Active ingredients: Temozolomide
Temodal 5 mg hard capsules
Temodal 20 mg hard capsules
Temodal 100 mg hard capsules
Temodal 140 mg hard capsules
Temodal 180 mg hard capsules
Temodal 250 mg hard capsules
Why is Temodal used? What is it for?
Temodal contains a medicine called temozolomide. This medicine is an anticancer agent.
Temodal is used to treat specific forms of brain tumor:
- in adults with first diagnosed glioblastoma multiforme. Temodal is initially used in combination with radiotherapy (concomitant treatment phase) and subsequently alone (monotherapy treatment phase).
- in children 3 years of age and older and in adult patients with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma. Temodal is used in these cancers that relapse or progress after standard therapy.
Contraindications When Temodal should not be used
Do not take Temodal
- if you are allergic to temozolomide or any of the other ingredients of this medicine (listed in section 6).
- if you have had a previous allergic reaction to dacarbazine (an anticancer medicine, sometimes called DTIC). Signs of an allergic reaction include itching, shortness of breath or wheezing, swelling of the face, lips, tongue or throat.
- if the number of certain types of blood cells is severely reduced (myelosuppression), such as the number of white blood cells and platelets. These blood cells are important for fighting infections and for proper blood clotting. Your doctor will have blood tests done to make sure that there are enough cells to start treatment.
Precautions for use What you need to know before taking Temodal
Talk to your doctor, pharmacist or nurse before taking Temodal,
- as he must be closely observed for the development of a severe form of chest infection called Pneumocystis jirovecii pneumonia (PCP). If you are a first-time diagnosed patient (glioblastoma multiforme) you can be given Temodal for 42 days in combination with radiotherapy. In this case, your doctor will also prescribe medicines to help you prevent this type of pneumonia (PCP).
- if you have ever had or may currently have a hepatitis B infection. This is because Temodal may cause hepatitis B to become reactivated, which in some cases can be fatal. Before starting treatment, patients will be carefully checked by their doctor to check if there are any signs of this infection.
- if you have low numbers of red blood cells (anemia), white blood cells and platelets, or blood clotting problems before starting treatment, or if you develop them during treatment. Your doctor may decide to reduce your dose, stop, stop or change your treatment. You may also need other treatments. In some cases, it may be necessary to stop taking Temodal.Samples of your blood will be tested frequently during treatment to check for side effects of Temodal on your blood cells.
- as you may have a low risk of developing other blood cell disorders, including leukemia.
- 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 a medicine (an anti-emetic) to help prevent vomiting. If you vomit frequently before or during treatment, ask your doctor for the best time to take Temodal until the vomiting is under control. If you vomit after taking one dose, do not take a second one on the same day.
- if you get fever or symptoms of an infection, contact your doctor immediately.
- if you are over 70, you may be more prone to infections, bruising or bleeding.
- if you have liver or kidney problems, your dose of Temodal may need to be adjusted.
Children and adolescents
Do not give this medicine to children under 3 years of age as it has not been studied. There is limited information in patients over 3 years of age who have taken Temodal.
Interactions Which drugs or foods may change the effect of Temodal
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
Warnings It is important to know that:
Pregnancy, breastfeeding 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 it should not be treated with Temodal in pregnancy unless clearly indicated by your doctor.
Effective contraceptive precautions should be taken by both male and female patients who are taking Temodal (see also "Male Fertility" below).
You must stop breast-feeding if you are being treated with Temodal.
Male fertility
Temodal can cause permanent infertility. Male patients should use effective contraceptive methods and not try to have a child for 6 months after stopping treatment. It is recommended to inquire about sperm storage before starting treatment.
Driving and using machines
Temodal can make you feel tired or sleepy. In this case, do not drive or use any tools or machines or bicycles until you see the effects this medicine has on you (see section 4).
Temodal contains lactose
Temodal contains lactose (a type 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.
Dosage and method of use How to use Temodal: Dosage
Always take this medicine exactly as your doctor or pharmacist has told you. If in doubt, consult your doctor or pharmacist.
Dosage and duration of treatment
Your doctor will determine your dose of Temodal. It depends on your size (height and weight) and, if you have a recurrent tumor, on any previous chemotherapy treatment.
Other medicines (anti-emetics) may be prescribed to be taken before and / or after taking Temodal to prevent or control nausea and vomiting.
Patients with glioblastoma multiforme first diagnosed:
If you are a patient who has been diagnosed with cancer for the first time, treatment will take place in two stages:
- Temodal is initially associated with radiotherapy (concomitant phase)
- Thereafter Temodal is given alone (monotherapy phase).
During the concomitant phase, your doctor will start Temodal at a dose of 75 mg / m2 (usual dose). You will take this dose every day for 42 days (up to a maximum of 49 days) in combination with radiotherapy. Your dose of Temodal may be delayed or stopped based on the number of your blood cells and how you are coping with the medicine during the concomitant phase.
Once the radiotherapy is completed, you will stop the treatment for 4 weeks. This will give your body a chance to recover.
Then, she will start monotherapy.
