TEMODAL 2.5 mg/mL POWDER FOR SOLUTION FOR INFUSION

2. What you need to know before you use Temodal

Do not use Temodal

• if you are allergic to temozolomide or any of the other ingredients of this medicine (listed in section 6).
• if you have had an allergic reaction to dacarbazine (a cancer medicine, sometimes called DTIC). Signs of an allergic reaction include itching, shortness of breath or wheezing, swelling of the face, lips, tongue, or throat.

• if you have a severely reduced number of certain types of blood cells (myelosuppression), as well as a low white blood cell count and low platelet count. These blood cells are important for fighting infections and for proper blood clotting. Your doctor will ask for blood tests to check that you have a sufficient number of these cells before starting treatment.

Warnings and precautions

Talk to your doctor, pharmacist, or nurse before starting Temodal.

• as you will need to be closely monitored for the possible development of a severe respiratory infection called Pneumocystis jirovecii pneumonia (PCP). If you are a newly diagnosed patient (glioblastoma multiforme) you may be receiving Temodal in the 42-day regimen, in combination with radiotherapy. In this case, your doctor will also prescribe a medicine to help prevent this type of pneumonia (PCP).
• if you have ever had or may have hepatitis B infection, as Temodal could reactivate hepatitis B, which can be fatal in some cases. Before starting treatment, your doctor will carefully examine you for signs of this infection.

• if you have low red blood cell counts (anaemia), low white blood cell counts, and low platelet counts, or blood clotting problems before treatment, or if you develop them during treatment. Your doctor may reduce your dose of Temodal or stop it, or you may need other treatment. In some cases, it may be necessary to stop Temodal treatment. You will have regular blood tests to monitor the effects of Temodal on your blood cells.
• as you may have a low risk of other changes in your blood cells, including leukaemia.

• if you have nausea (feeling sick) and/or vomiting, which are very common side effects with Temodal (see section 4), your doctor may prescribe you a medicine to prevent vomiting (antiemetic).
• if you have a fever or symptoms of an infection, contact your doctor immediately.
• if you are over 70 years old, you may be more susceptible to infection and more prone to infections, bruising, and bleeding.
• if you have liver or kidney problems, your dose of Temodal will be adjusted.

Children and adolescents

Do not give this medicine to children under 3 years of age, as its effect in this age group has not been studied. There is limited information available in patients over 3 years who have used Temodal.

Other medicines and Temodal

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines.

Pregnancy, breast-feeding, and fertility

If you are pregnant, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine, as Temodal should not be used in pregnant women unless specifically indicated by your doctor.

Effective contraceptive methods are recommended for female patients who may become pregnant during treatment with Temodal and for at least 6 months after completing treatment.

You should stop breast-feeding while being treated with Temodal.

Male fertility

Temodal may cause permanent infertility. Male patients should use effective contraceptive methods and not make their partner pregnant during and for at least 3 months after treatment. It is recommended to consult about sperm preservation before treatment.

Driving and using machines

Temodal may make you feel tired or sleepy. In this case, do not drive or use tools or machines, or ride a bicycle until you see how this medicine affects you (see section 4).

Temodal contains sodium

This medicine contains 55.2 mg of sodium (main component of cooking/table salt) per vial. This is equivalent to 2.8% of the maximum recommended daily intake of sodium for an adult.

3. How to use Temodal

Follow the instructions for administration of this medicine exactly as told by your doctor or pharmacist. If you are not sure, ask your doctor or pharmacist again.

Your doctor will decide what dose of Temodal you should have. This will be based on your body size (height and weight), whether you have a recurrent tumour, and whether you have been treated with chemotherapy before.

You may be prescribed another medicine (antiemetic) to take before and/or after Temodal to prevent or control nausea and vomiting.

Patients with glioblastoma multiforme of new diagnosis:

If you are a newly diagnosed patient, treatment will be in two phases:

• first, treatment in combination with radiotherapy (concomitant phase)
• followed by treatment with Temodal alone (monotherapy phase).

