Tomudex 2 mg / vial injection – patient leaflet, side effects, dosage

1. What Tomudex is and what it is used for

Tomudex contains a medicine called raltitrexed. This belongs to a group of medicines known as chemotherapy. These are used to treat cancer. What is it used for?

Tomudex is used to treat cancer which affects the colon and rectum (parts of your ‘bowel’ or gut). It works by killing cells within your body which cause certain types of cancer. Your doctor will probably explain this to you in more detail.

2. What you need to know before you use Tomudex

Do not use Tomudex:

• if you are allergic to raltitrexed or any of the other ingredients of this medicine (listed in section 6).
• if you have severe kidney disease.
• if you are pregnant, think you might be pregnant, are trying for a baby or you are breast-feeding (see the section on ‘Pregnancy and breast-feeding’).
• if you are taking leucovorin or folic acid or any vitamins containing these.

Tell your doctor if any of the above applies to you before this medicine is used.

Warnings and precautions

Talk to your doctor, pharmacist or nurse before using Tomudex:

• if you have any problems with your blood, kidneys or liver.
• if you have had radiotherapy (treatment with high dose X-rays).

Please tell your doctor or nurse if there is a change in your stomach or bowel (gut) problems whilst taking Tomudex.

If you are elderly, your doctor or nurse will monitor you more closely for side effects. Elderly people can be more affected by the side effects of this kind of medicine.

If you have any other treatment for other problems or illnesses, tell your doctor, nurse or pharmacist that you are having Tomudex.

If you are not sure if any of the above apply to you, talk to your doctor, nurse or pharmacist before having Tomudex.

Children

This medicine should not be used in children. Other medicines and Tomudex

Talk to your doctor, pharmacist or nurse if you are using, have recently used, or might use any other medicines. This includes medicines that you buy without a prescription and herbal medicines. This is because Tomudex can affect the way some medicines work and some medicines can have an effect on Tomudex.

In particular, tell your doctor, pharmacist or nurse if you are using any of the following:

• vitamins or vitamin supplements.

• medicines to thin your blood and stop it clotting

  (anti-coagulants).

Tomudex with food and drink

There are no special recommendations concerning the use of this medicine with food and drink.

Pregnancy and breast-feeding

Pregnancy

If you are pregnant or breast-feeding, think you might be pregnant or are planning to have a baby, you should not use Tomudex. Ask your doctor or pharmacist for advice before using Tomudex.

You should not try for a baby when either partner is using Tomudex, during the treatment or for at least six months after stopping treatment. This is because it may affect your baby.

Breast-feeding

Do not use this medicine if you are breast-feeding.

Package leaflet: Information for the user

Tomudex® 2mg powder for solution for infusion raltitrexed

Driving and using machines

You may feel generally unwell or have flu-like symptoms for a short time after having Tomudex. If this happens, do not drive or use any tools or machines. Information about the ingredients of Tomudex

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

3. How to use Tomudex Dosage and method of administration

You will be given this medicine by a doctor or nurse who is a specialist in the use of this type of medicine. Tomudex will be injected slowly into one of your veins. The injection will usually take 15 minutes. The exact dose you are given will be decided by your doctor. It will depend on your size and how you react to your treatment.

The usual dose is 3 milligrams for each square metre of your body surface area. Your doctor will calculate this from your height and weight.

Your doctor will need to take regular samples of your blood while you are having Tomudex. The results of your blood tests will also help the doctor to decide what dose you will receive. The dose you are given may be different each time.

Tomudex is usually given every three weeks, but it could be less often, depending on the results of your blood tests.

If you have any further questions on the use of this medicine, ask your doctor.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. The following side effects may happen with this medicine.

Tell your doctor or the hospital straight away if you notice any of the following side effects – you may need urgent medical treatment: Very common: may affect more than 1 in 10 people

• Diarrhoea.
• Being sick (vomiting).
• High temperature (fever) or chills.
• Mucositis (inflammation of the mouth and gut lining).

Common: may affect up to 1 in 10 people

• Sore throat.
• Any infections.
• Soreness or ulcers inside your mouth. Not known: frequency cannot be estimated from available data
• Bleeding from the gut.

