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TOMUDEX 2MG/VIAL INJECTION

Active substance(s): RALTITREXED / RALTITREXED / RALTITREXED

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PACKAGE LEAFLET:
INFORMATION FOR THE USER
Tomudex® 2 mg powder
for solution for infusion
raltitrexed
Read all of this leaflet carefully before you start having
this medicine.
• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor, nurse or
pharmacist.
• If you get any side effects talk to your doctor, pharmacist or
nurse. This includes any possible side effects not listed in
this leaflet. See section 4.
In this leaflet:
1. What Tomudex is and what it is used for
2. What you need to know before you are given Tomudex
3. How Tomudex will be given
4. Possible side effects
5. How to store Tomudex
6. Contents of the pack and other information

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.
Tomudex is used to treat cancer which affects the colon and rectum
(parts of your ‘bowel’ or gut).

(Issued to the Medical professional only)
1. NAME OF THE MEDICINAL PRODUCT
‘Tomudex’

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
‘Tomudex’ contains 2 mg raltitrexed in each vial.

3. PHARMACEUTICAL FORM
Powder for solution for infusion.

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 are given Tomudex
Do not have Tomudex if:
• You have severe kidney disease.
• 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’).
• You are taking leucovorin or folic acid or any vitamins containing
these.
Do not have Tomudex if any of the above apply to you. If you are
not sure, talk to your doctor or nurse before having Tomudex.
Tomudex should not be given to children.

Take special care with Tomudex
Check with your doctor or nurse before having Tomudex if you have
ever had:
• Any problems with your blood, kidneys or liver.
• 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.

Dose modification in the presence of renal impairment
Creatinine Clearance

Dose as % of 3.0 mg/m

Dosing Interval

> 65 ml/min

Full dose

3-weekly

2

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:

• Do not have Tomudex if you are pregnant, think you may be
pregnant or might become pregnant. This is because it may
affect your baby.
• You should not try for a baby when either partner is having
Tomudex, during the treatment or for at least 6 months after
stopping treatment. This is because it may affect the baby.
• Do not have Tomudex if you are breast‑feeding.

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.

3. How Tomudex will be given
• You will be given Tomudex 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.

4.6 Pregnancy and lactation
Pregnancy
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.

4-weekly

50%

4-weekly

‘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.

< 25 ml/min

No therapy

Not applicable

Breastfeeding

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.

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.

Pregnancy and breast-feeding

75%

4.1 Therapeutic indications

For instructions on reconstitution and dilution of the product before administration,
see section 6.6 Instructions for use/handling.

In particular, tell your doctor, nurse or pharmacist if you are taking
any of the following:
• Vitamins or vitamin supplements.
• Medicines to thin your blood and stop it clotting (anti-coagulants).

55 to 65 ml/min

See Contraindications for use in patients with severe renal impairment

4.2 Posology and method of administration

Please tell your doctor, nurse or pharmacist if you are taking, or
have recently taken, 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.

25 to 54 ml/min

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

Taking other medicines

4.3 Contraindications
‘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 (creatinine
clearance < 25ml/min).
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
‘Tomudex’ must only given by or under the supervision of a physician who is
experienced in cancer chemotherapy, and in the management of chemotherapyrelated 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.

‘Tomudex’ should not be given to women who are breast feeding.
Fertility
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.

4.7 Effects on ability to drive and use machines
‘Tomudex’ 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, ‘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: 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

Anaemia a

Patients whose disease progressed on previous treatment for advanced disease with
5-Fluorouracil based regimens may also be resistant to the effects of ‘Tomudex’.

Common

Thrombocytopenia a, b

Very Common

Anorexia

Common

Dehydration

Common

Headache

Elderly patients are more vulnerable to the toxic effects of ‘Tomudex’. 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 ‘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.

Metabolism and Nutrition
Disorders

Treatment with ‘Tomudex’ in patients with severe hepatic impairment is not
recommended.

Eye disorders

Common

Gastrointestinal disorders

Very Common

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).

Nervous system disorders

Hypertonia (usually muscular
cramps)
Taste perversion
Nausea c
Vomiting c,e
Constipation

‘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).

Abdominal Pain
Common

4.5 Interaction with other medicinal products and other forms of
interaction

Stomatitis
Dyspepsia

No specific clinical drug - drug interaction studies have been conducted in man.

Mouth ulceration

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.

‘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.

Conjunctivitis
Diarrhoea d,e

There is no clinical experience with extravasation. However, perivascular
tolerance studies in animals did not reveal any significant irritant reaction.

Clinical trials evaluating the use of Tomudex in combination with other antitumour
therapies are currently ongoing.

