TEYSUNO 15mg / 4.35mg / 11.8mg capsules medication leaflet

Teysuno 15 mg/4.35 mg/11.8 mg hard capsules

Each hard capsule contains 15 mg tegafur, pct. 4.35 mg gimeracil and 11.8 mg oteracil (asmonopotassium).

Each hard capsule contains 70.2 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

Hard capsule (capsule).

The capsule has an opaque white body and opaque brown cap imprinted “TC448” in grey.

Teysuno is indicated in adults:

- for the treatment of advanced gastric cancer when given in combination with cisplatin (see section5.1).

- as monotherapy or in combination with oxaliplatin or irinotecan, with or without bevacizumab, forthe treatment of patients with metastatic colorectal cancer for whom it is not possible to continuetreatment with another fluoropyrimidine due to hand-foot syndrome or cardiovascular toxicity thatdeveloped in the adjuvant or metastatic setting.

Teysuno should only be prescribed by a qualified physician experienced in treating cancer patientswith anti-neoplastic medicinal products.

Patients should be provided with outpatient prescriptions for anti-emetic and anti-diarrhoeal medicinalproducts.

The patient's BSA must be recalculated and the Teysuno dose adjusted accordingly if a patient’sweight increases or decreases by ≥10% from the one used for the previous calculation of BSA and thechange is clearly not related to fluid retention.

Advanced gastric cancer when given in combination with cisplatin

The recommended standard dose of Teysuno when administered in combination with cisplatin is25 mg/m2 (expressed as tegafur content) twice daily, morning and evening, for 21 consecutive daysfollowed by 7 days rest (1 treatment cycle). This treatment cycle is repeated every 4 weeks.

The standard and reduced Teysuno and cisplatin doses and calculations according to body surface area(BSA) for doses of Teysuno given in combination with cisplatin are provided in Table 1 and Table 2,respectively.

The recommended dose of cisplatin with this regimen is 75 mg/m2 by intravenous infusionadministered once every 4 weeks. Cisplatin should be discontinued after 6 cycles without withdrawalof Teysuno. If cisplatin is discontinued before 6 cycles, Teysuno treatment alone can be resumedwhen the criteria for restarting it are met.

Patients treated with Teysuno in combination with cisplatin should be closely monitored andlaboratory tests, including haematology, liver function, renal function, and serum electrolytes, shouldbe performed frequently. Treatment should be discontinued if progressive disease or intolerabletoxicity is observed.

Refer to the cisplatin summary of product characteristics (SmPC) for pretreatment hyperhydration.

Teysuno doses in advanced gastric cancer

Table 1: Standard dose and dose reductions allowed for Teysuno and/or for cisplatin in advanced gastriccancer

Medicinal Standard dose Dose reduction 1 Dose reduction 2product (mg/m2) (mg/m2) (mg/m2)

Teysuno 25a → 20a → 15aand/or

Cisplatin 75 → 60 → 45a Expressed as tegafur content.

Teysuno dose calculations in advanced gastric cancer

Table 2: Standard and reduced dose calculations in advanced gastric cancer by body surface area (m2)

Teysuno dose Each dose in mg Total daily dose Number of capsules for each dose(each dosing)a in mga (2 doses/day)

Standard dosea: 25 mg/m2 15 mg capsulea 20 mg capsulea(brown/white) (white)

BSA ≥ 2.30 m2 60 120 0 3

BSA = 2.10 - 2.29 m2 55 110 1 2

BSA = 1.90 - 2.09 m2 50 100 2 1

BSA = 1.70 - 1.89 m2 45 90 3 0

BSA = 1.50 - 1.69 m2 40 80 0 2

BSA = 1.30 - 1.49 m2 35 70 1 1

BSA ≤ 1.29 m2 30 60 2 0

First dose reductiona: to 20 mg/m2

BSA ≥ 2.13 m2 45 90 3 0

BSA = 1.88 - 2.12 m2 40 80 0 2

BSA = 1.63 - 1.87 m2 35 70 1 1

BSA = 1.30 - 1.62 m2 30 60 2 0

BSA ≤ 1.29 m2 20 40 0 1

Second dose reductiona: to 15 mg/m2

BSA ≥ 2.17 m2 35 70 1 1

BSA = 1.67 - 2.16 m2 30 60 2 0

BSA = 1.30 - 1.66 m2 20 40 0 1

BSA ≤ 1.29 m2 15 30 1 0

Calculate BSA to 2 decimal places.a Expressed as tegafur content.

Metastatic colorectal cancer, as monotherapy or in combination with oxaliplatin or irinotecan, withor without bevacizumab, for whom it is not possible to continue treatment with anotherfluoropyrimidine due to hand-foot syndrome (HFS) or cardiotoxicity

The proposed dose in mCRC for monotherapy is 30 mg/m2 b.i.d. days 1-14 with a one-week pause (±bevacizumab 7.5 mg/kg on day 1). For combination therapy (with oxaliplatin or irinotecan), 25mg/m2 b.i.d. d1-14 followed by one-week pause is recommended.

Teysuno doses in Metastatic colorectal cancer

Table 3a: Standard dose and dose reductions allowed for Teysuno monotherapy in metastatic colorectalcancer

Medicinal Standard dose Dose reduction 1 Dose reduction 2product (mg/m2) (mg/m2) (mg/m2)

Teysuno 30a → 25a → 20aa Expressed as tegafur content.

Table 3b: Standard dose and dose reductions allowed for Teysuno combination therapy in metastaticcolorectal cancer

Medicinal Standard dose Dose reduction 1product (mg/m2) (mg/m2)

Teysuno 25a → 20a,e

And/or

Oxaliplatinb,c,d 130 → 100e

Irinotecanc,d 150-225f → ga Expressed as tegafur content.b Chung KY, Saito K, Zergebel C, Hollywood E, Segal M, Saltz LB. Phase I study of two schedules of oral S-1in combination with fixed doses of oxaliplatin and bevacizumab in patients with advanced solid tumors.

Oncology. 2011;81(2):65-72.c Winther SB, Zubcevic K, Qvortrup C, et al. Experience with S-1 in older Caucasian patients with metastaticcolorectal cancer (mCRC): Findings from an observational chart review. Acta Oncol. 2016;55(7):881-885.d Österlund P, Kinos S, Pfeiffer P, et al. Continuation of fluoropyrimidine treatment with S-1 aftercardiotoxicity on capecitabine- or 5-fluorouracil-based therapy in patients with solid tumours: a multi-centreretrospective observational cohort study. Manuscript Submitted 2021.e Winther SB, Liposits G, Skuladottir H, et al. Reduced-dose combination chemotherapy (S-1 plus oxaliplatin)versus full-dose monotherapy (S-1) in older vulnerable patients with metastatic colorectal cancer (NORDIC9): arandomised, open-label phase 2 trial. Lancet Gastroenterol Hepatol. 2019;4(5):376-388.f While the best dose of irinotecan is not known and is used in combination with Teysuno in ranges between150-225 mg/m2, the most relevant experience comes from irinotecan dosing of 180-200 mg/m2g No recommendation can be made and dose reduction will be dependent on the starting dose

Teysuno dose calculations Metastatic colorectal cancer

Table 4: Standard and reduced dose calculations by body surface area (m2) in metastatic colorectalcancer

Teysuno dose Each dose in mg Total daily dose Number of capsules for each dose(each dosing)a in mga (2 doses/day)

Standard dosea: 30 mg/m2 15 mg capsulea 20 mg capsulea(brown/white) (white)

BSA ≥ 2.30 m2 70 140 2 2

BSA = 2.10 - 2.29 m2 65 130 3 1

BSA = 1.90 - 2.09 m2 60 120 0 3

BSA = 1.70 - 1.89 m2 55 110 1 2

BSA = 1.50 - 1.69 m2 50 100 2 1

BSA = 1.30 - 1.49 m2 40 80 0 2

BSA ≤ 1.29 m2 35 70 1 1

First dose reductiona: to 25 mg/m2#

BSA ≥ 2.30 m2 60 120 0 3

BSA = 2.10 - 2.29 m2 55 110 1 2

BSA = 1.90 - 2.09 m2 50 100 2 1

BSA = 1.70 - 1.89 m2 45 90 3 0

BSA = 1.50 - 1.69 m2 40 80 0 2

BSA = 1.30 - 1.49 m2 35 70 1 1

BSA ≤ 1.29 m2 30 60 2 0

Second dose reductiona: to 20 mg/m2

BSA ≥ 2.13 m2 45 90 3 0

BSA = 1.88 - 2.12 m2 40 80 0 2

BSA = 1.63 - 1.87 m2 35 70 1 1

BSA = 1.30 - 1.62 m2 30 60 2 0

BSA ≤ 1.29 m2 20 40 0 1

Calculate BSA to 2 decimal places.a Expressed as tegafur content.

