4.1. Therapeutic indications

The palliative treatment of advanced colorectal cancer where 5-fluorouracil and folinic acid based regimens are either not tolerated or inappropriate.

4.2. Posology and method of administration

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

Creatinine Clearance

Dose as % of 3.0 mg/m2

Dosing Interval

> 65 ml/min

Full dose

3-weekly

55 to 65 ml/min

75%

4-weekly

25 to 54 ml/min

50%

4-weekly

< 25 ml/min

No therapy

Not applicable

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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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. (see section 4.6).

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 (see section 4.5).

4.4. Special warnings and precautions for use

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).

Excipients:

Each vial contains 0.26 mg sodium. This medicine contains less than 1 mmol sodium (23 mg) per vial, that is to say essentially 'sodium-free'.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

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

System Organ Class

Frequency

Adverse drug reaction

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 increased i

ALT increased i

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.

4.9. Overdose

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.