Leucopenia (neutropenia in
particular) a, b

Frequency
unknown

Gastrointestinal Bleeding f,g

Hepato-biliary disorder

Common

Hyperbilirubinemia

Skin & subcutaneous tissue
disorders

Very Common

Rash

Common

Alopecia
Pruritus
Sweating

Uncommon

Desquamation
S10579

Date: 27 Apr 2017
Time:
Product Details:

15:22

S10579
Version No: 01
PAR-2017-0003988
United Kingdom
Perigord No: 309036

SVI006-2

Smallest Body Text
7 pt

Packaging Site

Black

Svus

Dimensions:
300 x 378 mm

Pharmacode:
N/A

Barcode:
N/A

• 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 3 weeks, but it could be less
often, depending on the results of your blood tests.
You should follow any instructions that your doctor gives you about
your treatment.
If you are not sure about anything ask your doctor or nurse.

4. Possible side effects
Like all medicines, Tomudex 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 (affects more than 1 user in 10)
• Diarrhoea.
• Being sick (vomiting).
• High temperature (fever) or chills.
• Mucositis (inflammation of the mouth and gut lining).
Common (affects 1 to 10 users in 100)
• Sore throat.
• Any infections.
• Soreness or ulcers inside your mouth.
Not known (frequency cannot be estimated from available data)
• Bleeding from the gut.

System Organ Class

Frequency

Adverse drug reaction

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

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.

Other possible side effects are:
Very common (affects more than 1 user in 10):
• 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 (affects 1 to 10 users in 100):
• 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).

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.

b

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.

c

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).

d

Diarrhoea and vomiting may be severe and if untreated may proceed to
dehydration, hypovolaemia and renal impairment

e

f

from spontaneous reporting

Gastrointestinal bleeding may be associated with mucositis and/or
thrombocytopenia.

g

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.

h

Increases in AST and ALT have usually been asymptomatic and self-limiting
when not associated with progression of the underlying malignancy.

i

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
Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard

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 ‘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.

5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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

What Tomudex contains

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 a
powder which is then made into a solution for injection into a vein.
The vials are packed in cartons.
Marketing Authorisation Holder and Manufacturer
The Marketing Authorisation Holder and Manufacturer is:
Hospira UK Limited, Queensway, Horizon, Honey Lane, Hurley
Maidenhead, SL6 6RJ , United kingdom

If you get any side effects, talk to your doctor, nurse or pharmacist.
This includes any possible side effects not listed in this leaflet. You
can also report side effects directly via:

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.

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
Vss

AUCo-∞

CL

CLr

(ng/ml)

(ng.h/ml)

(ml/min)

(ml/min)

(l)

656

1856

51.6

25.1

548

Key: Cmax: Peak plasma concentration.

This medicine will normally be stored for you by the hospital. The
doctor and hospital pharmacist are responsible for storing, using
and disposing of Tomudex correctly.
• Keep out of the reach and sight of children.
• Keep unopened vials in the outer carton to protect them from light.
• Do not store above 25°C.
• Do not use Tomudex after the expiry date which is stated on the
vial. The expiry date refers to the last day of that month.

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

Reporting of side effects

Cmax

5. How to store Tomudex

6. Contents of the pack and other information

Uncommon (affects 1 to 10 users in 1000):
• Red or peeling skin.

a

Yellow Card Scheme
Website: www.mhra.gov.uk/yellowcard
By reporting side effects you can help provide more information on
the safety of this medicine.

Leaflet updated: 04/2017
Ref TM 1_0

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.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Mannitol Ph Eur, USP
Dibasic sodium phosphate (heptahydrate USP or dodecahydrate Ph Eur)
Sodium hydroxide Ph Eur, USNF

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

6.3 Shelf-life
The expiry life of ‘Tomudex’ is 36 months when stored below 25°C, protected from
light.

t1/2γ

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

(h)

(h)

1.79

198

6.4 Special precautions for storage

t1/2β

AUC: Area under
plasma concentrationtime 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
‘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 antimetabolic 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.

Unopened vial - Do not store above 25°C. Keep container in the outer carton.
Reconstituted vial - Refrigerate at 2-8°C.

6.5 Nature and contents of container
‘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.

6.6 Instructions for use, handling and disposal
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.

7. MARKETING AUTHORISATION HOLDER
Hospira UK Limited
Horizon, Honey Lane, Hurley
Maidenhead,
SL6 6RJ
United Kingdom

S10579

Date: 27 Apr 2017
Time:
Product Details:

15:22

S10579
Version No: 01
PAR-2017-0003988
United Kingdom
Perigord No: 309036

SVI006-2

Smallest Body Text
7 pt

Packaging Site

Black

Svus

Dimensions:
300 x 378 mm

Pharmacode:
N/A

Barcode:
N/A

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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