Kwakman JJM et al. Randomized Phase III trial of S-1 versus capecitabine in the first-line treatment ofmetastatic colon cancer: SALTO study by the Dutch Colorectal Cancer group, Annals of Oncology 2017, 28;(6): 1288-93# 25 mg/m2 is the standard dose in case of combination therapy with oxaliplatin or irinotecan

Adjustments during treatment

Toxicity due to Teysuno administration should be managed with symptomatic treatment and/ortreatment interruption or dose reduction. Patients taking Teysuno should be informed of the risks andinstructed to contact their physician immediately if moderate or severe toxicity occurs.

Doses omitted for toxicity are not replaced; and, if a patient vomits after taking a dose, this doseshould not be replaced.

Once the Teysuno dose has been reduced, it should not be increased again.

Teysuno dose modification criteria

Dose modifications for toxicity should be made according to Tables 1, 3, 5, 6 and 7. A maximum oftwo consecutive dose reductions for each medicinal product, as described in Table 1 for advancedgastric cancer and table 3 for metastatic colorectal cancer, can be applied in case of toxicity. Eachdose reduction results in approximately 20-25% reduction of dose.

In case of advanced gastric cancer, see Table 2 for the details of the number of Teysuno capsules to beadministered for each dose level.

In case of metastatic colorectal cancer, see Table 4 for the details of the number of Teysuno capsulesto be administered for each dose level. For minimum criteria for resumption of Teysuno treatment, see

Table 8.

Teysuno dose modifications for toxicity when used in combination with cisplatin can be made in twoways.

During a 4-week cycle of treatment

Teysuno should only be given on Days 1 to 21 of each cycle, i.e., treatment should not be given on

Days 22 to 28 of a cycle. Treatment days missed in a cycle where medicinal product was held due totoxicity should not be replaced.

During a treatment cycle, dose adjustment should be performed for each individual medicinal productthat is considered to be causally related to the toxicity, if such a distinction can be made. If bothmedicinal products are considered to be causing the toxicity or it is not possible to distinguish them,then dose reduction should be performed for both according to the recommended dose reductionschedule.

At the initiation of subsequent cycles of treatment

If a treatment delay is indicated for either Teysuno or cisplatin, then administration of both medicinalproducts should be delayed until the requirements for restarting both are met unless one of themedicinal products has been permanently discontinued.

Dose modifications for Teysuno for adverse reactions in general except for haematologic and renaltoxicities

Table 5: Teysuno dose reduction schedule for treatment-related toxicities in general, except forhaematologic and renal toxicities

Toxicity gradesa Teysuno dose changes within a 21-day Teysuno dose adjustmenttreatment cycle for next dose/next cycle

Grade 1

Any occurrence Maintain treatment at same dose level None

Grade 2b,c

Any occurrence Suspend treatment until Grade 0 or 1 None

Grade 3 or higherc

First occurrence Suspend treatment until Grade 0 or 1 Reduce by 1 dose level fromprevious level

Second occurrence Suspend treatment until Grade 0 or 1 Reduce by 1 dose level fromprevious level

Third occurrence Discontinue treatment Discontinue treatmenta According to the Common Terminology Criteria for Adverse Events (CTCAE) of the Cancer Therapy

Evaluation Program, US National Cancer Institute, version 3.0.b For Grade 2 nausea and/or vomiting, the anti-emetic therapy should be optimized prior to a suspension of

Teysuno.c At the discretion of the treating physician, patients may continue with treatment without reduction orinterruption for adverse reactions (irrespective of grade) considered unlikely to become serious or life-threatening (e.g., alopecia, changes in sexual function, and dry skin).

Dose modifications for renal toxicities

Creatinine clearance (CrCl) must be determined for every cycle before the start of treatment on Day 1.

Table 6: Teysuno and cisplatin dose modification according to creatinine clearance values at the startof a cycle of treatment

Creatinine Teysuno dose modification at the Cisplatin dose modification at theclearance start of the cycle of treatment start of the cycle of treatment≥50 ml/min No dose modification No dose modification30 to 49 ml/min Start treatment at one reduced dose Start cisplatin treatment at a 50%level dose reduction from the previouscycle<30 ml/mina Suspend treatment until resumption Suspend cisplatin treatment untilcriterion (≥30 ml/min) is met and resumption criterion (≥30 ml/min) isthen start treatment at one reduced met and then start treatment at a 50%dose level dose reduction from the previouscyclea Treatment for patients with CrCl <30 ml/min is not recommended unless the benefits of Teysunotreatment clearly outweigh the risks. Refer to “Dose modifications for special populations/Renalimpairment for guidance.”

Dose modifications for haematologic toxicities

Table 7: Haematologic toxicities for which Teysuno treatment should be suspended

Units Neutrophils Platelets Haemoglobin Teysuno dose modification

Suspend treatment until

IU <0.5 x 109/l <25 x 109/l 4.0 mmol/l resumption criterion is met(see Table 8) and then resumedosing at one reduced dose level.

Resumption criteria for Teysuno treatment

Table 8: Minimum criteria to resume Teysuno treatment following its suspension due to a toxicity

Non-haematologic Haematologic

Baseline or Grade 1 Platelet count ≥100 x 109/l

Calculated creatinine clearance ≥30 ml/mina Neutrophils ≥1.5 x 109/l

Haemoglobin ≥6.2 mmol/l

CrCl must be calculated at the beginning of every cycle before the start of treatment with Teysunoon Day 1.a Treatment for patients with CrCl <30 ml/min is not recommended unless the benefits of Teysuno treatmentclearly outweigh the risks. Refer to “Dose modifications for special populations/Renal impairment forguidance.”

Dose modifications for special populations

* Mild renal impairment (CrCl 51 to 80 ml/min)

No adjustment of the standard dose is recommended in patients with mild renal impairment (seesection 5.2).

* Moderate renal impairment (CrCl 30 to 50 ml/min)

The recommended standard dose in patients with moderate renal impairment is 20 mg/m2 twicedaily (expressed as tegafur content) (see sections 4.8 and 5.2).

* Severe renal impairment (CrCl below 30 ml/min)

Although roughly similar daily exposure to 5-FU would be expected in patients with severerenal impairment at a dose of 20 mg/m2 once daily compared to 30 mg/m2 twice daily in patientswith normal renal function (see section 5.2), administration of Teysuno is not recommended dueto possibly higher incidence of adverse events of the blood and lymphatic system disordersunless the benefits clearly outweigh the risks (see sections 4.4 and 4.8).

No data is available regarding Teysuno administration in patients with end stage renal diseaserequiring dialysis (see section 4.3).

In both indications, no adjustment of the standard dose is recommended in patients >70 years old (seesection 4.8).

For elderly, more vulnerable patients, in case of metastatic colorectal cancer and where it is not possible tocontinue treatment with another fluoropyrimidine due to hand-foot syndrome or cardiotoxicity, therecommended dose is 20 mg/m2 (expressed as tegafur content) twice daily, morning and evening, for 14consecutive days followed by 7 days rest, in combination with a reduced oxaliplatin dose (100 mg/m2 onday 1 of a 3-week cycle).

No adjustment of the standard dose in both indications is recommended for patients withhepatic impairment (see section 5.2).

No adjustment of the standard dose in both indications is recommended for patients of Asian ethnicity (seesection 5.2).

The safety and efficacy of Teysuno in children and adolescents under 18 years old have not beenestablished. No data are available. Therefore, Teysuno should not be administered to children oradolescents under 18 years of age.

The capsules should be taken by mouth with water at least 1 hour before or 1 hour after a meal (seesection 5.2).

* Hypersensitivity to any of the active substances (tegafur, gimeracil, and oteracil) or to any of theexcipients listed in 6.1.

* History of severe and unexpected reactions to fluoropyrimidine therapy.

* Known complete dihydropyrimidine dehydrogenase (DPD) deficiency (see section 4.4).

* Pregnancy and breast-feeding.

* Severe bone marrow suppression (severe leukopaenia, neutropaenia, or thrombocytopaenia; seesection 4.2, Table 7).

* End stage renal disease patients requiring dialysis.

* Co-administration of other fluoropyrimidines with Teysuno.

* Recent or concomitant treatment with brivudine (see section 4.4 and 4.5 for drug-druginteraction).