During the monotherapy phase, the dose and the way you take Temodal will be different. Your doctor will work out your correct dose. There may be up to 6 treatment periods (cycles). Each lasts 28 days. You will take your new dose of Temodal on its own once a day for the first 5 days ("therapy days") of each cycle. The first dose will be 150 mg / m 2. Then 23 days without Temodal will follow. Thus the 28 days of the treatment cycle are reached.
After Day 28, the next cycle will begin. You will again take Temodal once a day for 5 days followed by 23 days without Temodal. The dose of Temodal may be adjusted, delayed or stopped based on your blood count and how you cope with the medicine during each treatment cycle.
Patients with tumors that have come back or have worsened (malignant gliomas, such as glioblastoma multiforme or anaplastic astrocytoma) treated with Temodal alone:
A treatment course with Temodal lasts 28 days. You will take Temodal on its own once a day for the first 5 days. This daily dose depends on any previous chemotherapy treatments.
If you have not previously been treated with chemotherapy, your first dose of Temodal will be 200 mg / m2 once a day for the first 5 days. If you have previously been treated with chemotherapy, your first dose of Temodal will be 150 mg / m 2 once a day for the first 5 days.
For the next 23 days you will no longer receive Temodal. This will complete the 28 day cycle.
After Day 28, the next cycle will begin. You will again take Temodal once a day for five days, followed by 23 days without Temodal.
Before each new cycle, you will be given blood tests to see if the dose of Temodal needs to be changed. Based on the results of your blood tests, your doctor may change your dose for the next cycle.
How to take Temodal
Take your prescribed dose of Temodal once a day, preferably at the same time each day.
Take the capsules on an empty stomach; for example, at least one hour before breakfast.
Swallow the capsule (s) whole with a glass of water. Do not open, crush or chew the capsules. If the capsule is damaged, avoid contact of the powder with the skin, eyes or nose. some powder should come into contact with your eyes or nose, rinse the affected area with water.
Depending on the prescribed dose, it may be necessary to take more than one capsule at the same time, possibly with different strengths (content of the active substance in mg). The color of the capsule shell is different for each strength (see table below).
You need to make sure you understand and remember the following:
- how many capsules you need to take for your daily dosage. Ask your doctor or pharmacist to write it down (including the color).
- what are the days of taking the therapy.
Review the dose with your doctor each time you have to start a new cycle, as it may be different from the previous cycle.
Always take Temodal exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. Mistakes in taking this medicine could cause serious harm to your health.
If you forget to take Temodal
Take the missed dose as soon as possible in the same day. If a full day has passed, contact your doctor. Do not take a double dose to make up for a forgotten dose, unless your doctor tells you to.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Overdose What to do if you have taken too much Temodal
If you accidentally take more capsules than prescribed, contact your doctor, pharmacist or nurse immediately.
Side Effects What are the side effects of Temodal
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Contact your doctor immediately if you experience:
- a severe allergic (hypersensitivity) reaction (hives, wheezing or other difficulty breathing),
- uncontrolled bleeding,
- fits (convulsions),
- fever,
- severe headache that does not go away.
Treatment with Temodal can cause a reduction in certain types of blood cells. This can lead to increased bruising or bleeding, anemia (reduced number of red blood cells), fever, and reduced resistance to infection. The reduction in the number of blood cells is usually short-lived. In some cases, it can be prolonged and can lead to a very severe form of anemia (aplastic anemia). Your doctor will check your blood regularly and decide if specific therapy is needed. In some cases the dose of Temodal will be reduced or the treatment ended.
Side effects from clinical studies:
Temodal in combination treatment with radiotherapy in newly diagnosed glioblastoma
Patients receiving Temodal in combination with radiotherapy may experience different side effects than those reported by patients receiving Temodal alone. The following side effects may occur and may require medical attention.
Very common (may affect more than 1 in 10 people):
loss of appetite, headache, constipation (difficulty passing stools), nausea (feeling sick in the stomach), vomiting, rash, hair loss, tiredness.
Common (may affect up to 1 in 10 people):
mouth infections, wound infections, reduced blood cell counts (neutropenia, thrombocytopenia, lymphopenia, leukopenia), increased blood sugar, weight loss, changes in mental status or alertness, anxiety / depression, sleepiness, difficulty talking, problems with balance, dizziness, confusion, memory loss, difficulty concentrating, inability to fall asleep or stay asleep, tingling sensation, bruising, tremor, abnormal or confused vision, double vision, impaired hearing, shortness of breath, cough, blood clots in the legs, fluid retention, swollen legs, diarrhea, stomach or abdominal pain, heartburn, stomach upset, difficulty swallowing, dry mouth, skin irritation or redness, dry skin, itching, weakness muscle, joint pain, muscle aches and pains, urinating frequently, difficulty holding urine, allergic reaction, fever, radiowheel injury pia, swelling of the face, pain, change in taste, abnormal liver function tests.
