Temodal 2.5 mg/ml powder for solution for infusion

Temodal is an antitumour agent.

Temodal is used for the treatment of patients with specific forms of brain tumours:

• newly-diagnosed glioblastoma multiforme. Temodal is first used together with radiotherapy (concomitant phase of treatment) and after that alone (monotherapy phase of treatment).
• malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma. Temodal is used in these tumours if they return or get worse after standard treatment.

Do not use Temodal

• if you are allergic (hypersensitive) to temozolomide or any of the other ingredients of Temodal.
• if you have had an allergic reaction to dacarbazine (an anticancer medicine, sometimes called DTIC). Signs of allergic reaction include feeling itchy, breathlessness or wheezing, swelling of the face, lips, tongue or throat.
• if certain kinds of blood cells are severely reduced (myelosuppression), such as your white blood cell count and platelet count. These blood cells are important for fighting infection and for proper blood clotting. Your doctor will check your blood to make sure you have enough of these cells before you begin treatment.

Take special care with Temodal

• you should be observed closely for the development of a serious form of chest infection called Pneumocystis carinii pneumonia (PCP) . If you are a newly-diagnosed patient (glioblastoma multiforme) you may be receiving Temodal for 42 days in combination with radiotherapy. In this case, your doctor will also prescribe medicine to help you prevent this type of pneumonia (PCP).
• if you have low counts of red blood cells (anaemia), white blood cells and platelets, or blood clotting problems before starting the treatment, or if you develop them during treatment. Your doctor may decide to reduce the dose, interrupt, stop or change your treatment. You may also need other treatments. In some cases, it may be necessary to stop treatment with Temodal. Your blood will be tested frequently during treatment to monitor the side effects of Temodal on your blood cells.
• you may have a small risk of other changes in blood cells, including leukaemia.
• if you have nausea (feeling sick in your stomach) and/or vomiting which are very common side effects of Temodal (see section 4 ?Possible side effects?), your doctor may prescribe you a medicine (an anti-emetic) to help prevent vomiting.
• if you develop fever or symptoms of an infection, contact your doctor immediately.
• if you are older than 70 years of age, you might be more prone to infections, bruising or bleeding.
• if you have liver or kidney problems, your dose of Temodal may need to be adjusted.

Due to lack of experience, Temodal should not be used in children younger than 3 years.

Temodal may cause permanent infertility. Male patients should use effective contraceptions and not father a child for up to 6 months after stopping treatment. It is recommended to seek advice on conservation of sperm prior to treatment.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant, think you might be or are planning to get pregnant. You must not be treated with Temodal during pregnancy unless clearly indicated by your doctor. Effective contraceptive precautions must be taken by both male and female patients who are taking Temodal (see also ?Take special care with Temodal? above).

You should stop breast-feeding while receiving treatment with Temodal.

Driving and using machines
Temodal may make you feel tired or sleepy. In this case, do not drive or use any tools or machines.

Important information about some of the ingredients of Temodal

This medicinal product contains 2.4 mmol sodium per vial. This should be taken into consideration by patients on a controlled sodium diet.

Your doctor will work out your dose of Temodal. This is based on your size (height and weight) and if you have a recurrent tumour and have had chemotherapy treatment in the past.
You may be given other medicines (anti-emetics) to take before and/or after receiving Temodal to prevent or control nausea and vomiting.

Patients with newly-diagnosed glioblastoma multiforme:
If you are a newly-diagnosed patient, treatment will occur in two phases:

• treatment together with radiotherapy (concomitant phase) first
• followed by treatment with only Temodal (monotherapy phase).

During the concomitant phase, your doctor will start Temodal at a dose of 75 mg/m 2 (usual dose). You will receive this dose every day for 42 days (up to 49 days) in combination with radiation therapy. The Temodal dose may be delayed or stopped, depending on your blood counts and how you tolerate your medicine during the concomitant phase.
Once the radiotherapy is completed, you will interrupt treatment for 4 weeks. This will give your body a chance to recover.
Then, you will start the monotherapy phase.

During the monotherapy phase, the dose and way you receive Temodal in this phase will be different. Your doctor will work out your exact dose.
There may be up to 6 treatment periods (cycles). Each one lasts 28 days.

