Tegafur/Gimeracil/Oteracil

Teysuno is an oral fluoropyrimidine anti-cancer medicinal product (antimetabolite) that combines tegafur, gimeracil and oteracil in a 1:0.4:1 molar ratio. The ratio was chosen to maintain 5-FU exposure, and so anti-tumour activity, while reducing the toxicity associated with 5-FU alone.

Mechanism of Action

• Tegafur: a prodrug of 5-FU with good oral bioavailability. After absorption it is converted gradually to 5-FU in the liver, mainly by the enzyme CYP2A6.
• 5-FU: activated inside cells by phosphorylation to 5-fluorodeoxyuridine monophosphate (FdUMP). FdUMP and reduced folate bind thymidylate synthase in a ternary complex that blocks DNA synthesis; in addition, 5-fluorouridine triphosphate (FUTP) is built into RNA and disrupts RNA functions.
• Gimeracil: reversibly and selectively inhibits DPD, the primary enzyme that breaks down 5-FU, so a lower tegafur dose gives higher 5-FU concentrations. 5-FU peak levels and exposure were about 3-fold higher than after tegafur alone, although the tegafur dose was 16-fold lower. Plasma uracil returned to baseline within about 48 hours of a dose, showing that the inhibition is reversible.
• Oteracil: inhibits orotate phosphoribosyltransferase (OPRT). In animal studies it reached high concentrations in normal gastrointestinal tissue and much lower ones in blood and tumour; in the normal gastrointestinal lining it lowers the activity of 5-FU and so gastrointestinal toxicity.

Pharmacokinetics

• Absorption: after a single 50 mg dose (expressed as tegafur), median peak times were 0.5 hours for tegafur, 1.0 hour for gimeracil, 2.0 hours for oteracil and 2.0 hours for 5-FU. With 30 mg/m² doses, steady state is reached for the three components at the latest by day 8. Taken with food, oteracil exposure falls by about 71%, gimeracil by about 25% and 5-FU by about 15%, while tegafur exposure is unchanged; a proton pump inhibitor reduces this food effect on oteracil but does not remove it.
• Distribution: plasma protein binding is 52.3% for tegafur, 32.2% for gimeracil, 8.4% for oteracil and 18.4% for 5-FU. Volumes of distribution, estimated from urinary excretion data, are roughly 16, 17 and 23 L/m² for tegafur, gimeracil and oteracil.
• Metabolism: CYP2A6 converts tegafur to 5-FU, and DPD degrades 5-FU. Part of oteracil is broken down without enzymes by gastric fluid to 5-azauracil and then to cyanuric acid in the gut; little oteracil is metabolised in the liver.
• Elimination: after a single dose, 3.8–4.2% of tegafur, 65–72% of gimeracil and 3.5–3.9% of oteracil are excreted unchanged in urine. Half-lives ranged from 6.7 to 11.3 hours for tegafur, 3.1 to 4.1 hours for gimeracil and 1.8 to 9.5 hours for oteracil.
• Special populations: gimeracil is cleared mainly by the kidneys, so 5-FU exposure rises in renal impairment (see Administration and Dosage). In a population analysis 5-FU exposure tended to rise with age, in line with falling creatinine clearance.

Teysuno is indicated in adults:

• Advanced gastric cancer: treatment in combination with cisplatin.
• Metastatic colorectal cancer: as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, in patients for whom it is not possible to continue treatment with another fluoropyrimidine because of hand-foot syndrome or cardiovascular toxicity that developed in the adjuvant or metastatic setting.

• Hypersensitivity to any of the active substances (tegafur, gimeracil and oteracil) or to any of the excipients.
• History of severe and unexpected reactions to fluoropyrimidine therapy.
• Known complete dihydropyrimidine dehydrogenase (DPD) deficiency.
• Pregnancy and breast-feeding.
• Severe bone marrow suppression (severe leukopenia, neutropenia or thrombocytopenia).
• End-stage renal disease requiring dialysis.
• Co-administration of other fluoropyrimidines with Teysuno.
• Recent or concomitant treatment with brivudine.
• Contraindications for cisplatin; for oxaliplatin, irinotecan and bevacizumab, refer to the corresponding SmPCs.

The safety profile with cisplatin rests mainly on 593 patients with advanced gastric cancer, supported by post-marketing experience in more than 866,000 patients in Asia (mostly Japan). The most common severe reactions (grade 3 or higher, in at least 10% of patients) were neutropenia, anaemia and fatigue.

