Drug Class Description

Generic Name

Drug Description

Presentation

Indications

Adult Dosage

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:

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.

Hepatic impairment: the effect of hepatic impairment on the elimination of Uftoral has not been assessed.

Child Dosage

The safety and efficacy of the Uftoral and calcium folinate combination has not been established and should not be used in these patient populations.

Elderly Dosage

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 agerelated impaired renal, hepatic or cardiac function or for concomitant medications or diseases.

Contra Indications

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.

Special Precautions

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. 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.

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. 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 fluoropyrimidinebased therapy and rare cardiac events of uncertain causality, including myocardial infarction, have been reported in patients receiving Uftoral.

Interactions

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.

In vitro, tegafur is partially metabolised by CYP2A6. 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.

Adverse Reactions

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.

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. 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%.

[MedDRA convention: very common ( 10%), common ( 1% to < 10%) or uncommon ( 0.1% to < 1%)]:

Infections and infestations:

• common: moniliasis
• uncommon: infection ^*, sepsis ^*

Blood and lymphatic system disorders:

• very common: myelosuppression, anaemia, trombocytopenia, leukopenia, neutropenia
• uncommon: coagulation disorder ^*, febrile neutropenia

Metabolism and nutrition disorders:

• common: dehydration ^* cachexia ^*

Nervous system disorders:

• common: taste perversion ^*, taste loss, somnolence, dizziness, insomnia, depression, paresthesia, confusion ^*

Eye disorders:

• common: lacrimation, conjunctivitis

Cardiac disorders:

• common: peripheral oedema ^*
• uncommon: arrhythmia ^*, congestive heart failure ^*, myocardial infarction ^*, heart arrest ^*

Vascular disorders:

• common: deep thrombophlebitis ^*
• uncommon: shock ^*

Respiratory, thoracic and mediastinal disorders:

• common: dyspnoea ^*, increased coughing, pharyngitis
• uncommon: pulmonary embolism ^*

Gastrointestinal disorders:

• very common: diarrhoea ^*, nausea ^*, stomatitis ^*, anorexia, vomiting ^*, abdominal pain ^*
• common: constipation ^*, flatulence, dyspepsia, mucositis ^*, dry mouth, eructation, anorexia ^*, intestinal obstruction ^*
• uncommon: enteritis ^*, gastritis ^*, ileitis ^*, intestinal perforation ^*

Hepato-biliary disorders:

• uncommon: hepatitis ^*, jaundice ^*, liver failure ^*

Skin and subcutaneous tissue disorders:

• common: alopecia, rash, exfoliative dermatitis, skin discoloration, pruritus, photosensitivity, sweating, dry skin, nail disorder

Musculoskeletal, connective tissue and bone disorders:

• common: myalgia, back pain ^*, arthralgia ^*

Renal and urinary disorders:

• uncommon: abnormal kidney function ^*, urinary retention ^*, haematuria ^*

Reproductive system and breast disorders:

• uncommon: impotence ^*

General disorders and administration site conditions:

• very common: asthenia ^*
• common: fever ^*, headache, malaise, chills, pain ^*
• uncommon: chest pain ^*

Investigations:

• very common: increased alkaline phosphatase, increased ALT, increased AST, increased total bilirubin ^**
• common: weight loss ^*

(^**)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:

• rare: leukoencephalopathy

Blood and lymphatic system disorders:

• very rare: haemolytic anaemia, myelodysplastic syndrome, acute myeloic leukaemia, acute promyelocytic leukaemia, agranulocytosis, pancytopenia, disseminated intravascular coagulation

Nervous system disorders:

• rare: anosmia, parosmia
• very rare: memory loss, movement disorders including extrapyramidal symptoms and paralysis in the extremities, speech disturbance, gait disturbance, disturbance of consciousness, hypoesthesia

Cardiac disorders:

• very rare: angina

Respiratory, thoracic and mediastinal disorders:

• rare: interstitial pneumonia
• ery rare: pneumonia

Gastrointestinal disorders:

• very rare: acute pancreatitis, gastro/duodenal ulcer, enterocolitis, ileus paralytic, ascites, ischemic colitis

Hepato-biliary disorders:

• •very rare: hepatic cirrhosis, fulminant hepatitis, hepatic fibrosis ^***

Skin and subcutaneous tissue disorders:

• very rare: discoid lupus erythematosus-like eruption, skin dyscrasia (including blistering, and dermatitis), urticaria, Stevens Jonhson syndrome, palmar-plantar erythrodysaesthesia

Renal and urinary disorders:

• very rare: acute renal failure, nephrotic syndrome, urinary incontinence

General disorders and administration site conditions:

• rare: fatigue
• very rare: multi-organ failure

(^***) 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.

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