Uftoral 100 mg/224 mg hard capsules

Each capsule contains 100 mg tegafur and 224 mg uracil.

For a full list of excipients, see section 6.1.

Hard capsule.

The capsules are white, opaque and imprinted with the code TC434.

Uftoral is indicated for first-line treatment of metastatic colorectal cancer in combination with calcium folinate (see section 5.1).

Adults: the dose of Uftoral is 300 mg/m²/day tegafur and 672 mg/m²/day uracil combined with 90 mg/day oral calcium folinate, given in three divided doses (preferably every 8 hours). Calcium folinate should be taken at the same time as Uftoral. Doses should be taken at least one hour before or one hour after meals for 28 consecutive days. Subsequent cycles should start after 7 days without Uftoral/calcium folinate (i.e. 35 days per treatment cycle). The daily dose per body surface area (BSA) is presented below:

Dose modification: to manage toxicity, the following dose reduction and stopping guidelines are provided:

^† Calcium folinate dose remains unchanged, even if < 3 Uftoral capsules/day are required. If Uftoral therapy is interrupted, calcium folinate must also be stopped. When Uftoral therapy is interrupted, doses that are missed during 28 consecutive days of treatment should not be taken later.

Adolescents, children, and infants: the safety and efficacy of the Uftoral and calcium folinate combination has not been established and should not be used in these patient populations (see section 4.3).

Elderly: the elderly population has been well studied as 45% of patients studied were at least 65 years old and 26% of these were at least 75 years old. However, elderly patients should be monitored for age-related impaired renal-, hepatic- or cardiac function or for concomitant medications or diseases (see sections 4.4 and 4.8).

Renal impairment: the effect of renal impairment on the excretion of Uftoral has not been assessed. Although the primary route of elimination for Uftoral is not renal, caution should be exercised in patients with impaired renal function. These patients should be monitored closely for any emergent toxicities (see section 4.4).

Hepatic impairment: the effect of hepatic impairment on the elimination of Uftoral has not been assessed (see sections 4.3 and 4.4).

Uftoral is contraindicated in patients who:

• have a known hypersensitivity to 5-FU, tegafur, uracil, or any of the excipients;

• are pregnant or attempting to become pregnant;

• are breast feeding;

• are adolescents, children or infants;

• have severe hepatic impairment;

• present with evidence of bone marrow suppression from previous radiotherapy or antineoplastic agents;

• have a known deficiency of hepatic CYP2A6;

• have a known or suspected dihydropyrimidine dehydrogenase deficiency;

• are currently treated or have recently been treated with dihydropyrimidine dehydrogenase inhibitors (see section 4.5).

Patient compliance with oral therapy: the physician should instruct the patient on the importance of full compliance with the posology and method of administration of this medicinal product. Specific guidance on the importance of following physician recommendations for dose reductions or treatment interruptions in cases of emerging toxicities should be provided (see sections 4.2 and 4.8). Individual patient characteristics that may negatively impact on this compliance should be considered in the selection of therapy for this disease.

Patients receiving the Uftoral/calcium folinate combination should be monitored by a physician experienced in the use of cytotoxic agents and who has the facilities for regular monitoring of clinical, biochemical and haematological effects during and after administration of chemotherapy. Any emergent toxicity should be handled as described in dose modifications (see section 4.2).

The Uftoral/calcium folinate combination should be used with caution in patients with, renal or hepatic impairment, signs and symptoms of bowel obstruction and in elderly patients.

Patients treated with coumarin anticoagulants (such as warfarin) concomitantly with Uftoral should be monitored regularly for alterations in prothrombin time or International Normalised Ratio.

Patients taking phenytoin concomitantly with Uftoral should be regularly monitored for increased phenytoin plasma concentrations.

Hepatic disorders: since hepatic disorders, including fatal fulminant hepatitis, have been reported in patients receiving single agent Uftoral, appropriate testing should be performed on any patient receiving the Uftoral/calcium folinate combination who presents signs and symptoms of hepatitis, other liver disease or hepatic impairment. Liver function should be monitored during treatment in patients with mild to moderate hepatic dysfunction.

