Consumer medicine information

Orion Temozolomide Capsules

Temozolomide

BRAND INFORMATION

Brand name

Orion Temozolomide Capsules

Active ingredient

Temozolomide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Orion Temozolomide Capsules.

What is in this leaflet?

This leaflet answers some common questions about Orion Temozolomide Capsules. It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor or pharmacist has weighed the benefits against the risks of you taking this medicine.

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

Keep this leaflet with the medicine.

You may want to read it again.

What Orion Temozolomide Capsules is used for

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

Your doctor, however, may prescribe Orion Temozolomide Capsules for another purpose.

Ask your doctor if you have any questions about why Orion Temozolomide Capsules has been prescribed for you.

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

Orion Temozolomide Capsules works by killing cancer cells from growing and multiplying.

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

Use in children

Orion Temozolomide 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).

Before you take Orion Temozolomide Capsules

When you must not take it

Do not take Orion Temozolomide Capsules if:

  1. you are allergic to temozolomide, dacarbazine (DTIC) or any of the ingredients listed at the end of this leaflet.
    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, difficulty breathing, wheezing, or a tight feeling in your chest.
  2. you or your partner are pregnant or intend to become pregnant.
    Orion Temozolomide Capsules may cause birth defects if either male or female is using Orion Temozolomide Capsules at the time of conception or during pregnancy. Therefore, female patients must have a negative pregnancy test before starting Orion Temozolomide Capsules. Both male and female patients and their partners should each use some kind of birth control while taking this medicine. Male patients whose partners are already pregnant should use a condom to minimise exposure of the unborn baby to temozolomide in the sperm.
  3. you are breastfeeding
  4. you have a very low level of white blood cells, red blood cells or platelets.

Do not use Orion Temozolomide Capsules after the expiry date printed on the bottle.

Do not use Orion Temozolomide Capsules if the packaging shows signs of tampering.

Before you start to take it

You must tell your doctor if:

  1. you vomit frequently
    Your doctor may give you medicine to control the vomiting.
  2. you are anaemic or have blood clotting problems.
  3. you intend to have children.
    Orion Temozolomide Capsules may cause infertility in men.
  4. you have liver or kidney problems.
  5. you have allergies to:
    - any other medicines
    - any other substances, such as foods, preservatives or dyes

Taking other medicines

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

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

How to take Orion Temozolomide Capsules

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

How much to take

Your doctor has worked out the exact dose of Orion Temozolomide Capsules for you according to your individual needs.

You may be given other medication to take before or after Orion Temozolomide Capsules to help stop nausea.

If you are taking Orion Temozolomide Capsules 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 Orion Temozolomide Capsules 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 Orion Temozolomide Capsules 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 Orion Temozolomide Capsules once daily for the first five days (“dosing days”) of each cycle, followed by 23 days without Orion Temozolomide Capsules; this adds up to a 28 day treatment cycle. After day 28, the next cycle will begin, in which you will again take this medicine once daily for five days followed by 23 days without Orion Temozolomide Capsules. Before each new treatment cycle begins, your blood will be tested to determine if the Orion Temozolomide Capsules dose needs to be adjusted.

If you are taking only Orion Temozolomide Capsules (patients treated for recurrent brain tumour):

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

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

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

How to take it

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
Orion Temozolomide Capsules come in different capsule strengths (shown on the outer label in mg). Each strength is a different colour. Depending on the dose of Orion Temozolomide Capsules 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 of each strength you need to take. Ask your doctor or pharmacist to write down the number of each strength (include colour) that you need to take on each dosing day.

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

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

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

When to take it

Take Orion Temozolomide Capsules without food at least one hour before a meal.

It is good practice to take Orion Temozolomide Capsules at about the same time each day.

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

How long to take it

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 double the next dose unless your doctor tells you to do so.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (Phone 13 11 26 for Australia or 0800 764 766 for New Zealand) for advice, if you think you or anyone else may have taken to much Orion Temozolomide Capsules. Do this even if there are no signs of discomfort or poisoning.

While you are taking Orion Temozolomide Capsules

Things you must do

Tell any of the doctors, dentists, and pharmacists who are treating you that you are being treated with Orion Temozolomide Capsules.