Very common (≥1/10): neutropenia, anaemia, leukopenia, thrombocytopenia; anorexia; peripheral neuropathy; nausea, diarrhoea, vomiting, constipation; fatigue, asthenia.

Common (≥1/100 to <1/10): lymphopenia, febrile neutropenia; dehydration, hyponatraemia, hypokalaemia, hypomagnesaemia, hypocalcaemia, hypoalbuminaemia, hyperkalaemia; insomnia; dizziness, headache, taste disturbance (dysgeusia); visual disorders, lacrimal disorders, other eye disorders, conjunctivitis, corneal disorders; hearing impairment, deafness; deep vein thrombosis, hypertension, hypotension; dyspnoea, epistaxis, hiccups, cough; abdominal pain, stomatitis, gastrointestinal inflammation, gastrointestinal haemorrhage, dysphagia, abdominal discomfort, dyspepsia, flatulence, dry mouth; hyperbilirubinaemia, increased alanine aminotransferase; skin hyperpigmentation, rash, palmar-plantar erythrodysaesthesia (hand-foot) syndrome, dry skin, alopecia, pruritus; musculoskeletal pain; renal impairment, increased blood creatinine, decreased glomerular filtration rate, increased blood urea; weight loss, fever, mucosal inflammation, peripheral oedema, chills.

Uncommon (≥1/1,000 to <1/100): sepsis (including neutropenic sepsis and septic shock), pneumonia, urinary and other infections; pancytopenia, changes in prothrombin time or INR; hypersensitivity; adrenal haemorrhage; hypophosphataemia, hyperglycaemia, gout; confusion, anxiety, depression, hallucinations; stroke and other cerebrovascular events, syncope, seizures, ataxia, loss of consciousness, encephalopathy; angina pectoris, atrial fibrillation, heart failure, pericardial effusion, acute myocardial infarction; arterial thrombosis of the limbs, thrombophlebitis, haematoma; pulmonary embolism; gastrointestinal perforation, obstruction, ileus, oesophagitis, ascites; abnormal liver function tests; exfoliative rash, allergic dermatitis; toxic nephropathy, renal failure, haematuria, oliguria; tumour haemorrhage; chest pain, multi-organ failure.

Rare and very rare (<1/1,000): hepatitis B reactivation; disseminated intravascular coagulation; hyperammonaemia; leukoencephalopathy, anosmia; interstitial lung disease; acute pancreatitis, terminal ileitis; acute hepatic failure; Stevens-Johnson syndrome, toxic epidermal necrolysis, photosensitivity reactions, nail disorders; rhabdomyolysis. These frequencies come from the post-marketing experience in Asia.

Lacrimal disorders (increased lacrimation, dry eye, acquired dacryostenosis) were the most common eye reactions. Reactions of grade 3 or higher and serious reactions were more frequent in patients aged 70 years or over. Severe diarrhoea with dehydration, febrile neutropenia and sepsis, renal failure, hepatitis B reactivation, severe skin reactions and severe toxicity in patients with DPD deficiency are the most important serious risks.

No interaction studies have been performed. The interactions below are those described in the SmPC; section 4.5 of the SmPC should be consulted for the complete list.