During the concomitant phase, your doctor will start Temodal at a dose of 75 mg/m2 (standard dose). You will receive doses every day for 42 days (up to a maximum of 49 days) in combination with radiotherapy. The dose of Temodal may be delayed or interrupted, depending on your blood counts and how well you tolerate the medicine during the concomitant phase.

Once radiotherapy is completed, you will stop treatment for 4 weeks to allow your body to recover.

After that, you will start the monotherapy phase.

During the monotherapy phase, the dose and the way you receive Temodal will be different. Your doctor will tell you the exact dose.

There may be up to 6 cycles of treatment. Each cycle lasts 28 days.

Initially, you will receive your new dose of Temodal only once a day for the first 5 days of each cycle. The first dose will be 150 mg/ml. Then, there will be 23 days without Temodal. This adds up to a total treatment cycle of 28 days.

After day 28, you will start the next cycle. You will receive Temodal again once a day for 5 days, followed by 23 days without Temodal.

The dose of Temodal may be adjusted, delayed, or stopped, depending on your blood tests and how well you tolerate your medicine during each treatment cycle.

Patients with recurrent or progressive tumours (malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma) receiving only Temodal:

A treatment cycle with Temodal is 28 days.

You will receive Temodal only once a day for the first 5 days. This daily dose will depend on whether you have been treated with chemotherapy before or not.

If you have not been treated with chemotherapy before, your first dose of Temodal will be 200 mg/m2 once a day for the first 5 days. If you have been treated with chemotherapy before, your first dose of Temodal will be 150 mg/m2 once a day for the first 5 days.

Then, there will be 23 days without Temodal. This adds up to a total treatment cycle of 28 days.

After day 28, you will start a new cycle. You will receive Temodal again once a day for 5 days, followed by 23 days without Temodal.

Each time you start a new treatment cycle, your blood will be tested to check if your dose of Temodal needs to be adjusted. Depending on the results, your doctor may adjust your dose for the next cycle.

How Temodal is administered

Your doctor will administer Temodal through a catheter inserted into a vein (intravenous infusion), only for about 90 minutes. It cannot be administered at an infusion site other than a vein.

If you receive more Temodal than you should

A healthcare professional will administer Temodal. It is therefore unlikely that you will receive more Temodal than you should. However, if this happens, your doctor or nurse will treat you accordingly.

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

4. Possible side effects

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

Contact your doctor immediatelyif you have any of the following:

• a severe allergic reaction (hypersensitivity), such as hives, wheezing, or other difficulty breathing,
• uncontrolled bleeding,
• seizures,

• fever,
• chills,

• severe headache that does not go away.

Treatment with Temodal may cause a reduction in certain types of blood cells. This can make you more likely to bruise or bleed, have anaemia (reduced number of red blood cells), fever, and reduced resistance to infections. The reduction in blood cell counts is usually temporary. In some cases, it can be prolonged and may cause a very severe form of anaemia (aplastic anaemia). Your doctor will regularly test your blood to detect any changes and decide if you need specific treatment. In some cases, the dose of Temodal may be reduced or stopped.

The following are other side effects that have been reported:

Very common side effects (may affect more than 1 in 10 people) are:

• loss of appetite, difficulty speaking, headache
• vomiting, nausea, diarrhoea, constipation
• skin rash, hair loss
• fatigue

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

• infections, oral infections
• reduced number of blood cells (neutropenia, lymphopenia, thrombocytopenia)
• allergic reaction
• increased blood sugar
• memory changes, depression, anxiety, confusion, inability to sleep or stay asleep
• coordination and balance changes
• difficulty concentrating, changes in mental state or alertness, tingling sensation
• dizziness, altered sensations, tingling, tremors, abnormal taste
• partial loss of vision, abnormal vision, double vision, painful eyes
• hearing loss, ringing in the ears, ear pain
• blood clots in the lungs or legs, high blood pressure
• pneumonia, shortness of breath, bronchitis, cough, nasal passage inflammation
• stomach or abdominal pain, stomach upset/acid reflux, difficulty swallowing
• dry skin, itching
• muscle damage, muscle weakness, muscle pain and discomfort
• joint pain, back pain
• frequent urination, difficulty holding urine
• fever, flu-like symptoms, pain, discomfort, cold or flu
• fluid retention, swollen legs
• increased liver enzymes
• weight loss, weight gain
• radiation injury