* Contraindications for cisplatin; oxaliplatin, irinotecan and bevacizumab refer to the corresponding

SmPCs.

Dose limiting toxicities include diarrhoea and dehydration. Most adverse reactions are reversible andcan be managed by symptomatic therapy, dose interruptions and dose reductions.

Bone marrow suppression

Treatment-related bone marrow suppression, including neutropaenia, leukopaenia, thrombocytopaenia,anaemia, and pancytopaenia, has been reported among patients treated with Teysuno in combinationwith cisplatin. Patients with low white blood cell counts should be monitored carefully for infectionand risk of other complications of neutropaenia and treated as medically indicated (e.g., withantibiotics, granulocyte-colony stimulating factor [G-CSF]). Patients with low platelet counts are atincreased risk for bleeding and should be monitored carefully. The dose should be modified asrecommended in section 4.2.

Administration of Teysuno in hepatitis B virus carriers, HBc antigen negative and HBc antibodypositive patients, or HBs antigen negative and HBs antibody positive patients may result inreactivation of hepatitis B.

Patients should be tested for HBV infection before initiating treatment with Teysuno. Experts in liverdisease and in the treatment of hepatitis B should be consulted before treatment is initiated in patientswith positive hepatitis B serology (including those with active disease) and for patients who testpositive for HBV infection during treatment. Carriers of HBV who require treatment with Teysunoshould be closely monitored for signs and symptoms of active HBV infection throughout therapy, andfollow-up monitoring for hepatic function tests or viral markers are recommended.

Patients with diarrhoea should be carefully monitored and given fluid and electrolyte replacement ifthey become dehydrated. Prophylactic treatment for diarrhoea should be administered as indicated.

Standard anti-diarrhoeal therapy (e.g., loperamide) and intravenous fluids/electrolytes should beinitiated early when diarrhoea develops. Dose suspension/adjustment should be implemented with theoccurrence of Grade 2 or higher diarrhoea if symptoms persist despite adequate treatment.

Dehydration and any associated electrolyte disturbances should be prevented or corrected at onset.

Patients with anorexia, asthenia, nausea, vomiting, diarrhoea, stomatitis, and gastrointestinalobstruction should be monitored closely for signs of dehydration. Dehydration should be managedaggressively with rehydration and other appropriate measures. If Grade 2 (or higher) dehydrationoccurs, treatment should be immediately suspended and the dehydration corrected. Treatment shouldnot be resumed until dehydration and its underlying causes are corrected or adequately controlled.

Dose modifications should be applied for the precipitating adverse reaction as necessary (seesection 4.2).

Renal toxicity

Treatment with Teysuno in combination with cisplatin may be associated with a transient decline ofglomerular filtration rate caused primarily by pre-renal factors (e.g., dehydration, electrolyteimbalance, etc). Adverse reactions of Grade 3 or higher such as increased blood creatinine, decreasedcreatinine clearance, toxic nephropathy, and acute renal failure have all been reported in patientsreceiving Teysuno in combination with cisplatin (see section 4.8). To detect early changes in renalfunction during treatment, renal parameters should be closely monitored (e.g., serum creatinine, CrCl).

If deterioration of glomerular filtration rate is observed, Teysuno and/or cisplatin dose should beadjusted according to Table 6, and appropriate supportive measures taken (see section 4.2).

Dehydration and diarrhoea may increase the risk of renal toxicity for cisplatin. Hyperhydration(forced diuresis) should be administered according to the cisplatin SmPC to reduce the risk of renaltoxicity associated with cisplatin therapy.

Gimeracil increases 5-fluorouracil (5-FU) exposure by inhibiting DPD, the primary enzyme formetabolizing 5-FU. Gimeracil is primarily cleared by the kidney (see section 5.2); so, in patients withrenal insufficiency gimeracil renal clearance is decreased and 5-FU exposure thus increased.

Treatment-related toxicities can be expected to increase as 5-FU exposure increases (see section 5.2).

Treatment with Teysuno is not recommended in patients with severe renal impairment due to possiblyhigher incidence of adverse events of the blood and lymphatic system and the possibility ofunexpectedly higher exposure to 5-FU as a result of fluctuations in renal function in these patients,unless the benefits clearly outweigh the risks (see sections 4.2, pct. 4.8 and 5.2).

Ocular toxicity

The most common treatment-related ocular disorders among patients in studies in Europe/United

States of America (EU/USA) treated with Teysuno in combination with cisplatin were lacrimaldisorders (8.8%), including increased lacrimation, dry eye, and acquired dacryostenosis (seesection 4.8).

Most ocular reactions will resolve or improve with suspension of medicinal product and propertreatment (instillation of artificial tears, antibiotic eye drops, implantation of glass or silicone tubes inlacrimal punctas or canaliculi, and/or use of spectacles rather than contact lenses). Efforts should bemade to ensure early detection of ocular reactions, including an early ophthalmologic consultation inthe event of any persistent or vision-reducing ocular symptoms such as lacrimation or cornealsymptoms.

Refer to the cisplatin SmPC for eye disorders observed with cisplatin therapy.

Hyperammonaemia

Hyperammonaemia has been observed with Teysuno. In patients who develop unexplained neurologicsymptoms (like ataxia, lethargy or changes in mental status), ammonia levels should be measured andappropriate clinical management should be initiated. If hyperammonaemia neurologic symptoms worsento hyperammonaemic encephalopathy, discontinuation of Teysuno should be considered.

Coumarin-derivative anticoagulant

Patients receiving oral coumarin-derivative anticoagulant therapy must have their anticoagulantresponse (International Normalized Ratio for prothrombin time [INR] or prothrombin time [PT])monitored closely and the anticoagulant dose adjusted accordingly (see section 4.5). The use ofcoumarin-derivative anticoagulant in clinical trials has been associated with elevated INR andgastrointestinal bleeding, bleeding tendency, haematuria, and anaemia in patients receiving Teysunotherapy.

Brivudine

Brivudine must not be administered concomitantly with Teysuno. Fatal cases have been reportedfollowing capecitabine interaction. There must be at least a 4-week waiting period between end oftreatment with brivudine and start of Teysuno therapy. Treatment with brivudine can be started 24hours after the last dose of Teysuno (see section 4.3 and 4.5).

In the event of accidental administration of brivudine to patients being treated with Teysuno, effectivemeasures should be taken to reduce the toxicity of Teysuno. Immediate admission to hospital isrecommended. All measures should be initiated to prevent systemic infections and dehydration.

DPD inducers

If a DPD inducer were to be concomitantly administered with Teysuno, the exposure of 5-FU mightnot reach the efficacious level. However, since no DPD inducers are currently known, the interactionbetween a DPD inducer and Teysuno cannot be evaluated.

Dihydropyrimidine dehydrogenase (DPD) deficiency:

DPD activity is rate limiting in the catabolism of 5-fluorouracil (see Section 5.2). Patients with DPDdeficiency are therefore at increased risk of fluoropyrimidines-related toxicity including for examplestomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.

DPD-deficiency related toxicity usually occurs during the first cycle of treatment or after dose increase.

Complete DPD deficiency

Complete DPD deficiency is rare (0.01-0.5% of Caucasians). Patients with complete DPD deficiencyare at high risk of life-threatening or fatal toxicity and must not be treated with Teysuno (see section4.3).

Partial DPD deficiency

Partial DPD deficiency is estimated to affect 3-9% of the Caucasian population. Patients with partial

DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reducedstarting dose should be considered to limit this toxicity. DPD deficiency should be considered as aparameter to be taken into account in conjunction with other routine measures for dose reduction. Initialdose reduction may impact the efficacy of treatment. In the absence of serious toxicity, subsequent dosesmay be increased with careful monitoring.

Testing for DPD deficiency

Phenotype and/or genotype testing prior to the initiation of treatment with Teysuno is recommendeddespite uncertainties regarding optimal pre-treatment testing methodologies. Consideration should begiven to applicable clinical guidelines.

When this was not done before, testing is recommended for patients for whom a switch to Teysunofrom another fluoropyrimidine is considered due to hand-foot syndrome or cardiovascular toxicity inorder to determine whether a DPD phenotype and/or genotype could have played a role in thedevelopment of toxicity on another fluoropyrimidine.

Genotypic characterisation of DPD deficiency

Pre-treatment testing for rare mutations of the DPYD gene can identify patients with DPD deficiency.

The four DPYD variants c.1905+1G>A [also known as DPYD*2A], c.1679T>G [DPYD*13],c.2846A>T and c.1236G>A/HapB3 can cause complete absence or reduction of DPD enzymaticactivity. Other rare variants may also be associated with an increased risk of severe or life-threateningtoxicity.

