Trifluridine/Tipiracil

Lonsurf combines two active substances in a molar ratio of 1:0.5 (weight ratio 1:0.471): trifluridine, a thymidine-based nucleoside analogue with antitumour activity, and tipiracil hydrochloride, an inhibitor of the enzyme thymidine phosphorylase (TPase). Trifluridine does the cytotoxic work; tipiracil protects it from rapid breakdown so that it can reach effective levels after oral dosing.

Mechanism of Action

• Trifluridine: after uptake into cancer cells it is phosphorylated by thymidine kinase, converted inside the cell into a DNA building block and incorporated directly into DNA, where it disturbs DNA function and stops cell proliferation. Its cytotoxic activity against several human tumour xenografts correlated closely with the amount of trifluridine built into DNA, which points to this as the main mechanism. Trifluridine monophosphate also inhibits thymidylate synthase reversibly, but this is not thought to explain much of the cell kill.
• Tipiracil: inhibits TPase, which otherwise degrades trifluridine rapidly and removes much of it in first-pass metabolism after an oral dose. Tipiracil is therefore included to raise trifluridine exposure. Because TPase is also an angiogenic factor often overexpressed in solid tumours, an additional anti-angiogenic effect of its inhibition has been suggested.
• Fluorouracil-resistant disease: in laboratory studies the combination was active against both 5-fluorouracil-sensitive and 5-fluorouracil-resistant colorectal cancer cell lines, and against KRAS wild-type and mutant colorectal cancer xenografts.
• Cardiac safety: there was no clinically relevant effect on QT/QTc interval compared with placebo in an open-label study in patients with advanced solid tumours.
• Clinical studies: the indications rest on the placebo-controlled phase III studies RECOURSE (previously treated metastatic colorectal cancer; primary endpoint overall survival) and TAGS (metastatic gastric cancer), and on SUNLIGHT, a controlled phase III study of Lonsurf alone and with bevacizumab in metastatic colorectal cancer.

Pharmacokinetics

• Absorption: at least 57% of an oral trifluridine dose is absorbed (only about 3% appears in faeces); at least 27% of tipiracil is absorbed, with 50% of its radioactivity in faeces, indicating moderate gastrointestinal absorption. After a single 35 mg/m² dose, peak concentrations occur after about 2 hours (trifluridine) and 3 hours (tipiracil). With the repeated schedule (twice daily for 5 days a week with 2 days’ rest, for 2 weeks, then 14 days’ rest, every 4 weeks), trifluridine AUC is about 3-fold and peak concentration about 2-fold higher on Day 12 of Cycle 1 than after the first dose, with no further accumulation in later cycles and no accumulation of tipiracil.
• Effect of tipiracil: a single dose of Lonsurf gave a 37-fold higher trifluridine AUC and a 22-fold higher peak concentration, with less variability, than trifluridine alone.
• Effect of food: after a high-fat, high-calorie meal the trifluridine AUC did not change, but the trifluridine peak concentration and the tipiracil peak concentration and AUC fell by about 40%.
• Distribution: apparent volume of distribution about 21 L for trifluridine and 333 L for tipiracil. Trifluridine is more than 96% bound to plasma proteins, mainly albumin (independent of concentration and of tipiracil); tipiracil is less than 8% bound.
• Metabolism: neither substance is metabolised by CYP enzymes. Trifluridine is cleared mainly by thymidine phosphorylase to an inactive metabolite, 5-trifluoromethyluracil (FTY); trifluridine glucuronide isomers also appear in urine. Tipiracil is hardly metabolised; its only minor metabolite is 6-hydroxymethyluracil.
• Elimination: mean half-life of trifluridine is 1.4 hours (2.1 hours at steady state) and of tipiracil 2.1 hours (2.4 hours at steady state). After a radiolabelled dose, most of the trifluridine radioactivity was excreted in urine within 24 hours (55% of the dose), as FTY and glucuronide isomers, while less than 3% of the dose was unchanged trifluridine. For tipiracil, 77% of radioactivity was recovered (27% in urine and 50% in faeces), mostly as unchanged tipiracil. Oral clearance is about 10.5 L/h for trifluridine and 109 L/h for tipiracil.
• Special populations: exposure to both substances is higher in moderate renal impairment than with normal function or mild impairment. In severe renal impairment treated with the reduced starting dose, trifluridine exposure was similar to normal renal function, while tipiracil exposure was higher than in normal, mild and moderate impairment. See Administration and Dosage for hepatic impairment, age and race.

