TOMUDEX 2 mg Proszek Do Sporządzania Roztworu Do Infuzji Dożylnej

Treść ulotki

1. TOMUDEX 2 mg powder for solution for infusion
   1. What is Tomudex and what is it used for
   2. What you need to know before using Tomudex
   3. How to use Tomudex
   4. Possible side effects
   5. How to store Tomudex
   6. Package Contents and Other Information

TOMUDEX 2 mg powder for solution for infusion

Raltitrexed

Read this leaflet carefully before you use this medicine as it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any questions, ask your doctor, pharmacist or nurse.
• This medicine has been prescribed for you only. Do not pass it on to others, even if their symptoms are the same as yours, as it could be harmful.
• If you get any side effects, even those not listed in this leaflet, tell your doctor, pharmacist or nurse. See section 4.

Contents of this leaflet:

• 1. What Tomudex is and what it is used for
• 2. What you need to know before you use Tomudex
• 3. How to use Tomudex
• 4. Possible side effects
• 5. How to store Tomudex
• 6. Contents of the pack and other information

1. What is Tomudex and what is it used for

Tomudex contains the active substance raltitrexed which is used for chemotherapy, and belongs to
the class of antimetabolites, folic acid analogues.
Tomudex is used:

• to relieve the symptoms of advanced colorectal cancer
• in association with another medicine (cisplatin), in the treatment of lung cancer (malignant pleural mesothelioma) that cannot be surgically removed in patients who have never been treated with these drugs.

2. What you need to know before using Tomudex

DO NOT use Tomudex

• if you are allergic to raltitrexed or to medicines similar to it or to any of the other components of this medicine (listed in section 6).
• if you suffer from severe kidney dysfunction (creatinine clearance < 25ml/min)
• if you are pregnant or if you are breastfeeding

Warnings and precautions
Consult your doctor or nurse before taking Tomudex.
Tomudex must only be administered by a doctor experienced in anticancer chemotherapy or
otherwise under their supervision.
The doctor will keep you under close observation to identify any adverse reactions, in particular
those relating to the gastrointestinal tract (diarrhea or mucositis) and to the bone marrow (reduction in the number
of white blood cells called neutrophils with a consequent risk of infections, platelets) and will reduce the
dose or delay treatment.

Use Tomudex with caution if:

• you suffer from a reduction in bone marrow function.
• your general health conditions are not good.
• you have undergone radiotherapy.
• you suffer from mild to moderate liver dysfunction
• you are an elderly patient

Before starting therapy and before each subsequent treatment, a complete examination of blood values (white blood cell count and platelets, liver transaminases, bilirubin and
serum creatinine) must be performed

Children
The use of Tomudex is not recommended in children as tolerability and efficacy have not been
evaluated in this patient group.

Other medicines and Tomudex
Tell your doctor or pharmacist if you are taking, have recently taken or might take
any other medicine.
Do not take immediately before or during the administration of Tomudex, other medicines that
may affect its anticancer effect, including:

• folinic acid
• folic acid
• vitamin preparations

Cisplatin
Concomitant use of cisplatin may increase the toxicity of Tomudex, therefore this combination
must be used with caution.

Pregnancy, breastfeeding and fertility
If you are pregnant, suspect you are pregnant, or are planning a pregnancy, or if you are breastfeeding, ask your doctor for advice before being given this medicine.
Pregnancy
You must not be given Tomudex during pregnancy or if potentially at risk of
pregnancy during treatment.
Before starting treatment with Tomudex, it must be ascertained that you are not pregnant.
You should avoid becoming pregnant if either partner is taking Tomudex. It is also recommended
to avoid conception for at least 6 months after the end of treatment.
Breastfeeding
You must not take Tomudex if you are breastfeeding.
Fertility
Studies on fertility in rats indicate that Tomudex may cause inability to conceive in male
rats. Fertility returned to normal after 3 months from the end of therapy.

Driving and operating machinery
You must not drive or operate machinery, due to possible discomfort or muscle weakness after
use of Tomudex.
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially ‘sodium-free’.

3. How to use Tomudex

Tomudex will be administered to you intravenously as a single intravenous infusion lasting
15 minutes by a doctor or nurse. If you have any doubts, consult your doctor, pharmacist or nurse.

Dosage
The dose will be calculated by the doctor based on your body surface area, the specific circumstances
listed in section 2 “Warnings and precautions” and based on your response to treatment and in
the absence of toxicity the treatment may be repeated every 3 weeks.

Use in children
The use of Tomudex is not recommended in children as tolerability and efficacy have not been
evaluated in this patient group.
Patients with renal impairment
For patients with abnormal renal function values (creatinine levels), creatinine
elimination from the blood should be assessed or calculated at the beginning of therapy and before each subsequent
treatment.

