TEMODAL 5 MG

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
TEMOZOLOMIDE
Available from:
MERCK SHARP & DOHME ISRAEL LTD
ATC code:
L01AX03
Pharmaceutical form:
CAPSULES
Composition:
TEMOZOLOMIDE 5 MG
Administration route:
PER OS
Prescription type:
Required
Manufactured by:
ORION CORPORATION, ORION PHARMA, FINLAND
Therapeutic group:
TEMOZOLOMIDE
Therapeutic area:
TEMOZOLOMIDE
Therapeutic indications:
Temodal capsules are indicated for the treatment of patients with malignant glioma such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy. Temodal capsules are also indicated as first line treatment for patients with advanced metastatic malignant melanoma. Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment.
Authorization number:
120 28 30114 22
Authorization date:
2016-02-29

Documents in other languages

Patient Information leaflet Patient Information leaflet - Arabic

23-01-2021

Patient Information leaflet Patient Information leaflet - Hebrew

29-07-2018

PATIENT PACKAGE INSERT IN ACCORDANCE WITH THE PHARMACISTS

REGULATIONS (PREPARATIONS) 1986

This medicine is marketed upon physician prescription only

TEMODAL

®

5 mg, 20 mg, 100 mg, 250 mg

Capsules

Each capsule contains:

Temozolomide 5 mg, 20 mg, 100 mg, 250 mg

For a list of inactive ingredients see section 6 Further Information”. See also section 2.7

Important information about some of the ingredients of TEMODAL”.

Read all of this leaflet carefully before you start taking this medicine.

This leaflet contains concise information about the medicine. If you have any further

questions, refer to the doctor or pharmacist.

This medicine has been prescribed for you. Do not pass it on to others. It may harm them,

even if their medical condition seems similar to yours.

This medicine is not intended for children under 3 years of age, since there are no data

related to the use in patients under the age of 3 years. The data about children above the

age of 3 years are limited.

1.

WHAT TEMODAL IS INTENDED FOR?

1.1 What is TEMODAL?

TEMODAL contains a medicine called temozolomide. This medicine is an antitumour agent

for the treatment of specific forms of brain tumours.

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

Therapeutic group: Antineoplastic preparation.

1.2 What is TEMODAL used for?

TEMODAL capsules are indicated for the treatment of:

Adult patients suffering from newly diagnosed glioblastoma multiforme (a specific form of

brain tumour) in a combination treatment with radiation and subsequently as monotherapy

treatment;

Children above the age of 3 years, adolescents and adults suffering from malignant

glioma such as glioblastoma multiforme or anaplastic astrocytoma (specific forms of brain

tumours), showing recurrence or progression after standard therapy;

TEMODAL capsules are also indicated as first line treatment for adult patients with

advanced metastatic malignant melanoma.

2.

BEFORE USING TEMODAL

2.1 Do not use TEMODAL if:

you are sensitive (allergic) to temozolomide or any of the other ingredients of this

medicine (listed in section 6).

you have had an allergic reaction to dacarbazine (an anticancer medicine sometimes

called DTIC). Signs of allergic reaction include feeling itchy, breathlessness or wheezing,

swelling of the face, lips, tongue or throat.

certain kinds of blood cells are severely reduced (myelosuppression), such as your white

blood cell count and platelet count. These blood cells are important for fighting infection

and for proper blood clotting. Your doctor will check your blood to make sure you have

enough of these cells before you begin treatment.

you are pregnant or breast-feeding.

2.2 Special Warnings and precautions concerning use of TEMODAL

Talk to your doctor, pharmacist or nurse before taking TEMODAL,

-

as you should be observed closely for the development of a serious form of chest

infection called Pneumocystis jirovecii pneumonia (PCP). If you are a newly-diagnosed

patient (glioblastoma multiforme) you may be receiving TEMODAL for 42 days in

combination with radiotherapy. In this case, your doctor will also prescribe medicine to

help you prevent this type of pneumonia (PCP).

-

if you have ever had or might now have a hepatitis B infection. This is because

TEMODAL could cause hepatitis B to become active again, which can be fatal in some

cases. Patients will be carefully checked by their doctor for signs of this infection before

treatment is started.

if you have low counts of red blood cells (anaemia), white blood cells and platelets, or

blood clotting problems before starting the treatment, or if you develop them during

treatment. Your doctor may decide to reduce the dose, interrupt, stop or change your

treatment. You may also need other treatments. In some cases, it may be necessary to

stop treatment with TEMODAL. Your blood will be tested frequently during treatment to

monitor the side effects of TEMODAL on your blood cells.

as you may have a small risk of other changes in blood cells, including leukaemia.

if you have nausea (feeling sick in your stomach) and/or vomiting which are very

common side effects of TEMODAL (see section 4), your doctor may prescribe you a

medicine (an anti-emetic) to help prevent vomiting.

If you vomit frequently before or during treatment, ask your doctor about the best time to

take TEMODAL until the vomiting is under control. If you vomit after taking your dose, do

not take a second dose on the same day.

if you develop fever or symptoms of an infection, contact your doctor immediately.

if you are older than 70 years of age, you might be more prone to infections, bruising or

bleeding.

if you have liver or kidney problems, your dose of TEMODAL may need to be adjusted.

When using the medicine, there is a risk of liver damage, including liver failure that may

be life-threatening. Therefore, it is necessary to perform liver function tests before and

during treatment with TEMODAL.

2.3 Interactions with other medicines

If you are taking or have recently taken other medicines, including non-prescription

medicines and nutritional supplements, you should tell the attending doctor or

pharmacist. Especially inform your doctor or pharmacist if you are taking: other medicines

used to treat cancer, other myelosuppressants, or valproic acid.

2.4 Taking TEMODAL with food and drink

Take the capsules on an empty stomach; for example, at least one hour before you plan to

eat breakfast. Swallow the capsule(s) whole with a glass of water.

2.5 Pregnancy, breast-feeding and fertility

If you are pregnant, think you may be pregnant or are planning to have a baby, ask your

doctor or pharmacist for advice before taking this medicine. This is because you must not be

treated with TEMODAL during pregnancy unless clearly indicated by your doctor.

Female patients and female partners of male patients should avoid pregnancy during

treatment and for 6 months following treatment completion.

Effective contraceptive precautions must be taken by both male and female patients who

are taking TEMODAL (see also “Male fertility” below).

You should stop breast-feeding while receiving treatment with TEMODAL.

Male fertility

TEMODAL may cause permanent infertility. Male patients should use effective contraception

and not father a child for up to 6 months after stopping treatment. It is recommended to seek

advice on conservation of sperm prior to treatment.

