Consumer medicine information

Temozolomide JUNO

Temozolomide

BRAND INFORMATION

Brand name

Temozolomide Juno

Active ingredient

Temozolomide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Temozolomide JUNO.

What is in this leaflet

This leaflet answers some common questions about Temozolomide JUNO.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking Temozolomide JUNO against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine. You may need to read it again.

What Temozolomide JUNO is used for

Temozolomide JUNO contains temozolomide as the active ingredient and belongs to a group of medicines called cytotoxics or chemotherapy medicines. It works by killing cancer cells and stopping cancer cells from growing and multiplying.

Temozolomide JUNO is used to treat:

  • patients with brain tumours
  • adult patients with advanced metastatic malignant melanoma.

Ask your doctor if you have any questions about why Temozolomide JUNO has been prescribed for you. Your doctor may have prescribed Temozolomide JUNO for another reason.

Use in children

Temozolomide JUNO can be used to treat children, 3 years of age and older, with specific forms of brain cancer (glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy).

Temozolomide JUNO is available only with a doctor's prescription.

Before you take it

When you must not take it

Do not take Temozolomide JUNO if you are allergic to medicines containing temozolomide, dacarbazine or any of the ingredients listed at the end of this leaflet. Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take Temozolomide JUNO if you have very low levels of white blood cells, red blood cells or platelets.

Do not take Temozolomide JUNO if you are pregnant.

Do not take Temozolomide JUNO if you or your partner intend to become pregnant. Temozolomide JUNO may cause birth defects if either the male or female is using Temozolomide JUNO at the time of conception or during pregnancy. Therefore, female patients must have a negative pregnancy test before starting Temozolomide JUNO. Both male and female patients and their partners should each use some kind of birth control while taking Temozolomide JUNO. Male patients whose partners are already pregnant should use a condom to minimise exposure of the unborn baby to Temozolomide JUNO in the sperm.

Do not take Temozolomide JUNO if you are breastfeeding.

Do not take Temozolomide JUNO if the expiry date (Exp.) printed on the pack has passed.

Do not take Temozolomide JUNO if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you intend to have children. Temozolomide JUNO may cause infertility in men.

Tell your doctor if you have any medical conditions, especially the following:

  • liver or kidney problems
  • anaemia or blood clotting problems

Tell your doctor if you vomit frequently. Your doctor may give you medicine to control the vomiting.

If you have not told your doctor about any of the above, tell them before you start taking Temozolomide JUNO.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by Temozolomide JUNO, or may affect how well it works. These include other medicines used to treat cancer or any other treatments that may affect your immune system. You may need different amounts of your medicine or you may need to use different medicines. Your doctor will advise you.

How to take it

Follow all directions given to you by your doctor carefully.

How much to take

Your doctor has worked out the exact dose of Temozolomide JUNO for you according to your individual needs. You may be given other medication to take before or after Temozolomide JUNO to help stop nausea.

Temozolomide JUNO in combination treatment with radiation (newly diagnosed patients):

If you are a patient with a newly diagnosed brain tumour, your doctor will start you on a dose of Temozolomide JUNO every day for 42 days (up to 49 days) in combination with radiation therapy. This is the first part of the treatment ("concomitant phase") in which you complete the radiation therapy. Your treatment will be interrupted for 4 weeks to give your body a chance to recover.

You will then start the next phase of treatment ("adjuvant phase") and your Temozolomide JUNO dose will change. In this phase, there are up to 6 treatment cycles. Each treatment cycle lasts 28 days. You will take your new dose of Temozolomide JUNO capsules once daily for the first five days ("dosing days") of each cycle, followed by 23 days without Temozolomide JUNO; this adds up to a 28 day treatment cycle. After day 28, the next cycle will begin, in which you will again take this medicine once daily for five days followed by 23 days without Temozolomide JUNO.

Before each new treatment cycle begins, your blood will be tested todetermine if the Temozolomide JUNO dose needs to be adjusted.

Taking Temozolomide JUNO alone (patients treated for recurrent brain tumour):

Take the dose the doctor has prescribed once a day for five days.

Depending on your response to Temozolomide JUNO, a new treatment cycle will begin each 28 days. You will then take this medicine again once daily for five days.

Before each new treatment cycle, your blood will be tested to see if the dose needs to be changed.

How to take it

Swallow the capsules whole with a glass of water. Do not open or chew the capsules.

Each time you start a new treatment cycle, be sure you understand exactly how many capsules of each strength you need to take on each day of dosing.

Temozolomide JUNO comes in different strength capsules (shown on the outer label in ‘mg’). Each strength is a different colour. Depending on the dose of Temozolomide JUNO that your doctor prescribes, you may have to take several capsules on each dosing day of the treatment cycle

Be sure you understand exactly how many capsules you need to take of each strength. Ask your doctor or pharmacist to write down the number of each strength (include colour) that you need to take on each dosing day.

Be sure you know exactly which days are your dosing days.

Be sure you review the dose with your health care provider each time you start a new cycle. Sometimes the dose or the mix of capsules you need to take will be different from the last cycle.

Once you take the medicine home, if you are confused or unsure about how to take your dose, call for re-instruction before beginning the treatment cycle. Errors in how you take this medicine may have serious health consequences.