Uncommon (may affect up to 1 in 100 people):
flu symptoms, red spots under the skin, low blood potassium, weight gain, mood changes, hallucinations and memory disturbances, partial paralysis, coordination disturbances, sensory disturbances, partial loss of vision, dry or painful eyes , deafness, middle ear infection, ringing in the ears, earache, palpitations (when you can hear your heartbeat), blood clots in the lung, high blood pressure, pneumonia, inflammation of the nasal passages, bronchitis, cold or flu, stomach bloating, difficulty controlling bowel movements, haemorrhoids, skin peeling, increased sensitivity of the skin to sunlight, changes in skin color, increased sweating, muscle damage, back pain, difficulty urinating, vaginal bleeding , sexual impotence, absent or heavy menstrual periods, vaginal irritation, breast pain, hot flashes, chills i, tongue discoloration, change in perception of odors, thirst, dental disorders.
Temodal on its own in glioma that has come back or got worse
The following side effects may occur and may require medical attention.
Very common (may affect more than 1 in 10 people):
decreased number of blood cells (neutropenia or lymphopenia, thrombocytopenia), loss of appetite, headache, vomiting, nausea (feeling sick in the stomach), constipation (difficulty passing stools), tiredness.
Common (may affect up to 1 in 10 people):
weight loss, sleepiness, dizziness, tingling sensation, shortness of breath, diarrhea, abdominal pain, stomach upset, rash, itching, hair loss, fever, weakness, chills, feeling unwell, pain, change in taste.
Uncommon (may affect up to 1 in 100 people):
reduction in the number of blood cells (pancytopenia, anemia, leukopenia).
Rare (may affect up to 1 in 1,000 people):
cough, infections including pneumonia.
Very rare (may affect up to 1 in 10,000 people):
redness of the skin, hives (wheals), rash, allergic reactions.
Other side effects:
Cases of liver enzyme elevations have been commonly reported. Cases of increased bilirubin, problems with the flow of bile (cholestasis), hepatitis and liver damage, including liver failure resulting in death, have been reported uncommonly.
Very rare cases of severe rash with swelling of the skin, including on the palms of the hands and soles of the feet or painful redness of the skin and / or blisters on the body or in the mouth have been observed. Tell your doctor immediately if these cases occur.
Very rare cases of lung side effects have been observed with Temodal. Patients usually present with shortness of breath and cough. Tell your doctor if you notice any of these symptoms.
In very rare cases, patients taking Temodal and similar medicines may have a small risk of developing secondary cancers, including leukemia.
New or reactivated (recurrent) cytomegalovirus infections and reactivated hepatitis B virus infections have been reported uncommonly.
Cases of diabetes insipidus have been uncommonly reported. Symptoms of diabetes insipidus include excretion of a large amount of urine and feeling thirsty.
Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children, preferably in a locked cabinet. Accidental ingestion can cause death to children.
Do not use this medicine after the expiry date which is stated on the label and carton. The expiry date refers to the last day of that month.
Bottle presentation
Do not store above 30 ° C.
Keep the capsules in the original bottle to protect them from moisture.
Keep the bottle tightly closed.
Presentation in sachet
Do not store above 30 ° C.
Tell your pharmacist if you notice any changes in the appearance of the capsules.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other information
What Temodal contains
- The active substance is temozolomide.
- Temodal 5 mg hard capsules: Each capsule contains 5 mg of temozolomide.
- Temodal 20 mg hard capsules: Each capsule contains 20 mg temozolomide.
- Temodal 100 mg hard capsules: Each capsule contains 100 mg temozolomide.
- Temodal 140 mg hard capsules: Each capsule contains 140 mg of temozolomide.
- Temodal 180 mg hard capsules: Each capsule contains 180 mg temozolomide.
- Temodal 250 mg hard capsules: Each capsule contains 250 mg of temozolomide.
The other ingredients are:
- capsule contents: anhydrous lactose, anhydrous colloidal silica, sodium starch glycolate type A, tartaric acid, stearic acid (see section 2 "Temodal contains lactose").
- capsule shell:
- Temodal 5 mg hard capsules: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, yellow iron oxide (E 172), indigo carmine (E 132),
- Temodal 20 mg hard capsules: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, yellow iron oxide (E 172),
- Temodal 100 mg hard capsules: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, red iron oxide (E 172),
- Temodal 140 mg hard capsules: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, indigo carmine (E 132),
- Temodal 180 mg hard capsules: gelatin, titanium dioxide (E 171), sodium lauryl sulfate, yellow iron oxide (E 172) and red iron oxide (E 172),
- Temodal 250 mg hard capsules: gelatin, titanium dioxide (E 171), sodium lauryl sulfate. printing ink: shellac, propylene glycol, purified water, ammonium hydroxide, potassium hydroxide and black iron oxide (E 172).
Description of what Temodal looks like and contents of the pack
- Temodal 5 mg hard capsules have an opaque white body, an opaque green cap and are imprinted with black ink.
- Temodal 20 mg hard capsules have an opaque white body, an opaque yellow cap and are imprinted with black ink.
- Temodal 100 mg hard capsules have an opaque white body, an opaque pink cap and are imprinted with black ink.
- Temodal 140 mg hard capsules have an opaque white body, blue cap and are imprinted with black ink.
- Temodal 180 mg hard capsules have an opaque white body, an opaque orange cap and are imprinted with black ink.
