DISEASE--GLIOBLASTOMA MEDICINE--TEMOZOLOMIDE

HI GUYS !!! HERE  I  M  BEGINNING  WITH  THE  DISCUSSION  OF  THE  MEDICINE  FOR  THE  LIFE-TAKING  CANCER  DISEASE  GLIOBLASTOMA,,,,

MEDICINE  :  TEMODAL

WHAT  IS  TEMODAL?????

Temodal is a medicine that contains the active substance temozolomide. It is available as capsules (white and green: 5 mg; white and yellow: 20 mg; white and pink: 100 mg; white and blue: 140 mg; white and orange: 180 mg; white: 250 mg) and as a powder to be made up into a solution for infusion (drip into a vein).

What is Temodal used for?

Temodal is an anticancer medicine. It is used to treat malignant glioma (brain tumours) in the following groups of patients:

·         adults with newly diagnosed glioblastoma multiforme (an aggressive type of brain tumour). Temodal is used first with radiotherapy and then on its own;

·         adults and children three years of age and over with malignant glioma such as glioblastoma multiforme or anaplastic astrocytoma, when the tumour has returned or got worse after standard treatment. Temodal is used on its own in these patients.

The medicine can only be obtained with a prescription.

How is Temodal used?

Treatment with Temodal should be prescribed by a doctor with experience in the treatment of brain tumours.

The dose of Temodal depends on body surface area (calculated using the patient’s height and weight) and ranges from 75 to 200 mg per square metre, once a day. The dose and the number of doses depend on the type of tumour being treated, whether the patient has been treated before, whether Temodal is being used alone or with other treatments, and how the patient responds to treatment. Temodal capsules should be taken without food. If the solution for infusion is used, it should be given over a period of 90 minutes.

Patients may also need to take medicines to prevent vomiting before taking Temodal. Temodal should be used with caution in patients with severe liver problems or with kidney problems.

For full details, see the Summary of Product Characteristics (also part of the EPAR).

How does Temodal work?

The active substance in Temodal, temozolomide, belongs to a group of anticancer medicines called alkylating agents. In the body, temozolomide is converted to another compound called MTIC. MTIC binds to the DNA of cells while they are reproducing, which stops cell division. As a result, the cancer cells cannot divide, slowing down the growth of tumours.

How has Temodal been studied?

Temodal capsules have been studied in four main studies.

The first study compared the effectiveness of Temodal and radiotherapy with that of radiotherapy on its own in 573 patients with newly diagnosed glioblastoma multiforme.

The other three main studies involved patients with malignant glioma that had come back or got worse after previous treatment. Two of these studies involved patients with glioblastoma multiforme: one looked at the effects of Temodal in 138 patients and the other compared Temodal with procarbazine (another anticancer medicine) in 225 patients. The final study looked at the safety and effectiveness of Temodal in the treatment of 162 patients with anaplastic astrocytoma who were in their first relapse.

The main measures of effectiveness were how long the patients survived or the length of time before the patient’s cancer started to get worse.

A further two studies were carried out in a total of 35 patients with brain tumours to show that the capsules and solution for infusion produce the same levels of temozolomide in the blood.

What benefit has Temodal shown during the studies?

In the study of newly diagnosed glioblastoma multiforme, patients survived for an average of 14.6 months when they received Temodal and radiotherapy, compared with 12.1 months with radiotherapy alone.

In the comparative study of glioblastoma multiforme that had come back or got worse after previous treatment, it took an average of 2.9 months until the cancer got worse in patients taking Temodal, compared with 1.9 months in the patients taking procarbazine. In anaplastic astrocytoma, it took an average of 5.4 months for the cancer to get worse in patients taking Temodal.

What is the risk associated with Temodal?

The most common side effects with Temodal (seen in more than 1 patient in 10) are nausea (feeling sick), vomiting, constipation, anorexia (loss of appetite), alopecia (hair loss), headache, fatigue (tiredness), convulsions (fits), rash, neutropenia or lymphopenia (low white blood cell counts), and thrombocytopenia (low blood platelet counts). Patients receiving the solution for infusion may also have injection site reactions, such as pain, irritation, itching, warmth, swelling and redness, as well as bruising. For the full list of all side effects reported with Temodal, see the Package Leaflet.

