TOMUDEX Powder for solution for infusion Ref.[9067] Active ingredients: Raltitrexed

Posology

Adults

The dose of raltitrexed is calculated on the basis of the body surface area. The recommended dose is 3 mg/m² given intravenously, as a single short, intravenous infusion in 50 to 250 ml of either 0.9% sodium chloride solution or 5% dextrose (glucose) solution. It is recommended that the infusion is given over a 15 minute period. Other drugs should not be mixed with raltitrexed in the same infusion container. In the absence of toxicity, treatment may be repeated every 3 weeks.

Dose escalation above 3 mg/m² is not recommended, since higher doses have been associated with an increased incidence of life-threatening or fatal toxicity.

Prior to the initiation of treatment and before each subsequent treatment a full blood count (including a differential count and platelets), liver transaminases, serum bilirubin and serum creatinine measurements should be performed.

The total white cell count should be greater than 4,000/mm³, the neutrophil count greater than 2,000/mm³ and the platelet count greater than 100,000/mm³ prior to treatment. In the event of toxicity the next scheduled dose should be withheld until signs of toxic effects regress. In particular, signs of gastrointestinal toxicity (diarrhoea or mucositis) and haematological toxicity (neutropenia or thrombocytopenia) should have completely resolved before subsequent treatment is allowed. Patients who develop signs of gastrointestinal toxicity should have their full blood counts monitored at least weekly for signs of haematological toxicity.

Based on the worst grade of gastrointestinal and haematological toxicity observed on the previous treatment and provided that such toxicity has completely resolved, the following dose reductions are recommended for subsequent treatment:

• 25% dose reduction: in patients with WHO grade 3 haematological toxicity (neutropenia or thrombocytopenia) or WHO grade 2 gastrointestinal toxicity (diarrhoea or mucositis).
• 50% dose reduction: in patients with WHO grade 4 haematological toxicity (neutropenia or thrombocytopenia) or WHO grade 3 gastrointestinal toxicity (diarrhoea or mucositis).

Once a dose reduction has been made, all subsequent doses should be given at the reduced dose.

Treatment should be discontinued in the event of any WHO grade 4 gastrointestinal toxicity (diarrhoea or mucositis) or in the event of a WHO grade 3 gastrointestinal toxicity associated with WHO grade 4 haematological toxicity. Patients with such toxicity should be managed promptly with standard supportive care measures including i.v. hydration and bone marrow support. In addition, preclinical data suggest that consideration should be given to the administration of leucovorin (folinic acid). From clinical experience with other antifolates, leucovorin may be given at a dose of 25 mg/m² i.v. every 6 hours until the resolution of symptoms. Further use of raltitrexed in such patients is not recommended.

It is essential that the dose reduction scheme should be adhered to since the potential for life threatening and fatal toxicity increases if the dose is not reduced or treatment not stopped as appropriate.

Elderly population

Dosage and administration as for adults. However, raltitrexed should be used with caution in elderly patients (see section 4.4).

Paediatric population

Raltitrexed is not recommended for use in children as safety and efficacy have not been established in this group of patients.

Renal impairment

For patients with abnormal serum creatinine, before the first or any subsequent treatment, a creatinine clearance should be performed or calculated.

For patients with a normal serum creatinine when the serum creatinine may not correlate well with the creatinine clearance due to factors such as age or weight loss, the same procedure should be followed. If creatinine clearance is ≤65 ml/min, the following dose modifications are recommended:

Dose modification in the presence of renal impairment:

See section 4.3 for use in patients with severe renal impairment.

Hepatic Impairment

No dosage adjustment is recommended for patients with mild to moderate hepatic impairment. However, given that a proportion of the drug is excreted via the faecal route, (see section 5.2) and that these patients usually form a poor prognosis group, patients with mild to moderate hepatic impairment need to be treated with caution (see section 4.4). Raltitrexed has not been studied in patients with severe hepatic impairment, clinical jaundice or decompensated liver disease and its use in such patients is not recommended.

Method of administration

Each vial, containing 2mg of raltitrexed, should be reconstituted with 4ml of sterile water for injections to produce a 0.5 mg/ml solution.

The appropriate dose of solution is diluted in 50-250 ml of either 0.9% sodium chloride or 5% glucose (dextrose) injection and administered by a short intravenous infusion over a period of 15 minutes.

There is no clinically proven antidote available. In the case of inadvertent or accidental administration of an overdose, preclinical data suggest that consideration should be given to the administration of leucovorin. From clinical experience with other antifolates leucovorin may be given at a dose of 25mg/m² i.v. every 6 hours. As the time interval between raltitrexed administration and leucovorin rescue increases, its effectiveness in counteracting toxicity may diminish.

The expected manifestations of overdose are likely to be an exaggerated form of the adverse drug reactions anticipated with the administration of the drug. Patients should, therefore, be carefully monitored for signs of gastrointestinal and haematological toxicity. Symptomatic treatment and standard supportive care measures for the management of this toxicity should be applied.

Unopened Vial: 3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/ dilution (etc) has taken place in controlled and validated aseptic conditions.

Once reconstituted, Tomudex is chemically stable for 24 hours at 25°C exposed to ambient light. For storage recommendation, see sections 6.4 and 6.6.

Unopened vial: Do not store above 25°C. Keep container in the outer carton to protect from light.

For storage conditions after reconstitution of the medical product, see section 6.3.

5 ml clear neutral type I glass vials, with a bromobutyl rubber closure and aluminium crimp seal with a plastic flip-off cover.

The vials are packed in individual cartons to protect the product from light.

There is no preservative or bacteriostatic agent present in Tomudex or the materials specified for reconstitution or dilution. Tomudex must therefore be reconstituted and diluted under aseptic conditions and it is recommended that solutions of Tomudex should be used as soon as possible. Reconstituted Tomudex solution is for single use only.

In accordance with established guidelines, when diluted in 0.9% sodium chloride or 5% glucose (dextrose) solution, it is recommended that administration of the admixed solution should commence as soon as possible after admixing. The admixed solution must be completely used or discarded within 24 hours of reconstitution of Tomudex intravenous injection.

Reconstituted and diluted solutions do not need to be protected from light.

Do not store partially used vials or admixed solutions for future patient use.

Any unused injection or reconstituted solution should be discarded in a suitable manner for cytotoxics.

Tomudex should be reconstituted for injection by trained personnel in a designated area for the reconstitution of cytotoxic agents. Cytotoxic preparations such as Tomudex should not be handled by pregnant women.

Reconstitution should normally be carried out in a partial containment facility with extraction e.g. a laminar air flow cabinet, and work surfaces should be covered with disposable plastic-backed absorbent paper.

Appropriate protective clothing, including normal surgical disposable gloves and goggles, should be worn. In case of contact with skin, immediately wash thoroughly with water. For splashes in the eyes irrigate with clean water, holding the eyelids apart, for at least 10 minutes. Seek medical attention.

Any spillages should be cleared up using standard procedures.

Waste material should be disposed of by incineration in a manner consistent with the handling of cytotoxic agents.