- Temodal 250 mg hard capsules have an opaque white body and cap and are imprinted with black ink.
Bottle presentation
The hard capsules for oral use are available in amber glass bottles containing 5 or 20 capsules.
The box contains one bottle.
Presentation in sachet
The hard capsules for oral use are available in cartons containing 5 or 20 hard capsules, which are individually sealed in sachets.
Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
TEMODAL 100 MG HARD CAPSULES
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each hard capsule contains 100 mg of temozolomide.
Excipient with known effects:
Each hard capsule contains 175.7 mg of anhydrous lactose.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Hard capsule (capsule).
The hard capsules have an opaque white body, an opaque pink cap and are imprinted with black ink.
"Temodal" is printed on the shell. "100 mg", the Schering-Plow logo and two stripes are printed on the body.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Temodal is indicated in the treatment of:
• adult patients with first diagnosed glioblastoma multiforme in combination with radiotherapy (RT) and later as monotherapy.
• pediatric patients ≥ 3 years of age, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, who experience relapse or progression after standard therapy.
04.2 Posology and method of administration
Temodal should only be prescribed by doctors who have experience in the oncology treatment of brain tumors.
Antiemetic therapy may be given (see section 4.4).
Dosage
Adult patients with first diagnosed glioblastoma multiforme
Temodal is given in combination with focal radiotherapy (concomitant phase) and subsequently as monotherapy for up to 6 temozolomide (TMZ) cycles (monotherapy phase).
Concurrent phase
TMZ is administered orally at a daily dosage of 75 mg / m2 for 42 days in combination with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductions are recommended, but based on haematological and non-haematological toxicity criteria, weekly decisions will be made whether to delay or discontinue the administration of TMZ. TMZ administration can be continued during the 42-day concomitant period (up to a maximum of 49 days) if all of the following conditions are met:
• absolute neutrophil count (ANC) ≥ 1.5 x 109 / L
• thrombocytic count ≥ 100 x 109 / l
• Common Toxicity Criteria (CTC) for non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting).
A complete blood count should be performed weekly during treatment. TMZ treatment should be temporarily or permanently discontinued during the concomitant phase based on the haematological and non-haematological toxicity criteria as indicated in Table 1.
a: Concomitant TMZ treatment can be continued when all of the following conditions are met: absolute neutrophil count ≥ 1.5 x 109 / L; thrombocytic count ≥ 100 x 109 / L; CTC non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea, vomiting).
Monotherapy phase
Four weeks after the end of the concomitant TMZ + RT phase, TMZ is administered for up to 6 cycles as monotherapy. The dose of Cycle 1 (monotherapy) is 150 mg / m2 once daily for 5 days followed by 23 days without treatment. At the beginning of Cycle 2, the dosage is increased to 200 mg / m2 if the CTC for non-haematological toxicity for Cycle 1 is Grade ≤ 2 (except for alopecia, nausea and vomiting), the absolute neutrophil count (ANC) is ≥ 1.5 x 109 / L and the thrombocyte count is ≥ 100 x 109 / L. If the dose is not increased to Cycle 2, no dose increases can be made in subsequent cycles. Once increased, the dose will remain at 200 mg / m2 per day for the first 5 days of each subsequent cycle unless toxicity occurs. Dose reductions and treatment interruptions during the monotherapy phase should be done in accordance with Tables 2 and 3.
A complete blood count should be performed on Day 22 (21 days after the first dose of TMZ) during treatment. Dosage should be reduced or administration interrupted according to Table 3.
Table 2. Dose Levels of TMZ Monotherapy
Table 3. TMZ dose reduction or discontinuation during monotherapy
a: TMZ dose levels are listed in Table 2.
b: TMZ must be discontinued if:
• dose level -1 (100 mg / m2) still causes unacceptable toxicity
• the same Grade 3 non-haematological toxicity still occurs after dose reduction (except for alopecia, nausea, vomiting).
Adult and pediatric patients at least 3 years of age with recurrent or progressive malignant glioma:
Therapy involves a 28-day course of treatment. In patients not previously undergoing chemotherapy, TMZ is administered orally at a dosage of 200 mg / m2 once daily for the first 5 days followed by a "discontinuation of treatment for 23 days (total 28-day treatment cycle)". patients previously undergoing chemotherapy the starting dose is 150 mg / m2 once daily, to be increased in the second cycle to 200 mg / m2 once daily for 5 days in the absence of haematological toxicity (see section 4.4).
Special populations
Pediatric population
In patients 3 years of age or older, TMZ should only 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 less than 3 years of age have not been established. No data are available.
Patients with hepatic or renal impairment
The pharmacokinetics of TMZ in patients with normal hepatic function are comparable to that of patients with moderate or moderate hepatic impairment. No data are available on the administration of TMZ in patients with severe hepatic impairment (Child's Class C) or renal impairment. Based on the pharmacokinetic properties of TMZ, it is unlikely that a dose reduction is required in patients with severe hepatic impairment or any degree of renal impairment. However TMZ should be administered with caution in these patients.
Elderly patients
Pharmacokinetic analysis on a population of patients aged 19 to 78 years, showed that TMZ clearance is not affected by age. However, in elderly patients (aged> 70 years) there appears to be an increased risk of neutropenia and thrombocytopenia (see section 4.4).