2.6 Driving and using machines

TEMODAL may make you feel tired or sleepy. In this case, do not drive or use any tools or

machines or cycle until you see how this medicine affects you (see section 4).

2.7 Important information about some of the ingredients of TEMODAL

TEMODAL contains lactose (a kind of sugar). If you have been told by your doctor that you

have an intolerance to some sugars, contact your doctor before taking this medicine.

2.8 Children and adolescents

Do not give this medicine to children under the age of 3 years because it has not been

studied. TEMODAL is intended for the treatment of children from the age of 3 years for

different forms of brain tumours (such as glioblastoma multiforme or anaplastic astrocytoma),

showing recurrence or progression after standard therapy. Nevertheless, information in

children over the age of 3 years is limited.

3. HOW SHOULD YOU USE TEMODAL?

Always take TEMODAL exactly as your doctor has told you. It is very important to check with

your doctor or pharmacist if you are not sure. Errors in how you take this medicine may have

serious health consequences.

Do not exceed the recommended dose.

This medicine is not intended for administration to infants and children under 3 years

of age

.

Your doctor will decide the exact TEMODAL dose you should take, based on your body size

(height, weight) and whether or not you have had chemotherapy treatment in the past. You

may be asked to take another medicine before or after taking TEMODAL to prevent

or control nausea and vomiting.

How to take the medicine (for all patients):

Take the prescribed TEMODAL dose once a day on an empty stomach, for example, at least

one hour before breakfast. It is preferable to take the dose at the same time every day.

Swallow the capsule whole with a glass of water.

Do not open, crush or chew the capsule.

TEMODAL belongs to a group of medicines called

cytotoxic or chemotherapy medicines. If capsules are opened, this creates a risk for

unintended exposure to the drug through inhalation or contact with the skin or mucous

membranes. To reduce the risk of unintended exposure to TEMODAL, capsules should not

be opened. If the capsule is damaged, avoid contact of the powder of the capsule with the

skin and mucous membranes (eyes, nose) (see section 2). In case of powder contact, the

hands should be washed.

Depending on the dosage that will be prescribed for you, you may need to swallow more

than one capsule at a time and you may need to swallow capsules of different doses

together (dose - the amount of active ingredient in the capsule, in milligrams). The color of

the capsule cap and the writing on the capsules is different for each strength (see details in

table below).

Strength

Colour of the cap

TEMODAL 5 mg capsules

green

TEMODAL 20 mg capsules

yellow

TEMODAL 100 mg capsules

pink

TEMODAL 250 mg capsules

white

You should make sure you fully understand and remember the following:

how many capsules you need to take every dosing day. Ask your doctor or pharmacist to

write it down (including the colour).

which days are your dosing days - the days you need to take your medicine.

Review the dose with your doctor each time you start a new cycle, since it may be different

from the last cycle.

Tests and follow-up

During the course of treatment, you must undergo blood tests frequently to monitor the status

of your blood cells.

In addition, a liver function test will be performed before and during the course of treatment,

since there is a risk of liver damage that may even be life-threatening (also see section 2).

In case of vomiting after taking the medicine, do not take another dose that same day.

If you have accidentally taken a higher dose than you should

If you accidentally take more TEMODAL capsules than you were told to, contact your doctor,

pharmacist or nurse immediately.

If you forget to take TEMODAL

Take the missed dose as soon as possible during the same day. If a full day has gone by,

check with your doctor. Do not take a double dose to make up for a forgotten dose, unless

your doctor tells you to do so.

Do not take medicines in the dark! Check the label and the dose each time you take

your medicine. Wear glasses if you need them.

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

pharmacist or nurse.

4. SIDE EFFECTS

As with other medicines, TEMODAL may cause side effects, in some users. Do not be

alarmed by reading the list of side effects, you may not suffer from any of them.

Contact your doctor immediately if you have any of the following:

a severe allergic (hypersensitive) reaction (hives, wheezing or other breathing difficulty),

uncontrolled bleeding,

seizures (convulsions),

fever,

chills

severe headache that does not go away.

TEMODAL treatment can cause a reduction in certain kinds of blood cells. This may cause

you to have increased bruising or bleeding, anaemia (a shortage of red blood cells), fever,

and reduced resistance to infections. The reduction in blood cell counts is usually short-lived.

In some cases, it may be prolonged and may lead to a very severe form of anaemia (aplastic

anaemia). Your doctor will monitor your blood regularly for any changes, and will decide if

any specific treatment is needed. In some cases, your TEMODAL dose will be reduced or

treatment stopped.

Other side effects that have been reported are listed below:

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

loss of appetite, difficulty speaking, headache

vomiting, nausea, diarrhoea, constipation

rash, hair loss

tiredness

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

infections, oral infections, wound infections

reduced number of blood cells (neutropenia, lymphopenia, thrombocytopenia)

allergic reaction

increased blood sugar

memory impairment, depression, anxiety, confusion, inability to fall asleep or stay

asleep

impaired coordination and balance

difficulty concentrating, change in mental status or alertness, forgetfulness

dizziness, impaired sensations, tingling sensations, shaking, abnormal taste

partial loss of vision, abnormal vision, double vision, dry or painful eyes

deafness, ringing in the ears, earache

blood clot in lung or legs, high blood pressure

pneumonia, shortness of breath, bronchitis, cough, inflammation of your sinuses

stomach or abdominal pain, upset stomach/heartburn, difficulty swallowing

dry skin, itching

muscle damage, muscle weakness, muscle aches and pain

painful joint, back pain

frequent urination, difficulty withholding your urine

fever, flu-like symptoms, pain, feeling unwell, a cold or the flu

fluid retention, swollen legs

liver enzyme elevations

loss of weight, weight gain

radiation injury

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

brain infections (meningoencephalitis herpetic) including fatal cases

new or reactivated cytomegalovirus infections

reactivated hepatitis B virus infections

secondary cancers including leukaemia

reduced blood cell counts (pancytopenia, anaemia, leukopenia)

red spots under the skin

diabetes insipidus (symptoms include increased urination and feeling thirsty), low

potassium level in the blood

mood swings, hallucination

partial paralysis, change in your sense of smell

hearing impairment, infection of the middle ear

palpitations (when you can feel your heart beat), hot flushes

swollen stomach, difficulty controlling your bowel movements, haemorrhoids, dry

mouth

hepatitis and injury to the liver (including fatal liver failure), cholestasis, increased

bilirubin

blisters on body or in mouth, skin peeling, skin eruption, painful reddening of the skin,

severe rash with skin swelling (including palms and soles)

increased sensitivity to sunlight, urticaria (hives), increased sweating, change in skin

colour

difficulty in urinating

vaginal bleeding, vaginal irritation, absent or heavy menstrual periods, breast pain,

sexual impotence

shivering, face swelling, discolouration of the tongue, thirst, tooth disorder

If a side effect appears, if any of the side effects gets serious or if you suffer from a

side effect not mentioned in this leaflet, consult your doctor.