Renal insufficiency: there is no experience with the Uftoral/calcium folinate combination in patients with renal impairment. Physicians should exercise caution when Uftoral/calcium folinate is administered to such patients.

Diarrhoea: Uftoral/calcium folinate often induces diarrhoea, however, this is mild in the majority of cases. Patients with severe diarrhoea should be carefully monitored and given fluid and electrolyte replacement to avoid the potentially fatal complications of dehydration (see section 4.2). Special attention should also be paid to the requirement to withhold therapy with Uftoral/calcium folinate upon occurrence of grade 2 or worse diarrhoea.

Significant cardiac disease: caution should also be exercised in patients with a history of significant cardiac disease as myocardial ischaemia and angina have been associated with fluoropyrimidine-based therapy and rare cardiac events of uncertain causality, including myocardial infarction, have been reported in patients receiving Uftoral.

Pharmacokinetic interactions of Uftoral with other concomitantly administered medications have not been formally investigated.

Co-administration of 5-fluorouracil or its pro-drugs with medicinal products that inhibit dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the catabolism of endogenous and fluorinated pyrimidines, may lead to increased fluoropyrimidine toxicity which is potentially fatal.

Therefore, Uftoral must not be co-administered with dihydropyrimidine dehydrogenase inhibitors.

In patients treated with DPD inhibitor a time interval must be respected before administration of Uftoral to allow for recovery of enzyme activity. In patients treated with irreversible dihydropyrimidine dehydrogenase inhibitors such as brivudine, a time interval of 4 weeks and in patients treated with reversible dihydropyrimidine dehydrogenase inhibitors such as gimeracil a time interval of 7 days must be respected.

After end of treatment with Uftoral a time interval of 7 days must be respected before administration of any DPD inhibitor to allow elimination of tegafur.

Marked elevations in prothrombin time (PT) or International Normalised Ratio (INR) have been reported in patients stabilised on warfarin therapy following initiation of Uftoral therapy.

Increased phenytoin plasma concentrations resulting in symptoms of phenytoin intoxication have been reported with the concomitant use of Uftoral and phenytoin (see section 4.4).

In vitro, tegafur is partially metabolised by CYP2A6 (see section 4.3). Uftoral should be administered with caution in combination with substrates or inhibitors of this enzyme, e.g. coumarin, methoxypsoralen, clotrimazole, ketoconazole, miconazole. Neither tegafur nor uracil significantly inhibits the in vitro activity of CYP3A4 or CYP2D6. Furthermore, in vitro, tegafur is not metabolised by CYP1A1, -1A2, -2B6, -2C8, -2C9, -2C19, -2D6, -2E1, or -3A4 suggesting it is unlikely that there will be interactions with medications metabolised by these enzymes.

The absorption of Uftoral is affected by food (see section 5.2).

Pregnancy: for Uftoral, no clinical data on exposed pregnancies are available. Uracil/tegafur is suspected to cause serious birth defects when administered during pregnancy. Uftoral is therefore contraindicated (see section 4.3) in pregnancy. Contraceptive measures must be taken by both male and female patients during (and up to 3 months after) treatment. If pregnancy occurs during treatment with Uftoral, genetic counselling would be considered.

Male patients who are considering to father a child during or after treatment should seek advice regarding cryoconservation of sperm prior to treatment because of the possibility of irreversible infertility due to therapy with Uftoral.

Lactation: it is not known whether tegafur, uracil, and 5-FU are excreted in human milk following Uftoral administration. Because of the potential for serious adverse reactions in nursing infants, the use of Uftoral in lactating women is contraindicated (see section 4.3).

The Uftoral/calcium folinate combination has not been demonstrated to interfere with the ability to drive or use machines. However, as confusion has occasionally been reported (see section 4.8), patients should be advised to exercise caution.