Method of administration
Temodal hard capsules should be taken on an empty stomach.
The capsules should be swallowed whole with a glass of water and should not be opened or chewed.
If vomiting occurs after administration of the dose, a second dose cannot be given on the same day.
04.3 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).
04.4 Special warnings and appropriate 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 treatment with TMZ (see section 4.8).
Pneumonia from Pneumocystis jirovecii
Patients who received TMZ in combination with RT in a pilot study following the 42-day extended treatment program were shown to be particularly at risk of developing pneumonia Pneumocystis jirovecii (PCP). Consequently, for all patients receiving TMZ and RT concomitantly for a 42-day regimen (with a maximum of 49 days), regardless of lymphocyte counts, PCP prophylaxis is required. Should lymphopenia occur, patients should continue prophylaxis until lymphopenia has regressed to Grade ≤ 1.
A wider recurrence of PCP may be seen when TMZ is administered on a longer dosing regimen. However, all patients treated with TMZ, especially those taking steroids, should be closely monitored for the development of PCP regardless of the dosing regimen. Cases of fatal respiratory failure have been reported in patients receiving TMZ, particularly in combination with dexamethasone or other steroids.
HBV
Hepatitis due to reactivation of hepatitis B virus (HBV), in some cases with fatal outcome, has been reported. Liver disease experts should be consulted before starting treatment in patients with positive hepatitis B serology (including those with active disease). Patients should be monitored and managed appropriately during treatment.
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 before starting treatment. If results are abnormal, physicians should evaluate the benefit / risk including the possibility of fatal liver failure before starting TMZ. For patients on a 42-day treatment course, liver function tests should be repeated midway through the course. For all patients, liver function tests should be performed after each course of treatment. For patients with significant liver function impairment, physicians should weigh the benefit / risk of continuing treatment. Liver toxicity can occur several weeks or more after the last temozolomide treatment.
Neoplasms
Cases of myelodysplastic syndrome and secondary malignancies, including myeloid leukemia, have also been reported very rarely (see section 4.8).
Antiemetic therapy
Nausea and vomiting are very common with TMZ.
Before or after administration of TMZ, anti-emetic therapy may be indicated.
Adult patients with first diagnosed glioblastoma multiforme
Antiemetic prophylaxis is recommended before the initial dose of the concomitant phase while it is strongly recommended during the monotherapy phase.
Patients with recurrent or progressive malignant glioma
In patients who have experienced severe (Grade 3 or 4) vomiting in previous treatment cycles, anti-emetic therapy may be required.
Laboratory parameters
Myelosuppression, including prolonged pancytopenia, may occur in patients treated with TMZ, which can lead to aplastic anemia, leading in some cases to a fatal outcome. In some cases, exposure to concomitant medicinal products associated with aplastic anemia, including carbamazepine, phenytoin, and sulfamethoxazole / trimethoprim, complicates the assessment. The following laboratory parameters should be evaluated prior to administration: ANC ≥ 1.5 x 109 / l and platelet count ≥ 100 x 109 / L. A complete and weekly blood count should be performed on Day 22 (21 days after first administration) or within 48 hours until ANC is> 1.5 x 109 / l and count platelet count is> 100 x 109 / L. If ANC reduces to platelets it is 2, 150 mg / m2 and 200 mg / m2. The lowest recommended dose is 100 mg / m2.
Pediatric population
There is no clinical experience with the use of TMZ in children under 3 years of age. Clinical experience in older children and adolescents is very limited (see sections 4.2 and 5.1).
Elderly patients (> 70 years of age)
Elderly patients appear to be at greater risk of neutropenia and thrombocytopenia than younger ones. Therefore TMZ should be administered with particular care to elderly patients.
Male patients
Men being treated with TMZ should be advised not to procreate until 6 months after the last dose and to inquire about cryopreservation of sperm prior to initiation of 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.
04.5 Interactions with other medicinal products and other forms of interaction
In a separate phase I study, administration of TMZ with ranitidine did not alter the absorption of temozolomide or the exposure to its active metabolite monomethyl triazenoimidazole carboxamide (MTIC).
Administration of TMZ with food results in a 33% decrease in Cmax and a 9% decrease in the area under the curve (AUC).
Since it cannot be excluded that the change in Cmax is of clinical significance, Temodal should be administered without food.
Population pharmacokinetic evaluation of phase II studies showed that co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 receptor antagonists or phenobarbital did not alter the clearance of TMZ. Concomitant administration of valproic acid is associated with a slight, but statistically significant, decrease in TMZ clearance.
No studies have been performed to determine the effect of TMZ on the metabolism or elimination of other medicinal products. However, as TMZ does not undergo hepatic metabolism and is characterized by low protein binding, it is unlikely to affect the pharmacokinetics of other medicinal products (see section 5.2).
The use of TMZ in combination with other myelosuppressive agents may increase the possibility of myelosuppression.