Colorectal cancer

• Metastatic colorectal cancer (CRC), in combination with bevacizumab: adults who have received two prior anticancer treatment regimens, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and/or anti-EGFR agents.
• Metastatic CRC, as monotherapy: adults who have been previously treated with, or are not considered candidates for, the available therapies, including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-VEGF agents and anti-EGFR agents.

Gastric cancer

• Metastatic gastric cancer, as monotherapy: adults with metastatic gastric cancer, including adenocarcinoma of the gastro-oesophageal junction, who have been previously treated with at least two prior systemic treatment regimens for advanced disease.

• Hypersensitivity to trifluridine, tipiracil or any of the excipients.

The most serious side effects are bone marrow suppression and gastrointestinal toxicity. In pooled monotherapy data (1,114 patients with metastatic colorectal or gastric cancer in controlled phase III studies), the most common reactions (at least 30%) were neutropenia (53%, of which 34% grade 3 or higher), nausea (31%), fatigue (31%) and anaemia (30%, of which 11% grade 3 or higher). With bevacizumab (246 patients with metastatic colorectal cancer in the SUNLIGHT study) they were neutropenia (69%, of which 48% grade 3 or higher), fatigue (35%) and nausea (33%). Compared with monotherapy, adding bevacizumab increased neutropenia (69% vs 53%), severe neutropenia (48% vs 34%), thrombocytopenia (24% vs 16%) and stomatitis (11% vs 6%). The most common reasons for stopping, reducing, delaying or interrupting treatment (at least 2%) were neutropenia, anaemia, fatigue, leukopenia, thrombocytopenia, diarrhoea and nausea with monotherapy, and neutropenia, fatigue, thrombocytopenia, nausea and anaemia with bevacizumab.

The frequencies below are for monotherapy (Table 6 of the SmPC).

Very common (≥1/10): anaemia, neutropenia, leukopenia, thrombocytopenia, decreased appetite, diarrhoea, vomiting, nausea, fatigue.

Common (≥1/100 to <1/10): lower respiratory tract infection, febrile neutropenia, lymphopenia, hypoalbuminaemia, dysgeusia, dyspnoea, abdominal pain, stomatitis, constipation, hyperbilirubinaemia, alopecia, dry skin, pruritus, rash, proteinuria, pyrexia, mucosal inflammation, malaise, oedema, weight decreased, increased liver enzymes, increased blood alkaline phosphatase.

Uncommon (≥1/1,000 to <1/100): neutropenic sepsis, biliary tract infection, infection, urinary tract infection, bacterial infection, Candida infection, conjunctivitis, herpes zoster, influenza, upper respiratory tract infection, cancer pain, pancytopenia, erythropenia, leukocytosis, monocytopenia, monocytosis, dehydration, hyperglycaemia, hyperkalaemia, hypocalcaemia, hypokalaemia, hyponatraemia, hypophosphataemia, anxiety, insomnia, dizziness, headache, peripheral neuropathy, paraesthesia, lethargy, neurotoxicity, vertigo, angina pectoris, arrhythmia, palpitations, hypertension, flushing, hypotension, pulmonary embolism (fatal cases reported), dysphonia, cough, epistaxis, ileus, gastrointestinal haemorrhage, colitis, mouth ulceration, oral disorder, abdominal distension, anal inflammation, dyspepsia, flatulence, gastritis, gastro-oesophageal reflux disease, glossitis, impaired gastric emptying, retching, dental disorder, hepatotoxicity, nail disorder, palmar-plantar erythrodysaesthesia syndrome, acne, hyperhidrosis, urticaria, arthralgia, myalgia, muscular weakness, pain in extremity, bone pain, limb discomfort, muscle spasms, renal failure, haematuria, micturition disorder, general physical health deterioration, pain, feeling of change in body temperature, increased blood lactate dehydrogenase, C-reactive protein, creatinine and urea, decreased haematocrit, increased INR.

