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

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 (see section 4.2).

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 (see section 5.2), 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 (see section 4.6).

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 (see section 6.6).

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 antitumour 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.

Pregnancy

Pregnancy should be avoided if either partner is receiving raltitrexed. It is also recommended that conception should be avoided for at least 6 months after cessation of treatment.

Raltitrexed should not be used during pregnancy or in women who may become pregnant during treatment (see section 5.3). Pregnancy should be excluded before treatment with raltitrexed is started.

Breast-feeding

Raltitrexed should not be given to women who are breast-feeding.

Fertility

Fertility studies in the rat indicate that raltitrexed can cause impairment of male fertility. Fertility returned to normal three months after dosing ceased. Raltitrexed caused embryo lethality and foetal abnormalities in pregnant rats.

Raltitrexed may cause malaise or asthenia following infusion and the ability to drive/use machinery could be impaired whilst such symptoms continue.

As with other cytotoxic drugs, raltitrexed may be associated with certain adverse drug reactions. These mainly include reversible effects on the haemopoietic system, liver enzymes and gastrointestinal tract. Table 1 presents the possible adverse drug reactions occurring with Tomudex treatment.

In this section undesirable effects are defined as follows: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to ≤1/100); rare (≥1/10,000 to ≤1/1,000); very rare (≤1/10,000), not known (cannot be estimated from the available data).

Table 1. Adverse drug reactions in patients treated with Tomudex for advanced colorectal carcinoma divided by System Organ Class and frequency:

Infections & infestations

Common: Cellulitis, Sepsis, Flu-like syndrome

Blood and lymphatic disorders

Very Common: Leukopenia (neutropenia in particular)^a,b, Anaemia^a

Common: Thrombocytopenia^a,b

Metabolism and Nutrition Disorders

Very Common: Anorexia

Common: Dehydration

Nervous system disorders

Common: Headache, Hypertonia (usually muscular cramps), Taste perversion

Eye disorders

Common: Conjunctivitis

Gastrointestinal disorders

Very Common: Nausea^c, Diarrhoea^d,e, Vomiting^c,e, Constipation, Abdominal Pain

Common: Stomatitis, Dyspepsia, Mouth ulceration

Frequency unknown: Gastrointestinal Bleeding^f,g

Hepato-biliary disorder

Common: Hyperbilirubinemia

Skin & subcutaneous tissue disorders

Very Common: Rash

Common: Alopecia, Pruritus, Sweating

Uncommon: Desquamation

Musculoskeletal, Connective tissue & bone disorders

Common: Arthralgia

General disorders and administration site conditions

Very Common: Asthenia^h, Fever^h, Mucositis

Common: Peripheral oedema, Pain, Malaise

Investigations

Very Common: AST increasedⁱ, ALT increasedⁱ

Common: Weight loss, 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 (see Section 4.2).
^e Diarrhoea and vomiting may be severe and if untreated may proceed to dehydration, hypovolaemia and renal impairment
^f from spontaneous reporting
^g Gastrointestinal bleeding may be associated with mucositis and/or thrombocytopenia.
^h 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.
ⁱ Increases in AST and ALT have usually been asymptomatic and self-limiting when not associated with progression of the underlying malignancy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

In the absence of compatibility studies, this medicinal product should not be mixed with other medicinal products.