Ftorafur®

For a full list of excipients, see section 6.1.

Hard capsules.

Hard gelatine capsules with yellow body and orange cap. The content - white powder.

FTORAFUR 400 mg hard capsules are indicated for the treatment of various types of neoplasms: gastric and colorectal cancer, breast cancer.

4.2 Posology and method of administration

Ftorafur 400 mg hard capsules for oral use are administered at doses 1200 mg-1600 mg daily; the dose should not exceed 2 g daily, and is divided for taking twice at 12 h intervals or 2-4 times a day. Total dose for treatment course is 30 to 40 g. If necessary, treatment course is repeated at 1.5 to 2 months intervals.  Ftorafur 400 mg can be administered also as monotherapy in smaller doses over more prolonged period of time. Ftorafur 400 mg in polychemotherapy regimens or as adjuvant to radiation treatment is used in doses equal or lower to that of monochemotherapy. In older patients Ftorafur 400 mg should be administered with caution, although oral treatment usually is tolerated well, and reduction of treatment dose rarely is necessary. The administration of Ftorafur 400 mg should be restricted to specific units, hospitals, out-patient departments and physicians with experience in administering anticancer drug treatment.

4.3 Contraindications

Ftorafur is contraindicated at terminal stages of the disease, in acute haemorrhage, severe impairment of kidneys and liver, in cases of leucopenia (<3 x 10⁹/l), thrombocytopenia (<1 x 10¹¹/l) and anaemia (level of haemoglobin <30 units), increased sensitivity to preparation. Ftorafur is contraindicated during pregnancy and lactation.

4.4  Special warnings and special precautions for use

Ftorafur administration should be done with precaution in cases of impairment of kidneys and liver functions and haematological disorders. Special precaution should be observed to patients with metabolic disturbances of glucose utilisation, and in cases of peptic ulcers with tendency to bleeding, in cases of infections.

Regular checking of blood count and liver and kidney functions is necessary. Side effects may intensify if application is prolonged.

Ftorafur should be used with special precaution in children; regular laboratory and clinical monitoring is mandatory.

The safety of administration of Ftorafur in infants has not been estimated.

Ftorafur has effect to reproduction functions of patients.

Safety usage of Ftorafur in childhood has no data available.

At the case of damage of haemopoietic organs transfusion of 100-150 ml blood should be administered 2-3 times a week. Blood count should be checked one week after treatment.

4.5  Interaction with other medicinal products and other forms of interaction

Co-administration has to avoid:

- with vaccines contain live virus.

Co-administer with caution:

- with myelodepressive drugs.

Ftorafur enhances action of phenitoine if administered simultaneously.

Incorporation of Ftorafur in polychemotherapy regimens increases not only the efficacy of treatment, but also the side effects of anticancer therapy.

Additional information. Simultaneous administration of oral anticancer prodrugs of 5FU and sorivudine (1-beta-D-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil), an antiviral drug, in patients with cancer and herpes zoster, turned out to be lethal, displaying severe symptoms of toxicity, including diarrhoea with bloody flux and marked decreases in white blood cell and platelet counts. The interaction has been shown to be due to suppression of 5FU catabolism, resulting in high levels of 5FU than normally be observed.

4.6  Pregnancy and lactation

There is no information on Ftorafur use in pregnant women. As with other cytotoxic agents Ftorafur may cause foetal harm and is contraindicated during pregnancy. Women should be advised to avoid becoming pregnant during Ftorafur treatment. If this occurs, treating physician should be informed immediately.

It is not known whether tegafur is excreted in human milk. Ftorafur is contraindicated during lactation. Breast-feeding should be discontinued for the duration of therapy.

4.7  Effects on ability to drive and use machines

As Ftorafur affects central nervous system, it is not advisable to drive and use machines while under treatment.

4.8  Undesirable effects

As with all cytotoxic agents, adverse reactions can be expected in the majority of patients.

Adverse reactions is presented according to the MedDRA system organ classes and MedDRA frequency convention: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10 000, <1/1000), very rare (<1/10 000).

Infections and infestations:

rare: symptoms of leukoencephalitis.

Blood and the lymphatic system disorders:

very common: action on haematopoiesis,

uncommon: severe leukopenia, thrombocytopenia, anaemia.

