Raltitrexed

Raltitrexed is a folic acid analogue of the antimetabolite family with potent inhibitory activity against thymidylate synthase (TS). Unlike fluorouracil and methotrexate, which act on this pathway indirectly, it inhibits the enzyme directly and specifically.

Mechanism of Action

• Thymidylate synthase: TS is a key enzyme in the de novo synthesis of thymidine triphosphate, a nucleotide essential for DNA synthesis. Inhibiting it causes DNA fragmentation and cell death.
• Cell entry: raltitrexed is carried into cells by a transporter for reduced folates.
• Polyglutamation: inside the cell, folylpolyglutamate synthetase converts raltitrexed into polyglutamates. These are retained in the cells and inhibit TS even more strongly and for longer, which may reinforce the antitumour activity. Retention in healthy tissue may also contribute to its toxicity.

Pharmacokinetics

• Profile: after an intravenous dose of 3 mg/m², the pharmacokinetics are triphasic: the peak is reached at the end of the infusion, followed by a rapid fall and then a slow elimination phase. Mean values in patients were a peak concentration of 656 ng/mL, an AUC of 1,857 ng·h/mL, a total clearance of 51.6 mL/min (renal clearance 25.1 mL/min), a steady-state volume of distribution of 548 L, a second-phase half-life of 1.79 hours and a terminal half-life of 198 hours. Peak levels rise in proportion to dose, and there is no clinically significant accumulation with 3-weekly dosing in patients with normal renal function.
• Distribution: more than 93% is bound to plasma proteins. In a radiolabelled study only about half of the dose was recovered within 29 days, which suggests that part is retained in tissues, probably as polyglutamates; traces were still found in red blood cells on day 29.
• Metabolism: apart from intracellular polyglutamation, raltitrexed is not metabolised.
• Elimination: it is excreted unchanged, mainly in urine (40–50% of the dose); about 15% appears in faeces over 10 days.
• Special populations: the pharmacokinetics do not depend on sex or age and have not been studied in children. Mild to moderate hepatic impairment lowers plasma clearance only slightly (by less than 25%). Mild to moderate renal impairment (creatinine clearance 25–65 mL/min) lowers plasma clearance by about 50%.

• Metastatic colorectal cancer: treatment of metastatic progression of colorectal cancer in patients who have not received a fluoropyrimidine in this situation.

These indications follow the French SmPC for Tomudex 2 mg. Raltitrexed is nationally authorised, so the wording of the national SmPC can differ between EU member states.

The SmPC summarises four studies in metastatic colorectal cancer, three of them comparing raltitrexed with different fluorouracil and folinic acid regimens. Response rates were comparable to those of fluorouracil with folinic acid, but raltitrexed was inferior to the comparators in overall survival in one study and in progression-free survival in two studies.

• Pregnancy, or women who could become pregnant during treatment; pregnancy must be excluded before treatment starts.
• Breast-feeding.
• Severe renal impairment (creatinine clearance below 25 mL/min).
• Combination with folinic acid or folic acid, or with vitamin preparations containing them.
• Combination with the yellow fever vaccine.
• WHO grade 4 digestive toxicity, or WHO grade 3 digestive toxicity together with WHO grade 4 myelotoxicity, caused by the treatment.

As with other cytotoxic medicines, raltitrexed is mainly associated with reversible effects on the blood-forming system, liver enzymes and gastrointestinal tract.

Very common (≥1/10): leukopenia (especially neutropenia), anaemia, anorexia, nausea, diarrhoea, vomiting, constipation, abdominal pain, skin rash, asthenia, fever, mucositis, increased AST and ALT.

Common (≥1/100 to <1/10): cellulitis, sepsis, flu-like syndrome, thrombocytopenia, dehydration, headache, hypertonia (usually muscle cramps), taste change, conjunctivitis, stomatitis, dyspepsia, mouth ulceration, hyperbilirubinaemia, alopecia, pruritus, sweating, arthralgia, peripheral oedema, pain, malaise, weight loss, increased alkaline phosphatase.