Rare (≥1/10,000 to <1/1,000): infectious enteritis, septic shock (fatal cases reported), gingivitis, tinea pedis, granulocytopenia, gout, hypernatraemia, burning sensation, dysaesthesia, hyperaesthesia, hypoaesthesia, syncope, cataract, diplopia, dry eye, blurred vision, reduced visual acuity, ear discomfort, embolism, rhinorrhoea, oropharyngeal pain, pleural effusion, ascites, acute pancreatitis, subileus, breath odour, mouth polyp, haemorrhagic enterocolitis, gingival bleeding, oesophagitis, periodontal disease, proctalgia, gastric reflux, bile duct dilatation, blister, erythema, photosensitivity reaction, skin exfoliation, joint swelling, non-infective cystitis, leukocyturia, menstrual disorder, xerosis, prolonged activated partial thromboplastin time, QT prolongation on the electrocardiogram, decreased total protein.

With bevacizumab: the same reactions occur, mostly in the same groups. The following move to a higher group: stomatitis (very common), and infection, dizziness, headache, hypertension, mouth ulceration, oral disorder, arthralgia and myalgia (common). Leukopenia (common), febrile neutropenia, proteinuria, pyrexia and mucosal inflammation (uncommon) sit lower. Reactions known with Lonsurf alone can also occur with the combination even if they were not reported in its trial.

Important Serious or Notable Reactions

• Infections: treatment-related infections were more frequent with Lonsurf (5.8%) than with placebo (1.8%) in the placebo-controlled phase III studies. With bevacizumab they were similar to Lonsurf alone (2.8% vs 2.4%). Septic shock and pulmonary embolism with fatal outcome have been reported.
• Proteinuria: 1.8% with Lonsurf vs 0.9% with placebo, all grade 1 or 2. In SUNLIGHT, one patient (0.4%) on Lonsurf with bevacizumab had grade 2 proteinuria.
• Lung disease: interstitial lung disease has been reported after marketing in patients with advanced unresectable or recurrent colorectal cancer.
• Older patients: in patients aged 65 and over, monotherapy caused more neutropenia (58.9% vs 48.2% in younger patients), 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%). With bevacizumab, 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%) were more frequent in patients aged 65 and over.
• Prior radiotherapy: in RECOURSE, blood and myelosuppression-related reactions were slightly more frequent with prior radiotherapy (54.6% vs 49.2%), with more febrile neutropenia. This was not seen in SUNLIGHT.

• CYP enzymes: in laboratory studies trifluridine, tipiracil and FTY neither inhibited nor induced human CYP isoforms, so CYP-based interactions are not expected.
• Nucleoside transporters: trifluridine is a substrate of CNT1, ENT1 and ENT2. Caution is needed with medicines that interact with these transporters.
• OCT2 and MATE1 inhibitors: tipiracil is a substrate of OCT2 and MATE1, so its concentration may rise when Lonsurf is given with inhibitors of these transporters.
• Thymidine kinase substrates such as zidovudine: these may compete with trifluridine for activation by thymidine kinases. If an antiviral that is a thymidine kinase substrate is used, watch for reduced antiviral effect and consider switching to an alternative that is not, such as lamivudine, didanosine or abacavir.
• Hormonal contraceptives: it is unknown whether Lonsurf reduces their effectiveness, so women using them must also use a barrier method.
• Bevacizumab: given at 5 mg/kg every 2 weeks as part of the combination; see its own product information.
• Food: tablets are taken within 1 hour after the morning and evening meals. A high-fat, high-calorie meal lowers some peak levels but did not change the trifluridine AUC.

