoside transporters CNT1, ENT1 and ENT2

• 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

Coadministration with human thymidine kinase substrates

• 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

Coadministration with hormonal contraceptives

• 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

Trifluridine/ tipiracil is comprised of an antineoplastic thymidine-based nucleoside analogue, trifluridine, and the thymidine phosphorylase (TPase) inhibitor, tipiracil hydrochloride. 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 non-clinical 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.

Film coated tablet 15mg/6.14mg

• Lonsurf (Servier) originator

Film coated tablet 20mg/8.19mg

• Lonsurf (Servier) originator