Unless otherwise indicated, the undesirable effect information relates to the 594 patients that have been treated with Uftoral/calcium folinate combination in two Phase III trials with a median of 3 to 3.5 courses (see section 5.1).

As with all cytotoxic agents, adverse reactions can be expected in the majority of patients. Most undesirable effects observed, including diarrhoea, nausea and vomiting were reversible and rarely required permanent discontinuation of therapy, although doses were withheld or reduced in some patients (see section 4.2). The most common severe and clinically relevant adverse events, regardless of attribution to Uftoral/calcium folinate were diarrhoea (20%), nausea/vomiting (12%), abdominal pain (12%) and asthenia (9%).

Approximately 45% of these patients were 65 years of age, and about 26% of these were 75 years. No clinically relevant differences in safety were observed, although older patients tended to have a higher incidence of anaemia, diarrhoea and stomatitis/mucositis.

The following information specifies undesirable effects of any severity, reported at a frequency of 1% and attributed to Uftoral/calcium folinate. Additionally, terms are (^*) when severe and clinically relevant undesirable effects, regardless of treatment attribution to Uftoral/calcium folinate, were reported in a proportion of patients at a frequency of 0.1%.

The following definitions apply to the frequency terminology used hereafter:

Very common ( 1/10)

Common ( 1/100, < 1/10)

Uncommon ( 1/1,000, < 1/100)

Rare ( 1/10,000, < 1/1,000)

Very rare (< 1/10,000,)

Infections and infestations:

Blood and lymphatic system disorders:

Metabolism and nutrition disorders:

Psychiatric disorders:

Nervous system disorders:

Eye disorders:

Cardiac disorders:

Vascular disorders:

Respiratory, thoracic and mediastinal disorders:

Gastrointestinal disorders:

Hepato-biliary disorders:

Skin and subcutaneous tissue disorders:

Musculoskeletal, connective tissue and bone disorders:

Renal and urinary disorders:

Reproductive system and breast disorders:

General disorders and administration site conditions:

Investigations:

(^**) Hyperbilirubinaemia was reported approximately twice as often when compared with the bolus 5-FU/calcium folinate control arm. When reported, it was usually isolated, reversible and not associated with an adverse clinical outcome.

After marketing the following additional adverse reactions, have been reported for single-agent Uftoral. Only those adverse reactions that are not described in the Uftoral plus CF clinical trial experience are noted.

Infections and infestations:

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

Blood and lymphatic system disorders:

Nervous system disorders:

Cardiac disorders:

Respiratory, thoracic and mediastinal disorders:

Gastrointestinal disorders:

Hepato-biliary disorders:

Skin and subcutaneous tissue disorders:

Renal and urinary disorders:

General disorders and administration site conditions:

(^***) Very rare cases of mild to moderate hepatic fibrosis without elevation of serum transaminase levels have been reported in patients with elevated serum 7S collagen and PIIINP levels receiving Uftoral alone.

In case of overdosing, the frequency and severity of undesirable effects can increase, leading to possibly fatal conditions. Anticipated manifestations include nausea, vomiting, diarrhoea, gastrointestinal ulceration, bleeding, and bone marrow suppression (thrombocytopenia, leukopenia, and agranulocytosis). No specific antidote is available; supportive care should be provided.

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, pyrimidine analogues. ATC code: L01B C53.

Uftoral, an orally administered dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine, is a fixed molar ratio (1:4) of tegafur and uracil. Uracil is a competitive inhibitor of 5-FU degradation.

The combined individual activities of uracil and calcium folinate give rise to dual biomodulation:

• Tegafur is an oral prodrug of 5-FU and uracil reversibly inhibits DPD, the primary catabolic enzyme for 5-FU, and

• Calcium folinate enhances the cytotoxicity of 5-FU via one of its intracellular metabolites, 5,10-methylenetetrahydrofolate.