Lonsurf should be prescribed by physicians experienced in anticancer therapy. The tablets are taken by mouth with a glass of water within 1 hour after finishing the morning and evening meals.

Recommended Dose

• Starting dose: 35 mg/m² of trifluridine per dose, twice daily, on Days 1 to 5 and Days 8 to 12 of each 28-day cycle, until disease progression or unacceptable toxicity. This applies alone or with bevacizumab.
• With bevacizumab (metastatic colorectal cancer): bevacizumab 5 mg/kg of body weight once every 2 weeks; see its product information.
• Calculation: the dose is based on body surface area (BSA) and must not exceed 80 mg per dose. Starting doses (trifluridine per dose, twice daily):
  • BSA below 1.07 m²: 35 mg (one 15 mg/6.14 mg tablet plus one 20 mg/8.19 mg tablet); 70 mg a day
  • 1.07 to 1.22 m²: 40 mg (two 20 mg/8.19 mg tablets); 80 mg a day
  • 1.23 to 1.37 m²: 45 mg (three 15 mg/6.14 mg tablets); 90 mg a day
  • 1.38 to 1.52 m²: 50 mg (two 15 mg/6.14 mg plus one 20 mg/8.19 mg); 100 mg a day
  • 1.53 to 1.68 m²: 55 mg (one 15 mg/6.14 mg plus two 20 mg/8.19 mg); 110 mg a day
  • 1.69 to 1.83 m²: 60 mg (three 20 mg/8.19 mg tablets); 120 mg a day
  • 1.84 to 1.98 m²: 65 mg (three 15 mg/6.14 mg plus one 20 mg/8.19 mg); 130 mg a day
  • 1.99 to 2.14 m²: 70 mg (two 15 mg/6.14 mg plus two 20 mg/8.19 mg); 140 mg a day
  • 2.15 to 2.29 m²: 75 mg (one 15 mg/6.14 mg plus three 20 mg/8.19 mg); 150 mg a day
  • 2.30 m² or more: 80 mg (four 20 mg/8.19 mg tablets); 160 mg a day

Dose Adjustments for Side Effects

• Up to 3 dose reductions are allowed, in steps of 5 mg/m² per dose (35, 30, 25, then 20 mg/m² twice daily). The dose must not be increased again once reduced. The SmPC gives the tablets per dose for each reduction level and BSA band. At a total daily dose of 50 mg, take one 20 mg/8.19 mg tablet in the morning and two 15 mg/6.14 mg tablets in the evening.
• Blood counts: interrupt dosing if neutrophils fall below 0.5 × 10⁹/L or platelets below 50 × 10⁹/L. Resume when neutrophils are 1.5 × 10⁹/L or more and platelets 75 × 10⁹/L or more; these resumption criteria apply at the start of the next cycle for every patient, whether or not the interruption criteria were met.
• Reduce by one level (5 mg/m² per dose) on resuming after: febrile neutropenia; grade 4 neutropenia (below 0.5 × 10⁹/L) or thrombocytopenia (below 25 × 10⁹/L) that delays the start of the next cycle by more than 1 week; or a grade 3 or 4 non-haematological reaction, except grade 3 nausea or vomiting controlled by antiemetics and diarrhoea that responds to antidiarrhoeal medicines. Dosing is interrupted until the toxicity resolves to grade 1 or baseline.