Temodal should not be used in people who may be hypersensitive (allergic) to temozolomide, any of the other ingredients or dacarbazine (another anticancer medicine). Temodal must not be used in patients with severe myelosuppression (a condition in which the bone marrow cannot make enough blood cells).

Why has Temodal been approved?

The Committee for Medicinal Products for Human Use (CHMP) decided that Temodal’s benefits are greater than its risks for treatment of newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment, and malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy. The Committee recommended that Temodal be given marketing authorisation.

Other information about Temodal:

The European Commission granted a marketing authorisation valid throughout the European Union for Temodal to SP Europe on 26 January 1999. The marketing authorisation was renewed on 26 January 2004 and on 26 January 2009.

The full EPAR for Temodal is available here.

This summary was last updated in 01-2009.

Manufacturer

·         Schering-Plough

Chemotherapy Drugs

Temodar ®

Generic Name: Temozolomide

Drug Type:

Temodar is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug.  Temodar is classified as an "alkylating agent."  (For more detail, see "How Temodar Works" section below).

What Temodar Is Used For:

·         Treatment of anaplastic astrocytoma and glioblastoma multiforme (GBM) brain tumors

Note:  If a drug has been approved for one use, physicians may elect to use this same drug for other problems if they believe it may be helpful.

How Temodar Is Given: 

·         Temodar is given in a capsule form by mouth. Capsules come in 5 mg, 20 mg, 100 mg, 250 mg, sizes.  Your health care provider will calculate your daily dosage for you (the combination and number of each pill size.)  

·         Take on an empty stomach (1 hour before or 2 hours after meals or at bedtime) to reduce stomach upset.

·         Do not open, crush, or chew capsules; swallow capsules whole with full 8 ounces of water. 

·         The frequency and the amount of Temodar you will receive depends on many factors, including your height and weight, your general health or other health problems, and the type of cancer you have.  Your doctor will determine your dosage and schedule.

Side Effects of Temodar:

Important things to remember about the side effects of Temodar:

·         Most people do not experience all of the side effects listed.

·         Side effects are often predictable in terms of their onset and duration. 

·         Side effects are almost always reversible and will go away after treatment is complete.

·         There are many options to help minimize or prevent side effects.

·         There is no relationship between the presence or severity of side effects and the effectiveness of the medication.

The following side effects are common (occurring in greater than 30%) for patients taking Temodar:

·         Nausea and vomiting

·         Constipation

·         Headache

·         Fatigue

These side effects are less common side effects (occurring in about 10-29%) of patients receiving Temodar:

·         Low blood counts.  Your white and red blood cells and platelets may temporarily decrease.  This can put you at increased risk for infection, anemia and/or bleeding.  This side effect is not common but can be severe.  Your blood counts will be monitored routinely throughout treatment.

Nadir: Meaning low point, nadir is the point in time between chemotherapy cycles in which you experience low blood counts.

Onset: none noted
Nadir: 7-10 days
Recovery: 22-28 days

Delayed Effects of Temodar:

·         Swelling (edema)

·         Central neurotoxicity; dizziness, problems with balance, weakness to one side of body (hemiparesis), seizures, or excessive sleepiness.  When used in treatment of brain tumors it is difficult to distinguish if these effects are due more to medication or disease.

·         Diarrhea

·         Weakness

·         Skin rash

·         Itching

·         Although uncommon, tell your healthcare provider immediately if you are experiencing an adverse reaction to Temodar, such as fever, chills, shortness of breath, facial flushing.

There is a slight risk of developing a blood cancer such as leukemia after taking Temodar.  Talk to your doctor about this risk.

Not all side effects are listed above. Some that are rare (occurring in less than 10% of patients) are not listed here.  However, you should always inform your health care provider if you experience any unusual symptoms.

When To Contact Your Doctor or Health Care Provider:

Seek emergency help immediately and notify your health care provider, it you experience the following symptoms:

·         Shortness of breath, wheezing, difficulty breathing, closing up of the throat, swelling of facial features, hives (possible allergic reaction).