Other possible side effects are:

Very common: may affect more than 1 in 10 people:

• Loss of appetite.
• Indigestion.
• Feeling sick (nausea).
• Stomach pain.
• Constipation.
• Weight loss.
• Itchy rash.

• Tomudex may cause changes to your blood.

  These occur because of effects on your bone marrow and your liver. Your doctor will take regular blood samples to check your blood.

Common: may affect up to 1 in 10 people:

• Painful joints.
• Muscle cramps.
• Swollen hands, ankles or feet.
• Yellow skin and eyes (jaundice).
• Tenderness and swelling under the skin (cellulitis).
• Sweating.
• Hair loss or thinning.
• Feeling thirsty or dry skin (signs of dehydration).
• Headache.
• Altered taste.
• Red or itchy eyes (conjunctivitis).
• Weakness (sometimes flu-like symptoms). Uncommon: may affect up to 1 in 100 people:
• Red or peeling skin.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly 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. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Tomudex

Keep this medicine out of the sight and reach of children.

Expiry date

Do not use Tomudex after the expiry date which is stated on the vial label and carton. The expiry date refers to the last day of that month.

Storage

This medicine will normally be stored for you by the hospital. The doctor and hospital pharmacist are

2102919

1. 5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antineoplastic agents,

antimetabolites, ATC code: L01BA03.

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, raltitrexed 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

raltitrexed in advanced colorectal cancer. Of the three

comparative trials, two showed no statistical difference

between raltitrexed 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. Raltitrexed

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.

5.2 Pharmacokinetic properties

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

Cmax

(ng/ml)

AUC^o-∞

(ng.h/ml)

CL

(ml/min)

CLr

(ml/min)

Vss

(l)

t1/2ββ

(h)

t1/2γγ

(h)

656 1856 51.6 25.1 548 1.79 198

Key: C_max: Peak plasma

concentration.

AUC: Area under plasma-

concentration time curve.

CL: Clearance. CLr: Renal clearance

Vss: Volume of

distribution at steady

state.

t½β: Half life of the second

(β) phase.

t½γ: Terminal half

life.

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.

5.3 Preclinical safety data

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

Raltitrexed was not mutagenic in the Ames test or in supplementary tests using E. coli or Chinese hamster ovary cells. Raltitrexed 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, raltitrexed is capable of causing chromosome damage in the bone marrow.

Reproductive toxicology

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.

Carcinogenicity

The carcinogenic potential of raltitrexed has not been evaluated.

1. 6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Mannitol

Dibasic sodium phosphate (heptahydrate or dodecahydrate)

Sodium hydroxide

6.2 Incompatibilities

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

6.3 Shelf-life

Unopened Vial - 3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2-8°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/ dilution (etc) has taken place in controlled and validated aseptic conditions.

Once reconstituted, Tomudex is chemically stable for 24 hours at 25°C exposed to ambient light. For storage recommendation, see sections 6.4 and 6.6. 6.4 Special precautions for storage

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

For storage conditions after reconstitution of the medical product, see section 6.3.

6.5 Nature and contents of container

Clear neutral type I glass vials, with a bromobutyl rubber closure and aluminium crimp seal with a plastic flip-off cover.

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

6.6 Special precautions for disposal and other handling

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 is for single use only.

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.

1. 7. MARKETING AUTHORISATION HOLDER

Hospira UK Limited

Walton Oaks

Walton-On-The-Hill

Dorking Road

Tadworth

Surrey

KT20 7NS

UK

responsible for storing, using and disposing of Tomudex correctly.

Do not store above 25°C. Keep unopened vials in the outer carton to protect them from light.

6. Contents of the pack and other information

What Tomudex contains

The active substance is raltitrexed. Each vial contains 2mg of raltitrexed.

The other ingredients are mannitol, dibasic sodium phosphate heptahydrate or

dodecahydrate and sodium hydroxide. What Tomudex looks like and the contents of the pack

Tomudex comes in containers of single glass vials containing white to cream coloured powder. Marketing Authorisation Holder

Hospira UK Limited, Walton Oaks,

Walton-On-The-Hill, Dorking Road, Tadworth, Surrey, KT20 7NS, UK

Manufacturer

Pfizer Service Company BV

Hermeslaan 11

1932 Zaventem

Belgium

This leaflet was last revised in 11/2025.

Ref gxTM 7_0

GUJ-DRUGS/G/28/1267