Side effects can be reported to the Ministry of Health by using the link “Adverse Drug

Reactions Report” at the home page of the Ministry of Health’s web site (www.health.gov.il

which refers to the online side effects reporting form, or by using the link:

https://sideeffects.health.gov.il/

5.

HOW TO STORE TEMODAL?

Avoid Poisoning! This medicine

and any other medicine must be stored in a safe place

out of the sight and reach of children and/or infants, preferably in a locked cupboard, in

order to avoid poisoning. Accidental ingestion can be lethal for children. Do not induce

vomiting unless explicitly instructed to do so by a doctor.

Do not use this medicine after the expiry date (exp. date) which is stated on the label and

carton. The expiry date refers to the last day of that month.

Storage Conditions: Do not store above 25

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

Do not throw away any medicines via wastewater or household waste. Ask your

pharmacist how to throw away medicines you no longer use. These measures will help

protect the environment.

6. FURTHER INFORMATION

In addition to the active ingredient TEMODAL also contains:

Capsule content:

Anhydrous lactose, sodium starch glycolate, stearic acid, tartaric acid, colloidal anhydrous

silica (see section 2.7 "Important information about some of the ingredients of

TEMODAL").

TEMODAL 5 mg capsules: Each capsule contains 132.8 mg of anhydrous lactose.

TEMODAL 20 mg capsules: Each capsule contains 182.2 mg of anhydrous lactose.

TEMODAL 100 mg capsules: Each capsule contains 175.7 mg of anhydrous lactose.

TEMODAL 250 mg capsules: Each capsule contains 154.3 mg of anhydrous lactose.

Capsule shell:

TEMODAL 5 mg capsules: gelatin, titanium dioxide, sodium lauryl sulfate, yellow iron oxide,

FD & C Blue 2.

TEMODAL 20 mg capsules: gelatin, titanium dioxide, yellow iron oxide, sodium lauryl sulfate.

TEMODAL 100 mg capsules: gelatin, titanium dioxide, sodium lauryl sulfate, red iron oxide.

TEMODAL 250 mg capsules: gelatin, titanium dioxide, sodium lauryl sulfate.

Printing ink:

Shellac, anhydrous ethyl alcohol, isopropyl alcohol, n-butyl alcohol, propylene glycol, purified

water, ammonium hydroxide, potassium hydroxide, and black iron oxide.

What TEMODAL looks like and contents of the pack

TEMODAL 5 mg capsules have an opaque white body, an opaque green cap, and are

imprinted with black ink.

TEMODAL 20 mg capsules have an opaque white body, an opaque yellow cap, and are

imprinted with black ink.

TEMODAL 100 mg capsules have an opaque white body, an opaque pink cap, and are

imprinted with black ink.

TEMODAL 250 mg capsules have an opaque white body and cap and are imprinted with

black ink.

Pack sizes: Sachet presentation

The capsules for oral use are individually sealed in sachets and dispensed in cartons

containing 5 or 20 capsules.

Not all pack sizes may be marketed.

Marketing Authorization Holder:

Merck Sharp & Dohme (Israel - 1996) Company Ltd., P.O.B. 7121, Petah-Tikva 49170.

Manufacturer:

Orion Corporation, Turku, Finland for Merck Sharp & Dohme Corp., New-Jersey, U.S.A.

Revised in August 2020.

Drug registration no. listed in the official registry of the Ministry of Health:

TEMODAL 5 mg:

120.28.30114.22

TEMODAL 20 mg:

120.29.30115.22

TEMODAL 100 mg:

120.30.30116.23

TEMODAL 250 mg:

120.31.30119.22

1.

NAME OF THE MEDICINAL PRODUCT

Temodal

5, 20, 100 or 250 mg capsules

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each capsule contains 5, 20, 100 or 250 mg temozolomide.

Excipient with known effect:

Each Temodal 5 mg capsule contains 132.8 mg of anhydrous lactose.

Each Temodal 20 mg capsule contains 182.2 mg of anhydrous lactose

Each Temodal 100 mg capsule contains 175.7 mg of anhydrous lactose

Each Temodal 250 mg capsule contains 154.3 mg of anhydrous lactose

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Capsule.

Temodal 5 mg capsules have an opaque white body, an opaque green cap, and are imprinted with

black ink. The cap is imprinted with “Temodal”. The body is imprinted with "5 mg", the Schering-

Plough logo and two stripes.

Temodal 20 mg capsules have an opaque white body, an opaque yellow cap, and are imprinted with

black ink. The cap is imprinted with “Temodal”. The body is imprinted with "20 mg", the Schering-

Plough logo and two stripes.

Temodal 100 mg capsules have an opaque white body, an opaque pink cap, and are imprinted with

black ink. The cap is imprinted with “Temodal”. The body is imprinted with "100 mg", the Schering-

Plough logo and two stripes.

Temodal 250 mg capsules have an opaque white body and cap and are imprinted with black ink. The

cap is imprinted with “Temodal”. The body is imprinted with "250 mg", the Schering-Plough logo and

two stripes.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Temodal capsules are indicated for the treatment of:

Adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy (RT)

and subsequently as monotherapy treatment.

Children from the age of three years, adolescents and adult patients with

malignant glioma, such as

glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard

therapy.

Temodal capsules are also indicated as first line treatment for adult patients with advanced metastatic

malignant melanoma.

4.2

Posology and method of administration

Temodal should only be prescribed by physicians experienced in the oncological treatment of brain

tumours.

Anti-emetic therapy may be administered (see section 4.4).

Posology

Adult patients with newly-diagnosed glioblastoma multiforme

Temodal is administered in combination with focal radiotherapy (concomitant phase) followed by up

to 6 cycles of temozolomide (TMZ) monotherapy (monotherapy phase).

Concomitant phase

TMZ is administered orally at a dose of 75 mg/m

daily for 42 days concomitant with focal

radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but delay or

discontinuation of TMZ administration should be decided weekly according to haematological and

non-haematological toxicity criteria. TMZ administration can be continued throughout the 42 day

concomitant period (up to 49 days) if all of the following conditions are met:

absolute neutrophil count (ANC) ≥ 1.5 x 10

thrombocyte count ≥ 100 x 10

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. TMZ administration should be

temporarily interrupted or permanently discontinued during the concomitant phase according to the

haematological and non-haematological toxicity criteria as noted in Table 1.

