TOMUDEX (raltitrexed): Tolerability Profile
As with other cytotoxic drugs, raltitrexed may be associated with certain adverse drug reactions. These mainly include reversible effects on the haematopoietic system, liver enzymes and gastrointestinal tract. The table below presents the possible very common (≥1/10) and common (≥1/100 to <1/10) adverse drug reactions occurring with TOMUDEX treatment. For the full list of adverse events, please refer to the TOMUDEX SPC.
|System Organ Class||Very Common (≥1/10)||Common (≥1/100 to <1/10)|
|Infections and infestations||
|Blood and lymphatic disorders||
Leukopenia (neutropenia in particular) a, b
|Thrombocytopenia a, b|
|Metabolism and nutrition disorders||Anorexia||Dehydration|
|Nervous system disorders||
Hypertonia (usually muscular cramps)
Diarrhoea d, e
Vomiting c, e
|Skin & subcutaneous disorder||Rash||
|Musculoskeletal, connective tissue & bone disorders||Arthralgia|
|General disorders and administration site conditions||
AST increased g
ALT increased g
Alkaline phosphatase increased
a Leukopenia (neutropenia in particular), anaemia and thrombocytopenia, alone or in combination, are usually mild to moderate and occur in the first or second week after treatment and recover by the third week.
b Severe (WHO grade 3 and 4) leukopenia (neutropenia in particular) and thrombocytopenia of WHO grade 4 can occur and may be life-threatening or fatal especially if associated with signs of gastrointestinal toxicity.
c Nausea and vomiting are usually mild (WHO grade 1 and 2), occur usually in the first week following the administration of Tomudex, and are responsive to antiemetics.
d Diarrhoea is usually mild or moderate (WHO grade 1 and 2) and can occur at any time following the administration of Tomudex. However, severe diarrhoea (WHO grade 3 and 4) can occur, and may be associated with concurrent haematological suppression especially leukopenia (neutropenia in particular). Subsequent treatment may need to be discontinued or dose reduced according to the grade of toxicity.
e Diarrhoea and vomiting may be severe and if untreated may proceed to dehydration, hypovolaemia and renal impairment
f Asthenia and fever were usually mild to moderate following the first week of administration of Tomudex and reversible. Severe asthenia can occur and may be associated with malaise and a flu-like syndrome.
g Increases in AST and ALT have usually been asymptomatic and self-limiting when not associated with progression of the underlying malignancy.
- Hypersensitivity to the active substance or to any of the excipients.
- Raltitrexed should not be used in pregnant women, in women who may become pregnant during treatment or women who are breast feeding. Pregnancy should be excluded before treatment with raltitrexed is commenced.
- Raltitrexed is contraindicated in patients with severe renal impairment (creatinine clearance < 25ml/min).
- Administration of leucovorin (folinic acid), folic acid or vitamin preparations containing these agents with raltitrexed is contraindicated.
Special Warnings and Precautions for Use1
- Raltitrexed must only given by or under the supervision of a physician who is experienced in cancer chemotherapy, and in the management of chemotherapy-related toxicity. Patients undergoing therapy should be subject to appropriate supervision so that signs of possible toxic effects or adverse reactions (particularly diarrhoea) may be detected and treated promptly.
- In common with other cytotoxic agents of this type, caution is necessary in patients with depressed bone marrow function, poor general condition, or prior radiotherapy.
- Patients whose disease progressed on previous treatment for advanced disease with 5-fluorouracil based regimens may also be resistant to the effects of raltitrexed.
- Elderly patients are more vulnerable to the toxic effects of raltitrexed. Since renal function tends to decline with age and the plasma clearance of raltitrexed is reduced with renal function impairment, there is a potential for accumulation of raltitrexed in elderly patients. Extreme care should be taken to ensure adequate monitoring of adverse reactions especially signs of gastrointestinal toxicity (diarrhoea or mucositis) and myelosuppression (neutropenia, thrombocytopenia, infection) and dose should be reduced and /or delayed as appropriate. A proportion of the raltitrexed is excreted via the faecal route, therefore patients with mild to moderate hepatic impairment should be treated with caution.
- Treatment with raltitrexed in patients with severe hepatic impairment is not recommended.
- It is recommended that pregnancy should be avoided during treatment and for at least 6 months after cessation of treatment if either partner is receiving raltitrexed.
- There is no clinical experience with extravasation. However, perivascular tolerance studies in animals did not reveal any significant irritant reaction.
- Raltitrexed is a cytotoxic agent and should be handled according to normal procedures adopted for such agents.
- No specific clinical drug - drug interaction studies have been conducted in man.
- Leucovorin (folinic acid), folic acid or vitamin preparations containing these agents must not be given immediately prior to or during administration of raltitrexed, since they may interfere with its action.
- Clinical trials evaluating the use of raltitrexed in combination with other anti-tumour therapies are currently ongoing.
- Raltitrexed is 93% protein bound and while it has the potential to interact with similarly highly protein bound drugs, no displacement interaction with warfarin has been observed in vitro. Data suggest that active tubular secretion may contribute to the renal excretion of raltitrexed, indicating a potential interaction with other actively secreted drugs such as non-steroidal anti-inflammatory drugs (NSAIDS). However, a review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with raltitrexed who also received concomitant NSAIDS, warfarin and other commonly prescribed drugs.
- TOMUDEX® Summary of Product Characteristics