'Tomudex'

'Tomudex' contains 2 mg raltitrexed (INN applied for) in each vial.

Powder for solution for injection.

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

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

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.

'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).

'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).

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.

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.

'Tomudex' 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, '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

_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.

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.

Raltitrexed is a folate analogue belonging to the family of anti-metabolites and has potent inhibitory activity against the enzyme thymidylate synthase (TS). Compared to other antimetabolites such as 5-Fluorouracil or methotrexate, raltitrexed acts as a direct and specific TS inhibitor. TS is a key enzyme in the de novo synthesis of thymidine triphosphate (TTP), a nucleotide required exclusively for deoxyribonucleic acid (DNA) synthesis. Inhibition of TS leads to DNA fragmentation and cell death. Raltitrexed is transported into cells via a reduced folate carrier (RFC) and is then extensively polyglutamated by the enzyme folyl polyglutamate synthetase (FPGS) to polyglutamate forms that are retained in cells and are even more potent inhibitors of TS. Raltitrexed polyglutamation enhances TS inhibitory potency and increases the duration of TS inhibition in cells which may improve antitumour activity. Polyglutamation could also contribute to increased toxicity due to drug retention in normal tissues.

In clinical trials, 'Tomudex' at the dose of 3mg/m² i.v. every 3 weeks has demonstrated clinical antitumour activity with an acceptable toxicity profile in patients with advanced colorectal cancer.

Four large clinical trials have been conducted with 'Tomudex' in advanced colorectal cancer. Of the three comparative trials, two showed no statistical difference between 'Tomudex' and the combination of 5-fluorouracil plus folinic acid for survival while one trial showed a statistically significant difference in favour of the combination of 5-fluorouracil plus folinic acid. 'Tomudex' as a single agent was as effective as the combination of 5-fluorouracil and folinic acid in terms of objective response rate in all trials.

Following intravenous administration at 3.0 mg/m², the concentration-time profile in patients was triphasic: Peak concentrations, found at the end of the infusion, were followed by a rapid initial decline in concentration. This was followed by a slow elimination phase. The key pharmacokinetic parameters are presented below:

Summary of mean pharmacokinetic parameters in patients administered 3.0 mg/m² Raltitrexed by intravenous infusion

The maximum concentrations of raltitrexed increased linearly with dose over the clinical dose range tested.

During repeated administration at three week intervals, there was no clinically significant plasma accumulation of raltitrexed in patients with normal renal function.

Apart from the expected intracellular polyglutamation, raltitrexed was not metabolised and was excreted unchanged, mainly in the urine, 40 - 50%. Raltitrexed was also excreted in the faeces with approximately 15% of the radioactive dose being eliminated over a 10 day period. In the [14C] - raltitrexed trial approximately half of the radiolabel was not recovered during the study period. This suggests that a proportion of the raltitrexed dose is retained within tissues, perhaps as raltitrexed polyglutamates, beyond the end of the measurement period (29 days). Trace levels of radiolabel were detected in red blood cells on Day 29.

Raltitrexed pharmacokinetics are independent of age and gender. Pharmacokinetics have not been evaluated in children.

Mild to moderate hepatic impairment led to a small reduction in plasma clearance of less than 25%.

Mild to moderate renal impairment (creatinine clearance of 25 to 65 ml/min) led to a significant reduction (approximately 50%) in raltitrexed plasma clearance.

Perivascular tolerance in studies in animals did not reveal any significant irritant reaction.

Acute toxicity

The approximate LD₅₀ values for the mouse and rat are 875-1249 mg/kg and >500 mg/kg respectively. In the mouse, levels of 750 mg/kg and above caused death by general intoxication.

Chronic toxicity

In one month continuous and six month intermittent dosing studies in the rat, toxicity was related entirely to the cytotoxic nature of the drug. Principal target organs were the gastrointestinal tract, bone marrow and the testes. In similar studies in the dog, cumulative dose levels similar to that used clinically, elicited only pharmacologically-related changes to proliferating tissue. Target organs in the dog were therefore similar to the rat.

Mutagenicity

'Tomudex' was not mutagenic in the Ames test or in supplementary tests using E. coli or chinese hamster ovary cells. 'Tomudex' caused increased levels of chromosome damage in an in vitro assay of human lymphocytes. This effect was ameliorated by the addition of thymidine, thus confirming it to be due to the anti-metabolic nature of the drug. An in vivo micronucleus study in the rat indicated that at cytotoxic dose levels, 'Tomudex' is capable of causing chromosome damage in the bone marrow.

Reproductive toxicology

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.

Carcinogenicity

The carcinogenic potential of 'Tomudex' has not been evaluated.

Mannitol Ph Eur, USP

Dibasic sodium phosphate (heptahydrate USP or dodecahydrate Ph Eur)

Sodium hydroxide Ph Eur, USNF

There is no information on incompatibilities at present and therefore 'Tomudex' should not be mixed with any other drug.

The expiry life of 'Tomudex' is 36 months when stored below 25°C, protected from light.

Once reconstituted, 'Tomudex' is chemically stable for 24 hours at 25°C exposed to ambient light. For storage recommendation, see Instructions for Use/Handling.

Unopened vial - Do not store above 25°C. Keep container in the outer carton.

Reconstituted vial - Refrigerate at 2-8°C.

'Tomudex' is packed in 5ml clear neutral type I glass vials, with a bromobutyl rubber closure and an aluminium crimp seal with a plastic flip-off cover.

The vials are packed in individual cartons to protect the product from light.

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.

There is no preservative or bacteriostatic agent present in 'Tomudex' or the materials specified for reconstitution or dilution. 'Tomudex' must therefore be reconstituted and diluted under aseptic conditions and it is recommended that solutions of 'Tomudex' should be used as soon as possible. Reconstituted 'Tomudex' solution may be stored refrigerated (2 - 8°C) for up to 24 hours.

In accordance with established guidelines, when diluted in 0.9% sodium chloride or 5% glucose (dextrose) solution, it is recommended that administration of the admixed solution should commence as soon as possible after admixing. The admixed solution must be completely used or discarded within 24 hours of reconstitution of 'Tomudex' intravenous injection.

Reconstituted and diluted solutions do not need to be protected from light.

Do not store partially used vials or admixed solutions for future patient use.

Any unused injection or reconstituted solution should be discarded in a suitable manner for cytotoxics.

'Tomudex' should be reconstituted for injection by trained personnel in a designated area for the reconstitution of cytotoxic agents. Cytotoxic preparations such as 'Tomudex' should not be handled by pregnant women.

Reconstitution should normally be carried out in a partial containment facility with extraction e.g. a laminar air flow cabinet, and work surfaces should be covered with disposable plastic-backed absorbent paper.

Appropriate protective clothing, including normal surgical disposable gloves and goggles, should be worn. In case of contact with skin, immediately wash thoroughly with water. For splashes in the eyes irrigate with clean water, holding the eyelids apart, for at least 10 minutes. Seek medical attention.

Any spillages should be cleared up using standard procedures.

Waste material should be disposed of by incineration in a manner consistent with the handling of cytotoxic agents.

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire

CV31 3RW

United Kingdom

PL 04515/0225

25^th June 2000

20^th October 2011