You will receive your new dose of Temodal alone once daily for the first 5 days of each cycle. The first dose will be 150 mg/m 2. Then you will have 23 days without Temodal. This adds up to a 28-day treatment cycle.
After Day 28, the next cycle will begin. You will again receive Temodal once daily for 5 days followed by 23 days without Temodal.
The Temodal dose may be adjusted, delayed or stopped depending on your blood counts and how you tolerate your medicine during each treatment cycle.

Patients with tumours that have returned or worsened (malignant glioma, such as glioblastoma

multiforme or anaplastic astrocytoma) receiving Temodal only:

A treatment cycle with Temodal lasts 28 days.

You will receive Temodal alone once daily for the first 5 days. This daily dose depends on whether or not you have received chemotherapy before.
If you have not been previously treated with chemotherapy, your first dose of Temodal will be 200 mg/m 2 once daily for the first 5 days. If you have been previously treated with chemotherapy, your first dose of Temodal will be 150 mg/m 2 once daily for the first 5 days.

Then, you will have 23 days without Temodal. This adds up to a 28 day treatment cycle.

After Day 28, the next cycle will begin. You will again receive Temodal once daily for 5 days, followed by 23 days without Temodal.

Before each new treatment cycle, your blood will be tested to see if the Temodal dose needs to be adjusted. Depending on your blood test results, your doctor may adjust your dose for the next cycle.

How Temodal is given

Temodal will be given to you by your doctor in a drip into a vein (intervenous infusion), only over approximately 90 minutes. No infusion site other than a vein is acceptable.

If you use more Temodal than you should
Your medicine is given to you by health care professionals. It is therefore unlikely that you will receive more Temodal than you should. However, if you do, the doctor or nurse will treat you accordingly.

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

Like all medicines, Temodal can cause side effects, although not everybody gets them.

Contact your doctorimmediatelyif you have any of the following:

• a severe allergic (hypersensitive) reaction (hives, wheezing or other breathing difficulty),
• uncontrolled bleeding,
• seizures (convulsions),
• fever,
• severe headache that does not go away.

Temodal treatment can cause a reduction in certain kinds of blood cells. This may cause you to have increased bruising or bleeding, anaemia (a shortage of red blood cells), fever, and reduced resistance to infections. The reduction in blood cell counts is usually short-lived. In some cases, it may be prolonged and may lead to a very severe form of anaemia (aplastic anaemia). Your doctor will monitor your blood regularly for any changes, and will decide if any specific treatment is needed. In some cases, your Temodal dose will be reduced or treatment stopped.

Side effects from clinical studies:

Side effects may occur with certain frequencies, which are defined as follows:
very common: affects more than 1 user in 10
common: affects 1 to 10 users in 100
uncommon: affects 1 to 10 users in 1,000
rare: affects 1 to 10 users in 10,000
very rare: affects less than 1 user in 10,000
not known: frequency cannot be estimated from the available data.

Temodal powder for solution for infusion

In addition to the side effects listed below, the following may also occur with the use of Temodal powder for solution for infusion: pain, irritation, itching, warmth, swelling or redness at the injection site; also bruising (haematoma).

Temodal in combination treatment with radiotherapy in newly-diagnosed glioblastoma

Patients receiving Temodal in combination with radiotherapy may experience different side effects than patients taking Temodal alone. The following side effects may occur, and may require medical attention.

Very common: loss of appetite, headache,constipation (difficulty passing stools), nausea (feeling sick in your stomach), vomiting, rash, hair loss, tiredness.

Common: oral infections, wound infection, reduced number of blood cells (neutropenia, thrombocytopenia, lymphopenia, leukopenia), increased sugar in the blood, loss of weight, change in mental status or alertness, anxiety/depression, sleepiness, difficulty speaking, impaired balance, dizziness, confusion, forgetfulness, difficulty concentrating, inability to fall asleep or stay asleep, tingling sensation, bruising, shaking, abnormal or blurry vision, double vision, hearing impairment, shortness of breath, cough, blood clot in the legs, fluid retention, swollen legs, diarrhoea, stomach or abdominal pain, heartburn, upset stomach, difficulty swallowing, dry mouth, skin irritation or redness, dry skin, itching, muscle weakness, painful joints, muscle aches and pains, frequent urination, difficulty with holding your urine, allergic reaction, fever, radiation injury, face swelling, pain, abnormal taste, abnormal liver function tests.