Tell your doctor if you feel sick or vomit while being treated with Orion Temozolomide Capsules.

Your doctor may give you another medicine to help stop this.

Tell your doctor if you become unusually pale or tired, get blood clotting problems or frequent infections while being treated with Orion Temozolomide Capsules.

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 Orion Temozolomide Capsules.

If you or your partner becomes pregnant while you are being treated with Orion Temozolomide Capsules, tell your doctor.

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 Orion Temozolomide Capsules 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 Orion Temozolomide Capsules.

Store Orion Temozolomide Capsules out of the reach of children.

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 give Orion Temozolomide Capsules to anyone else, even if they have the same condition as you.

Do not use Orion Temozolomide Capsules to treat any other complaints unless your doctor tells you to.

Things to be careful of

Be careful driving or operating machinery, until you know how

Orion Temozolomide Capsules affects you.

As with other medicines, Orion Temozolomide Capsules may make some people feel tired.

If this occurs do not drive.

Side effects

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

Like other medicines that treat cancer, Orion Temozolomide Capsules 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.

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

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

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

These are the more common side effects of Orion Temozolomide Capsules.

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

  • shortness of breath
  • tingling or numbness in hands or feet
  • bruising, bleeding or being unusually pale or tired
    This could be caused by a low level of platelets or red blood cells in the blood.
  • 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.

You may need medical attention.

These last two side effects of Orion Temozolomide Capsules may take some time to occur. Therefore, even after you have finished your treatment with Orion Temozolomide Capsules, you should tell your doctor immediately if you notice these side effects.

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

Tell your doctor if you notice anything else that is making you feel unwell.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After using Orion Temozolomide Capsules

Keep your Orion Temozolomide Capsules in a bottle until it is time to use them.

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

Do not leave it in the car or on windowsills.

Keep it where children cannot reach it.

A locked cupboard at least one and half meters above ground is a good place to store medicines.

Disposal

Return any unused medicine to your pharmacist.

Product description

What it looks like

  • Orion Temozolomide 5mg Capsules: White opaque capsules, with two stripes in green ink on the cap and with “T 5mg” in green ink on the body.
  • Orion Temozolomide 20mg Capsules: White opaque capsule, with two stripes in orange ink on the cap and with “T 20mg” in orange ink on the body.
  • Orion Temozolomide 100mg Capsules: White opaque capsule, with two stripes in pink ink on the cap and with “T 100mg” in pink ink on the body.
  • Orion Temozolomide 140mg Capsules: White opaque capsule, with two stripes in blue ink on the cap and with “T 140mg” in blue ink on the body.
  • Orion Temozolomide 180mg Capsules: White opaque capsule, with two stripes in red ink on the cap and with “T 180mg” in red ink on the body.
  • Orion Temozolomide 250mg Capsules: White opaque capsule, with two stripes in black ink on the cap and with “T 250mg” in black ink on the body.

Each glass bottle contains 5 or 20 capsules.

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

Ingredients

Active ingredient:

  • temozolomide

Inactive ingredients:

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

The capsule shells also contain the following ingredients:

  • gelatine
  • titanium dioxide
  • TekPrint SB-4020 Green Ink [ARTG No. 2652] (Orion Temozolomide 5mg Capsules)
  • TekPrint SB-2008 Orange Ink [ARTG No. 107473] (Orion Temozolomide 20mg Capsules)
  • Pink TekPrint SW-1105 [ARTG 3325] (Orion Temozolomide 100mg Capsules)
  • TekPrint SB-6018 Blue Ink [ARTG 2653] (Orion Temozolomide 140mg Capsules)
  • TekPrint SW-1102 Red Ink [ARTG 107015] (Orion 180mg Temozolomide Capsules)
  • OPACODE monogramming ink S- S-1-277002 black [ARTG 107581] (Orion Temozolomide 250mg Capsules)

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

Sponsor

Orion Laboratories Pty Ltd
25 - 29 Delawney Street
Balcatta WA 6021

Orion Temozolomide 5mg Capsules: AUST R 179874
Orion Temozolomide 20mg Capsules: AUST R 179872
Orion Temozolomide 100mg Capsules: AUST R 179869
Orion Temozolomide 140mg Capsules: AUST R 179870
Orion Temozolomide 180mg Capsules: AUST R 179871
Orion Temozolomide 250mg Capsules: AUST R 179873

This leaflet was prepared in: October 2011
Date of last amendment: June 2013

ACC03031P:2

BRAND INFORMATION

Brand name

Orion Temozolomide Capsules

Active ingredient

Temozolomide

Schedule

S4

 

Name of the medicine

Temozolomide.