• Brivudine (contraindicated): brivudine inhibits DPD, which sharply raises fluoropyrimidine toxicity and can be fatal. There must be at least 4 weeks between the end of brivudine and the start of Teysuno; brivudine can be started 24 hours after the last Teysuno dose.
• Other fluoropyrimidines (capecitabine, 5-FU, tegafur, flucytosine): additive toxicity, so co-administration is contraindicated. A washout of at least 7 days is recommended between Teysuno and other fluoropyrimidines; when Teysuno follows another fluoropyrimidine, the washout in that product’s SmPC applies.
• CYP2A6 inhibitors: avoid, because they reduce the conversion of tegafur to 5-FU and so the effectiveness of Teysuno.
• Folinic acid (folinate): no data with Teysuno plus cisplatin; folinic acid is known to enhance the activity of 5-FU, so caution is advised.
• Nitroimidazoles (including metronidazole and misonidazole): no data with Teysuno plus cisplatin; they may reduce the clearance of 5-FU and so raise its plasma levels, and caution is advised because the toxicity of Teysuno may increase.
• Methotrexate: no data with Teysuno plus cisplatin; polyglutamated methotrexate inhibits thymidylate synthase and dihydrofolate reductase and may increase the cytotoxicity of 5-FU, so caution is advised because the toxicity of Teysuno may increase.
• Clozapine: no data with Teysuno plus cisplatin; because of possible additive myelotoxicity, caution is advised, as co-administration may increase the risk and severity of the haematologic toxicity of Teysuno.
• Cimetidine: no data with Teysuno plus cisplatin; it may reduce the clearance of 5-FU and so raise its plasma levels, and caution is advised because the toxicity of Teysuno may increase.
• Coumarin-derivative anticoagulants: INR or prothrombin time must be monitored closely and the anticoagulant dose adjusted; in clinical trials this combination was associated with raised INR, gastrointestinal bleeding, bleeding tendency, haematuria and anaemia.
• Phenytoin: fluoropyrimidines may raise the plasma concentration of phenytoin and cause phenytoin toxicity. Phenytoin blood or plasma levels should be monitored frequently, the phenytoin dose adjusted if indicated according to its own SmPC, and appropriate measures taken if toxicity develops.
• Allopurinol: non-clinical data suggest it may decrease the anti-tumour activity of Teysuno by suppressing the phosphorylation of 5-FU, so concurrent use should be avoided.
• DPD inducers: none is currently known; if one were given, 5-FU exposure might not reach the effective level.
• Cisplatin, oxaliplatin, irinotecan, bevacizumab: follow the interaction sections of their own SmPCs.
• Food: the capsules are taken at least 1 hour before or after a meal because food reduces absorption of oteracil and gimeracil. Patients should drink plenty of fluids to help prevent dehydration.

Teysuno should only be prescribed by a qualified physician experienced in treating cancer patients with anti-neoplastic medicinal products. Patients should be given outpatient prescriptions for anti-emetic and anti-diarrhoeal medicines. The capsules are taken by mouth with water at least 1 hour before or 1 hour after a meal. The dose is calculated from body surface area (BSA) and expressed as tegafur content; BSA must be recalculated and the dose adjusted if body weight changes by 10% or more, when the change is clearly not due to fluid retention. The SmPC gives tables of the dose in mg and the number of 15 mg and 20 mg capsules for each BSA band.

Advanced Gastric Cancer (With Cisplatin)

• Teysuno: 25 mg/m² (tegafur content) twice daily, morning and evening, for 21 consecutive days, followed by 7 days of rest (one cycle). The cycle is repeated every 4 weeks.
• Cisplatin: 75 mg/m² by intravenous infusion once every 4 weeks. Cisplatin is stopped after 6 cycles without withdrawing Teysuno; if cisplatin is stopped earlier, Teysuno alone can be resumed when the criteria for restarting are met. See the cisplatin SmPC for pre-treatment hyperhydration.
• Monitoring: haematology, liver function, renal function and serum electrolytes are checked frequently. Treatment is stopped for progressive disease or intolerable toxicity.

Metastatic Colorectal Cancer

• Monotherapy: 30 mg/m² twice daily on days 1–14, followed by a one-week pause (with or without bevacizumab 7.5 mg/kg on day 1).
• With oxaliplatin or irinotecan: 25 mg/m² twice daily on days 1–14, followed by a one-week pause.

Dose Adjustments for Toxicity

• Dose levels: for gastric cancer, Teysuno is reduced from 25 to 20 and then 15 mg/m² (cisplatin 75, 60, 45 mg/m²). In colorectal cancer, monotherapy goes from 30 to 25 and then 20 mg/m², and the combination from 25 to 20 mg/m² (oxaliplatin 130 to 100 mg/m²; for irinotecan, used at 150–225 mg/m², the SmPC makes no reduction recommendation). A maximum of two consecutive reductions applies to each medicine, each lowering the dose by about 20–25%. A reduced dose is not increased again.
• General toxicity (CTCAE grade): grade 1, continue at the same dose; grade 2, suspend until grade 0 or 1, with no dose change (optimise anti-emetic therapy first for grade 2 nausea or vomiting); grade 3 or higher, suspend until grade 0 or 1 and reduce by one dose level at the first and second occurrence; stop at the third occurrence. At the physician’s discretion, treatment may continue for reactions unlikely to become serious, such as alopecia or dry skin.
• Renal function: creatinine clearance (CrCl) is determined on day 1 of every cycle. At 50 mL/min or more, no change; at 30–49 mL/min, start at one reduced dose level (cisplatin reduced by 50%); below 30 mL/min, suspend until CrCl is at least 30 mL/min, then start at one reduced dose level.
• Blood counts: treatment is suspended for severe haematologic toxicity (the SmPC table sets thresholds for neutrophils, platelets and haemoglobin) and resumed at one reduced dose level once the resumption criteria are met: platelets ≥100 × 10⁹/L, neutrophils ≥1.5 × 10⁹/L, haemoglobin ≥6.2 mmol/L, CrCl ≥30 mL/min and other toxicity at baseline or grade 1.
• With cisplatin: Teysuno is given only on days 1–21 of a cycle, and days missed for toxicity are not made up. If a delay is needed for either medicine, both are delayed until the restart criteria for both are met, unless one is permanently stopped.