Table 1. TMZ dosing interruption or discontinuation during

concomitant radiotherapy and TMZ

Toxicity

TMZ interruption

TMZ discontinuation

Absolute neutrophil count

0.5 and < 1.5 x 10

< 0.5 x 10

Thrombocyte count

10 and < 100 x 10

< 10 x 10

CTC non-haematological toxicity

(except for alopecia, nausea, vomiting)

CTC Grade 2

CTC Grade 3 or 4

Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil

count

1.5 x 10

/l; thrombocyte count

100 x 10

/l; CTC non-haematological toxicity

Grade 1 (except for alopecia,

nausea, vomiting).

Monotherapy phase

Four weeks after completing the TMZ + RT concomitant phase, TMZ is administered for up to

6 cycles of monotherapy treatment. Dose in Cycle 1 (monotherapy) is 150 mg/m

once daily for 5 days

followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m

the CTC non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia, nausea and

vomiting), absolute neutrophil count (ANC) is ≥ 1.5 x 10

/l, and the thrombocyte count is

≥ 100 x 10

/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/m

per day for the first 5 days of each subsequent

cycle except if toxicity occurs. Dose reductions and discontinuations during the monotherapy 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

TMZ). The dose should be reduced or administration discontinued according to Table 3.

Table 2.

TMZ dose levels for monotherapy treatment

Dose level

TMZ dose

(mg/m

/day)

Remarks

–1

Reduction for prior toxicity

Dose during Cycle 1

Dose during Cycles 2-6 in absence of toxicity

Table 3. TMZ dose reduction or discontinuation during monotherapy treatment

Toxicity

Reduce TMZ by 1 dose level

Discontinue TMZ

Absolute neutrophil count

< 1.0 x 10

See footnote b

Thrombocyte count

< 50 x 10

See footnote b

CTC non-haematological Toxicity

(except for alopecia, nausea, vomiting)

CTC Grade 3

CTC Grade 4

TMZ dose levels are listed in Table 2.

TMZ is to be discontinued if:

dose level -1 (100 mg/m

) still results in unacceptable toxicity

the same Grade 3 non-haematological toxicity (except for alopecia, nausea, vomiting) recurs after dose reduction.

Adult and paediatric patients 3 years of age or older with recurrent or progressive malignant glioma

(Recurrent glioblastoma multiforme or anaplastic astrocytoma):

A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is

administered orally at a dose of 200 mg/m

once daily for the first 5 days followed by a 23 day

treatment interruption (total of 28 days). In patients previously treated with chemotherapy, the initial

dose is 150 mg/m

once

daily, to be increased in the second cycle to 200 mg/m

once daily, providing

the absolute neutrophil count (ANC) is

1.5 x 10

/L and the platelet count is

100 x 10

/L on Day 1

of the next cycle.

Dose modification for TEMODAL 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/m

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, TEMODAL is administered orally at a dose of 200 mg/m

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/m

once daily for 5 days, with

escalation to 200 mg/m

once daily at the next cycle if there is no haematological toxicity.

In patients with recurrent glioblastoma multiforme/anaplastic astrocytoma or metastatic melanoma,

TEMODAL can be continued until disease progression or for a maximum of 2 years.

Special populations

Paediatric population

In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant

glioma. Experience in these children is very limited (see sections 4.4 and 5.1). The safety and efficacy

of TMZ in children under the age of 3 years have not been established. No data are available.

Patients with hepatic or renal impairment

The pharmacokinetics of TMZ were comparable in patients with normal hepatic function and in those

with mild or moderate hepatic impairment. No data are available on the administration of TMZ in

patients with severe hepatic impairment (Child’s Class C) or with renal impairment. Based on the

pharmacokinetic properties of TMZ, it is unlikely that dose reductions are required in patients with

severe hepatic impairment or any degree of renal impairment. However, caution should be exercised

when TMZ is administered in these patients.

Elderly patients

Based on a population pharmacokinetic analysis in patients 19-78 years of age, clearance of TMZ is

not affected by age. However, elderly patients (> 70 years of age) appear to be at increased risk of

neutropenia and thrombocytopenia (see section 4.4).

Method of administration

Temodal capsules should be administered in the fasting state.

The capsules must be swallowed whole with a glass of water and must not be opened or chewed.

If vomiting occurs after the dose is administered, a second dose should not be administered that day.

4.3

Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Hypersensitivity to dacarbazine (DTIC).

Severe myelosuppression (see section 4.4).

Women who are pregnant, who intend to become pregnant or breast feeding women

4.4

Special warnings and precautions for use

Opportunistic infections and reactivation of infections

Opportunistic infections (such as Pneumocystis jirovecii pneumonia) and reactivation of infections

(such as HBV, CMV) have been observed during the treatment with TMZ (see section 4.8).

Meningoencephalitis herpetic

In post marketing cases, meningoencephalitis herpetic (including fatal cases) has been observed in

patients receiving TMZ in combination with radiotherapy, including cases of concomitant steroids

administration.

Pneumocystis jirovecii

pneumonia

Patients who received concomitant TMZ and RT in a pilot trial for the prolonged 42-day schedule

were shown to be at particular risk for developing

Pneumocystis jirovecii

pneumonia (PCP). Thus,

prophylaxis against PCP is required for all patients receiving concomitant TMZ and RT for the 42-day

regimen (with a maximum of 49 days) regardless of lymphocyte count. If lymphopenia occurs, they

are to continue the prophylaxis until recovery of lymphopenia to grade ≤ 1.

There may be a higher occurrence of PCP when TMZ is administered during a longer dosing regimen.

However, all patients receiving TMZ, particularly patients receiving steroids, should be observed

closely for the development of PCP, regardless of the regimen. Cases of fatal respiratory failure have

been reported in patients using TMZ, in particular in combination with dexamethasone or other

steroids.

Hepatitis due to hepatitis B virus (HBV) reactivation, in some cases resulting in death, has been

reported. Experts in liver disease should be consulted before treatment is initiated in patients with

positive hepatitis B serology (including those with active disease). During treatment patients should be

monitored and managed appropriately

Hepatotoxicity

Hepatic injury, including fatal hepatic failure, has been reported in patients treated with TMZ (see

section 4.8). Baseline liver function tests should be performed prior to treatment initiation. If

abnormal, physicians should assess the benefit/risk prior to initiating temozolomide including the

potential for fatal hepatic failure. For patients on a 42 day treatment cycle liver function tests should

be repeated midway during this cycle. For all patients, liver function tests should be checked after

each treatment cycle. For patients with significant liver function abnormalities, physicians should

assess the benefit/risk of continuing treatment. Liver toxicity may occur several weeks or more after

the last treatment with temozolomide.