Excipients.

Anhydrous lactose, sodium starch glycolate, stearic acid, tartaric acid and anhydrous colloidal silica.

Capsule shell.

Gelatine and titanium dioxide (E171).

Printing ink.

TekPrint SB-4020 green ink [ARTG No. 2652] (5 mg); TekPrint SB-2008 orange ink [ARTG No. 107473] (20 mg); Pink TekPrint SW-1105 [ARTG No. 3325] (100 mg); TekPrint SB-6018 blue ink [ARTG No. 2653] (140 mg); TekPrint SW-1102 red ink [ARTG No. 107015] (180 mg) and OPACODE monogramming ink S-1-277002 black [ARTG No. 107581] (250 mg).

Description

Chemical name: imidazo[5,1-d]-1,2,3,5-tetrazine- 8-carboxamide,3,4-dihydro-3- methyl-4-oxo. Molecular formula: C6H6N6O2. MW: 194.15. CAS: 85622-93-1. Temozolomide is slightly soluble in water and methanol and practically insoluble in ethanol.

Pharmacology

Pharmacodynamic properties.

Temozolomide is an imidazotetrazine alkylating agent with antitumor activity, which undergoes rapid chemical conversion in the systemic circulation at physiologic 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.

Preclinical safety data.

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 nontreatment period.

Pharmacokinetic properties.

Preclinical data suggest that temozolomide crosses the blood brain barrier rapidly and is present in the cerebrospinal fluid. 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). 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. After oral administration of 14C-labelled temozolomide, mean faecal excretion of 14C over 7 days postdose was 0.8% indicating complete absorption. 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.
Administration of temozolomide with food resulted in a 33% decrease in Cmax, an increase in Tmax from about 1 hour to 2 hours and a 9% decrease in AUC. As it cannot be excluded that the change in Cmax is clinically significant, Orion Temozolomide capsules should not be administered with food.
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.
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.

Clinical Trials

Newly diagnosed glioblastoma multiforme.

A total of 573 patients were randomised to receive either temozolomide + 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 days 1-5 of every 28 day cycle for up to 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/ temozolomide 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 HRI = 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%) is higher for the RT + temozolomide arm. The addition of concomitant and adjuvant temozolomide to RT in the treatment of patients with newly diagnosed glioblastoma multiforme demonstrated a statistically significant improvement in overall survival (OS) compared with RT alone (Figure 1).

Recurrent glioblastoma multiforme.

Data on clinical efficacy in patients with glioblastoma multiforme (Karnofsky performance status [KPS] ≥ 70), progressive or recurrent after surgery and RT, 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 6 months was 19%, the median progression free survival was 2.1 months, and the median overall survival 5.4 months. The objective response rate (ORR) based on MRI scans was 8%.
In the randomised active controlled trial, the PFS at 6 months was significantly greater for temozolomide than for procarbazine (21% vs 8%, respectively; chi square p = 0.008) with median PFS of 2.89 and 1.88 months respectively (log rank p = 0.0063). The median survival was 7.34 and 5.66 months for temozolomide and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving patients was significantly higher in the temozolomide arm (60%) compared with the procarbazine arm (44%) (chi square p = 0.019). In patients with prior chemotherapy a benefit was indicated in those with a KPS ≥ 80.
Data on time to worsening of neurological status favoured temozolomide over procarbazine as did data on time to worsening of performance status (decrease to a KPS of < 70 or a decrease by at least 30 points). The median times to progression in these endpoints ranged from 0.7 to 2.1 months longer for temozolomide than for procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma.