Metabolism and nutrition disorders:

common: dehydration as a result of vomiting.

Nervous system disorders:

very common: dizziness,

common: somnolence, ataxia,

rare: dysosmia.

Cardiac disorders:

common: cardiac disturbances,

rare: rest angina pectoris.

Respiratory, thoracic and mediastinal disorders:

rare: interstitial pneumonia.

Gastrointestinal disorders:

very common: nausea, vomiting, diarrhoea,  anorexia, abdominal pains, mucositis,

common: stomatitis, acute pacreatitis, inflammatory reactions in the gastrointestinal tract,

uncommon: bleeding in the gastrointestinal tract.

Hepato-biliary disorders:

common: liver dysfunction,

rare: liver damage (acute hepatitis),

very rare: allergic liver injury (hypersensitivity reactions), chronic liver failure.

Skin and subcutaneous tissue disorders:

common: alopecia, rash, dermatitis, cutaneous pigmentation, hypersensitivity reactions.

Renal and urinary disorders:

common: kidney dysfunction.

General disorders and administration site conditions:

very common: malaise

Toxic effects of Ftorafur administration are dose and schedule dependent. Dose reduction and appropriate fractionating is necessary in these cases. If adverse reactions persist, administration must be discontinued until all symptoms resolves.

Repeated administration depends on clinical situation and the decision should be taken by a specialist in medical oncology.

4.9  Overdose

There is no known antidote for Ftorafur overdose. The primary anticipated complications of overdose of Ftorafur would consist of bone marrow suppression, CNS functional disturbances, mucositis, nausea and vomiting. Treatment of Ftorafur overdosing is symptomatic.

Pharmacotherapeutic group: Cytostatic agents, ATC code: L01B C03

Ftorafur possesses an antitumor activity similar to 5-fluorouracil (5FU) and is regarded as a transport form of 5FU. It is in vivo gradually converted to 5FU by microsom fractions of the liver, thus maintaining long-term 5FU level and showing high anticancer activity. 5FU displays its antitumor effect by phosphorilation, inhibiting thymidilate synthetase, the only enzyme producing TMP in de novo synthesis, blocking the DNA synthesis. Additionally, FUMP is being incorporated into RNA, causing the disfunctioning of the latter.

5.2 Pharmacokinetic properties

Tegafur is easily and completely absorbed in gastrointestinal tract when administered orally. Active metabolites appeared in the plasma not before 0.5-1.0 hour and are found in blood at least 24 h afterwards. Maximum concentration is reached 4 to 6 h after administration, and provides constant concentration of 5FU. Food slightly reduced absorption of medicine.

5.3 Preclinical safety data

The mutagenic properties of Ftorafur were studied in vitro and in vivo at the chromosomal level. In vivo Ftorafur did not increase the incidence of aberrations in the bone marrow of hamsters, nor in retransplanted tumours sensitive to it in vitro. CA-1 reinoculated in nude mice showed an increase in aberrant metaphases, whereas the chromosomes in bone marrow cells of these mice remained intact.  Probably the mutagenic action of Ftorafur consists of the disorders in DNA replication.

Administration of Ftorafur in doses 30, 60 and 90 mg/kg in mice and rats rendered no teratogenic effect, occasionally an embryotoxic effect was registered.

Preclinical acute, subacute and chronic toxicity investigations of Ftorafur action on mice, rats, cats, rabbits and dogs showed its lower toxicity in comparison of 5FU not only regarding its lethal effects, but also in action on hemopoiesis. Administration of Ftorafur does not cause substantial pathomorphological changes in internal organs of the experimental animals.

Stearic acid.

Hard gelatine capsule

Body composition:

Quinoline yellow (E 104)

Red iron oxide (E 172)

Titanium dioxide (E 171)

Gelatine

Cap composition:

Ponceau 4 R (E 124)

Quinoline yellow (E 104)

Titanium dioxide (E 171)

Gelatine

6.2  Incompatibilities

None stated.

6.3  Shelf life

4 years.

6.4  Special precautions for storage

Do not store above 25 °C. Protect from light.

Store in the original package.

6.5  Nature and contents of container

100 hard capsules of Ftorafur 400 mg in polyethylene containers with push-fit closures.

6.6  Special precautions for disposal and other handling

No special requirements.

Expediableness: Only for prescription to special units (group II).