Special Populations

• Renal impairment: no change to the starting dose in mild (CrCl 60 to 89 mL/min) or moderate (30 to 59 mL/min) impairment. In severe impairment (CrCl 15 to 29 mL/min) the starting dose is 20 mg/m² twice daily, with one reduction allowed, to a minimum of 15 mg/m² twice daily (BSA-based tablet table in the SmPC). Not recommended in end-stage renal disease (CrCl below 15 mL/min or dialysis), where there are no data.
• Hepatic impairment: no change to the starting dose in mild impairment. Not recommended in baseline moderate or severe impairment (NCI group C and D, total bilirubin above 1.5 times the upper limit of normal), because grade 3 or 4 hyperbilirubinaemia was more frequent in moderate impairment, although the data are very limited.
• Elderly: no change to the starting dose at 65 years or older. Efficacy and safety data above 75 years are limited.
• Children and adolescents: there is no relevant use in the paediatric population for metastatic colorectal or gastric cancer.
• Race: no adjustment of the starting dose. Data in Black/African American patients are limited, but there is no biological reason to expect a difference.

Missed Dose

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

Bone Marrow Suppression and Infections

Lonsurf increases anaemia, neutropenia, leukopenia and thrombocytopenia. Complete blood counts must be taken before starting and as needed, at the least before each treatment cycle. Treatment must not start if the neutrophil count is below 1.5 × 10⁹/L, the platelet count below 75 × 10⁹/L, or an unresolved grade 3 or 4 clinically relevant non-haematological toxicity from earlier therapy is present. Serious infections occurred, mostly during bone marrow suppression, so patients should be watched closely and given antimicrobials and granulocyte-colony stimulating factor (G-CSF) as clinically indicated.

Gastrointestinal Toxicity

Nausea, vomiting, diarrhoea and other gastrointestinal toxicities are more frequent. Patients should be monitored carefully and given antiemetics, antidiarrhoeal medicines and fluid and electrolyte replacement as clinically indicated, with dose delay or reduction as needed.

Renal Impairment

Lonsurf is not recommended in end-stage renal disease. Overall adverse events were similar with normal, mild or moderate renal impairment, but serious and severe events and events leading to dose modification rose as impairment advanced, and exposure was higher in moderate impairment. Patients with severe impairment on the reduced starting dose had a safety profile consistent with normal or mildly reduced renal function. All patients with renal impairment need close monitoring, and those with moderate or severe impairment need more frequent blood count checks.

Hepatic Impairment

Not recommended in baseline moderate or severe hepatic impairment (see Administration and Dosage).

Use With Bevacizumab

When combined with bevacizumab, follow its own product information for monitoring and warnings.

Pregnancy, Breastfeeding and Fertility

• Contraception: trifluridine may cause foetal harm. Women of childbearing potential must use highly effective contraception during treatment and for 6 months after stopping. Women using hormonal contraceptives should add a barrier method. Men with a partner who could become pregnant must use effective contraception during treatment and for up to 6 months after stopping.
• Pregnancy: there are no data in pregnant women. Trifluridine is suspected to cause congenital malformations, and animal studies showed reproductive toxicity. Lonsurf should not be used in pregnancy unless the woman’s clinical condition requires it.
• Breastfeeding: animal studies showed excretion in milk, and a risk to the suckling child cannot be excluded. Breastfeeding should be stopped during treatment.
• Fertility: no human data. Animal studies did not show an effect on male or female fertility.

Lactose

The tablets contain lactose monohydrate (90.735 mg in the 15 mg/6.14 mg tablet and 120.980 mg in the 20 mg/8.19 mg tablet). Patients with rare hereditary galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take them.

Effect on Driving

Lonsurf has a minor influence on the ability to drive and use machines. Fatigue, dizziness or malaise may occur during treatment.

Lonsurf needs no special storage conditions. The tablets are supplied in aluminium/aluminium blisters with a laminated desiccant (calcium oxide), 10 tablets per blister, in packs of 20, 40 or 60 tablets (not all pack sizes may be marketed). Keep out of the sight and reach of children.

3 years. Do not use after the expiry date on the pack.

Prescription only (Rx), subject to restricted medical prescription (Annex II B): prescribed by physicians experienced in the administration of anticancer therapy. Lonsurf is taken at home, so it is supplied to the patient or to the treating clinic on prescription.