Malignancies

Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukaemia, have

also been reported very rarely (see section 4.8).

Anti-emetic therapy

Nausea and vomiting are very commonly associated with TMZ.

Anti-emetic therapy may be administered prior to or following administration of TMZ.

Adult patients with newly-diagnosed glioblastoma multiforme

Anti-emetic prophylaxis is recommended prior to the initial dose of concomitant phase and it is

strongly recommended during the monotherapy phase.

Patients with recurrent or progressive malignant glioma

Patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles may

require anti-emetic therapy.

Laboratory parameters

Patients treated with TMZ may experience myelosuppression, including prolonged pancytopenia,

which may result in aplastic anaemia, which in some cases has resulted in a fatal outcome. In some

cases, exposure to concomitant medicinal products associated with aplastic anaemia, including

carbamazepine, phenytoin, and sulfamethoxazole/trimethoprim, complicates assessment. Prior to

dosing, the following laboratory parameters must be met: ANC

1.5 x 10

/l and platelet count

100 x 10

/l. A complete blood count should 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 10

/l and platelet count > 100 x 10

/l. If

ANC falls to < 1.0 x 10

/l or the platelet count is < 50 x 10

/l during any cycle, the next cycle should

be reduced one dose level (see section 4.2). Dose levels include 100 mg/m

, 150 mg/m

, and

200 mg/m

. The lowest recommended dose is 100 mg/m

Paediatric population

Anaplastic astrocytoma/Glioblastoma multiforme:

There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in

older children (over the age of 3 years) and adolescents with glioma is very limited (see sections 4.2

and 5.1).

Melanoma:

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

Elderly patients (> 70 years of age)

Elderly patients appear to be at increased risk of neutropenia and thrombocytopenia, compared with

younger patients. Therefore, special care should be taken when TMZ is administered in elderly

patients.

Male patients

Men being treated with TMZ should be advised not to father a child up to 6 months after receiving the

last dose and to seek advice on cryoconservation of sperm prior to treatment (see section 4.6).

Lactose

This medicinal product contains lactose. Patients with rare hereditary problems of galactose

intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this

medicine.

4.5

Interaction with other medicinal products and other forms of interaction

In a separate phase I study, administration of TMZ with ranitidine did not result in alterations in the

extent of absorption of temozolomide or the exposure to its active metabolite monomethyl

triazenoimidazole carboxamide (MTIC).

Administration of TMZ with food resulted in a 33% decrease in C

and a 9% decrease in area under

the curve (AUC).

As it cannot be excluded that the change in C

is clinically significant, Temodal should be

administered without food.

Based on an analysis of population pharmacokinetics in phase II trials, co-administration of

dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H

receptor antagonists, or

phenobarbital did not alter the clearance of TMZ. Co-administration with valproic acid was associated

with a small but statistically significant decrease in clearance of TMZ.

No studies have been conducted to determine the effect of TMZ on the metabolism or elimination of

other medicinal products. However, since TMZ does not undergo hepatic metabolism and exhibits low

protein binding, it is unlikely that it would affect the pharmacokinetics of other medicinal products

(see section 5.2).

Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of

myelosuppression.

Paediatric population

Interaction studies have only been performed in adults.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m

TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temodal should not be

administered to pregnant women.

Female patients and female partners of male patients should avoid

pregnancy during treatment and for the 6 months following treatment completion. If use during

pregnancy must be considered, the patient should be apprised of the potential risk to the foetus.

Breast-feeding

It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued

while receiving treatment with TMZ.

Women of childbearing potential

Women of childbearing potential should be advised to use effective contraception to avoid pregnancy

while they are receiving TMZ.

Male fertility

TMZ can have genotoxic effects. Therefore, men being treated with it should be advised not to father a

child up to 6 months after receiving the last dose and to seek advice on cryoconservation of sperm

prior to treatment, because of the possibility of irreversible infertility due to therapy with TMZ.

4.7

Effects on ability to drive and use machines

TMZ has minor influence on the ability to drive and use machines due to fatigue and somnolence (see

section 4.8).

4.8

Undesirable effects

Summary of the safety profile

Clinical trial experience

In patients treated with TMZ in clinical trials, the most common adverse reactions were nausea,

vomiting, constipation, anorexia, headache, fatigue, convulsions, and rash. Most haematologic adverse

reactions were reported commonly; the frequency of Grade 3-4 laboratory findings is presented after

Table 4.

For patients with recurrent or progressive glioma, nausea (43 %) and vomiting (36 %) were usually

Grade 1 or 2 (0 – 5 episodes of vomiting in 24 hours) and were either self-limiting or readily

controlled with standard anti-emetic therapy. The incidence of severe nausea and vomiting was 4 %.

Tabulated list of adverse reactions

Adverse reactions observed in clinical studies and reported from post-marketing use of TMZ are listed

in Table 4. These reactions are classified according to System Organ Class and frequency. Frequency

groupings are defined according to the following convention: Very common (≥ 1/10); Common

(≥ 1/100 to < 1/10); Uncommon (≥ 1/1,000 to < 1/100); Rare (≥1/10,000 to <1/1,000); Very rare

(<1/10,000); Not known (cannot be estimated from the available data). Within each frequency

grouping, undesirable effects are presented in order of decreasing seriousness.

Table 4. Adverse reactions in patients treated with temozolomide

Infections and infestations

Common:

Infections, herpes zoster, pharyngitis

, candidiasis oral

Uncommon:

Opportunistic infection (including PCP), sepsis

meningoencephalitis herpetic

, CMV infection, CMV

reactivation, hepatitis B virus

, herpes simplex, infection

reactivation, wound infection, gastroenteritis

Neoplasm benign, malignant, and unspecified

Uncommon:

Myelodysplastic syndrome (MDS), secondary

malignancies, including myeloid leukaemia

Table 4. Adverse reactions in patients treated with temozolomide

Blood and lymphatic system disorders

Common:

Febrile neutropenia, neutropenia, thrombocytopenia,

lymphopenia, leukopenia, anaemia

Uncommon:

Prolonged pancytopenia, aplastic anaemia

pancytopenia, petechiae

Immune system disorders

Common:

Allergic reaction

Uncommon:

Anaphylaxis

Endocrine disorders

Common:

Cushingoid

Uncommon:

Diabetes insipidus

Metabolism and nutrition disorders

Very common:

Anorexia

Common:

Hyperglycaemia

Uncommon:

Hypokalaemia, alkaline phosphatase increased

Psychiatric disorders

Common:

Agitation, amnesia, depression, anxiety, confusion,

insomnia

Uncommon:

Behaviour disorder, emotional lability, hallucination,

apathy

Nervous system disorders

Very common:

Convulsions, hemiparesis, aphasia/dysphasia, headache

Common:

Ataxia, balance impaired, cognition impaired,

concentration impaired, consciousness decreased,

dizziness, hypoesthesia, memory impaired, neurologic

disorder, neuropathy

, paraesthesia, somnolence, speech

disorder, taste perversion, tremor

Uncommon:

Status epilepticus, hemiplegia, extrapyramidal disorder,

parosmia, gait abnormality, hyperaesthesia, sensory

disturbance, coordination abnormal

Eye disorders

Common:

Hemianopia, vision blurred, vision disorder

, visual field

defect, diplopia, eye pain

Uncommon:

Visual acuity reduced, eyes dry

Ear and labyrinth disorders

Common:

Deafness

, vertigo, tinnitus, earache

Uncommon:

Hearing impairment, hyperacusis, otitis media

Cardiac disorders

Uncommon:

Palpitation

Vascular disorders

Common:

Haemorrhage, embolism pulmonary, deep vein

thrombosis, hypertension

Uncommon:

Cerebral haemorrhage, flushing, hot flushes

Table 4. Adverse reactions in patients treated with temozolomide

Respiratory, thoracic and mediastinal disorders

Common:

Pneumonia, dyspnoea, sinusitis, bronchitis, coughing,

upper respiratory infection

Uncommon:

Respiratory failure

, interstitial

pneumonitis/pneumonitis, pulmonary fibrosis, nasal

congestion

Gastrointestinal disorders

Very common:

Diarrhoea, constipation, nausea, vomiting

Common:

Stomatitis, abdominal pain

, dyspepsia, dysphagia

Uncommon:

Abdominal distension, faecal incontinence,

gastrointestinal disorder, haemorrhoids, mouth dry

Hepatobiliary disorders

Uncommon:

Hepatic failure

, hepatic injury, hepatitis, cholestasis,

hyperbilirubinemia

Skin and subcutaneous tissue disorders

Very Common:

Rash, alopecia

Common:

Erythema, dry skin, pruritus

Uncommon:

Toxic epidermal necrolysis, Stevens-Johnson syndrome,

angioedema, erythema multiforme, erythroderma, skin

exfoliation, photosensitivity reaction, urticaria,

exanthema, dermatitis, sweating increased, pigmentation

abnormal

Not known:

Drug reaction with eosinophilia and systemic symptoms

(DRESS)

Musculoskeletal and connective tissue disorders

Common:

Myopathy, muscle weakness, arthralgia, back pain,

musculoskeletal pain, myalgia

Renal and urinary disorders

Common:

Micturition frequency, urinary incontinence

Uncommon:

Dysuria

Reproductive system and breast disorders

Uncommon:

Vaginal haemorrhage, menorrhagia, amenorrhoea,

vaginitis, breast pain, impotence

General disorders and administration site conditions

Very common:

Fatigue

Common:

Fever, influenza-like symptoms, asthenia, malaise, pain,

oedema, oedema peripheral

Uncommon:

Condition aggravated, rigors, face oedema, tongue

discolouration, thirst, tooth disorder

Investigations

Common:

Liver enzymes elevation

, weight decreased, weight

increased

Uncommon:

Gamma-glutamyltransferase increased

Injury, poisoning and procedural complications

Common:

Radiation injury

Table 4. Adverse reactions in patients treated with temozolomide

Includes pharyngitis, nasopharyngeal pharyngitis, pharyngitis Streptococcal

Includes gastroenteritis, gastroenteritis viral

Includes cushingoid, Cushing syndrome

Includes neuropathy, peripheral neuropathy, polyneuropathy, peripheral sensory neuropathy,

peripheral motor neuropathy

Includes visual impairment, eye disorder

Includes deafness, deafness bilateral, deafness neurosensory, deafness unilateral

Includes earache, ear discomfort

Includes abdominal pain, abdominal pain lower, abdominal pain upper, abdominal discomfort

Includes oedema peripheral, peripheral swelling

Includes liver function test increased, alanine aminotransferase increased, aspartate aminotransferase

increased, hepatic enzymes increased

Includes radiation injury, radiation skin injury

Including cases with fatal outcome

Newly-diagnosed glioblastoma multiforme

Laboratory results

Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for

most cytotoxic agents, including TMZ, was observed. When laboratory abnormalities and adverse

events were combined across concomitant and monotherapy treatment phases, Grade 3 or Grade 4

neutrophil abnormalities including neutropenic events were observed in 8% of the patients. Grade 3 or

Grade 4 thrombocyte abnormalities, including thrombocytopenic events were observed in 14% of the

patients who received TMZ.

Recurrent or progressive malignant glioma (anaplastic astrocytoma, glioblastoma multiforme) or

malignant melanoma

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 TEMODAL 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 Day 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.

The presence of thrombocytopenia may increase the risk of bleeding, and the presence of neutropenia

or leukopenia may increase the risk of infection.

Gender

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 10

/l), 12%

vs

5%, and thrombocytopenia (< 20 x 10

/l), 9%

vs

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

vs

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.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or

recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Although

the data is limited, tolerance in children is expected to be the same as in adults. The safety of TMZ in

children under the age of 3 years has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

https://sideeffects.health.gov.il

4.9

Overdose

Doses of 500, 750, 1,000, and 1,250 mg/m

(total dose per cycle over 5 days) have been evaluated

clinically in patients. Dose-limiting toxicity was haematological and was reported with any dose but is

expected to be more severe at higher doses. An overdose of 10,000 mg (total dose in a single cycle,

over 5 days) was taken by one patient and the adverse reactions reported were pancytopenia, pyrexia,

multi-organ 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.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group:

Antineoplastic agents - Other alkylating agents, ATC code: L01A X03

Mechanism of action

Temozolomide is a triazene, which undergoes rapid chemical conversion at physiologic pH to the

active monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to

be due primarily to alkylation at the O

position of guanine with additional alkylation also occurring at

the N

position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of

the methyl adduct.

Clinical efficacy and safety

Newly-diagnosed glioblastoma multiforme

A total of 573 patients were randomised to receive either TMZ + RT (n=287) or RT alone (n=286).

Patients in the TMZ + RT arm received concomitant TMZ (75 mg/m

) 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

monotherapy TMZ (150 - 200 mg/m

) 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 jirovecii

pneumonia (PCP) prophylaxis was required during RT and combined TMZ 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.