Certain homozygous and compound heterozygous mutations in the DPYD gene locus (e.g. combinationsof the four variants with at least one allele of c.1905+1G>A or c.1679T>G) are known to cause completeor near complete absence of DPD enzymatic activity.

Patients with certain heterozygous DPYD variants (including c.1905+1G>A, c.1679T>G, c.2846A>Tand c.1236G>A/HapB3 variants) have increased risk of severe toxicity when treated withfluoropyrimidines.

The frequency of the heterozygous c.1905+1G>A genotype in the DPYD gene in Caucasian patients isaround 1%, 1.1% for c.2846A>T, 2.6-6.3% for c.1236G>A/HapB3 variants and 0.07 to 0.1% forc.1679T>G.

Data on the frequency of the four DPYD variants in other populations than Caucasian is limited. At thepresent, the four DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T and c.1236G>A/HapB3) areconsidered virtually absent in populations of African (-American) or Asian origin.

Phenotypic characterisation of DPD deficiency

For phenotypic characterisation of DPD deficiency the measurement of pre-therapeutic blood levels ofthe endogenous DPD substrate uracil (U) in plasma is recommended.

Elevated pre-treatment uracil concentrations are associated with an increased risk of toxicity. Despiteuncertainties on uracil thresholds defining complete and partial DPD deficiency, a blood uracil level ≥16 ng/ml and < 150 ng/ml should be considered indicative of partial DPD deficiency and associated withan increased risk for fluoropyrimidine toxicity. A blood uracil level ≥ 150 ng/ml should be consideredindicative of complete DPD deficiency and associated with a risk for life-threatening or fatalfluoropyrimidine toxicity.

Microsatellite instability (MSI)

Teysuno has not been studied in gastric cancer patients with MSI. The association between 5-FUsensitivity and MSI in patients with gastric cancer is unclear and the association between Teysuno and

MSI in gastric cancer is unknown.

Glucose/galactose intolerance/malabsorption

This medicinal product contains lactose. Patients with rare hereditary problems of galactoseintolerance, the Lapp lactase deficiency or glucose/galactose malabasorption should not take thismedicinal product.

Other oral fluoropyrimidines

No clinical trials are available comparing Teysuno versus other oral 5-FU compounds. Therefore,

Teysuno cannot be used as a substitute for other oral 5-FU products.

No interaction studies have been performed in adult or paediatric patients.

Brivudine

A clinically significant interaction between brivudine and fluoropyrimidines (e.g. capecitabine, 5-

Fluorouracil, tegafur), resulting from the inhibition of dihydropyrimidine dehydrogenase by brivudine,has been described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentiallyfatal. Therefore, brivudine must not be administered concomitantly with Teysuno (see section 4.3 and4.4). There must be at least a 4-week waiting period between end of treatment with brivudine and startof Teysuno therapy. Treatment with brivudine can be started 24 hours after the last dose of Teysuno.

Other fluoropyrimidines

Co-administration of other fluoropyrimidines such as capecitabine, 5-FU, tegafur, or flucytosine canlead to additive toxicities, and is contraindicated. A minimum washout period of 7 days isrecommended between administration of Teysuno and other fluoropyrimidines. The washout perioddescribed in the SmPC of other fluoropyrimidine medicinal products should be followed if Teysuno isto be administered subsequent to other fluoropyrimidine medicinal products.

CYP2A6 inhibitors

As CYP2A6 is the major enzyme responsible for the conversion of tegafur to 5-FU, co-administrationof a known CYP2A6 inhibitor and Teysuno should be avoided as effectiveness of Teysuno could bedecreased (see section 5.2).

Folinate/folinic acid

No data are available on the concomitant use of folinic acid with Teysuno in combination withcisplatin. However, metabolites of folinate/folinic acid will form a ternary structure with thymidylatesynthase and fluorodeoxyuridine monophosphate (FdUMP), potentially increasing the cytotoxicity of5-FU. Caution is advised as folinic acid is known to enhance the activity of 5-FU.

Nitroimidazoles, including metronidazole and misonidazole

No data are available on the concomitant use of nitromidazoles with Teysuno in combination withcisplatin. However, nitromidazoles may reduce clearance of 5-FU and thus increase plasma levels of5-FU. Caution is advised as co-administration may increase the toxicity of Teysuno.

No data are available on the concomitant use of methotrexate with Teysuno in combination withcisplatin. However, polyglutamated methotrexate inhibits thymidylate synthase and dihydrofolatereductase, potentially increasing cytotoxicity of 5-FU. Caution is advised as co-administration mayincrease the toxicity of Teysuno.

Clozapine

No data are available on the concomitant use of clozapine with Teysuno in combination with cisplatin.

However, due to possible additive pharmacodynamic effects (myelotoxicity), caution is advised as co-administration may increase the risk and severity of haematologic toxicity of Teysuno.

Cimetidine

No data are available on the concomitant use of cimetidine with Teysuno in combination withcisplatin. However, co-administration may decrease clearance and, thus increase plasma levels of5-FU. Caution is advised as co-administration may increase the toxicity of Teysuno.

Coumarin-derivative anticoagulant

The activity of a coumarin-derivative anticoagulant was enhanced by Teysuno. Caution is advised asco-administration of Teysuno and coumarin anticoagulation therapy may increase the risk of bleeding(see section 4.4).

Fluoropyrimidines may increase phenytoin plasma concentration when administered concomitantlywith phenytoin causing phenytoin toxicity. Frequent monitoring of phenytoin blood/plasma levels isadvised when Teysuno and phenytoin are administered concomitantly. If indicated, the dose ofphenytoin should be adjusted according to the phenytoin SmPC. If phenytoin toxicity develops,appropriate measures should be taken.

Based on non-clinical data, allopurinol may decrease anti-tumour activity due to suppression ofphosphorylation of 5-FU. Therefore, concurrent administration with Teysuno should be avoided.

Administration of Teysuno with a meal reduced exposure to oteracil and gimeracil, with a morepronounced effect for oteracil than for gimeracil (see section 5.2). It should be taken with water atleast 1 hour before or 1 hour after a meal (see section 4.2).

Women of childbearing potential should be advised to avoid becoming pregnant while receivingtreatment with this medicinal product.

Contraceptive measures must be taken by male patients during and up to 3 months after stoppingtreatment with Teysuno.

Contraceptive measures must be taken by female patients during and up to 6 months after stoppingtreatment with Teysuno.

Teysuno is contraindicated in pregnancy (see section 4.3). There have been some case reports offoetal abnormalities. Studies in animals have shown reproductive toxicity. As with otherfluoropyrimidines, Teysuno administration caused embryolethality and teratogenicity in animals (seesection 5.3). If the patient becomes pregnant while receiving Teysuno, treatment should bediscontinued and the potential risk to the foetus must be explained. Genetic counseling should beconsidered.

Teysuno is contraindicated during breast-feeding (see section 4.3). It is not known whether Teysunoor its metabolites are excreted in human milk. Available pharmacodynamic/toxicological data inanimals have shown excretion of Teysuno or its metabolites in milk (for details see section 5.3).

A risk to newborns/infants cannot be excluded. Breast-feeding must be discontinued while receivingtreatment with Teysuno.

No data are available on the effect of Teysuno in combination with cisplatin on human fertility. Non-clinical studies demonstrated that Teysuno did not appear to affect male or female fertility in the rat(see section 5.3).

Refer to the cisplatin SmPC for the effects of cisplatin on fertility, pregnancy and lactation.

Teysuno has moderate influence on the ability to drive and use machines as fatigue, dizziness, blurredvision, and nausea are common adverse reactions of Teysuno in combination with cisplatin.

The overall safety profile of Teysuno in combination with cisplatin is based primarily on clinical studydata from 593 patients with advanced gastric cancer treated with this regimen. In addition, there ispost-marketing experience in over 866,000 Asian (mainly Japanese) patients.

Among 593 patients treated with Teysuno in combination with cisplatin, the most common severeadverse reactions (Grade 3 or higher with frequency of at least 10%) were neutropaenia, anaemia, andfatigue.