5-FU undergoes intracellular activation into its active metabolites, 5-fluoro-deoxyuridine-monophosphate (FdUMP) and 5-fluorouridine-triphosphate (FUTP). FdUMP inhibits DNA synthesis by forming inhibitory tertiary complexes with thymidylate synthetase (TS) and reduced intracellular folates. FUTP is integrated into cellular RNA, causing disruption of RNA function. Following competitive inhibition of DPD by uracil, tegafur-derived plasma concentrations of 5-FU are elevated.

The efficacy of the Uftoral/calcium folinate combination in metastatic colorectal carcinoma has been established in 2 randomised and comparative phase III trials vs. the Mayo regimen (IV 5-FU [425 mg/m²/day] and calcium folinate [20 mg/m²/day]) administered for 5 days every 4 weeks (study-011) or every 5 weeks (study-012).

In study -011 (n= 816), there was no statistically significant difference in the primary endpoint of survival between the two treatment arms. The median survival time was 12.4 months (95% CI: 11.2-13.6 months) and 13.4 months (95% CI: 11.6-15.4 months) in the Uftoral/calcium folinate and the 5FU/calcium folinate treatment groups, respectively. The hazard ratio for 5-FU/calcium folinate over Uftoral/calcium folinate was 0.96 (95% CI: 0.83-1.13). The assessment of the secondary endpoint of time to progression in this study was complicated by the difference in cycle duration between the two treatment arms. The median time to progression was 3.5 months (95% CI: 3.0-4.4 months) and 3.8 months (95% CI: 3.6-5.0 months) in the Uftoral/calcium folinate and 5-FU/calcium folinate treatment groups, respectively (p= 0.01).

In study -012 (n= 380), there was no statistically significant difference in the primary endpoint of time to progression nor in the secondary endpoint of survival between the two treatment arms. The median time to progression was 3.4 months (95% CI: 2.6-3.8 months) and 3.3 months (95% CI: 2.5-3.7 months) in the Uftoral/calcium folinate and 5-FU/calcium folinate treatment groups, respectively. The median survival time was 12.2 months (95% CI: 10.4-13.8 months) and 10.3 months (95% CI: 8.2-13.0 months) in the Uftoral/calcium folinate and 5-FU/calcium folinate treatment groups, respectively. The hazard ratio for 5-FU/calcium folinate over Uftoral/calcium folinate was 1.14 (95% CI: 0.92-1.42).

In the first-line treatment of metastatic colorectal carcinoma, combinations of novel agents with 5-FU have been authorised. However, the use of Uftoral in combination with novel agents is still under investigation.

The single dose and steady-state plasma pharmacokinetics of oral Uftoral have been evaluated in patients with colorectal cancer.

Absorption

Following Uftoral administration, tegafur and uracil are rapidly absorbed. C_max of tegafur, uracil, and 5-FU were achieved within 1 to 2 hours. Concurrent administration of oral calcium folinate with Uftoral did not significantly alter the plasma pharmacokinetics of tegafur, uracil, or 5-FU. Similarly, Uftoral did not affect the absorption of oral calcium folinate. Following a high-fat meal, plasma AUC for uracil and 5-FU were 66% and 37% lower, respectively, compared with Uftoral under fasting conditions. Plasma tegafur AUC was not significantly altered. C_max was reduced and delayed for tegafur, uracil, and 5-FU.

Distribution

Following oral administration of Uftoral, plasma concentrations over time for Uftoral and uracil generally display monoexponential absorption and elimination processes. The mean apparent oral volume of distribution for tegafur and uracil following Uftoral dosing at steady state are 59 and 474 L, respectively. Serum protein binding is 52% for tegafur but negligible for uracil.

Metabolism

Conversion of tegafur to 5-FU occurs via C-5' oxidation (microsomal enzymes) and C-2' hydrolysis (cytosolic enzymes). Microsomal oxidation of tegafur is partially mediated by CYP2A6. The cytosolic enzymes responsible for the metabolism of tegafur are not known. Other metabolic products of tegafur include 3'-hydroxy tegafur, 4'-hydroxy tegafur, and dihydro tegafur which are all significantly less cytotoxic than 5-FU. The metabolism of 5-FU formed from tegafur follows the intrinsic de novo pathways for the naturally occurring pyrimidine, uracil.

