1 Dosing Considerations As with other cytotoxic drugs, the administration of TOMUDEX (raltitrexed) is associated with certain adverse reactions; these mainly include reversible effects on the gastrointestinal tract, haematopoietic system and liver enzymes.
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.
2 Recommended Dose and Dosage Adjustment). Pregnancy should be excluded before treatment with TOMUDEX is commenced (see 2 CONTRAINDICATIONS). 2 Recommended Dose and Dosage Adjustment The dose of TOMUDEX (raltitrexed) is calculated on the basis of body surface area.
9% sodium chloride or 5% dextrose (glucose) solution. It is recommended that the infusion be given over a 15 minute period. 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.
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 resolved completely 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. Treatment in patients with suspected drug-related rises in liver enzymes should be deferred until they show evidence of reversibility to at least WHO grade 2.
Based on the worst grade of gastrointestinal and haematological toxicity observed on the previous treatment and provided that such toxicity has resolved completely, 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 level.
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. v. hydration and bone marrow support to help neutrophil and platelet recovery thus reducing the likelihood of fatal sepsis or haemorrhage.
Based on data in animals where delayed administration of leucovorin after TOMUDEX (raltitrexed) produced earlier recovery from weight loss and some improvement to intestinal damage and recovery of neutrophil and platelet numbers, consideration should be given to the administration of leucovorin (folinic acid).
v. every 6 hours until the resolution of symptoms. Further use of TOMUDEX in such patients is not recommended. It is essential that the dose reduction scheme 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.
Geriatric Patients:
Dosage and administration as for adults. 4 Geriatrics).
PrTomudex® (raltitrexed) – Product Monograph Page 6 of 27 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.
0 mg/m2 Dosing interval > 65 mL/min Full dose 3-weekly 55 to 65 mL/min 75% 4-weekly 25 to 54 mL/min % equivalent to mL/min* 4-weekly <25 mL/min No therapy Not applicable *For example, if the creatinine clearance = 30 mL/min, 30% of the full dose should be given.
Patients with renal impairment may have an increased propensity for side-effects and should be monitored appropriately.
Hepatic Impairment:
No dosage adjustment is necessary for patients with mild (WHO grade 2) to moderate (WHO grade 3) hepatic impairment. However, given that a proportion of the drug is excreted via the faecal route (see 10 CLINICAL PHARMACOLOGY) and that these patients usually form a poor prognosis group, patients with mild (WHO grade 2) to moderate (WHO grade 3) hepatic impairment need to be treated with caution.
Treatment in patients with suspected drug -related rises in liver enzymes should be deferred until they show evidence of reversibility to at least WHO grade 2. TOMUDEX 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.
Health Canada has not authorized an indication for pediatric use. 3 Reconstitution Parenteral Products: Each vial, […]