4.2 Posology and method of administration
TEXT ADDED AND REMOVED
For instructions on reconstitution and dilution of the product before administration, see section 6.6 Instructions for use/handling.
Adults: ‑ The dose of ‘Tomudex’ 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 ‘Tomudex’ 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 ‘Tomudex’ 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: ‑ Dosage and administration as for adults. However, ‘Tomudex’ should be used with caution in elderly patients (see section 4.4 Special warnings and precautions for use).
Children: ‑ ‘Tomudex’ 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
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|
|
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> 65 ml/min
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Full dose
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3-weekly
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55 to 65 ml/min
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75%
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4-weekly
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25 to 54 ml/min
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50%
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4-weekly
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< 25 ml/min
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No therapy
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Not applicable
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See Contraindications 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 Pharmacokinetic Properties) 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 Special warnings and special precautions for use). ‘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.
4.3 Contraindications
TEXT ADDED AND REMOVED
‘Tomudex’ 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 ‘Tomudex’ is commenced. (see section 4.6 Pregnancy and lactation).
‘Tomudex’ is contraindicated in patients with severe renal impairment.
Administration of leucovorin (folinic acid), folic acid or vitamin preparations containing these agents with ‘Tomudex’ is contraindicated (see section 4.5 Interaction with other medicinal products and other forms of interaction).
4.4 Special warnings and special precautions for use
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‘Tomudex’ 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 Posology and method of administration).
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 ‘Tomudex’.
Elderly patients are more vulnerable to the toxic effects of ‘Tomudex’. Extreme care should be taken to ensure adequate monitoring of adverse reactions especially signs of gastrointestinal toxicity (diarrhoea or mucositis).
A proportion of the ‘Tomudex’ is excreted via the faecal route, (see section 5.2 Pharmacokinetic properties) therefore, patients with mild to moderate hepatic impairment should be treated with caution.
Treatment with ‘Tomudex’ 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 ‘Tomudex’ (see also section 4.6 Pregnancy and lactation).
There is no clinical experience with extravasation. However, perivascular tolerance studies in animals did not reveal any significant irritant reaction.
‘Tomudex’ is a cytotoxic agent and should be handled according to normal procedures adopted for such agents (see section 6.6 Instructions for use/handling).
4.5 Interaction with other medicinal products and other forms of interaction
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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 ‘Tomudex’, since they may interfere with its action.
Clinical trials evaluating the use of Tomudex in combination with other antitumour therapies are currently ongoing.
‘Tomudex’ 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 antiinflammatory drugs (NSAIDS). However, a review of the clinical trial safety database did not reveal evidence of clinically significant interaction in patients treated with ‘Tomudex’ who also received concomitant NSAIDS, warfarin and other commonly prescribed drugs.
4.6 Pregnancy and lactation
TEXT ADDED AND REMOVED
Pregnancy should be avoided if either partner is receiving ‘Tomudex’. It is also recommended that conception should be avoided for at least 6 months after cessation of treatment.
‘Tomudex’ should not be used during pregnancy or in women who may become pregnant during treatment (see section 5.3 Preclinical safety data). Pregnancy should be excluded before treatment with ‘Tomudex’ is started. ‘Tomudex’ should not be given to women who are breast feeding.
Fertility studies in the rat indicate that ‘Tomudex’ can cause impairment of male fertility. Fertility returned to normal three months after dosing ceased. ‘Tomudex’ caused embryolethality and foetal abnormalities in pregnant rats.
4.8 Undesirable effects
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As with other cytotoxic drugs, ‘Tomudex’ 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 Tomudex adverse drug reactions by System Organ Class and
frequency
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System Organ Class
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Frequency
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Adverse drug reaction
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Infections & infestations
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Common
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Cellulitis
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Sepsis
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Flu-like syndrome
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Blood and lymphatic disorders
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Very Common
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Leucopenia (neutropenia in particular) a, b
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Anaemia a
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Common
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Thrombocytopenia a, b
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Metabolism and Nutrition Disorders
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Very Common
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Anorexia
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Common
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Dehydration
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Nervous system disorders
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Common
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Headache
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|
|
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Hypertonia (usually muscular cramps)
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|
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Taste perversion
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Eye disorders
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Common
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Conjunctivitis
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Gastrointestinal disorders
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Very Common
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Nausea c
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Diarrhoea d,e
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Vomiting c,e
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Constipation
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Abdominal Pain
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Common
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Stomatitis
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Dyspepsia
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Mouth ulceration
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Frequency unknown
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Gastrointestinal Bleeding f,g
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|
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Hepato-biliary disorder
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Common
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Hyperbilirubinemia
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Skin & subcutaneous tissue
disorders
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Very Common
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Rash
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Common
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Alopecia
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Pruritus
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|
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Sweating
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|
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Uncommon
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Desquamation
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Musculoskeletal, Connective
tissue & bone disorders
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Common
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Arthralgia
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General disorders and
administration site conditions
|
Very Common
|
Asthenia h
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Fever h
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Mucositis
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|
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Common
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Peripheral oedema
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|
|
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Pain
|
|
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Malaise
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Investigations
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Very Common
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AST increased i
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ALT increased i
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Common
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Weight loss
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|
|
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Alkaline phosphatase increased
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a Leucopenia (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) leucopenia (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 leucopenia (neutropenia in particular). Subsequent treatment may need to be discontinued or dose reduced according to the grade of toxicity (see Section 4.2 Posology and method of administration).
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.
4.9 Overdose
TEXT ADDED AND REMOVED
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 ‘Tomudex’ 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.
10. Date of revision of the text
DATE CHANGE
20th October 2011