The following headings are used to rank the adverse reactions by frequency: very common (≥1/10),common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare(<1/10,000), and not known (cannot be estimated from the available data). The frequencies of verycommon, common, and uncommon adverse reactions are from 593 patients treated with Teysuno incombination with cisplatin in clinical trials. The frequencies of medically relevant rare and very rareadverse reactions are estimated from post-marketing surveillance of 866,000 patients in Asia (mostly

Japanese) treated with Teysuno-based therapy. Each term is presented in its most common categoryonly and within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Table 9: Adverse reactions reported by decreasing seriousness in each frequency grouping

System Organ Very Common Uncommon Rare/Very

Classa common rare

Infections and Neutropenic sepsis, septic shock, sepsis, Hepatitis Binfestations infection, pneumonia, bacteremia, reactivationrespiratory tract infection, upperrespiratory tract infection, pyelonephritisacute, urinary tract infection,pharyngitis, nasopharyngitis, rhinitis,tooth infection, candidiasis, oral herpes,paronychia, furuncle

Neoplasms Tumour haemorrhage, cancer painbenign,malignant andunspecified(Incl. cysts andpolyps)

Blood and Neutropenia, Febrile neutropenia, Pancytopenia, prothrombin time Disseminatedlymphatic leukopenia, lymphopenia prolonged, international normalised ratio intravascularsystem anaemia, increased, hypoprothrombinaemia, coagulationdisorders thrombo- prothrombin time shortened,cytopenia granulocytosis, leukocytosis,eosinophilia, lymphocytosis, monocytecount decreased, monocyte countincreased, thrombocythaemia

Immune system Hypersensitivitydisorders

Endocrine Adrenal haemorrhagedisorders

Metabolism and Anorexia Dehydration, Hyperglycaemia, blood alkaline Hyperammonaemianutrition hypokalaemia, phosphatase increased, blood lactatedisorders hyponatraemia, dehydrogenase increased,hypocalcaemia, hypophosphatameia, hypermagnesaemia,hypomagnesaemia, gout, hypoproteinaemia,hypoalbuminaemia, hyperglobulinaemia, hyperlipidaemia,hyperkalaemia oral intake reduced

Psychiatric Insomnia Confusional state, restlessness,disorders personality disorder, hallucination,depression, anxiety, libido decreased,sexual inhibition

System Organ Very Common Uncommon Rare/Very

Classa common rare

Nervous system Peripheral Dizziness, Cerebrovascular accident, cerebellar Leukoenceph-disorders neuropathy headache, infarction, cerebrovascular disorder, alopathy,dysgeusia convulsion, ischaemic stroke, syncope, anosmiahemiparesis, aphasia, ataxia, metabolicencephalopathy, loss of consciousness,acoustic neuritis, memory impairment,balance disorder, somnolence, tremor,ageusia, parosmia, burning sensation,formication

Eye disorders Vision disorder, Eye allergy, eyelid ptosis, erythema oflacrimal disorder, eyelidconjunctivitis,corneal disorder b

Ear and Hearing Vertigo, ear congestion, ear discomfortlabyrinth impairment,disorders deafness

Cardiac Cardiac failure, acute myocardialdisorders infarction, pericardial effusion, atrialfibrillation, angina pectoris, cardiacfibrillation, tachycardia, palpitations

Vascular Hypotension, deep Iliac artery thrombosis, hypovolaemicdisorders vein thrombosis, shock, arterial limb thrombosis,hypertension thrombosis, flushing, pelvic venousthrombosis, thrombophlebitis, phlebitis,phlebitis superficial, orthostatichypotension, haematoma, hyperaemia,hot flush

Respiratory, Dyspnoea, Pulmonary embolism, respiratory tract Interstitial lungthoracic and epistaxis, hiccups, haemorrhage, exertional dyspnoea, diseasemediastinal cough pharyngolaryngeal pain, rhinorrhoea,disorders pharyngeal erythema, rhinitis allergic,dysphonia, productive cough, nasalcongestion

Gastrointestinal Diarrhoea, Gastrointestinal Gastrointestinal perforation, Acutedisorders vomiting, haemorrhage, oesophagitis, gastrointestinal infection, pancreatitisnausea, stomatitis, ileus, gastrointestinal obstruction, , terminalconstipation gastrointestinal ascites, lip oedema, oesophageal spasm, ileitisinflammation, gastric ulcer, gastroesophageal refluxflatulence, disease, reflux gastritis, retroperitonealabdominal pain, fibrosis, gastrointestinal disorder, analdysphagia, haemorrhage, haemorrhoids, salivaryabdominal hypersecretion, retching, salivary glanddiscomfort, disorder, cheilitis, aerophagia,dyspepsia, dry eructation, glossodynia, oral pain, teethmouth brittle

Hepatobiliary Hyperbilirubin-aem Liver function test abnormal, gamma Acute hepaticdisorders ia, alanine glutamyltransferase increased failureaminotransferaseincreased, aspartateaminotransferaseincreased

Skin and Palmar-plantar Exfoliative rash, skin exfoliation, Toxic epidermalsubcutaneous erythrodysaesthesia necrolytic migratory erythema, blood necrolysis,tissue disorders syndrome, rash, blister, dermatitis allergic, skin reaction, Stevens-Johnsonskin dermatitis acneiform, erythema, syndrome,hyperpigmentation, increased tendency to bruise, purpura, photosensitivitydry skin, pruritus, hyperhidrosis, night sweats, nail atrophy, reaction, nailalopecia, pigmentation disorder, skin disorderdiscoloration, hypertrichosis

Musculoskeleta Musculoskeletal Muscle spasms, arthralgia, pain in Rhabdomyolysisl and pain extremity, back pain, neck pain, boneconnective pain, joint swelling, limb discomfort,tissue disorders muscle tightness, muscular weakness

System Organ Very Common Uncommon Rare/Very

Classa common rare

Renal and Renal failure, blood Toxic nephropathy, oligouria,urinary creatinine haematuria, renal impairment,disorders increased, pollakiuria, blood creatine increased,glomerular blood creatinine decreasedfiltration ratedecreased, bloodurea increased

Reproductive Erectile dysfunction, breast tenderness,system and nipple painbreast disorders

General Fatigue. Mucosal Multi-organ failure, performance statusdisorders and asthenia inflammation, decreased, pain, oedema, chest pain,administration pyrexia, weight chest discomfort, generalized oedema,site conditions decreased, face oedema, local swelling, localizedperipheral oedema, oedema, weight increased, early satiety,chills feeling cold, injection site reaction,malaise

Injury, Contusion, medication errorpoisoning andproceduralcomplicationsa Adverse reactions in the Investigations system organ class (SOC) have been reallocated to clinically appropriate SOCsrelated to their target organ.

Different MedDRA preferred terms that were considered clinically similar have been grouped into a single term.b incl corneal epithelium defect, corneal erosion, corneal lesion, corneal opacity, corneal perforation, keratitis, punctatekeratitis, ulcerative keratitis, limbal stem cell deficiency, visual acuity reduced, visual impairment, vision blurred.

Other clinical studies with Teysuno in combination with cisplatin

Although studies of Teysuno in combination with cisplatin that were conducted in Japan utilised dosesand dosing schedules that differed from this regimen, the safety profile from these studies was similar,with the most common toxicities being haematologic, gastrointestinal, fatigue, and anorexia.

Post-marketing surveillance experience in gastric cancer patients

The safety profile of Teysuno in a post-marketing safety surveillance study in Japan of 4,177 patientstreated with Teysuno for advanced gastric cancer was generally similar to that seen with this regimenand in the Japanese registration studies (i.e., major toxicities were leukocytopaenia, anorexia, andnausea/vomiting).

Safety of Teysuno in patients with metastatic colorectal cancer for whom it is not possible tocontinue treatment with another fluoropyrimidine due to hand-foot syndrome or cardiovasculartoxicity

In a subgroup of 53 mCRC patients, within a cohort study of 200 patients with different solid tumours,the majority of these mCRC patients (92%) who developed cardiotoxicity while on capecitabine- or 5-FU-based chemotherapy could safely switch to S-1 and continue treatment, with recurrent cardiotoxicity(grade 1) seen in 8%. Other adverse events during S-1 treatment in this subgroup included grade 3-4haematologic toxicity in 8% and grade 2-4 non-haematologic adverse events in 36% (neuropathy 15%,infection 7%, thromboembolic event 6%, diarrhoea 4%, nausea 2%, hand-foot syndrome 2%).

In a retrospective cohort study of 47 metastatic colorectal cancer patients from the Dutch colorectal cancerregistry (PLCRC) switching to S-1 due to capecitabine-induced hand-foot syndrome (n=36) orcardiotoxicity (n=10) the severity of HFS decreased or completely resolved during treatment with S-1 andno case of recurrence of cardiac toxicity was reported in any of the 10 patients that switched to S-1 due tocardiac adverse events.

Ocular toxicity

Terms for treatment-related ocular toxicities have been combined as follows. The only Grade 3 orhigher adverse reaction was reduced visual acuity.