TMZ 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 TMZ + RT arm.

The hazard ratio (HR) for overall survival was 1.59 (95 % CI for HR=1.33 -1.91) with a log-rank

p < 0.0001 in favour of the TMZ arm. The estimated probability of surviving 2 years or more (26 %

vs

10 %) is higher for the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ

monotherapy 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).

HR (95% C.I.) = 1.59 (1.33 – 1.91)

log-rank p-value < .0001

12.1

14.6

RT+TMZ

RT Only

26%

10%

Figure 1

Kaplan-Meier curves for overall survival (intent-to-treat population)

The results from the trial were not consistent in the subgroup of patients with a poor performance

status (WHO PS=2, n=70), where overall survival and time to progression were similar in both arms.

However, no unacceptable risks appear to be present in this patient group.

Recurrent or progressive malignant glioma

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 with oral

TMZ. One was a non-comparative trial in 138 patients (29 % received prior chemotherapy), and the

other was a randomised active-controlled trial of TMZ

vs

procarbazine in a total of 225 patients (67 %

received prior treatment with nitrosourea based chemotherapy). In both trials, the primary endpoint

was progression-free survival (PFS) defined by MRI scans or neurological worsening. In the non-

comparative trial, the PFS at 6 months was 19 %, the median progression-free survival was

2.1 months, and the median overall survival 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 TMZ 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

TMZ and procarbazine, respectively (log rank p = 0.33). At 6 months, the fraction of surviving

patients was significantly higher in the TMZ 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

Data on time to worsening of neurological status favoured TMZ 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 TMZ than for

procarbazine (log rank p = < 0.01 to 0.03).

Recurrent anaplastic astrocytoma

In a multicentre, prospective phase II trial evaluating the safety and efficacy of oral TMZ in the

treatment of patients with anaplastic astrocytoma at first relapse, 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 (ITT)

n=162. In 43 patients stable disease was reported. 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

TEMODAL (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.

primary

endpoint

overall

survival.

Progression-free

survival and response rate were secondary endpoints.

Median overall survival was longer for patients treated with TEMODAL 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 TEMODAL compared to DTIC (1.9 months vs. 1.5 months respectively,

p=0.012). The overall response rate was 13.5 % for TEMODAL and 12.1 % for DTIC.

Paediatric population

Oral TMZ has been studied in paediatric patients (age 3-18 years) with recurrent brainstem glioma or

recurrent high grade astrocytoma, in a regimen administered daily for 5 days every 28 days. Tolerance

to TMZ is similar to adults.

5.2

Pharmacokinetic properties

TMZ is spontaneously hydrolyzed at physiologic pH primarily to the active species, 3-methyl-(triazen-

1-yl)imidazole-4-carboxamide (MTIC). MTIC is spontaneously hydrolyzed to 5-amino-imidazole-4-

carboxamide (AIC), a known intermediate in purine and nucleic acid biosynthesis, and to

methylhydrazine, which is believed to be the active alkylating species. The cytotoxicity of MTIC is

thought to be primarily due to alkylation of DNA mainly at the O

and N

positions of guanine.

Relative to the AUC of TMZ, the exposure to MTIC and AIC is ~ 2.4 % and 23 %, respectively.

In

vivo

, the t

of MTIC was similar to that of TMZ, 1.8 hr.

Absorption

After oral administration to adult patients, TMZ is absorbed rapidly, with peak concentrations reached

as early as 20 minutes post-administration (mean time between 0.5 and 1.5 hours). After oral

administration of

C-labelled TMZ, mean faecal excretion of

C over 7 days post-dose was 0.8 %

indicating complete absorption.

Distribution

TMZ demonstrates low protein binding (10 % to 20 %), and thus it is not expected to interact with

highly protein-bound substances.

PET studies in humans and preclinical data suggest that TMZ crosses the blood-brain barrier rapidly

and is present in the CSF. CSF penetration was confirmed in one patient; CSF exposure based on

AUC of TMZ was approximately 30 % of that in plasma, which is consistent with animal data.

Elimination

The half-life (t

) in plasma is approximately 1.8 hours. The major route of

C elimination is renal.

Following oral administration, approximately 5 % to 10 % of the dose is recovered unchanged in the

urine over 24 hours, and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-

carboxamide (AIC) or unidentified polar metabolites.

Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and

half-life are independent of dose.

Special populations

Analysis of population-based pharmacokinetics of TMZ revealed that plasma TMZ clearance was

independent of age, renal function

or tobacco use. In a separate pharmacokinetic study, plasma

pharmacokinetic profiles in patients with mild to moderate hepatic impairment were similar to those

observed in patients with normal hepatic function.

Paediatric patients had a higher AUC than adult patients; however, the maximum tolerated dose

(MTD) was 1,000 mg/m

per cycle both in children and in adults.

5.3

Preclinical safety data

Single-cycle (5-day dosing, 23 days non-treatment), 3- and 6-cycle toxicity studies were conducted in

rats and dogs. The primary targets of toxicity included the bone marrow, lymphoreticular system,

testes, the gastrointestinal tract and, at higher doses, which were lethal to 60 % to 100 % of rats and

dogs tested, degeneration of the retina occurred. Most of the toxicity showed evidence of reversibility,

except for adverse events on the male reproductive system and retinal degeneration. However, because

the doses implicated in retinal degeneration were in the lethal dose range, and no comparable effect

has been observed in clinical studies, this finding was not considered to have clinical relevance.

TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic to the rat and

dog than to humans, and the clinical dose approximates the minimum lethal dose in rats and dogs.

Dose-related reductions in leukocytes and platelets appear to be sensitive indicators of toxicity. A

variety of neoplasms, including mammary carcinomas, keratocanthoma of the skin and basal cell

adenoma were observed in the 6-cycle rat study while no tumours or pre-neoplastic changes were

evident in dog studies. Rats appear to be particularly sensitive to oncogenic effects of TMZ, with the

occurrence of first tumours within 3 months of initiating dosing. This latency period is very short even

for an alkylating agent.

Results of the Ames/salmonella and Human Peripheral Blood Lymphocyte (HPBL) chromosome

aberration tests showed a positive mutagenicity response.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Capsule content:

anhydrous lactose,

sodium starch glycolate,

stearic acid,

tartaric acid,

colloidal anhydrous silica.

Capsule shell:

gelatin,

titanium dioxide,

sodium lauryl sulfate,

yellow iron oxide [for Temodal 5 and 20 mg],

FD & C Blue 2 [for Temodal 5 mg]

Red Iron oxide [for Temodal 100 mg]

Printing ink:

shellac,

anhydrous ethyl alcohol

isopropyl alcohol

n-butyl alcohol

propylene glycol,

purified water,

ammonium hydroxide,

potassium hydroxide,

black iron oxide.