When to take it

Take Temozolomide JUNO without food at least one hour before a meal. It is good practice to take it at about the same time each day.

If vomiting occurs after you take your capsules, do not take another dose that day.

How long to take it for

Keep taking Temozolomide JUNO exactly as your doctor recommends. Your doctor will tell you when your treatment should be stopped.

If you forget to take it

If you miss a dose, take the missed dose as soon as possible during the same day. If a full day has gone by, check with your doctor.

Do not take a double dose to make up for the dose you missed unless your doctor tells you to.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much Temozolomide JUNO. Do this even if there are no signs of discomfort or poisoning.

While you are taking it

Things you must do

Tell all doctors, dentists and pharmacists who are treating you that you are taking Temozolomide JUNO.

Tell your doctor if you feel sick or vomit while being treated with Temozolomide JUNO. Your doctor may give you another medicine to help with this.

Tell your doctor if you become unusually pale or tired, get blood clotting problems or frequent infections while being treated with Temozolomide JUNO. These could be caused by a low level of red blood cells, platelets or white blood cells in the blood. This is more common in patients over 70years of age. Your doctor may need to change your dose of Temozolomide JUNO.

Tell your doctor immediately if you or your partner becomes pregnant while taking Temozolomide JUNO.

Be sure to keep all your doctor's appointments so your progress can be checked. Your doctor may need to do some blood and other tests from time to time to check on your progress and detect any unwanted side effects.

Keep follow-up appointments with your doctor. It is important to have your follow-up doses of Temozolomide JUNO at the appropriate times to get the best effects from your treatment.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are being treated with Temozolomide JUNO.

Things you must not do

Do not open the capsules. If a capsule is damaged, avoid contact with your skin, eyes and nose. Avoid inhaling the powder. If you touch the powder or get some in your eyes or nose, wash the area with water.

Do not use Temozolomide JUNO to treat any other conditions unless your doctor tells you to.

Do not give Temozolomide JUNO to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how Temozolomide JUNO affects you.

Temozolomide JUNO may cause drowsiness, in some people.

If this occurs, do not drive, operate machinery or do anything else that could be dangerous.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Temozolomide JUNO.

Like all other medicines, Temozolomide JUNO may have unwanted side effects in some people. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they worry you:

  • nausea, vomiting, feeling unwell
  • tiredness, sleepiness
  • constipation
  • headache
  • loss of appetite or weight
  • diarrhoea
  • fever or high temperature
  • rash, hair loss, itching
  • dizziness, weakness
  • general body pain
  • stomach pain, indigestion
  • different taste sensation
  • mouth ulcers
  • coughing
  • sleeplessness.

These are the more common side effects of Temozolomide JUNO.

Tell your doctor as soon as possible if you notice any of the following:

  • shortness of breath
  • tingling or numbness in hands or feet
  • bruising, bleeding or being unusually pale or tired. This could be caused by a low level of platelets or red blood cells in the blood
  • any signs of infection, such as shivering that is associated with chills and fever, joint pain and loss of appetite. This could be a sign of an infection caused by a low level of white blood cells in the blood
  • symptoms such as fever, headache, personality change, seizures and/or vomiting which could be associated with a brain infection caused by a herpes virus.
  • fever, skin rash, swollen lymph nodes and/or facial swelling.
  • symptoms of diabetes, such as passing large amounts of urine and constant thirst.
  • development of red or purple spots under the skin.

These may be serious side effects. You may need medical attention.

Shivering associated with chills and fever or the development of red or purple spots under the skin may take some time to occur.

Therefore, even after you have finished your treatment with Temozolomide JUNO, you should tell your doctor immediately if you notice these side effects.

Tell your doctor if you notice anything else that is making you feel unwell. Other side effects not listed above may also occur in some patients.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking it

Storage

Keep Temozolomide JUNO where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Keep your capsules in the original sachets or bottles until it is time to take them.

Keep your capsules in a cool dry place where the temperature stays below 25°C.

Do not store Temozolomide JUNO or any other medicine in the bathroom or near a sink. Do not leave it in the car or on windowsills. Heat and dampness can destroy some medicines.

Disposal

Return any unused medicine to your pharmacist.

Product description

What it looks like

Temozolomide JUNO capsules come in 5 strengths:

  • 5 mg– green and white capsule printed with “TMZ” and “5” in black
  • 20 mg– yellow and white capsule printed with “TMZ” and “20” in black
  • 100 mg– pink and white capsule printed with “TMZ” and “100” in black
  • 140 mg– blue and white capsule printed with “TMZ” and “140” in black
  • 180 mg – maroon and white capsule printed with “TMZ” and “180” in black
  • 250 mg– white capsule printed with “TMZ” and “250” in black.

Sachet Pack: Each sachet contains 1 capsule. There are 5 sachets or 20 sachets in a pack.

Bottle Pack: Each bottle contains 5 capsules or 20 capsules.

Ingredients

The active ingredient in Temozolomide JUNO is temozolomide:

  • each Temozolomide JUNO 5 capsule contains 5 mg of temozolomide
  • each Temozolomide JUNO 20 capsule contains 20 mg of temozolomide
  • each Temozolomide JUNO 100 capsule contains 100 mg of temozolomide
  • each Temozolomide JUNO 140 capsule contains 140 mg of temozolomide
  • each Temozolomide JUNO 180 capsule contains 180 mg of temozolomide
  • each Temozolomide JUNO 250 capsule contains 250 mg of temozolomide.

