Consumer medicine information

APO-Temozolomide

Temozolomide

BRAND INFORMATION

Brand name

APO-Temozolomide

Active ingredient

Temozolomide

Schedule

What is in this leaflet

This leaflet answers some common questions about this medicine. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

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

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

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

What this medicine is used for

The name of your medicine is APO-Temozolomide. It contains the active ingredient temozolomide.

It is used to treat:

patients with certain types of brain tumours called glioblastoma multiforme and anaplastic astrocytoma
adult patients with advanced metastatic malignant melanoma

Temozolomide belongs to a group of medicines called cytotoxic or chemotherapy medicines.

It works by killing cancer cells and stopping cancer cells from growing and multiplying.

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

There is no evidence that this medicine is addictive.

This medicine is available only with a doctor's prescription.

Use in children

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

Before you take this medicine

When you must not take it

Do not take this medicine if you or your partner are pregnant or intend to become pregnant. Temozolomide may cause birth defects if either the male or female is using this medicine at the time of conception or during pregnancy.

Therefore, female patients must have a negative pregnancy test before starting this medicine and avoid pregnancy for 6 months after discontinuation of treatment with temozolomide.

Both male and female patients and their partners should each use birth control while taking temozolomide. Male patients whose partners are already pregnant should use a condom to minimise exposure of the unborn baby to temozolomide in the sperm.

Do not take this medicine if you are breastfeeding. It is not known whether temozolomide passes into human breast milk and there is a possibility that your baby may be affected.

Do not take this medicine if you have a very low level of white blood cells, red blood cells or platelets.

Do not take this medicine if you have an allergy to:

temozolomide
dacarbazine (DTIC)
any of the ingredients listed at the end of this leaflet

Some of the symptoms of an allergic reaction may include:

shortness of breath
wheezing or difficulty breathing
swelling of the face, lips, tongue or other parts of the body
rash, itching or hives on the skin

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

anaemia or blood clotting problems
liver or kidney problems
tendency to vomit frequently or experience nausea
viruses such as cytomegalovirus and hepatitis B

Tell your doctor if you are pregnant, plan to become pregnant or are breastfeeding, or you intend to have children.

Temozolomide may cause infertility in men.

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

Taking other medicines

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

Some medicines may interact with temozolomide. These include:

other medicines used to treat cancer or that may lower your immune system
valproic acid, used to treat epilepsy and bipolar disorder

These medicines may be affected by temozolomide or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Other medicines not listed above may also interact with temozolomide.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take this medicine

Follow carefully all directions given to you by your doctor. They may differ from the information contained in this leaflet.

If you do not understand the directions, ask your doctor or pharmacist for help.

How much to take

Your doctor will tell you how much of this medicine you should take.

This will depend on your condition and whether you are taking any other medicines.

You may be given other medications to take before or after this medicine to help stop nausea.

Newly diagnosed glioblastoma multiforme (in combination with radiotherapy):

Concomitant Phase

Your doctor will start you on a dose of temozolomide every day for 42 days (up to 49 days if needed due to radiotherapy interruption). Your treatment will then be interrupted for 4 weeks to give your body a chance to recover.

Adjuvant Phase

In the next phase, there are up to 6 treatment cycles. Each treatment cycle lasts 28 days. You will take your new dose of temozolomide once daily for the first 5 days of each cycle, followed by 23 days without temozolomide. After day 28, the next cycle will begin, in which you will again take temozolomide once daily for 5 days followed by 23 days without temozolomide. Before each new treatment cycle begins, your blood will be tested to determine if the temozolomide dose needs to be adjusted.

Recurrent gliobastoma multiforme or anaplastic astrocytoma:

Take the dose the doctor has prescribed once a day for 5 days.

Depending on your response to temozolomide, a new treatment cycle will begin each 28 days. You will then again take temozolomide once daily for 5 days.

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

Metastatic malignant melanoma:

Take the dose the doctor has prescribed once a day for 5 days.

Depending on your response to temozolomide, a new treatment cycle will begin each 28 days. You will then again take temozolomide once daily for 5 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.