Uncommon (≥1/1,000 to <1/100): skin desquamation.

Not known: gastrointestinal haemorrhage (from spontaneous reports; it may be associated with mucositis and/or thrombocytopenia).

Blood count changes are usually mild to moderate, appear in the first or second week and return to normal by the third week. Severe leukopenia (neutropenia) and grade 4 thrombocytopenia can be life-threatening or fatal when combined with signs of digestive toxicity. Nausea and vomiting are usually mild and respond to antiemetics. Diarrhoea is usually mild to moderate but can be severe and, with vomiting, can lead to dehydration, hypovolaemia and renal failure if untreated. Asthenia and fever are usually mild to moderate and occur in the first week. Rises in liver enzymes and bilirubin are usually reversible, but fatal liver damage has been reported. Renal failure is possible, and frequent, after WHO grade 3 or 4 diarrhoea or another predisposing condition such as severe dehydration, hypovolaemia or severe haemorrhage.

No specific interaction studies have been carried out.

• Folinic acid, folic acid and vitamin preparations containing them: contraindicated. None should be given immediately before or during treatment, because of possible interference with raltitrexed.
• Yellow fever vaccine: contraindicated, because of the risk of fatal generalised vaccine disease.
• Other live attenuated vaccines: not recommended, because of the risk of generalised and possibly fatal vaccine disease, greater in patients already immunocompromised by their disease. Use an inactivated vaccine where one exists (for example against poliomyelitis).
• Phenytoin and fosphenytoin: not recommended. The cytotoxic may reduce phenytoin absorption and so risk convulsions, or phenytoin may increase hepatic metabolism of the cytotoxic, raising its toxicity or reducing its efficacy.
• Immunosuppressants (ciclosporin, everolimus, sirolimus, tacrolimus): to be taken into account, because of excessive immunosuppression with a risk of lymphoproliferative syndrome.
• Oral anticoagulants: tumour disease raises thrombotic risk and coagulability varies widely, so if oral anticoagulants are used the INR should be checked more often.
• NSAIDs and other actively secreted medicines: active tubular secretion contributes to renal excretion of raltitrexed, so an interaction is possible. Clinical trial safety data showed no clinically significant interaction with NSAIDs or other commonly prescribed medicines.

Raltitrexed must be used under the supervision of a physician experienced in cancer chemotherapy and in managing chemotherapy toxicity. It is prepared and handled according to the usual rules for cytotoxic medicines (SmPC section 6.6).

Recommended Dose

• Adults: 3 mg/m² body surface area as a single intravenous infusion over 15 minutes in 50–250 mL of 0.9% sodium chloride or 5% glucose solution. No other medicine may be mixed in the infusion container.
• Repeat courses: if there are no signs of toxicity, treatment may be repeated every 3 weeks.
• Do not exceed 3 mg/m²: higher doses were associated with increased life-threatening toxicity.
• Extravasation: stop the infusion immediately.

Checks Before Each Course

• Before starting and before every later course: full blood count with differential and platelets, liver transaminases, bilirubin and creatinine.
• Treatment may start if leukocytes are above 4,000/mm³, neutrophils above 2,000/mm³ and platelets above 100,000/mm³.
• If toxicity occurs, the next course is postponed until digestive toxicity (diarrhoea or mucositis) and myelotoxicity (neutropenia or thrombocytopenia) have completely resolved.
• Patients with signs of digestive toxicity need their blood count checked at least once a week for myelotoxicity.