Temozolomide JUNO contains sugars as lactose.

The capsules also contain:

  • colloidal anhydrous silica
  • sodium starch glycollate
  • tartaric acid
  • stearic acid.

The capsule shells contain:

  • gelatin
  • water
  • titanium dioxide
  • indigo carmine CI73015 (5 mg and 140 mg capsules only)
  • iron oxide yellow (5 mg and 20 mg capsules only)
  • iron oxide red (100 mg capsules only)
  • sodium lauryl sulfate (250 mg capsules only)
  • TekPrint SW-9008 black ink, (ARTG 2328).

Temozolomide JUNO does not contain sucrose, gluten, tartrazine or other azo dyes.

Sponsor

Juno Pharmaceuticals Pty Ltd
42 Kelso Street,
Cremorne,
VIC – 3121

Australian registration numbers (sachets):

  • Temozolomide JUNO 5 - AUST R 206042
  • Temozolomide JUNO 20 - AUST R 206043
  • Temozolomide JUNO 100 - AUST R 206044
  • Temozolomide JUNO 140 - AUST R 206215
  • Temozolomide JUNO 180 - AUST R 206045
  • Temozolomide JUNO 250 - AUST R 206046.

Australian registration numbers (bottles):

  • Temozolomide JUNO 5 - AUST R 354885
  • Temozolomide JUNO 20 - AUST R 354886
  • Temozolomide JUNO 100 - AUST R 354887
  • Temozolomide JUNO 140 - AUST R 354890
  • Temozolomide JUNO 180 - AUST R 354888
  • Temozolomide JUNO 250 - AUST R 354889.

This leaflet was revised in May 2021.

Published by MIMS July 2021

BRAND INFORMATION

Brand name

Temozolomide Juno

Active ingredient

Temozolomide

Schedule

S4

 

1 Name of Medicine

Temozolomide.

2 Qualitative and Quantitative Composition

Temozolomide Juno capsules come in 6 strengths and contain 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg of temozolomide.

List of excipients with known effect.

Contains sugars as lactose. For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Temozolomide Juno (temozolomide) 5 mg.

Green and white hard capsules, printed in black ink with "TMZ" on the cap and "5" on the body.

Temozolomide Juno (temozolomide) 20 mg.

Yellow and white hard capsules, printed in black ink with "TMZ" on the cap and "20" on the body.

Temozolomide Juno (temozolomide) 100 mg.

Pink and white hard capsules, printed in black ink with "TMZ" on the cap and "100" on the body.

Temozolomide Juno (temozolomide) 140 mg.

Blue and white hard capsules, printed in black ink with "TMZ" on the cap and "140" on the body.

Temozolomide Juno (temozolomide) 180 mg.

Maroon and white hard capsules, printed in black ink with "TMZ" on the cap and "180" on the body.

Temozolomide Juno (temozolomide) 250 mg.

White hard capsules, printed in black ink with "TMZ" on the cap and "250" on the body.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and then as adjuvant treatment.
Treatment of recurrence of anaplastic astrocytoma and glioblastoma multiforme following standard therapy.
Temozolomide Juno is also indicated as a first-line treatment for patients with advanced metastatic malignant melanoma.

4.2 Dose and Method of Administration

Antiemetic therapy may be administered prior to or following administration of temozolomide.
Temozolomide should be administered in the fasting state at least one hour before a meal. If vomiting occurs after the dose is administered, a second dose should not be administered that day. Temozolomide capsules must not be opened or chewed, but are to be swallowed whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membrane.

Adult patients with newly diagnosed glioblastoma multiforme.

Concomitant phase.

Temozolomide is administered orally at 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions) followed by adjuvant temozolomide for six cycles. No dose reductions are recommended, however, dose interruptions may occur based on patient tolerance. The temozolomide dose can be continued throughout the 42 day concomitant period up to 49 days (if needed due to radiotherapy interruption) if all of the following conditions are met: ANC greater than or equal to 1.5 x 109/L, thrombocyte count greater than or equal to 100 x 109/L, common toxicity criteria (CTC) nonhaematological toxicity less than or equal to grade 1 (except for alopecia, nausea and vomiting). During treatment a complete blood count should be obtained weekly. Temozolomide dosing should be interrupted or discontinued during concomitant phase according to the haematological and nonhaematological toxicity criteria as noted in Table 1.

Adjuvant phase.

Four weeks after completing the temozolomide + radiotherapy phase, temozolomide is administered for an additional six cycles of adjuvant treatment. Dosage in cycle 1 (adjuvant) is 150 mg/m2 once daily for five days followed by 23 days without treatment. At the start of cycle 2, the dose is escalated to 200 mg/m2 if the CTC nonhaematological toxicity for cycle 1 is grade less than or equal to 2 (except for alopecia, nausea and vomiting), ANC is greater than or equal to 1.5 x 109/L and the thrombocyte count is greater than or equal to 100 x 109/L. If the dose was not escalated at cycle 2, escalation should not be done in subsequent cycles. The dose remains at 200 mg/m2 per day for the first five days of each subsequent cycle except if toxicity occurs. Dose reductions during the adjuvant phase should be applied according to Tables 2 and 3.
During treatment a complete blood count should be obtained on day 22 (21 days after the first dose of temozolomide). The temozolomide dose should be reduced or discontinued according to Table 3.

