Merck Serono

Changes to section 4.6 and 4.8

4.6          Pregnancy and lactation

Pregnancy: for UFT, no clinical data on exposed pregnancies are available. Uracil/tegafur is suspected to cause serious birth defects when administered during pregnancy. UFT 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 UFT, 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 UFT.

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

4.8          Undesirable effects

Unless otherwise indicated, the undesirable effect information relates to the 594 patients that have been treated with UFT/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 UFT/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 UFT/calcium folinate. Additionally, terms are (^*) when severe and clinically relevant undesirable effects, regardless of treatment attribution to UFT/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, including isolated cases)

Infections and infestations:

common: moniliasis, pharyngitis

uncommon: infection ^*, sepsis ^*

Blood and lymphatic system disorders:

very common:     myelosuppression, anaemia, thrombocytopenia, leukopenia, neutropenia

uncommon: coagulation disorder ^*, febrile neutropenia

Metabolism and nutrition disorders:

very common:     anorexia

common: dehydration ^*, cachexia ^*

Psychiatric disorders:

common: insomnia, depression, confusion ^*

Nervous system disorders:

common: taste perversion ^*, taste loss,

somnolence, dizziness,  insomnia, depression, paraesthesia, confusion^*, headache

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 discolouration, 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: peripheral oedema ^*, 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 UFT. Only those adverse reactions that are not described in the UFT plus CF clinical trial experience are noted.

Infections and infestations:

rare: leukoencephalopathy

very rare: pneumonia

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

very rare: myelodysplastic syndrome, acute myeloic leukaemia, acute promyelocytic leukaemia

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, leukoencephalopathy

very rare:  memory loss, movement disorders

including extrapyramidal symptoms and paralysis

in the extremities, speech disturbance, gait

disturbance,  disturbance of consciousness,

hypaesthesia

Cardiac disorders:

very rare: angina

Respiratory, thoracic and mediastinal disorders:

rare: interstitial pneumonia

very rare: pneumonia

Gastrointestinal disorders:

1.       NAME OF THE MEDICINAL PRODUCT

               Uftoral▼ 100 mg/224 mg hard capsules

-         are treated or have recently been treated with dihydropyrimidine dehydrogenase inhibitors such as brivudine (see 4.5)

4.4 Special warnings and …

Deletion of sentence regarding dihydropyrimidine dehydrogenase deficiency

 4.5 Interaction with other medicinal products and other forms of interaction