Special Populations

• Elderly: no adjustment of the standard dose over 70 years in either indication. For elderly, more vulnerable patients with metastatic colorectal cancer in whom another fluoropyrimidine cannot be continued because of hand-foot syndrome or cardiotoxicity, the recommended dose is 20 mg/m² twice daily for 14 consecutive days followed by 7 days of rest, with a reduced oxaliplatin dose (100 mg/m² on day 1 of a 3-week cycle).
• Renal impairment: mild (CrCl 51–80 mL/min), no adjustment; moderate (30–50 mL/min), 20 mg/m² twice daily; severe (below 30 mL/min), not recommended unless the benefit clearly outweighs the risk, because of a possibly higher incidence of blood and lymphatic adverse events. End-stage renal disease requiring dialysis is a contraindication.
• Hepatic impairment: no adjustment of the standard dose.
• Ethnicity: no adjustment for patients of Asian ethnicity.
• Children and adolescents: safety and efficacy under 18 years have not been established, and Teysuno should not be given to them.

Missed or Vomited Doses

Doses omitted because of toxicity are not made up. If a patient vomits after taking a dose, that dose should not be replaced.

DPD Deficiency and Pre-Treatment Testing

• Risk: DPD activity is rate-limiting in the breakdown of 5-FU. Patients with DPD deficiency are at increased risk of fluoropyrimidine toxicity such as stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity. This toxicity usually appears in the first cycle or after a dose increase.
• Complete deficiency: rare (0.01–0.5% of Caucasians). These patients are at high risk of life-threatening or fatal toxicity and must not be treated with Teysuno.
• Partial deficiency: estimated to affect 3–9% of the Caucasian population, with increased risk of severe and potentially life-threatening toxicity. A reduced starting dose should be considered. DPD deficiency is one parameter to weigh alongside other routine measures for dose reduction; an initial reduction may affect efficacy, and in the absence of serious toxicity later doses may be increased with careful monitoring.
• Testing: phenotype and/or genotype testing before starting treatment is recommended, despite uncertainty about the best pre-treatment method, and applicable clinical guidelines should be considered. If testing was not done earlier, it is recommended for patients being switched to Teysuno from another fluoropyrimidine because of hand-foot syndrome or cardiovascular toxicity, to see whether DPD status played a part in that toxicity.
• Genotype: four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) can cause complete absence or reduction of DPD activity, and other rare variants may also raise the risk. Certain homozygous and compound heterozygous combinations cause complete or near-complete absence of activity; heterozygous carriers have an increased risk of severe toxicity. In Caucasian patients the heterozygous frequencies are about 1% for c.1905+1G>A, 1.1% for c.2846A>T, 2.6–6.3% for c.1236G>A/HapB3 and 0.07–0.1% for c.1679T>G. The four variants are considered virtually absent in people of African(-American) or Asian origin.
• Phenotype: measurement of the pre-treatment blood level of uracil, the natural DPD substrate, is recommended. Despite uncertainty about thresholds, a blood uracil level of 16 ng/mL or more and below 150 ng/mL indicates partial DPD deficiency, and 150 ng/mL or more indicates complete DPD deficiency.

Brivudine

Brivudine must not be given with Teysuno; fatal cases have been reported with capecitabine. If brivudine is given by accident, effective measures to reduce Teysuno toxicity should be taken, immediate admission to hospital is recommended, and all measures to prevent systemic infection and dehydration should be started.

Hepatitis B Reactivation

Teysuno may reactivate hepatitis B in virus carriers and in patients with a past infection pattern (HBc antigen negative and HBc antibody positive, or HBs antigen negative and HBs antibody positive). Patients should be tested for HBV infection before treatment. Experts in liver disease and hepatitis B should be consulted for patients with positive serology, including active disease, and for those who test positive during treatment. Carriers who need Teysuno should be monitored closely throughout therapy, with follow-up liver function tests or viral markers.