Adults with recurrent glioblastoma multiforme or anaplastic astrocytoma.

In recurrent adult patients previously untreated with chemotherapy, temozolomide is administered orally at a dose of 200 mg/m2 once daily for five days per 28 day cycle. For those previously treated with chemotherapy, the initial dose is 150 mg/m2 once daily, to be increased in the second cycle to 200 mg/m2 daily providing the ANC is greater than or equal to 1.5 x 109/L and the platelet count is greater than or equal to 100 x 109/L on day 1 of the next cycle.
Dose modification for temozolomide should be based on toxicities according to nadir ANC or platelet counts.

Adults with metastatic malignant melanoma.

For patients with metastatic malignant melanoma, the recommended dose is 200 mg/m2 once daily for five days per 28 day cycle.

Paediatric patients with recurrent glioblastoma multiforme or anaplastic astrocytoma.

In patients 3 years of age or older, temozolomide is administered orally at a dose of 200 mg/m2 once daily for five days per 28 day cycle. Paediatric patients previously treated with chemotherapy or craniospinal irradiation should receive an initial dose of 150 mg/m2 once daily for five days, with escalation to 200 mg/m2 once daily at the next cycle if there is no toxicity.
The efficacy of temozolomide for the treatment of recurrent glioblastoma multiforme in patients who received the drug as concomitant/adjuvant treatment has not been established.
In patients with recurrent glioblastoma multiforme/anaplastic astrocytoma or metastatic melanoma, can be continued until disease progression or for a maximum of two years.

4.3 Contraindications

History of hypersensitivity reaction to components of temozolomide or to DTIC.
Use during pregnancy and in women who intend to become pregnant (see Section 4.6 Fertility, Pregnancy and Lactation).
Must not be used by breastfeeding women (see Section 4.6 Fertility, Pregnancy and Lactation).
Severe myelosuppression.

4.4 Special Warnings and Precautions for Use

Pneumocystis carinii pneumonia.

Patients who received concomitant temozolomide and radiotherapy in a pilot trial for the prolonged 42 day schedule were shown to be at particular risk for developing Pneumocystis carinii pneumonia (PCP).
Thus, prophylaxis against PCP is required for all patients receiving concomitant temozolomide and radiotherapy for the 42 day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphocytopenia occurs PCP prophylaxis should continue to a lymphocyte count less than or equal to grade 1.
There may be a higher occurrence of PCP when temozolomide is administered during a longer dosing regimen. However, all patients receiving temozolomide, particularly patients receiving steroids, should be observed closely for the development of PCP regardless of the regimen.

Hepatotoxicity.

Hepatic injury, including fatal hepatic failure, has been reported very rarely in patients treated with temozolomide. Baseline liver function tests should be performed prior to treatment initiation. If abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should be repeated midway during this cycle. For all patients, liver function tests should be checked after each treatment cycle. For patients with significant liver function abnormalities, physicians should assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after the last treatment with temozolomide.

HBV reactivation.

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been reported. Patients should be screened for HBV infection before treatment initiation. Patients with evidence of prior HBV infection should be monitored for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with temozolomide. Therapy should be discontinued for patients with evidence of active hepatitis B infection.

Antiemetic therapy.

Nausea and vomiting are very commonly associated with temozolomide and guidelines are provided as follows.

Patients with newly diagnosed glioblastoma multiforme.

Antiemetic prophylaxis is recommended prior to the initial dose of concomitant temozolomide.
Antiemetic prophylaxis is strongly recommended during the adjuvant phase.

Patients with recurrent glioma.

Patients who have experienced severe (grade 3 or 4) vomiting in previous treatment cycles may require antiemetic therapy.

All patients.

Keep this medication out of the reach of children.

Myelosuppression.

Temozolomide causes myelosuppression. Patients treated with temozolomide may also experience prolonged pancytopenia. This may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some cases, exposure to concomitant medications associated with aplastic anaemia, including carbamazepine, phenytoin and sulfamethoxazole/trimethoprim complicates assessment. Prior to dosing, the following laboratory parameters must be met: absolute neutrophil count (ANC) of > 1.5 x 109/L and platelets of > 100 x 109/L. During cyclical treatment a complete blood count must be obtained on day 22 (21 days after the first dose) or within 48 hours of that day, and weekly until ANC is above 1.5 x 109/L and platelet count exceeds 100 x 109/L. If ANC falls to < 1.0 x 109/L or the platelet count is < 50 x 109/L during any cycle, the next cycle should be reduced one dose level. Dose levels include 100, 150 and 200 mg/m2. The lowest recommended dose is 100 mg/m2.

Use in hepatic impairment.

No data are available on the administration of temozolomide in patients with hepatic dysfunction. Based on the pharmacokinetic properties of temozolomide, it is unlikely that dose reductions are required in such patients. However, caution should be exercised when temozolomide is administered to these patients. See Section 4.4 Special Warnings and Precautions for Use, Hepatotoxicity.