* Vision disorder includes adverse reactions of blurred vision, diplopia, photopsia, reduced visualacuity, and blindness;

* Lacrimal disorder includes adverse reactions of increased lacrimation, dry eye, and acquireddacryostenosis;

* Eye disorder includes adverse reactions of eye pruritus, ocular hyperaemia, eye irritation, eyedisorder, and foreign body sensation in eyes.

Neuropathy

Central and peripheral neuropathy has been reported in patients treated with Teysuno in combinationwith cisplatin. The term peripheral neuropathy includes the following reported adverse reactions:peripheral sensory neuropathy, paraesthesia, hypoaesthesia, peripheral neuropathy, polyneuropathy,neurotoxicity, and dysaesthesia.

Elderly (see section 4.2)

Comparison of safety between 71 patients ≥70 years old (elderly) and 450 patients <70 years oldtreated with Teysuno in combination with cisplatin in the FLAGS study demonstrated that theincidence of all Grade 3 or higher adverse reactions (62% vs 52%), all serious adverse reactions (30%vs 19%), and the rate of premature withdrawal due to adverse reactions from both Teysuno andcisplatin (21% vs 12%) appeared to be higher among patients ≥70 years old. A populationpharmacokinetics analysis demonstrated that 5-FU exposure also tended to increase with age, but theextent of the increase was within the range of individual variability. These changes with age wererelated to changes in renal function as measured by creatinine clearance (see section 5.2).

There were no clinically relevant differences in safety between males (N=382) and females (N=139) inthe FLAGS study.

Patients with renal impairment (see sections 4.2, pct. 4.3, pct. 4.4, and 5.2)

Comparison of 218 patients with mild renal impairment at baseline (CrCl 51 to 80 ml/min) to297 patients with normal renal function at baseline (CrCl >80 ml/min) treated with Teysuno incombination with cisplatin in the FLAGS study indicated that there were no clinically significantdifferences in safety between patients with mild renal impairment and patients with normal renalfunction.

In a study performed in patients with renal impairment, the most common adverse reactions reportedover all cycles across all cohorts were diarrhoea (57.6%), nausea (42.4%), vomiting (36.4%), fatigue(33.3%) and anaemia (24.2%). In this study, 7 patients with moderate renal impairment were treatedwith 20 mg/m2 Teysuno twice daily, while 7 patients with severe renal impairment received Teysuno20 mg/m2 once daily. No dose limiting toxicities were observed in Cycle 1 in patients with moderateor severe renal impairment. The incidence of blood and lymphatic systems disorders adverse reactionsobserved across all cycles in the moderate and severe renal impairment patients were 28.6% and44.4%, respectively. The dose for one patient in the severe cohort was reduced to 13.2 mg/m2 oncedaily at the start of Cycle 12 due to an adverse reaction (Grade 2 diarrhoea) in Cycle 11.

No studies have been performed with Teysuno alone or in combination with cisplatin in paediatricpatients.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

The highest single dose of Teysuno taken was 1400 mg; this patient developed leukopenia (Grade 3).

Manifestations of acute overdose reported include nausea, vomiting, diarrhoea, mucositis,gastrointestinal irritation, bleeding, bone marrow depression, and respiratory failure. Medicalmanagement of overdose should include customary therapeutic and supportive medical interventionsaimed at correcting the presenting clinical manifestations and preventing their possible complications.

There is no known antidote available in case of overdose.

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, ATC code: L01BC53.

Teysuno is an oral fluoropyrimidine anti-cancer medicinal product. It is a fixed dose combination ofthree active substances, tegafur, which after absorption is converted into the anti-cancer substance5-FU; gimeracil, a dihydropyrimidine dehydrogenase (DPD) inhibitor to prevent degradation of 5-FUby the body; and, oteracil, an orotate phosphoribosyltransferase (OPRT) inhibitor that decreases theactivity of 5-FU in normal gastrointestinal mucosa. The combination of tegafur, gimeracil, andoteracil was set at 1:0.4:1 molar ratio as optimum in order to maintain 5-FU exposure and thus sustainanti-tumour activity while reducing toxicity associated with 5-FU alone.

Tegafur is a prodrug of 5-FU with good oral bioavailability. Following oral administration, tegafur isgradually converted to 5-FU in vivo, mainly by CYP2A6 enzyme activity in the liver. 5-FU ismetabolised by the liver enzyme DPD. 5-FU is activated within cells by phosphorylation to its activemetabolite, 5-fluoro-deoxyuridine-monophosphate (FdUMP). FdUMP and reduced folate are boundto thymidylate synthase leading to formation of a ternary complex which inhibits DNA synthesis. Inaddition, 5-fluorouridine-triphosphate (FUTP) is incorporated into RNA causing disruption of RNAfunctions.

Gimeracil inhibits the metabolism of 5-FU by reversibly and selectively inhibiting DPD, the primarymetabolic enzyme for 5-FU, so that higher plasma concentrations of 5-FU are achieved with theadministration of a lower dose of tegafur.

After oral administration, oteracil was distributed at high concentrations in normal gastrointestinaltract tissues while considerably lower concentrations were seen in blood and tumour tissue in animalstudies.

In a dose escalation study comparing the tolerability of 5-FU in Teysuno and tegafur + gimeracil (nooteracil), the 25 mg/m2 dose level could not be attained in the absence of oteracil due to the occurrenceof dose limiting toxicities (Grade 3 diarrhoea in 2 patients, and cardio-respiratory arrest in 1 patient) inthe tegafur+gimeracil arm. The 5-FU pharmacokinetic profile was similar in the presence and absenceof oteracil.

Mean 5-FU maximum plasma concentration (Cmax) and area under the concentration-time curve(AUC) values were approximately 3-fold higher after Teysuno administration than after administrationof tegafur alone, despite a 16-fold lower Teysuno dose (50 mg of tegafur) compared to tegafur alone(800 mg), and are attributed to inhibition of DPD by gimeracil. Maximum plasma uracil concentrationwas observed at 4 hours, with a return to baseline levels within approximately 48 hours after dosing,indicating the reversibility of the DPD inhibition by gimeracil.

A study of the effect of Teysuno on cardiac repolarisation conducted in advanced cancer patients metthe definition for a negative study according to International Conference on Harmonisation (ICH)guidelines. No consistent relationship was seen between absolute QTcF interval values or changefrom Baseline values and maximum plasma concentration of Teysuno components.

A Phase I study established the current regimen by evaluating cohorts of Teysuno and cisplatin of30 mg/m2 and 60 mg/m2 (dose-limiting toxicities [DLTs] seen were fatigue, and diarrhoea anddehydration); 25 mg/m2 and 60 mg/m2; and 25 mg/m2 and 75 mg/m2. Despite the lack of DLTs in thelast cohort, the dose of cisplatin was not elevated beyond 75 mg/m2.

In the Phase III FLAGS study, there was no apparent relationship between 5-FU AUC(Teysuno/cisplatin arm) and 5-FU concentration (5-FU/cisplatin arm) during Cycle 1 and efficacyoutcomes of overall survival (OS) or progression-free survival (PFS).

In the Phase III FLAGS study, there was no apparent relationship between 5-FU AUC(Teysuno/cisplatin arm) and 5-FU concentration (5-FU/cisplatin arm) during Cycle 1 and efficacyoutcomes of overall survival (OS) or progression-free survival (PFS).

A Phase I study was conducted to evaluate the PK of the components of Teysuno and their metabolitesin cancer patients with impaired renal function compared to those with normal renal function. In thisstudy, antitumor activity was measured by best overall tumour response. The majority (70.4%) ofpatients had Stable Disease as a best response (based on Investigator’s assessment using RECISTcriteria) and 29.6% patients had Progressive Disease as their best overall response. No dose limitingtoxicities were observed in the first cycle of treatment.

Advanced gastric cancer

Data from a multicentre, multinational (excluding Asia), randomised, controlled, open-label Phase IIIclinical study (FLAGS) support the use of Teysuno in combination with cisplatin for the treatment ofpatients with advanced gastric cancer. In this study, 521 patients were randomised to treatment with

Teysuno (25 mg/m2 orally twice daily for 21 days followed by a 7-day rest period) and cisplatin(75 mg/m2 intravenous infusion once every 4 weeks); and 508 patients were randomised to treatmentwith 5-FU (1000 mg/m2/24 hours as a continuous intravenous infusion on Days 1 through 5 repeatedevery 4 weeks) and cisplatin (100 mg/m2 as an intravenous infusion on Day 1 repeated every 4 weeks).