If you use more Tomudex than you should
Since this medicine is administered in hospital it is unlikely to be administered in an incorrect quantity.
However, if you have any doubts, talk to your doctor, nurse or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Tomudex for the treatment of advanced colorectal cancer may cause the following side effects:
Very common side effects (may affect more than 1 in 10 people)

• abnormal decrease in white blood cells (leukopenia)
• anemia
• excessive weight loss (anorexia)
• nausea, diarrhea, vomiting
• difficulty passing stools (constipation), abdominal pain
• skin irritation (rash)
• lack of energy and muscle weakness (asthenia)
• fever
• inflammation of the mucous membranes (mucositis)
• increased levels of liver enzymes in the blood (GOT and GTP)

Common side effects (may affect up to 1 in 10 people)

• increased fluid under the skin (cellulitis)
• exaggerated body response to a bacterial infection (sepsis)
• illness with flu-like symptoms
• reduction in platelets in the blood (thrombocytopenia)
• loss of body fluids (dehydration)
• headache
• muscle cramps (hypertonia)
• changes in taste
• inflammation of the white membrane of the eye (conjunctivitis)
• inflammation of the mouth and burning or pain in the stomach (stomatitis, dyspepsia, mouth ulcers)
• increased levels of bilirubin in the blood (hyperbilirubinemia)
• hair loss (alopecia), itching, sweating
• joint pain/inflammation (arthralgia)
• fluid accumulation in the lower limbs (peripheral edema)
• pain
• malaise
• weight loss
• increased levels of alkaline phosphatase in the blood

Uncommon side effects (may affect up to 1 in 100 people)

• scaling

Side effects with unknown frequency

• gastrointestinal bleeding

Tomudex in combination with Cisplatin for the treatment of lung cancer may cause the following side effects:
Very common side effects (may affect more than 1 in 10 people)

• infections due to a decrease in white blood cells (neutrophils), cough, difficulty breathing (dyspnea), chest pain (not related to the heart or the membrane lining the lungs), pain in the membrane lining the lungs (pleura)
• headache, dizziness
• nervous system disease (sensory neuropathy)
• ringing in the ears (tinnitus)
• nausea, vomiting, constipation, diarrhea
• anorexia
• inflammation of the mouth/pharynx (stomatitis/pharyngitis)
• hair loss (alopecia)
• fatigue
• fluid accumulation (edema)
• fever with a decrease in white blood cells in the blood (neutropenia)

Common side effects (may affect up to 1 in 10 people)

• decrease in the number of white blood cells (leukopenia)
• hearing loss
• abdominal pain, inflammation of the stomach wall (gastritis)
• sweating, dehydration
• skin irritation (erythema)/scaling
• joint pain/inflammation (arthralgia)
• weight loss

Leukopenia (particularly neutropenia), anemia, and thrombocytopenia, alone or in combination, are usually mild to moderate and occur during the first or second week of treatment with recovery within the third week.
Severe leukopenia (particularly neutropenia) and thrombocytopenia may occur, which may be life-threatening or fatal, especially if associated with signs of gastrointestinal toxicity.
Nausea and vomiting are usually mild and occur during the first week of treatment with Tomudex, and respond to antiemetics.
Diarrhea and vomiting can be severe and, if left untreated, can cause dehydration, hypovolemia, and kidney damage.
After the first week of Tomudex treatment, asthenia and fever are usually mild to moderate and reversible. Severe asthenia may occur, which may be associated with malaise and a flu-like syndrome.
Elevated GOT and GPT are usually asymptomatic and self-limiting if not associated with progression of the underlying malignancy.
Gastrointestinal bleeding which may be associated with mucositis and/or thrombocytopenia.

Reporting of side effects
If you experience any side effects, including those not listed in this leaflet, please inform your doctor, pharmacist or nurse. You can also report side effects directly through the national reporting system at http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Tomudex

Store at a temperature below 25°C. Keep the vial in the cardboard box to protect the medicine from light.
Once reconstituted, Tomudex is chemically stable for 24 hours at 25°C under normal light conditions.
The reconstituted solution of Tomudex can be stored in a refrigerator (between 2°C and 8°C) for up to 12 hours.
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the packaging.
The expiry date refers to the last day of that month.
Do not dispose of any medicine in wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package Contents and Other Information

What Tomudex Contains

• The active ingredient is raltitrexed 2 mg
• The other ingredients are mannitol, dibasic sodium phosphate dodecahydrate, sodium hydroxide

Description of the appearance of Tomudex and contents of the pack
Powder for solution for infusion: 1 vial of 2 mg

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Pfizer Italia S.r.l.
Via Isonzo, 71
04100 Latina