Bone Marrow Suppression

Neutropenia, leukopenia, thrombocytopenia, anaemia and pancytopenia have been reported with Teysuno plus cisplatin. Patients with low white cell counts should be watched for infection and treated as medically indicated (for example with antibiotics or granulocyte colony-stimulating factor); patients with low platelet counts are at increased risk of bleeding. Doses are modified as described above.

Diarrhoea and Dehydration

Diarrhoea and dehydration are the dose-limiting toxicities, but most reactions are reversible and can be managed with symptomatic therapy, dose interruptions and dose reductions. Standard anti-diarrhoeal therapy (for example loperamide) and intravenous fluids and electrolytes should start early, and prophylaxis should be given as indicated. Dose suspension or adjustment is needed for grade 2 or higher diarrhoea that persists despite adequate treatment. Dehydration and electrolyte disturbance should be prevented or corrected at onset; patients with anorexia, asthenia, nausea, vomiting, diarrhoea, stomatitis or gastrointestinal obstruction should be monitored closely. Grade 2 or higher dehydration calls for immediate suspension and correction, and treatment is not resumed until the dehydration and its causes are controlled.

Renal Toxicity

With cisplatin, a transient fall in glomerular filtration rate may occur, mainly from pre-renal factors such as dehydration and electrolyte imbalance. Grade 3 or higher reactions, including increased creatinine, decreased creatinine clearance, toxic nephropathy and acute renal failure, have been reported. Serum creatinine and CrCl should be monitored closely, and doses adjusted. Gimeracil is cleared mainly by the kidney, so in renal insufficiency its clearance falls and 5-FU exposure rises. Treatment is not recommended in severe renal impairment unless the benefit clearly outweighs the risk, partly because fluctuating renal function can lead to unexpectedly high 5-FU exposure.

Eye Toxicity

Lacrimal disorders (8.8% in the SmPC’s studies of Teysuno with cisplatin) were the most common treatment-related eye disorders. Most resolve or improve after suspension and treatment, such as artificial tears, antibiotic eye drops, tubes in the lacrimal canaliculi, or spectacles instead of contact lenses. Early detection and an early ophthalmology consultation are advised for persistent or vision-reducing symptoms such as lacrimation or corneal symptoms.

Other Warnings

• Hyperammonaemia: ammonia should be measured in patients with unexplained neurological symptoms (ataxia, lethargy, changed mental status); discontinuation should be considered if hyperammonaemic encephalopathy develops.
• Gastric cancer with microsatellite instability (MSI): Teysuno has not been studied in these patients.
• Other oral fluoropyrimidines: there are no trials against other oral 5-FU compounds, so Teysuno cannot be used as a substitute for them.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated. Foetal abnormalities have been reported in some cases, and animal studies showed embryolethality and teratogenicity, as with other fluoropyrimidines. If a patient becomes pregnant, treatment should be stopped, the risk to the foetus explained and genetic counselling considered.
• Contraception: women of childbearing potential should avoid becoming pregnant. Male patients must use contraception during treatment and for up to 3 months after stopping; female patients during treatment and for up to 6 months after stopping.
• Breastfeeding: contraindicated. Animal data show excretion in milk, and a risk to the infant cannot be excluded; breast-feeding must be stopped during treatment.
• Fertility: no human data. In the rat, Teysuno did not appear to affect male or female fertility. See the cisplatin SmPC for its effects.

Lactose

Each 15 mg capsule contains 70.2 mg and each 20 mg capsule 93.6 mg of lactose monohydrate. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take Teysuno.

Effect on Driving

Teysuno has a moderate influence on the ability to drive and use machines, because fatigue, dizziness, blurred vision and nausea are common with cisplatin.

Teysuno does not require any special storage conditions, and no cold chain is needed. The capsules come in opaque PCTFE/PVC/aluminium blisters of 14 capsules, in packs of 42, 84 or 126 capsules; not all pack sizes may be marketed.

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

Prescription only (Rx), on the prescription of a qualified physician experienced in treating cancer patients with anti-neoplastic medicinal products. The capsules are taken at home, so Teysuno is supplied to the patient or to the treating clinic on prescription. Testing for DPD deficiency is recommended before the first prescription.