Use in renal impairment.

No data are available on the administration of temozolomide in patients with renal dysfunction. Based on the pharmacokinetic properties of temozolomide, it is unlikely that dose reductions are required in such patients. However, caution should be exercised when temozolomide is administered to these patients.

Use in the elderly.

Elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients.

Paediatric use.

Anaplastic astrocytoma/ glioblastoma multiforme.

There is limited experience in children over the age of 3 years with glioma (see Section 5.1 Pharmacodynamic Properties, Clinical trials). There is no clinical experience with use of temozolomide in children under the age of 3 years.

Melanoma.

There is no clinical experience in patients under 18 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Administration of temozolomide with ranitidine did not result in clinically significant alterations in the extent of absorption of temozolomide. Coadministration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2-receptor antagonists or phenobarbitone did not alter the clearance of temozolomide. Coadministration with valproic acid was associated with a small but statistically significant decrease in clearance of temozolomide.
Use of temozolomide in combination with other alkylating agents or O6-alkylguanine-DNA alkyltransferases may increase the likelihood of myelosuppression and general toxicity.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Temozolomide is contraindicated in women who intend to become pregnant, and effective contraception should be used by female patients during and for at least 6 months after treatment with temozolomide (see Section 4.3 Contraindications; Section 4.6 Fertility, Pregnancy and Lactation).

Use in men.

Effective contraception should be used by male patients treated with temozolomide as it can have genotoxic effects. Therefore, men being treated with temozolomide are advised not to father a child for at least 3 months after receiving the final dose and to seek advice on cryoconservation of spermatozoa prior to treatment because of the possibility of irreversible impairment in fertility due to therapy with temozolomide. Semen donation is also not advised during treatment and for at least 3 months after the final dose. (see Section 5.3 Preclinical Safety Data; Section 4.6 Fertility, Pregnancy and Lactation).
(Category D)
Cytotoxic agents can produce spontaneous abortion, foetal loss and birth defects. There are no studies in pregnant women. In preclinical studies in rats and rabbits administered 150 mg/m2, (associated with systemic exposure below that anticipated in humans) teratogenicity and/or foetal toxicity were demonstrated. Temozolomide, therefore, should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus. Women of childbearing potential should be advised to avoid pregnancy if they are going to receive temozolomide treatment and for six months after discontinuation of therapy.
 It is not known whether temozolomide is excreted in human milk. A peri/postnatal study in rats found that treatment with temozolomide at doses of greater than 25 mg/m2/day decreased pup growth and retarded development. Given its potential adverse effects in the newborn, temozolomide must not be used by breastfeeding women.

4.7 Effects on Ability to Drive and Use Machines

Temozolomide may influence the ability to drive and use machines due to fatigue and somnolence (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Newly diagnosed glioblastoma multiforme.

See Table 4.

Patients with recurrent anaplastic astrocytoma, glioblastoma multiforme or malignant melanoma.

The frequency of adverse drug reactions reported in clinical trials or spontaneously is listed below and classified according to body system. Frequency estimates: Very common (≥ 10%), Common (≥ 1% and < 10%).

Neurological.

Very common: fatigue, headache.
Common: somnolence, asthenia, dizziness, paraesthesia.

Gastrointestinal.

Very common: nausea, vomiting, constipation, anorexia.
Common: diarrhoea, abdominal pain, dyspepsia, taste perversion.

Haematological.

Very common: thrombocytopenia, neutropenia.
Common: anaemia, leucopenia.

Dermatological.

Common: rash, alopecia, pruritus, petechiae.

Respiratory.

Common: dyspnoea.

General.

Common: fever, pain, malaise, weight decrease, rigors.
In clinical trials, the most frequently occurring undesirable effects were gastrointestinal disturbances, specifically nausea (43%) and vomiting (36%). These effects were usually grade 1 or 2 (mild to moderate in severity) and were either self limiting or readily controlled with standard antiemetic therapy. The incidence of severe nausea and vomiting was 4%. Severe myelosuppression, predominantly thrombocytopenia, was dose limiting and occurred in 7% of all patients. Anaemia was reported in 5% of patients. Severe neutropenia and leucopenia occurred in 3 and 2% of patients, respectively.
In children, the incidence of the more common adverse events (nausea, vomiting, various CNS events and those of haematological origin) are consistent with the results from studies in adults as well as the underlying disease.

Myelosuppression.