Pediatric population
Interaction studies have only been performed in adults.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no data on pregnant women. Teratogenic and / or fetal toxicity was demonstrated in preclinical studies in rats and rabbits treated with 150 mg / m2 of TMZ (see section 5.3). Temodal should not be given to pregnant women. If use in pregnancy is considered, the patient should be informed of the potential risk to the fetus.
Feeding time
It is not known whether TMZ is excreted in human milk; therefore breastfeeding should be discontinued during TMZ treatment.
Women of childbearing age
Women of childbearing potential should be advised to use effective contraceptive methods to avoid pregnancy while being treated with TMZ.
Male fertility
TMZ can have genotoxic effects.Therefore, men being treated with TMZ should be advised not to procreate until 6 months after the last dose and to inquire about cryopreservation of sperm prior to initiation of treatment due to possible, irreversible infertility associated with TMZ therapy.
04.7 Effects on ability to drive and use machines
TMZ has minimal influence on the ability to drive and use machines due to the onset of fatigue and somnolence (see section 4.8).
04.8 Undesirable effects
Experience from clinical trials
In patients treated with TMZ, either on concomitant treatment with RT or as monotherapy after RT for newly diagnosed glioblastoma multiforme, or as monotherapy in patients with relapsing or progressive glioma, the very common adverse reactions reported are similar and are: nausea, vomiting, constipation, anorexia, headache and fatigue. Seizures were very commonly reported in patients with first diagnosed glioblastoma multiforme who received monotherapy, and rash was very commonly reported in patients with first diagnosed glioblastoma multiforme who received TMZ concomitantly with RT and also as monotherapy and commonly in recurrent glioma. Most haematological adverse reactions are reported as common or very common in both indications (Tables 4 and 5); the frequency of grades 3-4 of laboratory values is given after each table.
In the tables, undesirable effects are classified according to the System Organ Class and frequency. The frequency classes are defined according to the following conventions: Very Common (≥ 1/10); Common (≥ 1/100,
Early diagnosis of glioblastoma multiforme
Table 4 lists the undesirable effects that occurred during treatment in patients with newly diagnosed glioblastoma multiforme during the concomitant and monotherapy treatment phases.
* One patient who was randomized to the RT-only arm received TMZ + RT.
Laboratory results
Myelosuppression (neutropenia and thrombocytopenia), which is known dose-limiting toxicity for most cytotoxic agents, including TMZ, has been observed. When laboratory abnormalities add to undesirable effects during the concomitant phase and the monotherapy phase, Grade 3 or 4 neutrophil abnormalities including neutropenic events were observed in 8% of patients. Grade 3 or 4 thrombocytic changes, including thrombocytopenic events, were observed in 14% of patients receiving TMZ.
Recurrent or progressive malignant glioma
In clinical studies, the most frequent treatment-related undesirable effects were gastrointestinal disorders, namely nausea (43%) and vomiting (36%). These events were usually Grade 1 or 2 (0 - 5 vomiting episodes in 24 hours), self-limiting or rapidly controlled by conventional anti-emetic therapy. The incidence of severe nausea and vomiting was 4%.
Table 5 lists the adverse reactions found during clinical trials in relapsing or progressive malignant glioma and following the placing on the market of Temodal.
Laboratory results
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19% and 17% of patients treated for malignant glioma, respectively. This resulted in hospitalization and / or discontinuation of TMZ treatment in 8% and 4% of patients, respectively. Myelosuppression was predictable (usually within the first few cycles, with nadir between Day 21 and Day 28), and recovery was rapid usually within 1-2 weeks No evidence of cumulative myelosuppression was observed The presence of thrombocytopenia may increase the risk of bleeding and the presence of neutropenia or leukopenia that of infections.
Sex
In a population pharmacokinetic analysis from clinical trials, 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. Higher frequencies of Grade 4 neutropenia (ANC vs 5%, and thrombocytopenia (vs 3%, in women versus men, in the first cycle of therapy) were found. In a dataset of 400 subjects with recurrent glioma, Grade 4 neutropenia occurred in 8% of female subjects vs 4% of males and Grade 4 thrombocytopenia in 8% of females vs 3% of males, 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 subjects vs 0% of males and Grade 4 thrombocytopenia in 1% of females vs 0% of males, in the first cycle of therapy.
Pediatric population
Oral TMZ has been studied in pediatric patients (aged 3 to 18 years) with recurrent brain stem glioma or recurrent high grade astrocytoma, on a daily dosing regimen for 5 days every 28 days. Although data are limited, tolerance in children is expected to be similar to that in adults. The safety of TMZ in children aged less than 3 years has not been established.
Post-marketing experience
The following additional serious adverse reactions were identified during post-marketing exposure:
† Including cases with a fatal outcome
* Frequencies estimated based on relevant clinical studies.
Reporting of suspected adverse reactions
The reporting of suspected adverse reactions that occur after the authorization of the medicinal product is important, as it allows continuous monitoring of the benefit / risk ratio of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Italian Medicines Agency. , website: http://www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Doses of 500, 750, 1,000 and 1,250 mg / m2 (total dose per cycle over 5 days) have been evaluated clinically in patients. Haematological toxicity was dose-limiting and reported at each dose but is expected to be more severe at higher doses. One patient received an overdose of 10,000 mg (total single cycle dose, over 5 days) and reported adverse reactions were pancytopenia, pyrexia, multifunctional failure and death. There have been reports of patients taking the recommended dose for more than 5 days (up to 64 days) reporting side effects including bone marrow ablation, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is required. Supportive measures should be instituted as needed.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antineoplastic agents - Other alkylating agents, ATC code: L01A X03.