Manufacturer
Pfizer Service Company BVBA
Hoge Wei 10
1930 Zaventem
Belgium
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The following information is intended exclusively for healthcare professionals:
For information on prescribing the medicine, please refer to the Summary of Product Characteristics.
Adult Patients
Before treatment, the total white blood cell count must be greater than 4000/mm³, the neutrophil count
greater than 2000/mm³ and the platelet count greater than 100,000/mm³.
In case of toxicity, the administration of the next dose should be delayed until the signs of the
toxic effects have regressed.
Once the dose has been reduced, all subsequent treatments must be administered at the reduced dose.
The recommended dose is 3 mg/m² diluted in 50 - 250 ml of 0.9% sodium chloride solution or 5% dextrose (glucose) solution and administered intravenously as a single short infusion. It is recommended to
administer the infusion over the course of 15 minutes.
No other drugs should be added to the vial containing the Tomudex solution. In the absence of
toxicity, treatment may be repeated every 3 weeks.
Treatment with Tomudex should be discontinued in case of gastrointestinal toxicity (diarrhea or mucositis)
grade 4 WHO or in case of gastrointestinal toxicity grade 3 WHO associated with hematological toxicity of
grade 4 WHO.
It is essential to observe the dose reduction schedule as the potential lethal or life-threatening toxicity increases if the dose is not reduced or treatment is not discontinued as appropriate.
Cisplatin
When used in combination with Tomudex, cisplatin must be administered after each infusion
of Tomudex. The recommended dose of cisplatin is 80 mg/m² for intravenous infusion over 1-2 hours. In case of
toxicity, the next dose should be suspended until the signs of toxic effects regress,
as with Tomudex. Patients must receive adequate hydration before and after receiving cisplatin
and may require anti-emetic therapy. For these and other recommendations on dosage and method
of administration of cisplatin, refer to the Summary of Product Characteristics for this
medicinal product.
Patients with renal insufficiency
For patients with abnormal creatinine values, creatinine clearance should be assessed or
calculated at the beginning of therapy and before each subsequent treatment.
For patients with normal creatinine values, which may not correlate well with creatinine clearance due to age-related factors or weight loss, the same approach should be followed.
If creatinine clearance is equal to or less than 65 ml/min, the following dose reduction is recommended:
Dosage adjustment in the presence of renal insufficiency
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Percentage clearance of the 3 mg/m² dose interval between
of creatinine doses
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> 65 ml/min full dose every 3 weeks
55 to 65 ml/min 75% every 4 weeks
25 to 54 ml/min 50% every 4 weeks
<25 ml min no treatment ----------
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Patients with hepatic insufficiency
No dosage adjustment is necessary in patients with mild or
moderate hepatic insufficiency. However, since a portion of the drug is excreted via the feces and patients with
hepatic insufficiency usually represent a group with a poor prognosis, treatment should be administered with caution in case of mild or moderate hepatic insufficiency (see section
Precautions for use). Tomudex has not been studied in patients with severe hepatic insufficiency, jaundice
or decompensated hepatic insufficiency and its use in these patients is not recommended.
Instructions for reconstitution and dilution
Tomudex must be reconstituted by adding 4 ml of sterile water for injections to the contents of each vial (containing 2 mg of
raltitrexed) to obtain a 0.5 mg/ml solution.
The individual dose for each patient must be further diluted in 50-250 ml of 0.9% sodium chloride solution or 5% dextrose (glucose) solution and administered as a short intravenous infusion
over 15 minutes.
The chemical and physical stability in use of the diluted infusion solutions has been demonstrated for 24 hours at
25°C under normal light conditions.
Neither Tomudex nor the substances specified for reconstitution or dilution contain preservatives or
bacteriostatic agents.
From a microbiological point of view, the reconstituted and diluted solutions must be used
immediately. If not used immediately, the storage times in use and storage conditions before use are the responsibility of the user and should generally not exceed 12 hours between 2°C and 8°C, unless the reconstitution and dilution have taken place
under controlled and validated aseptic conditions.
It is recommended that the administration of the solution obtained after dilution in 0.9% sodium chloride solution or 5% dextrose (glucose) solution, be started as soon as possible after preparation.
This solution must be used completely within 24 hours of preparing the reconstituted product or discarded.
Reconstituted or diluted solutions do not need to be protected from light.
Do not store partially used vials or reconstituted solutions for subsequent use in the
patient.
Any remaining reconstituted or diluted product must be disposed of according to the procedures provided for
cytotoxins.
Tomudex must be reconstituted by personnel experienced in a designated area for the reconstitution of
cytotoxic agents. Preparations based on cytotoxins such as Tomudex must not be handled by pregnant women.
Reconstitution should normally be carried out in a partial containment facility with
extraction systems such as laminar flow hoods and work surfaces must be covered with
disposable absorbent paper with a plastic backing.
Appropriate protective clothing, including surgical gloves and disposable goggles, must be worn. If
contact with the skin occurs, wash thoroughly with water. In case of accidental splashes in the eyes
irrigate with running water, keeping the eyelids apart, for at least 10 minutes. Consult a doctor.
Any spillage must be cleaned up using standard procedures.
Waste material must be disposed of by incineration according to the procedures provided for
cytotoxic agents.
Overdosage
No clinically tested antidotes are available. In the event of accidental administration of
overdosage, preclinical data suggest considering the administration of folinic acid, which, from clinical experience with other drugs of the same class, can be administered at
a dose of 25 mg/m² intravenously every 6 hours. If the time interval between
administration of Tomudex and folinic acid increases, the effectiveness of the latter in counteracting
toxic effects may decrease.
Manifestations of overdosage can easily be represented by a more severe form of adverse reaction than expected from the administration of the drug. Patients should therefore be
closely monitored for the onset of gastrointestinal and hematological toxicity. Symptomatic treatment and standard supportive measures should be used to treat such toxicities.