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

When to take it

Take your medicine at about the same time each day. Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

Take this medicine without food at least one hour before a meal.

If vomiting occurs after you take this medicine, do not take another dose that day.

How long to take it for

Continue taking your medicine for as long as your doctor tells you. 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 missed doses. This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

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 that you or anyone else may have taken too much of this medicine. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine. It may affect other medicines used during surgery.

If you or your partner become pregnant or start to breastfeed while taking this medicine, tell your doctor immediately.

Tell your doctor if you become unusually pale or tired, get blood clotting problems or frequent infections while being treated with temozolomide. 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 70 years of age. Your doctor may need to change your dose of temozolomide.

If you are about to have any blood tests, tell your doctor that you are taking this medicine. It may interfere with the results of some tests.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

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 take this medicine to treat any other complaints unless your doctor tells you to.

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

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. This medicine may cause drowsiness, sleepiness or tiredness in some people and affect alertness. If this occurs, do not drive.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking temozolomide or if you have any questions or concerns.

All medicines can have side effects. Sometimes they are serious but most of the time they are not.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Tell your doctor if you notice any of the following:

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.

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

frequent urination, unquenchable thirst
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.
new or recurring cytomegalovirus infection and return of hepatitis B
symptoms such as fever, headache, personality change, seizures, and/or vomiting which could be associated with a brain infection caused by herpes virus
shivering that is associated with chills and fever.
This could be sign of an infection caused by a low level of white blood cells in the blood.
development of red or purple spots under the skin.

These may be serious side effects and you may need medical attention.

The last two side effects may also take some time to occur. Therefore, even after you have finished your treatment with temozolomide, you should tell your doctor immediately if you notice these side effects.

Other side effects not listed above may occur in some patients.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital:

symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing; swelling of the face, lips, tongue, throat or other parts of the body; rash, itching or hives on the skin

Storage and disposal

Storage

Keep your medicine in its original packaging until it is time to take it. If you take your medicine out of its original packaging it may not keep well.

Keep your medicine in a cool dry place where the temperature will stay below 25°C.

Do not store your medicine, or any other medicine, in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep this medicine 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.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What APO-Temozolomide looks like

5 mg capsules:
Light green opaque, size 4, marked with black imprint "TMZ 5 mg". AUST R 231523.

20 mg capsules:
Rich yellow opaque, size 1, marked with black imprint "TMZ 20 mg". AUST R 231524.

100 mg capsules:
Flesh opaque, size 1, marked with black imprint "TMZ 100 mg". AUST R 231527.

140 mg capsules:
Powder blue opaque, size 1, marked with black imprint "TMZ 140 mg". AUST R 231528.

180 mg capsules:
Medium orange opaque, size 1, marked with black imprint "TMZ 180 mg". AUST R 231525.

250 mg capsules:
Buff opaque, size 0, marked with black imprint "TMZ 250 mg". AUST R 231526.

Available in bottles of 5 capsules.

Not all strengths may be available.

Ingredients

Each capsule contains 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg of temozolomide as the active ingredient.

It also contains the following inactive ingredients:

lactose (in the 5 mg and 20 mg capsules only)
sodium starch glycollate
stearic acid
tartaric acid
microcrystalline cellulose
colloidal anhydrous silica.

Temozolomide capsule shells contain:

gelatin
purified water
titanium dioxide
iron oxide yellow (5 mg, 20 mg and 250 mg capsules only)
indigo carmine (5 mg and 140 mg capsules only)
iron oxide red (100 mg and 250 mg capsules only
iron oxide black (100 mg and 250 mg capsules only)
sunset yellow FCF (180 mg capsules only)
allura red AC (180 mg capsules only).

Capsule printing ink is Opacode monogramming ink S-1-277002 BLACK.

This medicine is gluten-free, sucrose-free, tartrazine-free and free of other azo dyes. Contains trace amounts of sulfites.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia

APO is a registered trademark of Apotex Inc.

This leaflet was last updated in:
October 2020.

Published by MIMS December 2020

BRAND INFORMATION

Brand name

APO-Temozolomide

Active ingredient

Temozolomide

Schedule

1 Name of Medicine

Temozolomide.