Mechanism of action
Temozolomide is a triazene that undergoes a rapid chemical conversion, at physiological pH, into the active compound monomethyl triazenoimidazole carboxamide (MTIC). The cytotoxicity of MTIC is thought to be mainly due to alkylation at the O6 7 position of guanine with an additional alkylation at the N position. Cytotoxic lesions that subsequently develop are thought to involve aberrant repair of the methyl adduct.
Clinical efficacy and safety
Early diagnosis of glioblastoma multiforme
A total of 573 patients were randomized to receive either TMZ + RT (n = 287) or RT alone (n = 286). Patients in the TMZ + RT arm concomitantly received TMZ (75 mg / m2) once daily, starting on the first day of RT through the last day of RT, for 42 days (with a maximum of 49 days). phase was followed by administration of TMZ monotherapy (150 - 200 mg / m) on Days 1 - 5 of each 28-day cycle, up to a maximum of 6 cycles, starting 4 weeks after the end of RT. control arm received RT only. Prophylaxis against pneumonia was required during RT and combined therapy with TMZ. Pneumocystis jirovecii (PCP).
TMZ was administered as rescue therapy in the follow-up phase in 161 patients of the 282 (57%) in the RT alone arm and in 62 patients of the 277 (22%) in the TMZ + RT arm.
L"hazard ratio (HR) for overall survival was 1.59 (95% CI for HR = 1.33 - 1.91) with a log-rank p vs 10%) is higher in the RT + TMZ arm. The addition of concomitant TMZ to RT, followed by TMZ alone, in the treatment of patients with newly diagnosed glioblastoma multiforme, demonstrated a statistically significant increase in overall survival (OS) compared to RT alone.
The study results were not consistent in the subgroup of patients with low performance status (WHO PS = 2, n = 70), in whom overall survival and time to progression were similar in both arms. However, an unacceptable level of risk does not appear to be present in this group of patients.
Recurrent or progressive malignant glioma
Clinical efficacy data on patients with progressive or relapsed glioblastoma multiforme (Karnofsky performance status [KPS] ≥ 70) after surgery and RT were obtained in two clinical trials with oral TMZ. One conducted on 138 patients (29% of whom had previously received chemotherapy) was non-comparative and the other, conducted with TMZ vs procarbazine in 225 patients (67% of whom had previously undergone nitrosourea-based chemotherapy) were randomized to active control. In both studies, the primary endpoint was MRI-defined progression-free survival (PFS) or neurologic worsening. In the non-comparative study, 6-month PFS was 19%, median progression-free survival was was 2.1 months and the median overall survival was 5.4 months. The incidence of objective response (ORR) based on MRI was 8%.
In the randomized, active-controlled study, PFS at 6 months was significantly greater for TMZ than for procarbazine (21% vs 8%, respectively - chi-squared p = 0.008) with a median PFS of 2.89 and 1.88, respectively. months (log rank test p = 0.0063). Median survival for TMZ and procarbazine was 7.34 and 5.66 months, respectively (log rank test p = 0.33). At 6 months the percentage of surviving patients was significantly higher in the TMZ arm (60%) than in the procarbazine arm (44%) (chi-squared p = 0.019). A benefit was seen in previously undergoing chemotherapy patients with a KPS ≥ 80.
Data on time to worsening of neurological status were favorable for TMZ compared to procarbazine as well as data on time to worsening of performance status (KPS decrease at
Recurrent anaplastic astrocytoma
In a multicenter, prospective phase II study 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 central reviewer assessment, was 35% (13 CR and 43 PR) for the intent-to-treat population ( ITT) n = 162 Stable disease was reported for 43 patients. 6-month event-free survival for the ITT population was 44% with a median event-free survival of 4.6 months; these results are similar. to those for progression-free survival. For the population eligible for histology, efficacy results were similar. Achievement of an objective radiological response or maintenance of progression-free was strongly associated with maintenance or improvement of the quality of life.
Pediatric population
Oral TMZ has been studied in pediatric patients (aged 3 to 18 years) with recurrent brain stem glioma or recurrent high grade astrocytoma, on a daily dosing regimen for 5 days every 28 days. Tolerance to TMZ was similar in adults.
05.2 Pharmacokinetic properties
TMZ is spontaneously hydrolyzed at physiological pH primarily in the active form, 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 form. MTIC is primarily due to the alkylation of DNA mainly in the O6 7 and N positions of guanine. Regarding the AUC of TMZ, the exposure to MTIC and AIC is 2.4% and 23%, respectively. In vivo, t1 / 2 of MTIC was similar to that of TMZ, and equal to 1.8 h.