Patient characteristics are provided in Table 10.

Table 10: Demographics and baseline characteristics of patients in the FLAGS study

Teysuno + Cisplatin 75 mg/m2 5-FU + Cisplatin 100 mg/m2(N=521) (N=508)

Gender, n (%)

Male 382 (73) 347 (68)

Female 139 (27) 161 (32)

Age, years

Median (Range) 59 (18-83) 60 (20-85)≥65, n (%) 160 (31) 164 (32)

Race, n (%)

White 447 (86) 438 (86)

Black or African American 5 (1.0) 7 (1.4)

Asian 4 (0.8) 4 (0.8)

American Indian or Alaska Native 4 (0.8) 6 (1.2)

Other 61 (12) 53 (10)

ECOG Performance Status, n (%)0 226 (43) 200 (39)1 295 (57) 308 (61)

Location of primary lesion, n (%)

Stomach 438 (84) 417 (82)

Gastro-oesophageal junction 82 (16) 88 (17)

Both 1 (0.2) 3 (0.6)

Metastatic disease, n (%) 497 (95) 488 (96)≥2 metastatic sites 340 (65) 327 (64)

For the primary endpoint of overall survival, Teysuno in combination with cisplatin was non-inferiorto 5-FU in combination with cisplatin (see Table 11). At the time of primary analysis, the medianfollow-up for overall survival in the full analysis set was 18.3 months.

Table 11: Overall survival and progression-free survival in FLAGS

Teysuno + Cisplatin 5-FU + Cisplatin

Endpoint Median [95% CI]. Median [95% CI], Hazard Ratio

Population N months N months [95% CI]

Overall Survival

Intent-to-treat 527 8.5 [7.9, 9.3] 526 7.9 [7.2, 8.5] 0.94 [0.82, 1.07]

Full analysis set 521 8.6 [7.9, 9.5] 508 7.9 [7.2, 8.5] 0.92 [0.80, 1.05]

Progression-free Survival

Full analysis set 521 4.8 508 5.5 [4.4, 5.8] 0.99 [0.86, 1.14][4.0, 5.5]

CI = confidence interval; Full analysis set = all randomised, treated patients analysed as allocated (primary analysispopulation)

The European Medicines Agency has waived the obligation to submit the results of studies with

Teysuno in all subsets of the paediatric population in gastric adenocarcinoma (see section 4.2 forinformation on paediatric use).

Metastatic colorectal cancer after switch to Teysuno when it was not possible to continue treatmentwith another fluoropyrimidine due to hand-foot syndrome or cardiovascular toxicity.

Within a European cohort study of 200 patients who were switched from 5-FU or capecitabine basedtherapy because of cardiotoxicity to continue with Teysuno based therapy, there is a subgroup ofmetastatic colorectal cancer patients (n=53). In this mCRC subgroup, the majority of patients (92%)were able to safely switch to Teysuno and continue treatment irrespective of the treatment combinations,with recurrent cardiotoxicity seen in 8% (all grade 1). With this switch, 100% of the patients were ableto complete their planned chemotherapy. In addition, for the CRC patients with metastatic disease, themedian overall survival was 26 months (95% CI 22-31), with a 5-year survival rates of 12%.

In a retrospective cohort study of 47 metastatic colorectal cancer patients from the Dutch colorectalcancer registry (PLCRC) switching to S-1 due to capecitabine-induced hand-foot syndrome (n=36) orcardiotoxicity (n=10), the median time from initiation of treatment with capecitabine to first documentedprogression of disease after initiation of treatment with S-1 was 414 days (95% confidence interval 332-568 days).

The single and multiple dose pharmacokinetics (PK) of Teysuno in combination with cisplatin wereevaluated in three studies. Eighteen additional PK studies were performed using the relevant regimenas monotherapy. All studies were performed in cancer patients.

After administration of a single dose of 50 mg Teysuno (expressed as tegafur content) in man(approximately 30 mg/m2 based on body surface area of 1.56 to 2.10 m2 for a typical patient; N=14),the median Tmax for Teysuno components tegafur, gimeracil, and oteracil was 0.5, 1.0, and 2.0 hours,respectively, and the mean ± standard deviation (SD) AUC0-inf and Cmax was 14595 ± 4340 ng.hr/mland 1762 ± 279 ng/ml for tegafur, 1884 ± 640 ng.hr/ml and 452 ± 102 ng/ml for gimeracil,556 ± 281 ng.hr/ml and 112 ± 52 ng/ml for oteracil. The median Tmax for 5-FU was 2.0 hours and themean AUC0-inf and Cmax was 842 ± 252 ng.hr/ml and 174 ± 58 ng/ml. Levels of tegafur, gimeracil,oteracil and 5-FU were quantifiable through 10 hours postdose. After administration of 30 mg/m2doses, steady-state conditions are reached for tegafur, gimeracil, and oteracil at the latest by Day 8.

After multiple dose administration (30 mg/m2, expressed as tegafur content, twice daily for 14 days;

N=10), the median Tmax of tegafur, gimeracil, and oteracil was 0.8, 1.0, and 2.0 hours, respectively,and the corresponding mean ± SD AUC(0-12h) and Cmax was 19967 ± 6027 ng.hr/ml and2970 ± 852 ng/ml for tegafur, 1483 ± 527 ng.hr/ml and 305 ± 116 ng/ml for gimeracil, and692 ± 529 ng.hr/ml and 122 ± 82 ng/ml for oteracil. The median Tmax for 5-FU was 2.0 hours and themean AUC(0-12h) and Cmax was 870 ± 405 ng.hr/ml and 165 ± 62 ng/ml, respectively.

Administration of Teysuno under fed conditions resulted in decreased AUC0-inf for oteracil ofapproximately 71% and gimeracil of approximately 25% relative to fasting administration.

Concomitant administration of a proton pump inhibitor (PPI) reduced the effect of food on thepharmacokinetic profile of oteracil, but not by a sufficient margin to completely negate the food effect.

There was a 15% decrease in AUC0-inf for 5-FU under fed versus fasting conditions, and tegafurexposure was not altered by food (thus demonstrating absence of a food effect).

Mean AUC0-inf and Cmax for 5-FU were approximately 3-fold greater following administration of

Teysuno (50 mg expressed as tegafur content) than following administration of tegafur alone(800 mg), while AUC0-inf and Cmax values for the 5-FU metabolite α-fluoro-β-alanine (FBAL) wereapproximately 15- to 22-fold lower following administration of Teysuno than following administrationof tegafur.

The oteracil component of Teysuno did not affect the pharmacokinetic profiles of 5-FU, tegafur,gimeracil, FBAL, or uracil. The gimeracil component did not affect the pharmacokinetic profile oftegafur.

Oteracil, gimeracil, 5-FU, and tegafur were 8.4%, 32.2%, 18.4%, and 52.3% protein bound,respectively. The protein binding in human serum was not concentration-dependent over a range of0.1 to 1.0 µg/ml for oteracil, gimeracil, and 5-FU and 1.2 to 11.8 µg/ml for tegafur.

There are no clinical data on the distribution of radiolabeled components of Teysuno. Although nointravenous data are available for Teysuno in humans, the volume of distribution could be roughlyestimated from the apparent volume of distribution and urinary excretion data as 16 l/m2, 17 l/m2, and23 l/m2 for tegafur, gimeracil and oteracil, respectively.

The main metabolic pathway for tegafur is through conversion to 5-FU via CYP2A6 in the liver,whereas gimeracil was stable in human liver homogenate (S9 fraction) with adenosine 3’-phosphate5'-phosphosulfphate lithium salt (PAPS; a co-factor for sulfotransferase) or nicotinamide adeninedinucleotide phosphate (NADPH). Based on the results of in vitro studies, a part of oteracil isnon-enzymatically degraded to 5-azauracil (5-AZU) by gastric fluid, and is then converted to cyanuricacid (CA) in the digestive tract. 5-AZU and CA do not inhibit OPRT enzyme activity. Only a smallamount of oteracil is metabolised in the liver because of its low permeability.

In vitro evaluation using human liver microsomes indicated that neither tegafur, gimeracil nor oteracilshowed any relevant inhibitory effects on enzyme activities of the cytochrome P450 isoforms tested(i.e., CYP1A1/2, CYP2A6, CYP2C8/9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4).

In vitro evaluation using primary cultures of human hepatocytes indicated that tegafur (0.7-70 µM),gimeracil (0.2-25 µM) and oteracil (0.04-4 µM) had little or no inductive effect on CYP1A2, CYP2B6or CYP3A4/5 metabolic activities.