In adult patients myelosuppression was common, with grade 3 or 4 thrombocytopenia and neutropenia observed in 19 and 17% of patients, respectively, treated for glioma and 20 and 22%, respectively, of patients with metastatic melanoma. This led to hospitalisation and/or discontinuation of temozolomide in 8 and 4%, respectively, of patients with glioma and 3 and 1.3%, respectively, of those with melanoma. Myelosuppression was predictable (usually within the first few cycles, with the nadir between day 21 and 28), and recovery was rapid, usually within one to two weeks. No evidence of cumulative myelosuppression was observed. Pancytopenia, leucopenia and anaemia have also been reported. Lymphopenia has also been reported very commonly.
In a population pharmacokinetics analysis of clinical trial experience, there were 101 female and 169 male subjects for whom nadir neutrophil counts were available and 110 female and 174 male subjects for whom nadir platelet counts were available. There were higher rates of grade 4 neutropenia (ANC < 0.5 x 109/L) (12 versus 5%) and thrombocytopenia (< 20 x 109/L) (9 versus 3%), in women versus men in the first cycle of therapy. In a 400 subject recurrent glioma data set, grade 4 neutropenia occurred in 8% of female versus 4% of male subjects and grade 4 thrombocytopenia in 8% of female versus 3% of male subjects in the first cycle of therapy. In a study of 288 subjects with newly diagnosed glioblastoma multiforme, grade 4 neutropenia occurred in 3% of female versus 0% of male subjects and grade 4 thrombocytopenia in 1% of female versus 0% of male subjects in the first cycle of therapy.
In children the incidence of myelosupression was similar to that seen in adults. In the phase II clinical trial, the incidences of grade 4 thrombocytopenia and neutropenia were 16 and 11%, respectively. Myelosupression was usually transient and reversible with cessation of temozolomide treatment.

Postmarketing experience with temozolomide.

During the marketing of temozolomide, allergic reactions, including anaphylaxis, have been reported very rarely. Very rare cases of erythema multiforme, toxic epidermal necrolysis and Stevens-Johnson syndrome have also been observed. Drug reaction with eosinophilia and systemic symptoms has been reported with a frequency of unknown. There have been reported cases of hepatotoxicity including elevations of liver enzymes, hyperbilirubinaemia, cholestasis and hepatitis. Hepatic injury, including fatal hepatic failure, has been reported very rarely (see Section 4.4 Special Warnings and Precautions for Use).
Rarely, cases of opportunistic infections including Pneumocystis carinii pneumonia (PCP) and both primary and reactivated cytomegalovirus (CMV) infection have been reported. Cases of reactivation of hepatitis B infections, including some cases with fatal outcomes have also been reported (see Section 4.4 Special Warnings and Precautions for Use). Cases of herpes simplex encephalitis, including cases with fatal outcomes, have also been reported. Cases of sepsis have also been reported. Cases of interstitial pneumonitis/pneumonitis and pulmonary fibrosis have been reported very rarely. Very rare cases of myelodysplastic syndrome (MDS) and secondary malignancies, including myeloid leukaemia, have also been observed. Prolonged pancytopenia which may result in aplastic anaemia has been reported and in some cases resulted in a fatal outcome. Diabetes insipidus has also been reported.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Doses of 500, 750, 1,000 and 1,250 mg/m2 (total dose per cycle over five days) have been evaluated clinically in patients. Dose limiting toxicity was haematological and was reported at any dose but is expected to be more severe at higher doses. An overdose of 2,000 mg per day for five days was taken by one patient and the adverse events reported were pancytopenia, pyrexia, multiorgan failure and death.
There are reports of patients who have taken more than five days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Temozolomide is an imidazotetrazine alkylating agent with antitumour activity. It undergoes rapid chemical conversion in the systemic circulation at physiological pH to the active compound, monomethyl triazeno imidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be due primarily to alkylation at the O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.
Single dose toxicity studies of temozolomide were conducted in mice, rats and dogs. Estimated LD50 doses by the oral route were moderately higher in the rat (approximately 1,900 mg/m2) than in the mouse (approximately 1,000 mg/m2). The minimum lethal dose in dogs was 600 mg/m2. In the single dose studies, clinical signs of toxicity and death were generally delayed, reflecting a delayed toxicity to tissues that normally proliferate more rapidly resulting in general deterioration of organ function; toxicity is consistent with that expected of an alkylating agent.
Temozolomide is rapidly absorbed following oral administration. Systemic exposure at the therapeutic dose level in humans is similar to that of the rat and dog.
Single cycle (five day dosing, 23 days nontreatment), three and six cycle toxicity studies were conducted in rats and dogs. In multiple cycle studies, the primary targets of toxicity included bone marrow, lymphoreticular system, testes and gastrointestinal tract with evidence of toxic effects on the lung, liver, kidney, thyroid gland, urinary bladder, central nervous system (CNS) and retina. Temozolomide appears to be more toxic to rats and dogs than to humans, as the therapeutic dose regimen (200 mg/m2), which has been well tolerated in humans, approximates the minimum lethal dose following multiple doses in both rats and dogs. At this dose level, the plasma area under the curve (AUC) for temozolomide in rats was similar to that anticipated in adult patients and about 60% of that in children; the corresponding value in dogs was about 65 and 40% of that in adult and paediatric patients, respectively. Dose related reductions in leucocytes and platelets appear to be sensitive indicators of toxicity in both rats and dogs. During intervals when dosing is discontinued, significant evidence of recovery from most haematological, biochemical and histopathological changes occurs. However, due to the delayed toxicity of temozolomide, patients should be closely monitored throughout the whole treatment cycle, including the nontreatment period.

Clinical trials.

Newly diagnosed glioblastoma multiforme.