In a multicentre, global, prospective phase II trial evaluating the safety and efficacy of oral temozolomide in the treatment of 162 adult patients with anaplastic astrocytoma at first relapse (60% received prior chemotherapy), the 6 month PFS was 46%. The median PFS was 5.4 months. 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 radiological objective response or maintaining progression free status was strongly associated with maintained or improved quality of life.

Metastatic melanoma.

The pivotal trial involving 305 adult patients with advanced metastatic melanoma at first presentation of metastatic disease was a large multicentre randomised phase III trial comparing the efficacy of temozolomide (156 patients) with the standard treatment, dacarbazine (DTIC, 149 patients). Patients were balanced in regard to demographics and disease characteristics between the two treatment groups. Patients may not have had previous treatment for metastatic melanoma and may not have had brain metastases from melanoma. The primary endpoint was overall survival. 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 has 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.

Indications

Orion Temozolomide capsules are 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.
Orion Temozolomide capsules are also indicated as first line treatment for patients with advanced metastatic malignant melanoma.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity to dacarbazine (DTIC).
Severe myelosuppression.
Temozolomide is contraindicated for use during pregnancy and in women who intend to become pregnant (see Precautions, Use in pregnancy).
Temozolomide must not be used by breastfeeding women (see Use in lactation).

Precautions

Pneumocystis carinii pneumonia (PCP).

Patients who received concomitant temozolomide and RT in a pilot trial for the prolonged 42 day schedule were shown to be at particular risk for developing PCP.
Thus, prophylaxis against PCP is required for all patients receiving concomitant temozolomide and RT for the 42 day regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphocytopenia occurs, they are to continue the prophylaxis 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.

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.

Laboratory parameters.

Temozolomide causes myelosuppression. Therefore, 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 > 1.5 x 109/L and platelet count > 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 patients with hepatic or renal dysfunction.

No data is available on the administration of temozolomide in patients with severe hepatic or renal impairment. Based on the pharmacokinetic properties of temozolomide, it is unlikely that dose reductions are required in such patients. However, caution should be exercised when Orion Temozolomide capsules are administered in these patients.

All patients.

Keep this medication out of the reach of children.

Use in children.

Anaplastic astrocytoma/ glioblastoma multiforme.

There is limited experience in children over the age of 3 years with glioma (see Clinical Trials). There is no clinical experience with use of temozolomide use in children under the age of 3 years.

Melanoma.

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

Use in elderly patients.

Elderly patients (> 70 years of age) appear to be at increased risk of neutropenia and thrombocytopenia, compared with younger patients. Therefore, special care should be taken when Orion Temozolomide capsules are administered in elderly patients.

Carcinogenicity, genotoxicity and impairment of fertility.

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.
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.
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 Orion Temozolomide capsules (see Contraindications, Use in pregnancy and Use in men).

Use in pregnancy.

(Category D)
There are no studies in pregnant women. In nonclinical studies in rats and rabbits receiving 50 mg/m2 (associated with systemic exposure below that anticipated in humans), teratogenicity and/or foetal toxicity were demonstrated. Orion Temozolomide capsules 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 use effective contraception to avoid pregnancy while they are receiving Orion Temozolomide capsules and for 6 months after discontinuation of therapy.

Use in lactation.

It is not known whether temozolomide is excreted in human milk. A perinatal/ postnatal study in rats found that treatment with temozolomide at doses of greater that 25 mg/m2/day decreased pup growth and retarded development. Given its potential adverse effects in the newborn, Orion Temozolomide capsules must not be used by breastfeeding women.

Use in men.

Effective contraception should be used by male patients treated with Orion Temozolomide capsules. Temozolomide can have genotoxic effects. Therefore, men being treated with it should be advised not to father a child and to seek advice on cryoconservation of sperm prior to treatment, because of the possibility of irreversible infertility due to therapy with temozolomide (see Carcinogenicity, genotoxicity and impairment of fertility).

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 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.

Adverse Effects

Newly diagnosed glioblastoma multiforme.

See Table 1.

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

Frequency of adverse drug reactions reported in clinical trials or spontaneously, classified according to body system: very vommon (≥ 10%); common (≥ 1% and < 10%).

Neurological.