Absorption
After oral administration in adult patients, TMZ is rapidly absorbed, with peak concentrations reached as early as 20 minutes post dose (mean times between 0.5 and 1.5 hours). After oral administration of 1414C-labeled TMZ, the mean faecal excretion of C over 7 days post-dose was 0.8% demonstrating complete absorption.
Distribution
TMZ is characterized by a low tendency to bind to proteins (10% to 20%) and therefore is not expected to interact with agents that strongly bind to proteins.
PET studies in humans and preclinical data suggest that TMZ rapidly crosses the blood-brain barrier and is present in CSF. CSF penetration was confirmed in one patient; CSF exposure calculated based on AUC. of TMZ, was approximately 30% of that of plasma, consistent with the animal data.
Elimination
The half-life (t1 / 2) in plasma is approximately 1.8 hours. The major route of elimination of 14C is via the kidney. Following oral administration approximately 5% - 10% of the dose is recovered unchanged in the urine in 24 hours. hours and the remainder excreted as temozolomide acid, 5-aminoimidazole-4-carboxamide (AIC) or as unidentified polar metabolites.
Plasma concentrations increase in a dose-related manner. Plasma clearance, volume of distribution and half-life are independent of the dose.
Special populations
Population pharmacokinetic analysis showed that plasma TMZ clearance was independent of age, renal function and tobacco use. In a separate pharmacokinetic study, plasma pharmacokinetic profiles in patients with mild hepatic impairment to moderate were similar to those seen in patients with normal liver function.
Pediatric patients had a higher AUC than adult patients; however the maximum tolerated dose (MDT) was 1,000 mg / m2 per cycle in both children and adults.
05.3 Preclinical safety data
Single cycle toxicity studies (5 days of treatment and 23 days without treatment), 3 and 6 cycles in rats and dogs were conducted. Primary toxicity targets included the bone marrow, lymphoreticular system, testes, and gastrointestinal tract, and at higher doses, which were fatal in 60% -100% of the rats and dogs tested, retinal degeneration occurred. Most of the toxic effects were reversible, except for adverse events affecting the male reproductive system and retinal degeneration. However, since the doses leading to retinal degeneration are in the lethal dose range, and no comparable effects have been observed in clinical trials, no clinical relevance has been attributed to this finding.
TMZ is an embryotoxic, teratogenic and genotoxic alkylating agent. TMZ is more toxic in rats and dogs than in humans, and the clinical dosage approaches the lowest lethal dose for rats and dogs. The dose-related reduction in leukocytes and platelets appears to be a significant indicator of toxicity. In the 6-study study. In rat cycles, various neoplasms were observed including breast carcinoma, keratoacanthoma of the skin, basal cell adenoma while in the dog studies neither tumors nor pre-neoplastic changes were observed. Rats appear to be particularly sensitive to the oncogenic effects of TMZ. the first tumors appear within 3 months from the start of administration. This latency period is also very short for an alkylating agent.
The results of the Ames / Salmonella test and the Human Peripheral Blood Lymphocyte Chromosome Aberration Test (HPBL) showed a positive mutagenicity response.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Capsule contents:
anhydrous lactose,
anhydrous colloidal silica,
sodium starch glycolate type A,
tartaric acid,
stearic acid.
Capsule shell:
jelly,
titanium dioxide (E 171),
sodium lauryl sulfate,
red iron oxide (E 172)
Printing ink:
shellac,
propylene glycol,
purified water,
ammonium hydroxide,
potassium hydroxide,
black iron oxide (E 172).
06.2 Incompatibility
Not relevant.
06.3 Period of validity
3 years
06.4 Special precautions for storage
Bottle presentation
Do not store above 30 ° C.
Keep the capsules in the original bottle to protect them from moisture.
Keep the bottle tightly closed.
Presentation in sachet
Do not store above 30 ° C.
06.5 Nature of the immediate packaging and contents of the package
Bottle presentation
Type I amber glass bottles with child resistant polypropylene closures containing 5 or 20 hard capsules.
The box contains one bottle.
Presentation in sachet
The sachets are composed of linear low density polyethylene (innermost layer), aluminum or polyethylene terephthalate.
Each sachet contains 1 hard capsule and is supplied in a cardboard box.
The carton contains 5 or 20 hard capsules, in individually sealed sachets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
Do not open the capsules. If a capsule is damaged, avoid contact of the powder contained in it with the skin or mucous membranes. If there is contact with the skin or mucous membranes, immediately and thoroughly wash the affected area with soap and water.
Patients should be advised to keep the capsules out of the sight and reach of children, preferably in a locked cabinet. Accidental ingestion can be fatal to children.
Unused medicine and waste derived from this medicine must be disposed of in accordance with local regulations.
07.0 MARKETING AUTHORIZATION HOLDER
Merck Sharp & Dohme Limited
Hertford Road, Hoddesdon
Hertfordshire EN11 9BU
UK
08.0 MARKETING AUTHORIZATION NUMBER
EU / 1/98/096/005
EU / 1/98/096/006
EU / 1/98/096/015
EU / 1/98/096/016
034527059
034527061
034527150
034527162
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: January 26, 1999
Date of most recent renewal: January 26, 2009
10.0 DATE OF REVISION OF THE TEXT
May 27, 2015