Uncommon: flu-like symptoms, red spots under the skin, appearance of a swollen face or muscle weakness, low potassium level in the blood, weight gain, mood swings, hallucination and memory impairment, partial paralysis, impaired coordination, difficulty swallowing, impaired sensations, partial loss of vision, dry or painful eyes, deafness, infection of the middle ear, ringing in the ears, earache, palpitations (when you can feel your heart beat), blood clot in the lung, high blood pressure, pneumonia, inflammation of your sinuses, bronchitis, a cold or the flu, swollen stomach, difficulty controlling your bowel movements, haemorrhoids, peeling skin, increased skin sensitivity to sunlight, change in skin colour, increased sweating, muscle damage, back pain, difficulty in urinating, vaginal bleeding, sexual impotence, absent or heavy menstrual periods, vaginal irritation, breast pain, hot flushes, shivering, discolouration of your tongue, change in your sense of smell, thirst, tooth disorder.

Temodal monotherapy in recurrent or progressive glioma

The following side effects may occur, and may require medical attention.

Very common: reduced number of blood cells (neutropenia or lymphopenia, thrombocytopenia), loss of appetite, headache, vomiting, nausea (feeling sick in your stomach), constipation (difficulty passing stools).

Common: loss of weight, tiredness, dizziness, tingling sensation, shortness of breath, diarrhoea, abdominal pain, upset stomach, rash, itching, hair loss, fever, weakness, shivering, feeling unwell, pain, change in taste.

Uncommon: reduced blood cell counts (pancytopenia, anaemia, leukopenia).

Rare: cough, infections including pneumonia.

Very rare: skin redness, urticaria (hives), skin eruption, allergic reactions.

Other side effects:

Very rare cases of severe rash with skin swelling, including on the palms of the hands and soles of the feet, or painful reddening of the skin and/or blisters on the body or in the mouth have been observed. Tell your doctor immediately if this occurs.

Very rare cases of lung side effects have been observed with Temodal. Patients usually present with shortness of breath and cough. Tell your doctor if you notice any of these symptoms.

In very rare cases, patients receiving Temodal and medicines like it may have a small risk of developing secondary cancers, including leukaemia.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Keep out of the reach and sight of children.

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

Store in a refrigerator (2°C ? 8°C).

Once your medicine is prepared for infusion (reconstituted), the solution may be stored at room temperature (25°C) for up to 14 hours, including infusion time.
The reconstituted solution should not be used if discolouration or particulate matter is observed.

Medicines should not be disposed of via wastewater of household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment.

What Temodal contains

The active substance is temozolomide. Each vial contains 100 mg temozolomide. After reconstitution, each ml solution for infusion contains 2.5 mg of temozolomide.

The other ingredients are mannitol (E421), threonine, polysorbate 80, sodium citrate (for pH-adjustment) and hydrochloric acid concentrated (for pH-adjustment).

What Temodal looks like and contents of the pack

The powder for solution for infusion is a white powder. Temodal is available in a glass vial, with a butyl rubber stopper and aluminium seal with a flip-off bonnet.
Each pack contains 1 vial of 100 mg temozolomide.

Marketing Authorization Holder and Manufacturer

Marketing Authorisation Holder: SP Europe, Rue de Stalle 73, B-1180 Bruxelles, Belgium

Manufacturer: SP Labo N.V., Industriepark 30, B-2220 Heist-op-den-Berg, Belgium

For any information about this medicinal product, please contact the local representative of the Marketing Authorisation Holder:

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The following information is intended for medical or health care professional use only:

Caution must be exercised in handling Temodal 2.5 mg/ml powder for solution for infusion. The use of gloves and aseptic technique is required. If Temodal 2.5 mg/ml comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

Each vial must be reconstituted with 41 ml sterilised water for injections. The resulting solution contains 2.5 mg/ml TMZ. The vials should be gently swirled and not shaken. The solution should be inspected and any vial containing visible particulate matter should not be used. Reconstituted product must be used within 14 hours, including infusion time.

A volume up to 40 ml reconstituted solution should be withdrawn, according to the total prescribed dose and transferred into an empty 250 ml PVC infusion bag. Studies with non-PVC bags have not been conducted. The pump tubing should be attached to the bag, the tubing purged and then capped. Temodal 2.5 mg/ml must be administered by intravenous infusion only over a period of 90 minutes.

In absence of compatibility studies this medicinal product must not be mixed with other medicinal products or infused simultaneously through the same intravenous line.

This medicinal product is for single use only. Any unused product or waste material should be disposed of in accordance with local requirements.