573 patients were randomised to receive either temozolomide (TMZ) + focal radiotherapy (RT) (n=287) or focal RT alone (n=286). Patients in the temozolomide + RT arm received concomitant temozolomide (75 mg/m2) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by adjuvant temozolomide (150 to 200 mg/m2) on day 1 to 5 of every 28 day cycle for six cycles, starting four weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis carinii pneumonia (PCP) prophylaxis was required during RT and combined temozolomide therapy. PCP prophylaxis was given regardless of lymphocyte count and was continued during RT/TMZ until lymph recovery to less than or equal to grade 1.
The trial excluded patients below 18 years old and greater than 70 years old. Also excluded were patients with a World Health Organization (WHO) PS (performance status) greater than 2 and who had received prior chemotherapy or radiotherapy.
Temozolomide was administered as salvage therapy in the follow-up phase in 161 patients of the 282 (57%) in the RT alone arm and 62 patients of the 277 (22%) in the temozolomide + RT arm. The hazard ratio (HR) for overall survival was 1.59 (95% confidence interval (CI) for HR=1.33 to 1.91) with a log rank p < 0.0001 in favour of the temozolomide arm. The estimated probability of surviving two years or more (26 versus 10%) was higher for the RT + temozolomide arm. The addition of concomitant and adjuvant temozolomide to radiotherapy in the treatment of patients with newly diagnosed GBM demonstrated a statistically significant improved overall survival compared with radiotherapy alone (see Figure 1).

Recurrent glioblastoma multiforme.

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status (KPS) greater than or equal to 70), progressive or recurrent after surgery and radiotherapy, were based on two clinical trials. One was a noncomparative trial in 138 patients (29% received prior chemotherapy) and the other was a randomised reference controlled trial of temozolomide and procarbazine in a total of 120 patients (37.5% received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint was progression free survival (PFS) defined by magnetic resonance imaging (MRI) scans or neurological worsening. In the noncomparative trial, the PFS at six months was 19%, the median PFS was 2.1 months and the median overall survival was 5.4 months. The objective response rate based on MRI scans was 8%.
In the randomised trial, the six month PFS was significantly greater for temozolomide (20%, 95% CI: 9 to 30%) than for procarbazine (10%, 95% CI: 2 to 18%) with median PFS of 3.5 and 1.9 months, respectively (log rank, p=0.015). The median survival was 7.7 and 6.1 months for temozolomide and procarbazine, respectively (log rank, p=0.61).
At six months the fraction of surviving patients was significantly higher in the temozolomide arm (66%, 95% CI: 54 to 78%) compared with the procarbazine arm (51%, 95% CI: 38 to 64%). The study has later been completed (225 patients) and results reinforce those of the interim report.

Anaplastic astrocytoma.

In a multicentre, global, prospective phase II trial evaluating the safety and efficacy of temozolomide in the treatment of 162 adult patients with anaplastic astrocytoma at first relapse (60% received prior chemotherapy), the six month PFS was 46%. The median PFS was 5.4 months and median overall survival was 14.6 months. Response rate, based on the central reviewer assessment, was 35% (13 CR and 43 PR) for the intent to treat (ITT) population. Including 43 stable disease responses, the response rate was 61%. The six month event free survival for the ITT population was 44% with a median event free survival of 4.6 months, which was similar to the results for the PFS. For the eligible histology population, the efficacy results were similar. Achieving a radiological objective response or maintaining progression free status was strongly associated with maintained or improved quality of life.

Metastatic melanoma.

The pivotal trial involving 305 adult patients with advanced metastatic melanoma at first presentation of metastatic disease was a large, multicentre, randomised phase III trial comparing the efficacy of temozolomide (156 patients) with the standard treatment, dacarbazine (DTIC, 149 patients). Patients were balanced in regard to demographics and disease characteristics between the two treatment groups. Patients may not have had previous treatment for metastatic melanoma and may not have had brain metastases from melanoma. The primary endpoint was overall survival. PFS and response rate were secondary endpoints.
Median overall survival was longer for patients treated with temozolomide compared to patients treated with DTIC (7.7 versus 6.4 months, respectively, p=0.2). Median PFS was statistically significantly longer with temozolomide compared to DTIC (1.9 versus 1.5 months, respectively, p = 0.012). The overall response rate was 13.5% for temozolomide and 12.1% for DTIC.

Paediatric patients.

Temozolomide capsules have been studied in two open label phase II studies in paediatric patients with advanced recurrent CNS malignancies at a dose of 160 to 200 mg/m2 daily for five days every 28 days. In a phase I trial, 29 patients with recurrent brainstem glioma and 34 patients with recurrent high grade astrocytoma were enrolled. All patients had been previously treated with standard radiation therapy, while 50% of high grade astrocytoma patients and 31% of brainstem glioma patients had previously received chemotherapy. The objective response rate, based on a central review of all subjects deemed to have eligible histologies, (16 brain stem glioma and 26 high grade astrocytoma subjects), was 0% for brain stem glioma subjects although 19% achieved stable disease; responses were documented in 12% of high grade astrocytoma subjects while 15% had stable disease. Based on investigator reviews, three patients with brain stem glioma had a partial response (10%) and an additional 14 patients had stable disease (48%). Eleven patients with high grade astrocytoma had a partial response (32%) and an additional seven patients had stable disease (21%). For all subjects, the median time to progression in the high grade astrocytoma arm was 2.9 months and the median time to progression in the brain stem glioma arm was 2.8 months.
In the phase II open label study, 117/122 patients treated for various recurrent CNS malignancies were evaluable for efficacy with an overall response rate of 5%. Of 23 patients with high grade astrocytomas seven patients (19%) had stable disease after two cycles. Disease progressed thereafter (cycle 3, 4, 5, 6, 7, 8 and 9, respectively); however, one patient had a partial response. In 16 patients with brainstem gliomas, six had stable disease after two cycles, but disease progressed in all patients by the end of the fifth cycle, with no further response.
No clinical trials have been conducted in patients under 18 years of age with malignant melanoma.