Using plasma uracil concentrations to assess DPD activity in clinical studies, no marked changes inplasma uracil concentrations were observed after administration of a single 800 mg dose of tegafurwhile plasma uracil concentrations increased markedly after administration of a single 50 mg dose of

Teysuno (reflecting DPD inhibition by gimeracil). Following both single dose (50 mg) and multipledose (30 mg/m2 twice daily) administration of Teysuno in man, maximum uracil concentrationsreflecting DPD inhibition were observed approximately 4 hours postdose. Similar inhibition was seenfollowing single and multiple dosing. The plasma concentrations of uracil returned to baseline levelsapproximately 48 hours after dosing indicating reversibility of DPD inhibition by gimeracil.

In man, the apparent terminal elimination half-life (T1/2) of 5-FU observed after administration of

Teysuno (containing tegafur, a 5-FU prodrug) was longer (approximately 1.6 - 1.9 hours) than thatpreviously reported after intravenous administration of 5-FU (10 to 20 minutes). Following a singledose of Teysuno, T1/2 values ranged from 6.7 to 11.3 hours for tegafur, from 3.1 to 4.1 hours forgimeracil, and from 1.8 to 9.5 hours for oteracil.

Following a single dose of Teysuno, approximately 3.8% to 4.2% of administered tegafur, 65% to72% of administered gimeracil, and 3.5% to 3.9% of administered oteracil were excreted unchanged inthe urine. Among the metabolites, 9.5% to 9.7% of the administered tegafur was excreted in the urineas 5-FU and approximately 70% to 77% as FBAL, accounting for approximately 83% to 91% of theadministered Teysuno dose (total tegafur + 5-FU + FBAL). There was no effect of gimeracil on renalclearance of tegafur, FBAL, and 5-FU following administration of Teysuno as compared to theirclearance following administration of tegafur alone.

In a Japanese Phase I study that utilized 5 dose groups with doses ranging from 25 to 200 mg/body,there was a dose-proportional increase in exposure for tegafur, gimeracil and oteracil. However, theincrease in 5-FU exposure tended to be greater than proportional to the increasing tegafur dose.

A population PK analysis of Teysuno components and metabolites assessed the influence of variousfactors, including gender, age, food, ethnicity (Caucasian vs Asian), renal function, and hepaticfunction in 315 patients. Renal function, as reflected by creatinine clearance, was the primary factorthat influenced gimeracil exposure and 5-FU exposure. As renal function decreased, there was anincrease in 5-FU steady state exposure. This analysis also demonstrated that the trend in changes in

Teysuno pharmacokinetics observed with increasing age was related to change in renal function asmeasured by creatinine clearance.

In a Phase I Teysuno monotherapy study that investigated the pharmacokinetics of components andmetabolites in patients with normal and impaired renal function, patients with mild renal impairment(CrCl 51 to 80 ml/min) receiving the same monotherapy dose of 30 mg/m2 twice daily (the maximumtolerated dose for monotherapy) as patients with normal renal function (CrCl >80 ml/min) had anincrease in mean 5-FU AUC0-inf relative to that of the normal patients. Patients with moderate renalimpairment (CrCl 30 to 50 ml/min) who received a reduced dose of 20 mg/m2 twice daily showed nosignificant increase in mean 5-FU AUC0-inf relative to that of the normal group. The increase in 5-FUexposure in patients with mild renal impairment in this study together with the results of simulation inthe population pharmacokinetic analysis suggest that a Teysuno dose of 25 mg/m2 twice daily inpatients with mild renal impairment could achieve 5-FU plasma concentrations similar to thoseobtained in patients with normal renal function receiving 30 mg/m2 twice daily as monotherapy andalso those with moderate renal impairment receiving 20 mg/m2 twice daily.

Following a reduced dose of Teysuno 20 mg/m2 administered once daily to the severe renalimpairment group (CrCl < 30 ml/min), the single-dose AUC0-inf and multiple-dose AUC0-τ values for5-FU were approximately 2-fold higher in the severe renal impairment group compared to thoseobserved in the normal renal function group receiving 30 mg/m2 twice daily. Therefore, the dailyexposure to 5-FU would be expected to be comparable in these groups, since the daily exposure inpatients in the severe renal impairment group is based on the administration of Teysuno once a day,while the daily exposure to 5-FU in the patients with normal renal function is based on theadministration of Teysuno twice daily. However, it is to be noted that the exposure to 5-FU can bevariable and unexpectedly higher in patients with severe renal impairment due to the impact offluctuations in renal function in these patients.

There were no significant differences in AUCs of 5-FU, tegafur, gimeracil, or oteracil after eithersingle or multiple dose administration of Teysuno 30 mg/m2 twice daily in patients with mild,moderate, or severe hepatic impairment compared to those with normal hepatic function. After singledose administration, there was a statistically significant decrease in 5-FU and gimeracil Cmax for thesevere hepatic impairment group relative to that of the normal group, but this difference was notobserved after multiple dose administration.

Ethnic differences

A Phase I study investigated the pharmacokinetics of Teysuno monotherapy in Asian (Chinese/Malay)and Caucasian (US) patients. Consistent with the lower CYP2A6 activity in the Asian patients,tegafur AUC0-12 was higher and T1/2 was longer in the Asian group compared to the Caucasian group.

Gimeracil and uracil AUC0-12 values were comparable between the two groups, suggesting that DPDinhibition was similar for the Asian and Caucasian groups. Exposure of 5-FU was not statisticallysignificantly different between the two groups. Oteracil AUC0-12 in the Asian group wasapproximately half that of the Caucasian group, however, this difference was not statisticallysignificant due to its large individual variability.

Studies in Japanese patients have suggested an effect of CYP2A6*4 polymorphism on Teysunopharmacokinetics. Although CYP2A6 variants are associated with pharmacokinetic variability of tegafur,the AUC of gimeracil, which is affected by renal function, is the key determinant in the pharmacokineticvariability of 5-FU. In the Phase III (FLAGS) study, tegafur AUC was significantly higher in patients withthe CYP2A6*4 allele, however, no significant difference was found for 5-FU AUC and for the incidenceof adverse reactions. Therefore, the CYP2A6 polymorphism differences between Asian and Westernpopulations do not appear to be the key determinant for differences in the MTD between populations.

However, limited data available on CYP2A6*4/*4 genotype in Japanese patients treated with Teysunosuggest significantly decreased 5-FU levels in this subpopulation. No dose advice for this subpopulationcan be provided. This CYP2A6*4 allele is uncommon in the Caucasian population.

No pharmacokinetic studies have been conducted with Teysuno in paediatric patients.

Repeat-dose toxicity studies in rats, dogs and monkeys produced changes typically associated withadministration of an anti-cancer medicinal product eliciting cytotoxic effects on populations of rapidlydividing cells, such as anaemia, decrease in the immune and digestive system function, disruption ofspermatogenesis, and atrophy in male and female reproductive organs.

Treatment with Teysuno produced various skin effects in rat (keratosis of footpad and tail) and dog(skin crusts and erosions). In addition, hyperpigmentation in the skin and eyes and corneal opacity indogs and cataracts in rats were observed following repeat dosing. These changes were reversible.

Teysuno does not appear to affect male or female fertility in the rat; however, administration at anytime after conception resulted in a range of external, visceral, and skeletal foetal abnormalities in ratand rabbit. There is therefore a high risk for developmental toxicity at clinical doses, primarily due totegafur (5-FU) and to oteracil to a lesser extent.

Teysuno was not carcinogenic in either the rat or the mouse. Teysuno was not found to be mutagenicwhen tested in the in vitro Ames assay. Teysuno was clastogenic in vitro using Chinese hamster lungcells and was weakly clastogenic in vivo in mouse bone marrow.

Lactose monohydrate

Magnesium stearate

Gelatin

Red iron oxide (E172)

Titanium dioxide (E171)

Sodium lauryl sulphate

Talc

Red iron oxide (E172)

Yellow iron oxide (E172)

Indigo carmine (E132)

Carnauba wax

Bleached shellac

Glyceryl monooleate

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

PCTFE/PVC/Al opaque blisters containing 14 capsules each. Each pack contains either 42 capsules,84 capsules or 126 capsules.

Not all pack sizes may be marketed.

Hands should be washed after handling capsules.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Nordic Group B.V.

Siriusdreef 412132 WT Hoofddorp

The Netherlands

EU/1/11/669/001

EU/1/11/669/002

EU/1/11/669/005

Date of first authorisation: 14 March 2011

Date of latest renewal: 19 November 2015

Detailed information on this medicinal product is available on the website of the European Medicines

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