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

Gastrointestinal.

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

Haematological.

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

Dermatological.

Common: rash, alopecia, pruritus, petechiae.

Respiratory.

Common: dyspnoea.

General.

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

Laboratory results.

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 myelosupression was similar to that seen in adults. In the phase II clinical trial, the incidences of grade 4 thrombocytopenia and neutropenia were 16% and 11% respectively. Myelosupression was usually transient and reversible with cessation of temozolomide treatment.

Postmarketing experience with temozolomide.

During the marketing of temozolomide, allergic reactions, including anaphylaxis, have been reported very rarely. Very rare cases of erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome have also been observed. Rarely, cases of opportunistic infections including Pneumocystis carinii pneumonia (PCP) have been reported. Cases of interstitial pneumonitis/ pneumonitis have been reported very rarely. Very rare cases of myelodysplastic syndrome (MDS) and secondary malignancies, including myeloid leukaemia, have been reported in patients treated with regimens that included temozolomide. Prolonged pancytopenia, which may result in aplastic anaemia has been reported very rarely.

Dosage and Administration

Antiemetic therapy may be administered prior to or following administration.
Orion 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. Orion Temozolomide capsules must not be opened or chewed, but are to be swallowed whole with a glass of water. If a capsule becomes damaged, avoid contact of the powder contents with skin or mucous membrane.

Adult patients with newly diagnosed glioblastoma multiforme.

Concomitant phase.

Orion Temozolomide capsules are administered orally at a dose of 75 mg/m2 daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions), followed by adjuvant Orion Temozolomide capsules for 6 cycles. No dose reductions are recommended, however, dose interruptions may occur based on patient tolerance. Administration of Orion Temozolomide capsules 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) nonhaematological toxicity ≤ grade 1 (except for alopecia, nausea and vomiting).
During treatment a complete blood count should be obtained weekly. Administration of Orion Temozolomide capsules should be temporarily interrupted or discontinued during the concomitant phase according to the haematological and nonhaematological toxicity criteria as noted in Table 2.

Adjuvant phase.

Four weeks after completing the temozolomide + RT concomitant phase, Orion Temozolomide capsules are administered for up to 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 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. Once escalated, the dose remains at 200 mg/m2 per day for the first 5 days of each subsequent cycle except if toxicity occurs. Dose reductions and discontinuations during the adjuvant phase should be applied according to Tables 3 and 4.
During treatment a complete blood count should be obtained on day 22 (21 days after the first dose of Orion Temozolomide capsules). The dose should be reduced or administration discontinued according to Table 4.

Adults: recurrent glioblastoma multiforme or anaplastic astrocytoma.

In recurrent adult patients previously untreated with chemotherapy, Orion Temozolomide capsules are 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 Orion Temozolomide capsules should be based on toxicities according to nadir ANC or platelet counts.

Adults: metastatic malignant melanoma.

For patients with metastatic malignant melanoma, the recommended dose is 200 mg/m2 once daily for 5 days per 28 day cycle.

Paediatric patients: recurrent glioblastoma multiforme or anaplastic astrocytoma.

In patients 3 years of age or older, Orion Temozolomide capsules are 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, Orion Temozolomide capsules can be continued until disease progression or for a maximum of 2 years.

Overdosage

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 were pancytopenia, pyrexia, multiorgan failure and death.
There are reports of patients who have taken the recommended dose for 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, haematological evaluation is needed. Supportive measures should be provided as necessary.
Contact the Poisons Information Centre on 131 126 for advice on management of overdosage.

Presentation

Capsule (white, opaque, hard gelatine, marked with 2 stripes on cap), 5 mg (size 3, marked T 5 mg in green), 20 mg (size 2, marked T 20 mg in orange), 100 mg (size 1, marked T 100 mg in pink), 140 mg (size 0, marked T 140 mg in blue), 180 mg (size 0, marked T 180 mg in red), 250 mg (size 0, marked T 250 mg in black): 5's, 20's (amber glass bottle, white propylene child resistant screw cap with polyethylene induction seal).

Storage

Store below 25°C. Keep container tightly closed and protect from moisture. Store in the original container.

Poison Schedule

S4.