2 Qualitative and Quantitative Composition

Each capsule contains 5 mg, 20 mg, 100 mg, 140 mg, 180 mg or 250 mg temozolomide, as the active ingredient.

Excipients with known effect.

Lactose.
Contains trace amounts of sulfites.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

5 mg capsules.

Light green opaque, size 4, marked with black imprint "TMZ 5 mg".

20 mg capsules.

Rich yellow opaque, size 1, marked with black imprint "TMZ 20 mg".

100 mg capsules.

Flesh opaque, size 1, marked with black imprint "TMZ 100 mg".

140 mg capsules.

Powder blue opaque, size 1, marked with black imprint "TMZ 140 mg".

180 mg capsules.

Medium orange opaque, size 1, marked with black imprint "TMZ 180 mg".

250 mg capsules.

Buff opaque, size 0, marked with black imprint "TMZ 250 mg".

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

APO-Temozolomide capsules are intended for oral administration.

Dosage.

Anti-emetic therapy may be administered prior to or following administration of temozolomide.
Temozolomide capsules 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.
Newly diagnosed glioblastoma multiforme (adults).

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 6 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: absolute neutrophil count ≥ 1.5 x 10⁹/L thrombocyte count ≥ 100 x 10⁹/L common toxicity criteria (CTC) non-haematological toxicity ≤ 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 non-haematological toxicity criteria as noted in Table 1.

Adjuvant phase.

Four weeks after completing the temozolomide + Radiotherapy phase, temozolomide is administered for an additional 6 cycles of adjuvant treatment. Dosage in Cycle 1 (adjuvant) is 150 mg/m² once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m² if the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia, nausea and vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 10⁹/L, and the thrombocyte count is ≥ 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 5 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.

Recurrent glioblastoma multiforme or anaplastic astrocytoma (adults). In recurrent adult patients previously untreated with chemotherapy, temozolomide is administered orally at a dose of 200 mg/m² once daily for 5 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 absolute neutrophil count (ANC) is ≥ 1.5 x 10⁹/L and the platelet count is ≥ 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.
Metastatic malignant melanoma (adults). For patients with metastatic malignant melanoma, the recommended dose is 200 mg/m² once daily for 5 days per 28-day cycle.
Recurrent glioblastoma multiforme or anaplastic astrocytoma (paediatric). In patients 3 years of age or older, temozolomide is administered orally at a dose of 200 mg/m² once daily for 5 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 5 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, temozolomide can be continued until disease progression or for a maximum of 2 years.

4.3 Contraindications

Temozolomide is contraindicated in patients who have a history of hypersensitivity reaction to its components or to dacarbazine (DTIC).
Temozolomide is contraindicated for use during pregnancy and in women who intend to become pregnant (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy).
Temozolomide must not be used by breastfeeding women (see Section 4.6 Fertility, Pregnancy and Lactation, Use in lactation).
Temozolomide is contraindicated in patients with severe myelosuppression.

4.4 Special Warnings and Precautions for Use

Pneumocystis carinii pneumonia (PCP).

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.
Thus, prophylaxis against Pneumocystis carinii pneumonia 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 Pneumocystis carinii pneumonia 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.

Patients with newly diagnosed glioblastoma multiforme.

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant temozolomide; anti-emetic 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 anti-emetic 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) > 1.5 x 10⁹/L and platelets > 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 mg/m², 150 mg/m² 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.

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. Co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H₂-receptor antagonists or phenobarbital did not alter the clearance of temozolomide. Co-administration 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; Use in pregnancy, Use in men, below.)
(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 6 months after discontinuation of temozolomide 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.

Use in men.

Effective contraception should be used by male patients treated with temozolomide. Temozolomide 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, Genotoxicity, Carcinogenicity.)

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.

See Table 5.

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 anti-emetic 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 haematologic 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 1-2 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 vs. 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 vs. 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 vs. 0% of male subjects and Grade 4 thrombocytopenia in 1% of female vs. 0% of male subjects in the first cycle of therapy.
In children the incidence of myelosuppression 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. Myelosuppression was usually transient and reversible with cessation of temozolomide treatment.

Post-marketing experience with temozolomide.

During the marketing of temozolomide, cases of erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome and allergic reactions, including anaphylaxis, have been reported very rarely. 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).
Rare 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 has resulted in a fatal outcome. Diabetes insipidus has also been reported.
Frequency not known: drug reaction with eosinophilia and systemic symptoms (DRESS).

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 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 5 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 5 days was taken by one patient and the adverse events reported were pancytopenia, pyrexia, multi-organ failure and death.
There are reports of patients who have taken more than 5 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, haematologic evaluation is needed. Supportive measures should be provided as necessary.
For information on the management of overdose, contact the Poisons 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 1900 mg/m²) than in the mouse (approximately 1000 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 (5-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, 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 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 non-treatment period.

Clinical trials.

Newly diagnosed glioblastoma multiforme.

Five hundred and seventy-three 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 (150-200 mg/m²) on day 1-5 of every 28-day cycle for 6 cycles, starting 4 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 WHO PS 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% CI for HR = 1.33-1.91) with a log-rank p < 0.0001 in favour of the temozolomide arm. The estimated probability of surviving 2 years or more (26% vs. 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 adult patients with glioblastoma multiforme (Karnofsky performance status [KPS] ≥ 70), progressive or recurrent after surgery and radiotherapy, were based on two clinical trials.
One was a non-comparative 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 MRI scans or neurological worsening. In the non-comparative trial, the PFS at 6 months was 19%, the median progression-free survival 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 6 month PFS was significantly greater for temozolomide (20%, 95% confidence interval, CI: 9-30%) than for procarbazine (10%, 95% CI: 2-18%) 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 6 months the fraction of surviving patients was significantly higher in the temozolomide arm (66%, 95% CI: 54-78%) compared with the procarbazine arm (51%, 95% CI: 38-64%). The study has later been completed (225 patients) and results reinforce those of the interim report.

Anaplastic astrocytoma.

In a multi-centre, 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 6 month progression-free survival was 46%. The median progression-free survival 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 population. Including 43 stable disease responses, the response rate was 61%. The 6 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 progression-free survival. For the eligible histology population, the efficacy results were similar. Achieving a radiologic 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. Progression-free survival and response rate were secondary endpoints.
Median overall survival was longer for patients treated with temozolomide compared to patients treated with DTIC (7.7 vs. 6.4 months respectively, p=0.2). Median progression-free survival was statistically significantly longer with temozolomide compared to DTIC (1.9 months vs. 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 160-200 mg/m² daily for 5 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, whilst 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 7 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 postdose (mean times between 0.5 and 1.5 hours).
After oral administration of ¹⁴C-labelled temozolomide, mean faecal excretion of ¹⁴C over 7 days post-dose was 0.8% indicating complete absorption.
Administration of temozolomide with food resulted in a 33% decrease in C_max, an increase in T_max from about 1 hour to 2 hours and a 9% decrease in AUC. As it cannot be excluded that the change in C_max 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.

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.

Excretion.

In relation to adults, analysis of population-based pharmacokinetics of temozolomide revealed that plasma temozolomide clearance was independent of age, renal function, hepatic function or tobacco use.

Paediatric pharmacokinetics.

Among paediatric age groups 3-12 and > 12-16 years, dose-normalised C_max 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 1000 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 non-treatment 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 tumourigenic potential is not unexpected and has been observed with other alkylating agents, including those producing MTIC.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose (5 mg and 20 mg capsules only), sodium starch glycollate, stearic acid, tartaric acid, microcrystalline cellulose, colloidal anhydrous silica, gelatin, purified water, titanium dioxide, iron oxide yellow (5 mg, 20 mg and 250 mg capsules only), indigo carmine (5 mg and 140 mg capsules only), iron oxide red (100 mg and 250 mg capsules only), iron oxide black (100 mg and 250 mg capsules only), sunset yellow FCF (180 mg capsules only), and allura red AC (180 mg capsules only).
Capsule printing ink is Opacode monogramming ink S-1-277002 Black.

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.