Dose Adjustments for Toxicity

• 25% reduction: after WHO grade 3 myelotoxicity (neutropenia or thrombocytopenia) or WHO grade 2 digestive toxicity (diarrhoea or mucositis) in the previous course, once the toxicity has fully resolved.
• 50% reduction: after WHO grade 4 myelotoxicity or WHO grade 3 digestive toxicity.
• The reduced dose is kept for later courses. The SmPC stresses that the reduction must be respected: the risk of life-threatening or fatal toxicity rises if the dose is not reduced or treatment is not stopped appropriately.
• Stop treatment for WHO grade 4 digestive toxicity, or WHO grade 3 digestive toxicity with WHO grade 4 myelotoxicity. Such patients need prompt management, including intravenous rehydration and support for bone marrow failure. Folinic acid may be considered on the basis of preclinical data, at 25 mg/m² intravenously every 6 hours until symptoms resolve (a dose based on experience with other antifolates). Raltitrexed must not be used again in these patients.

Special Populations

• Elderly: same dose and method as adults, but use with caution, as with other cytotoxics.
• Renal impairment: creatinine and creatinine clearance must be determined before the first course and before each later course. If creatinine clearance is 65 mL/min or lower, adjust as follows: 55–65 mL/min, 75% of the dose (2.25 mg/m²) every 4 weeks; 25–54 mL/min, 50% of the dose (1.5 mg/m²) every 4 weeks; below 25 mL/min, no treatment (contraindicated). Above 65 mL/min the full dose of 3 mg/m² is given every 3 weeks.
• Hepatic impairment: no dose adjustment in mild to moderate impairment, but treat with caution, because part of the dose is excreted in faeces and these patients generally have a poor prognosis. In severe impairment, clinical jaundice or hepatic decompensation it is not recommended, for lack of clinical experience.
• Children: not recommended; safety and efficacy have not been established.

Toxicity Monitoring

Patients must be followed closely so that toxicity, especially diarrhoea, is detected early and treated promptly. Particular care is needed in patients with bone marrow suppression, poor general condition or previous radiotherapy.

Elderly Patients

Elderly patients are more sensitive to the toxic effects of raltitrexed. They need careful monitoring for gastrointestinal toxicity (diarrhoea, mucositis) and myelosuppression (neutropenia, thrombocytopenia, infection), with dose reduction or postponement when necessary. Kidney function tends to decline with age and raltitrexed clearance falls in renal impairment, so the medicine can accumulate.

Liver Function

Part of the dose is excreted in faeces, so patients with mild to moderate hepatic impairment must be treated with caution. Treatment is not recommended in severe hepatic impairment.

Vaccines and Phenytoin

Live attenuated vaccines, phenytoin and fosphenytoin are not advised during treatment (see Drug Interactions).

Pregnancy, Breastfeeding and Fertility

• Pregnancy: raltitrexed must not be used in pregnant women or women who could become pregnant during treatment. Pregnancy must be excluded before treatment starts, with appropriate contraception.
• Conception: if either partner is treated, avoid conception during treatment and for at least 6 months after it stops.
• Breastfeeding: raltitrexed must not be used in women who are breast-feeding.
• Fertility: studies in rats show that raltitrexed can impair male fertility; fertility returned to normal 3 months after treatment stopped.

Sodium

Each vial contains less than 1 mmol (23 mg) of sodium, so it is essentially sodium-free.

Effect on Driving

Raltitrexed can cause malaise or asthenia after the infusion, which may impair the ability to drive or use machines.

Unopened vials: do not store above 25 °C, and keep the vial in the outer carton to protect it from light. No cold chain is needed. After reconstitution, immediate use is recommended; stability has been shown for 24 hours at up to 25 °C, and the solution may be kept at 2–8 °C to reduce the risk of bacterial contamination. Each reconstituted or diluted solution is for single use. Tomudex is supplied as a powder in a 10 mL clear glass vial with a siliconised bromobutyl rubber stopper; one vial per box.

3 years before reconstitution. After reconstitution or dilution the solution should be used immediately (see Storage Conditions).

Prescription only (Rx). Raltitrexed is a cytotoxic medicine for intravenous infusion under the supervision of a physician experienced in cancer chemotherapy, so it is supplied to the hospital or clinic that administers it.