Neither tegafur, uracil or 5-FU inhibited the catalytic conversion of cDNA-derived cytochrome P450 CYP1A2, -2C9, -2C19, -2D6 and -3A4 at concentrations of at least 100 μM. This data suggests that Uftoral is unlikely to significantly alter the metabolic clearance of drugs metabolised by these routes.

Elimination

Less than 20% of tegafur is excreted intact into the urine. The terminal elimination half-lives of tegafur and uracil following Uftoral are approximately 11 hours and 20-40 minutes, respectively. The three hydroxy metabolites of tegafur are excreted in the urine. The plasma half-life for S-tegafur (10.3 hours) is 4.4 times longer relative to R-tegafur (2.4 hours).

Following Uftoral 300 mg/m²/day, in three divided doses, tegafur plasma concentrations of > 1,000 ng/ml are maintained, whereas uracil concentrations decline rapidly following C_max 5-FU plasma concentrations peak in 30 to 60 minutes at approximately 200 ng/ml, and remain detectable (> 1 ng/ml) over each 8-hour dosing interval. No significant accumulation of tegafur, uracil or 5-FU occurred over a 28-day course of Uftoral therapy.

Linearity/Non-Linearity

Following single dose Uftoral (100 to 400 mg), increases in plasma exposures (C_max and AUC) of tegafur were generally in proportion to dose. Increases in uracil and 5-FU plasma exposures were greater than in proportion to dose.

Pharmacokinetics in Special Populations

A pooled statistical analysis of single dose Uftoral (200 mg) pharmacokinetic data (C_max and AUC) from three studies (46 patients, average age 60 years, 28 male, 18 female) did not identify clinically significant associations between patient age, gender and presence of metastatic liver involvement and the pharmacokinetics of tegafur, uracil or 5-FU following single dose Uftoral. In view of the predominant reliance of hepatic processes for the metabolism and elimination of both tegafur and uracil, renal abnormalities are unlikely to have significant effect on the pharmacokinetics of Uftoral.

In rats and dogs, repeated dosing with Uftoral produces toxicity in the gastrointestinal tract, lymphoid organs, bone marrow, liver, kidney and testes. Round vacuoles, were observed histologically in the cerebrum of dogs that did not exhibit any clinical signs. With the exception of testicular changes and the vacuoles in the cerebrum of dogs, all of these findings were reversible.

Following Uftoral administration, tegafur, uracil and 5-FU are excreted in breast milk in rats. Also in rats, Uftoral showed maternal toxicity and a decrease in conception rate. Embryomortality, foetal toxicity and teratogenicity were observed in rats, mice and rabbits. Uftoral was not mutagenic in bacterial strains but did induce chromosomal aberrations in Chinese Hamster Ovary cells and was genotoxic in a rat micronucleus test. Long-term animal carcinogenicity studies have not been conducted. However, the positive mutagenicity data are indicative of a carcinogenic potential.

Low-substituted hydroxypropylcellulose, sodium laurilsulfate.

Capsule shell: gelatin and titanium dioxide (E171).

Capsule shell imprints (edible ink): titanium dioxide (E171), synthetic iron oxide red (E172), carnauba wax, shellac and glyceryl monooleate.

Not applicable.

2 years.

Do not store above 25°C.

PVC/PVDC/Aluminium blisters.

Packs of 21, 28, 35, 36, 42, 56, 70, 84, 112, 120, 140, 144 (4x36) or 168 capsules.

Not all pack sizes may be marketed.

Procedures for the proper handling and disposal of cytotoxic drugs should be followed.

Merck Serono Ltd

Bedfont Cross

Stanwell Road

Feltham

Middlesex

TW14 8NX

UK

PL 11648/0065

2000-12-15/2010-03-23

2011-04-20