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

The expiry date of the product is indicated on the packaing material.

6.4

Special precautions for storage

Do not store above 25

6.5

Nature and contents of container

Sachet presentation

Sachets are composed of linear low density polyethylene (innermost layer), aluminium and

polyethylene terephthalate.

Each sachet contains 1 capsule and is dispensed in a cardboard carton.

The carton contains 5 or 20 capsules, individually sealed in sachets.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal and other handling

Capsules should not be opened. If a capsule becomes damaged, contact of the powder contents with

skin or mucous membrane must be avoided. If Temodal comes into contact with skin or mucosa, it

should be washed immediately and thoroughly with soap and water.

Patients should be advised to keep capsules out of the sight and reach of children, preferably in a

locked cupboard. Accidental ingestion can be lethal for children.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7.

License numbers:

Temodal 5 mg:

120.28.30114.22

Temodal 20 mg:

120.29.30115.22

Temodal 100 mg: 120.30.30116.23

Temodal 250 mg: 120.31.30119.22

8. MANUFACTURER

Orion Corporation, Turko, Finland for Merck Sharp & Dohme Corp., NJ, USA

9. LICENSE HOLDER

Merck Sharp & Dohme (Israel – 1996) Company Ltd.,P.O.Box 7121, Petah-Tikva 49170.

Revised in August 2020.

Page 1 of 2

גוא טסו

2020

ה/דבכנ ה/אפור

/חקור

ה/דבכנ

Temodal

®

5, 20, 100 or 250 mg

:ןודנה לאדומט

5

,ג"מ

20

,ג"מ

100

,ג"מ וא

250

ג"מ

Dosage Form: capsules

Composition: Each capsule contains 5, 20, 100 or 250 mg temozolomide.

פראש קרמ תרבח

לארשי םהודו

MSD)

ןוכדע לע עדייל תשקבמ (

ןולעה

ל

אפור

ןכרצל ןולעהו

לש

לאדומט

היוותהה ןושל ןלהל

רישכתל תרשואמה

םי

:

Temodal capsules are indicated for the treatment of:

Adult patients with newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and

subsequently as monotherapy treatment.

Children from the age of three years, adolescents and adult patients with malignant glioma, such

as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after

standard therapy.

Temodal capsules are also indicated as first line treatment for adult patients with advanced

metastatic malignant melanoma.

עדימל

אלמ

תוארוהלו

ןתמ

תוטרופמ

שי

ןייעל

ןולעב

אפורל

רשואמה

לע

ידי

דרשמ

תואירבה

םינוכדע ל ןולעב םייתוהמ אפור

:

טסקט

ףסוותהש

ב ןמוסמ

ןותחת וק

קרפה ךותמ ןכדעתהש יתוהמה עדימה קר עיפומ ןלהלש טוריפב

4.8

Undesirable effects

הלבט

קרפב הנכדוע תפסוהל

יאוול תועפות .יאוולה תועפות תויוחיכש תניחבמ הבתכושו

האר

אפורל ןולע

Table 4. Adverse reactions in patients treated with temozolomide

Infections and infestations

Uncommon:

Opportunistic infection (including PCP), sepsis

meningoencephalitis herpetic

, CMV infection, CMV

reactivation, hepatitis B virus

, herpes simplex,

infection reactivation, wound infection, gastroenteritis

Skin and subcutaneous tissue disorders

Not known:

Drug reaction with eosinophilia and systemic symptoms

(DRESS)

Including cases with fatal outcome

ל ןולעב םייתוהמ םינוכדע ןכרצ

:

טסקט

ףסוותהש

.ןותחת וקב ןמוסמ

קרפה ךותמ ןכדעתהש יתוהמה עדימה קר עיפומ ןלהלש טוריפב

?לאדומטב שמתשת דציכ

דציכ

לוטיל

תא

הפורתה

רובע)

לכ

םילוחה

:(

Page 2 of 2

שי

לוטיל

תא

הנמה

המשרנש

ךל

לש

לאדומט

םעפ

םויב

לע

הביק

הקיר

לשמל

תוחפל

העש

ינפל

תחורא

רקובה

ףידע

לוטיל

תא

הנמה

התואב

העשה

לכ

םוי

.םימ סוכ םע התומלשב הסומכה תא עולבל שי .

ןיא

חותפל

שותכל

וא

סועלל

תא

הסומכה

לאדומט

תופורת תצובקל תכייש

תוארקנה

תופורת תויסקוטוטיצ

וא תויפרתומיכ

אל הפישחל ןוכיסל תמרוג תוסומכה תחיתפ

הפורתל תנווכמ

םע וא רועה םע עגמ וא הפיאש ידי לע

אל הפישחל ןוכיסה תא תיחפהל תנמ לע .תויריר תומקר

ל תנווכמ

לאדומט

ןיא

חותפל

תא

תוסומכה

הדימב

הסומכש

המגפנ

ענמיה

עגממ

לש

תקבא

הסומכה

םע

רועה

תומקרהו

תוירירה

ףיעס האר) (ףא ,םייניע)

םע עגמ לש הרקמב

.םיידיה תא ףוטשל שי ,הקבאה

4

.

יאוול תועפות

...

אפורל תונפל שי

דימ

םא

ךל שי

לכ

:םיאבה םינמיסהמ דחא

,(םירחא המישנ יישק וא םיפוצפצ ,תדפרס) הרומח (רתי תושיגר) תיגרלא הבוגת

,טלשנ יתלב םומיד

,(תותיווע) ןויפכ יפקתה

,םוח

תורומרמצ

.ףלוח וניאש רומח שאר באכ

בתכוש יאוולה תועפות קרפ

יאוולה תועפות תויוחיכש תניחבמ

.וז העדוהב םיללכנ םניאו םייתוהמ םניאש םיפסונ םינוכדע ויה ןכרצלו אפורל םינולעב

ולעה

ןכרצל ןולעהו אפורל ן םמוסרפ ךרוצל וחלשנ

רגאמב

תופורתה

רתאבש

טנרטניאה

לש

דרשמ

תואירבה

םלבקל ןתינ .

היינפ ידי לע םיספדומ לעבל

תרבח ,םושירה

ןופלטב ,

09-9533333

Temodal

.מ"עב גולובונ תרבח י"ע ץפומ

,הכרבב

ןיליב תירוא

הנוממ תחקור

לארשי

References:

Israeli revised SPC and PIL Aug 2020

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