5.2 Pharmacokinetic Properties

Absorption.

After oral administration to adult patients, temozolomide is absorbed rapidly with peak concentrations reached as early as 20 minutes post-dose (mean times between 0.5 and 1.5 hours). After oral administration of 14C-labelled temozolomide, mean faecal excretion of 14C over seven days post-dose was 0.8% indicating complete absorption.
Administration of temozolomide with food resulted in a 33% decrease in Cmax, an increase in Tmax from about one to two hours and a 9% decrease in AUC. As it cannot be excluded that the change in Cmax is clinically significant, temozolomide should not be administered with food.

Distribution.

Preclinical data suggest that temozolomide crosses the blood brain barrier rapidly and is present in the cerebrospinal fluid. Plasma concentrations increase in a dose related manner. Plasma clearance, volume of distribution and half-life are independent of dose. Temozolomide demonstrates low protein binding (10 to 20%), and thus is not expected to interact with highly protein bound agents.

Metabolism and excretion.

Following oral administration approximately 5 to 10% of the dose is recovered unchanged in the urine over 24 hours, and the remainder excreted as AIC (4-amino-5-imidazole-carboxamide hydrochloride) or unidentified polar metabolites.
In relation to adults, analysis of population based pharmacokinetics of temozolomide revealed that plasma clearance was independent of age, renal function, hepatic function or tobacco use.
Among paediatric age groups 3 to 12 and > 12 to 16 years, dose normalised Cmax and AUC value were the same. Similarly, clearance, volume of distribution and half-life were not different between the two paediatric age groups. Mean dose normalised AUC was approximately 30% higher in paediatric patients than in adult patients. Volume of distribution and clearance appeared lower in paediatric patients compared to adult patients. Terminal phase half-life was the same in adults and children.
The maximum tolerated dose (MTD) was 1,000 mg/m2 per cycle both in children and in adults.

5.3 Preclinical Safety Data

Genotoxicity.

Temozolomide was genotoxic in assays for gene mutations (Salmonella typhimurium and Escherichia coli) and chromosomal changes (human blood lymphocytes).
Pathological lesions of necrosis, degeneration, hypospermatogenesis and presence of syncytial cells and immature/abnormal spermatozoa in the testes, epididymis and seminal vesicles have been observed in the mouse, rat and dog at systemic exposure levels to temozolomide well within the anticipated human exposure. Decreased ovarian weight was noted in rats at temozolomide exposure comparable to that anticipated clinically. The reversibility of these changes has not been investigated, but no evidence of recovery was noted during the 23 day nontreatment period.

Carcinogenicity.

No long-term carcinogenicity studies have been conducted, but evidence of carcinogenic potential of temozolomide was observed in the three and six cycle studies in rats. Neoplasms observed in the rat studies included mammary carcinoma, keratoacanthoma of the skin, basal cell adenoma and a variety of mesenchymal neoplasms. These neoplasms occurred at systemic exposure to temozolomide less than that anticipated clinically. No tumours or preneoplastic changes were observed in the dog studies of up to six cycles. Considering that temozolomide is a prodrug of the alkylating agent MTIC, its tumorigenic potential is not unexpected and has been observed with other alkylating agents, including those producing MTIC.

6 Pharmaceutical Particulars

6.1 List of Excipients

The capsules also contain lactose, colloidal anhydrous silica, sodium starch glycollate, tartaric acid and stearic acid. The capsule shells contain gelatin, purified water, titanium dioxide, indigo carmine (5 mg, 140 mg capsules only), iron oxide yellow (5 mg, 20 mg, 180 mg capsules only), iron oxide red (100 mg, 180 mg capsules only), and TekPrint SW-9008 Black Ink (ARTG 2328). The capsules are gluten free.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in original container.

6.5 Nature and Contents of Container

Container type.

Sachets are comprised of a laminated foil (Polyethylene/aluminium/polymer).
Bottles are glass (amber) with a polypropylene child resistant closure.

Pack sizes.

Sachet pack or bottles of 5's and 20's.

Note.

Not all strengths or pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Temozolomide is a white to pale brown/pink, crystalline powder which is odourless or almost odourless and hygroscopic. It is slightly soluble in water (3.1 mg/mL), methanol (4.4 mg/mL) and ethanol (0.6 mg/mL).
The chemical name for temozolomide is 4-methyl-5-oxo- 2,3,4,6,8-pentazabicyclo [4.3.0] nona-2,7,9-triene- 9-carboxamide.

Chemical structure.


CAS number.

85622-93-1.
Molecular formula: C6H6N6.HCl.
Molecular weight: 194.15.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes