Consumer medicine information

Temozolomide Alphapharm

Temozolomide

BRAND INFORMATION

Brand name

Temozolomide Alphapharm

Active ingredient

Temozolomide

Schedule

Temozolomide Alphapharm

 Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

 1. Why am I using Temozolomide Alphapharm?

Temozolomide Alphapharm contains the active ingredient Temozolomide. Temozolomide Alphapharm is used to treat patients with brain tumours. Temozolomide Alphapharm is also used to treat adult patients with advanced metastatic malignant melanoma.

For more information, see Section 1. Why am I using Temozolomide Alphapharm? in the full CMI.

 2. What should I know before I use Temozolomide Alphapharm?

Do not use if you have ever had an allergic reaction to Temozolomide Alphapharm or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Temozolomide Alphapharm? in the full CMI.

 3. What if I am taking other medicines?

Some medicines may interfere with Temozolomide Alphapharm and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

 4. How do I use Temozolomide Alphapharm?

Your doctor has worked out the exact dose of Temozolomide Alphapharm for you according to your individual needs.
You may be given other medication to take before or after Temozolomide Alphapharm to help stop nausea.
Take Temozolomide Alphapharm without food at least one hour before a meal.
It is good practice to take Temozolomide Alphapharm at about the same time each day.

More instructions can be found in Section 4. How do I use Temozolomide Alphapharm? in the full CMI.

 5. What should I know while using Temozolomide Alphapharm?

Things you should do	Remind any doctor, dentist or pharmacist you visit that you are using Temozolomide Alphapharm. Tell your doctor if you feel sick or vomit, become unusually pale or tired, get blood clotting problems or frequent infections while being treated with Temozolomide Alphapharm. If you or your partner becomes pregnant while you are being treated with Temozolomide Alphapharm, tell your doctor. Be sure to keep all your doctor's appointments so your progress can be checked.
Things you should 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.
Driving or using machines	Be careful driving or operating machinery, until you know how Temozolomide Alphapharm affects you.
Looking after your medicine	Keep your Temozolomide Alphapharm capsules in the bottle until it is time to use them. Keep Temozolomide Alphapharm in a cool dry place where the temperature stays below 25°C.

For more information, see Section 5. What should I know while using Temozolomide Alphapharm? in the full CMI.

 6. Are there any side effects?

Serious side effects may include: 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; 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; symptoms such as fever, headache, personality change, seizures and/or vomiting which could be associated with a brain infection caused by a herpes virus; new or recurring cytomegalovirus infection and return of hepatitis B; symptoms of diabetes, such as passing large amounts of urine and constant thirst; development of red or purple spots under the skin; 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. Nausea, tiredness, dark urine and yellowing of the skin which could be symptoms of hepatotoxicity.

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

Temozolomide Alphapharm

Active ingredient(s): Temozolomide

 Consumer Medicine Information (CMI)

This leaflet provides important information about using Temozolomide Alphapharm. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Temozolomide Alphapharm.

Where to find information in this leaflet:

1. Why am I using Temozolomide Alphapharm?
2. What should I know before I use Temozolomide Alphapharm?
3. What if I am taking other medicines?
4. How do I use Temozolomide Alphapharm?
5. What should I know while using Temozolomide Alphapharm?
6. Are there any side effects?
7. Product details

 1. Why am I using Temozolomide Alphapharm?

Temozolomide Alphapharm contains the active ingredient Temozolomide. Temozolomide Alphapharm belongs to a group of medicines called cytotoxic or chemotherapy medicines. Temozolomide Alphapharm works by killing cancer cells and stopping cancer cells from growing and multiplying.

Temozolomide Alphapharm is used to treat patients with brain tumours. Temozolomide Alphapharm is also used to treat adult patients with advanced metastatic malignant melanoma.

Your doctor, however, may prescribe Temozolomide Alphapharm for another purpose. Ask your doctor if you have any questions about why Temozolomide Alphapharm has been prescribed for you.

Use in children: Temozolomide Alphapharm capsules are 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).

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

 2. What should I know before I use Temozolomide Alphapharm?

Warnings

Do not use Temozolomide Alphapharm if:

you are allergic to Temozolomide Alphapharm (temozolomide), dacarbazine (DTIC) or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

Symptoms of an allergic reaction may include:
- hives, itching or skin rash
- swelling of the face, lips or tongue. This may lead to difficulty swallowing.
- shortness of breath, wheezing, difficulty breathing or a tight feeling in your chest.

you or your partner are pregnant or intend to become pregnant.
you are breastfeeding.
you have a very low level of white blood cells, red blood cells or platelets.
the expiry date has passed or the packaging is torn, damaged or shows signs of tampering.

Check with your doctor if you:

vomit frequently. Your doctor may give you medicine to control the vomiting
are anaemic or have blood clotting problems
intend to have children. Temozolomide Alphapharm may cause infertility in men
have liver or kidney problems
have viruses such as cytomegalovirus and hepatitis B
have allergies to:
- any other medicines
- any other substances, such as foods, preservatives or dyes
take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Temozolomide Alphapharm may cause birth defects if either the male or female is using Temozolomide Alphapharm at the time of conception or during pregnancy. Therefore, female patients must have a negative pregnancy test before starting Temozolomide Alphapharm. Both male and female patients and their partners should each use some kind of birth control while taking Temozolomide Alphapharm. Male patients whose partners are already pregnant should use a condom to minimise exposure of the unborn baby to Temozolomide Alphapharm in the sperm.

 3. What if I am taking other medicines?

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

Some medicines may interfere with Temozolomide Alphapharm and affect how it works. These include other medicines used to treat cancer or any other treatment that may lower your immune system, and valproic acid, used to treat epilepsy and bipolar disorder. You may need different amounts of your medicine or you may need to use different medicines. Your doctor will advise you.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Temozolomide Alphapharm.

 4. How do I use Temozolomide Alphapharm?

How much to take

Follow all directions given to you by your doctor carefully. They may differ from the information contained in this leaflet.
Your doctor has worked out the exact dose of Temozolomide Alphapharm for you according to your individual needs.
You may be given other medication to take before or after Temozolomide Alphapharm to help stop nausea.
If you are taking Temozolomide Alphapharm 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 Alphapharm 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.

Then, you will start the next phase of treatment ("adjuvant phase") and your Temozolomide Alphapharm 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 Alphapharm capsules once daily for the first 5 days ("dosing days") of each cycle, followed by 23 days without Temozolomide Alphapharm; 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 5 days followed by 23 days without Temozolomide Alphapharm. Before each new treatment cycle begins, your blood will be tested to determine if the Temozolomide Alphapharm dose needs to be adjusted.

If you are taking only Temozolomide Alphapharm (patients treated for recurrent brain tumour):
Take the dose the doctor has prescribed once a day for 5 days. Depending on your response to Temozolomide Alphapharm, a new treatment cycle will begin each 28 days. You will then take this medicine again once daily for 5 days. Before each new treatment cycle, your blood will be tested to see if the dose needs to be changed.
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.
All patients: Temozolomide Alphapharm comes in different strength capsules (shown on the outer label in mg). Each strength is a different colour. Depending on the dose of Temozolomide Alphapharm 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 reinstruction before beginning the treatment cycle. Errors in how you take this medicine may have serious health consequences.
Swallow the capsules whole with a glass of water. Do not open or chew the capsules.

When to take Temozolomide Alphapharm

Take Temozolomide Alphapharm without food at least one hour before a meal.
It is good practice to take Temozolomide Alphapharm at about the same time each day.
If vomiting occurs after you take your capsules, do not take another dose that day.
Your doctor will tell you when your treatment should be stopped.

If you forget to take Temozolomide Alphapharm

Temozolomide Alphapharm should be used regularly at the same time each day. 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 double the next dose unless your doctor tells you to do so.

If you take too much Temozolomide Alphapharm

If you think that you have used too much Temozolomide Alphapharm, you may need urgent medical attention.

You should immediately:

phone the Poisons Information Centre (by calling 13 11 26),
or
contact your doctor,
or
go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

 5. What should I know while using Temozolomide Alphapharm?

Things you should do

Call your doctor straight away if you:

Feel sick or vomit while being treated with Temozolomide Alphapharm. Your doctor may give you another medicine to help stop this.
Become unusually pale or tired, get blood clotting problems or frequent infections while being treated with Temozolomide Alphapharm. 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 Alphapharm.
Or your partner becomes pregnant while you are being treated with Temozolomide Alphapharm.

Remind any doctor, dentist or pharmacist you visit that you are using Temozolomide Alphapharm.

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.

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 Alphapharm 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 Alphapharm.

Things you should 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 give Temozolomide Alphapharm to anyone else, even if they have the same condition as you.
Do not use Temozolomide Alphapharm to treat any other complaints unless your doctor tells you to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Temozolomide Alphapharm affects you. As with other medicines, Temozolomide Alphapharm may make some people feel tired. If this occurs do not drive.

Looking after your medicine

Keep your Temozolomide Alphapharm capsules in the bottle until it is time to use them.
Keep Temozolomide Alphapharm in a cool dry place where the temperature stays below 25°C.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on window sills.

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

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

 6. Are there any side effects?

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

Like other medicines that treat cancer, Temozolomide Alphapharm may have unwanted side effects. Sometimes they may be serious, most of the time they are not. You may need medical attention if you get some of these side effects.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effects

What to do

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
difficulty swallowing
mouth ulcers
coughing
sleeplessness
difficulty concentrating
losing balance
swelling of the face, mouth, legs
hearing loss
high blood sugar

Speak to your doctor if you have any of these less serious side effects and they worry you.

These are the more common side effects of Temozolomide Alphapharm.

Serious side effects

Serious side effects

What to do

shortness of breath
tingling or numbness in hands or feet
nausea, tiredness, dark urine and yellowing of the skin associated with hepatotoxicity
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
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
symptoms such as fever, headache, personality change, seizures and/or vomiting which could be associated with a brain infection caused by a herpes virus
new or recurring cytomegalovirus infection and return of hepatitis B
symptoms of diabetes, such as passing large amounts of urine and constant thirst
development of red or purple spots under the skin

Tell your doctor as soon as possible if you notice any of these serious side effects.

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 Alphapharm, you should tell your doctor immediately if you notice these side effects.

Very serious side effects

Very serious side effects	What to do
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	Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of these very serious side effects.

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

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

 7. Product details

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

What Temozolomide Alphapharm contains

Active ingredient
(main ingredient)

temozolomide

Other ingredients
(inactive ingredients)

lactose (in the 5mg and 20mg capsules only), sodium starch glycollate, stearic acid, tartaric acid, microcrystalline cellulose, colloidal anhydrous silica.
The capsule shells also contain the following ingredients: gelatin, titanium dioxide, purified water, Opacode Monogramming Ink S-1-277002 Black, and:

Indigo carmine (5 mg and 140 mg capsules only)
Iron oxide yellow (5 mg, 20 mg and 250 mg capsules only)
Iron oxide red (100 mg and 250 mg capsules only)
Iron oxide black (100mg and 250mg capsules only)
Sunset yellow FCF (250 mg capsules only)
Allura red AC (180 mg capsules only)

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

Do not take this medicine if you are allergic to any of these ingredients.

What Temozolomide Alphapharm looks like

The 5 mg capsules are light green opaque, marked with black imprint "TMZ 5 mg". (AUST R 192687)

The 20 mg capsules are rich yellow marked with black imprint "TMZ 20 mg". (AUST R 192678)

The 100 mg capsules are flesh coloured, marked with black imprint "TMZ 100 mg". (AUST R 192684)

The 140 mg capsules are powder blue marked with black imprint "TMZ 140 mg". (AUST R 192680)

The 180 mg* capsules are orange marked with black imprint "TMZ 180 mg". (AUST R 192692)

The 250 mg capsules are buff coloured marked with black imprint "TMZ 250 mg". (AUST R 192681)

*The 180mg capsules are not marketed.

Tell your pharmacist if you notice any change in the appearance of the capsule.

Who distributes Temozolomide Alphapharm

Alphapharm Pty Ltd (Mylan Australia)
Cnr Garnet and Antimony Streets
Carole Park, QLD 4300
Australia

This leaflet was prepared in February 2020.

Published by MIMS February 2020

BRAND INFORMATION

Brand name

Temozolomide Alphapharm

Active ingredient

Temozolomide

Schedule

1 Name of Medicine

Temozolomide.

6.7 Physicochemical Properties

Temozolomide is slightly soluble in water (3.1 mg/mL), methanol (4.4 mg/mL) and ethanol (0.6 mg/mL).
Chemical Name: imidazo[5,1-d]- 1,2,3,5-tetrazine- 8-carboxamide, 3,4-dihydro-3-methyl-4-oxo.
Molecular Formula: C₆H₆N₆O₂.
Molecular weight: 194.15.

Chemical structure.

CAS number.

85622-93-1.

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.

Gelatin (contains sulfites), sugars (as lactose) in the 5 mg and 20 mg capsules.
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".

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 (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, 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 nontreatment 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 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 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 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% 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 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 MRI scans or neurological worsening. In the noncomparative trial, the PFS at six 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 six month PFS was significantly greater for temozolomide (20%, 95% confidence interval, 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 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 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, 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 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 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 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 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 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.

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.

4.3 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.

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 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.

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.

Myelosupression.

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. Also 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 phenobarbital (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 in both male and female patients during and for a prolonged period 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 six 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 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 (see Section 5.3 Preclinical Safety Data, Genotoxicity, Carcinogenicity).

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 selflimiting 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, leukopenia, 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 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.

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. 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 medical 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.

4.2 Dose and Method of Administration

Temozolomide Alphapharm capsules are intended for oral administration.
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.

Dosage.

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 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 ≤ 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 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.

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 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 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 five 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 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, temozolomide can be continued until disease progression or for a maximum of two years.

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)).

4.9 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, 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).

7 Medicine Schedule (Poisons Standard)

S4.

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.