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

• brain infections (herpetic meningoencephalitis), including fatal cases
• wound infections
• new or reactivated cytomegalovirus infections
• reactivated hepatitis B virus infections
• secondary cancers, including leukaemia
• reduced blood cell counts (pancytopenia, anaemia, leucopenia)
• red spots under the skin
• diabetes insipidus (symptoms include increased urination and thirst), low potassium levels in the blood
• mood changes, hallucinations
• partial paralysis, change in sense of smell
• hearing impairment, middle ear infection
• palpitations (when you can feel your heart beating), hot flushes
• bloated stomach, difficulty controlling bowel movements, haemorrhoids, dry mouth
• hepatitis and liver damage (including fatal liver failure), cholestasis, increased bilirubin
• blisters on the body or in the mouth, skin peeling, skin rash, redness, painful skin redness (including on the palms of the hands and soles of the feet)
• increased sensitivity to sunlight, hives (urticaria), increased sweating, skin colour changes
• difficulty urinating
• vaginal bleeding, vaginal irritation, absent or heavy menstrual periods, breast pain, impotence
• chills, facial swelling, discolouration of the tongue, thirst, tooth disorder
• dry eyes

Temodal powder for solution for infusion

In addition to the side effects mentioned above, the following can 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).

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse, even if it is not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Temodal

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 label and carton. The expiry date refers to the last day of the month shown.

Store in a refrigerator (between 2°C and 8°C).

Once your medicine has been prepared for infusion (reconstituted), the solution should be stored at room temperature (25°C) for up to a maximum of 14 hours, including the infusion time.

The reconstituted solution should not be used if discolouration or particles are observed.

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

6. Container Contents and Additional Information

Temodal Composition

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

The other components are mannitol (E421), threonine, polysorbate 80, sodium citrate (for pH adjustment), and concentrated hydrochloric acid (for pH adjustment) (see section 2).

Product Appearance and Container Contents

The powder for solution for infusion is a white powder. Temodal is available in a glass vial, with a butyl rubber stopper and an aluminum cap with a easy-to-remove seal.

Each container contains 1 vial of 100 mg of temozolomide.

For further information about this medicinal product, please contact the local representative of the marketing authorization holder:

Date of Last Revision of this Leaflet:

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website: https://www.ema.europa.eu.

This information is intended solely for medical or healthcare professionals:

Caution should be exercised when handling Temodal 2.5 mg/ml powder for solution for infusion. Gloves and aseptic technique should be used. If Temodal 2.5 mg/ml comes into contact with skin or mucous membranes, the area should be washed immediately and thoroughly with water and soap.

Each vial should be reconstituted with 41 ml of sterile water for injections. The resulting solution contains 2.5 mg/ml of TMZ. These vials should be rotated gently and not shaken. The solution should be inspected, and any vial containing visible particulate matter should not be used. The reconstituted product should be used before 14 hours, including infusion time.

A volume of up to 40 ml of reconstituted solution should be withdrawn, according to the total prescribed dose, and transferred to an empty 250 ml infusion bag (PVC or polyolefin). The infusion set should be connected to the bag, the line should be purged, and then closed. Temodal 2.5 mg/ml should be administered by intravenous infusion onlyover a period of 90 minutes.

Temodal 2.5 mg/ml powder for solution for infusion can be administered through the same intravenous line as sodium chloride 0.9%. It is incompatible with dextrose solutions.

In the absence of additional data, this medicinal product should not be mixed with other medicinal products or infused simultaneously through the same intravenous line.

This medicinal product is for single use only. Disposal of unused medicinal product and all materials that have come into contact with it should be carried out in accordance with local regulations.