Contact your health care provider immediately, day or night, if you should experience any of the following symptoms:

·         Fever of 100.5º F (38º C) or higher, chills (possible signs of infection)

The following symptoms require medical attention, but are not an emergency.  Contact your health care provider within 24 hours of noticing any of the following:

·         Nausea (interferes with ability to eat and unrelieved with prescribed medication)

·         Vomiting (vomiting more than 4-5 times in a 24 hour period)

·         Fever of 100.5º F (38º C), chills (possible signs of infection)

·         Shortness of breath, chest pain or discomfort, jaw pain

·         Bleeding that does not stop

The following symptoms require medical attention, but are not emergency situations.  Contact your health care provider within 24 hours of noticing any of the following:

·         Unusual bleeding or bruising

·         Black or tarry stools, or blood in your stools or urine

·         Constipation unrelieved by laxative use

·         Diarrhea (4-6 episodes in a 24-hour period)

·         Unusual bleeding or bruising

·         Black or tarry stools, or blood in your stools or urine

·         Extreme fatigue (unable to carry on self-care activities)

·         Signs of infection such as redness or swelling, pain on swallowing, coughing up mucous, or painful urination.

·         Unable to eat or drink for 24 hours or have signs of dehydration: tiredness, thirst, dry mouth, dark and decrease amount of urine, or dizziness.

Always inform your health care provider if you experience any unusual symptoms.

Temodar Precautions: 

·         Before starting Temodar treatment, make sure you tell your doctor about any other medications you are taking (including prescription, over-the-counter, vitamins, herbal remedies, etc.).  Do not take aspirin, or products containing aspirin unless your doctor specifically permits this.

·         Do not receive any kind of immunization or vaccination without your doctor's approval while taking Temodar.

·         Let your health care provider know if you've had an allergic reaction to Temodar or dacarbazine (DTIC) in the past, you may not be able to take temozolamide.

·         Inform your health care professional if you are pregnant or may be pregnant prior to starting this treatment.  Pregnancy category D (Temodar may be hazardous to the fetus.  Women who are pregnant or become pregnant must be advised of the potential hazard to the fetus.) For both men and women: Do not conceive a child (get pregnant) while taking Temodar. Barrier methods of contraception, such as condoms, are recommended. Discuss with your doctor when you may safely become pregnant or conceive a child after therapy.

·         Do not breast feed while taking Temodar.

Temodar Self Care Tips:

·         Take capsules as directed, take on an empty stomach (one hour before or two hours after eating or at bedtime) to help prevent stomach upset.  

·         Keep your bowels moving. Your health care provider may prescribe a stool softener to help prevent constipation that may be caused by this medicine. 

·         Drink 2 to 3 quarts of fluid every 24 hours, unless you were told to restrict your fluid intake, and maintain good nutrition. This will decrease your chances of being constipated, and prevent dehydration.

·         You may be at risk of infection so try to avoid crowds or people with colds and those not feeling well, and report fever or any other signs of infection immediately to your health care provider.

·         Wash your hands often.

·         Use an electric razor and a soft toothbrush to minimize bleeding.

·         Avoid contact sports or activities that could cause injury.

·         To reduce nausea, take anti-nausea medications as prescribed by your doctor, and eat small, frequent meals. 

·         Avoid sun exposure.  Wear SPF 15 (or higher) sunblock and protective clothing.

·         In general, drinking alcoholic beverages should be kept to a minimum or avoided completely.  You should discuss this with your doctor.

·         You may experience drowsiness or dizziness; avoid driving or engaging in tasks that require alertness until your response to the drug is known.

·         Get plenty of rest. 

·         Maintain good nutrition.

·         If you experience symptoms or side effects, be sure to discuss them with your health care team.  They can prescribe medications and/or offer other suggestions that are effective in managing such problems.

Monitoring and Testing While Taking Temodar:

You will be checked regularly by your health care professional while you are taking Temodar, to monitor side effects and check your response to therapy.  Periodic blood work to monitor your complete blood count (CBC) as well as the function of other organs (such as your kidneys and liver) will also be ordered by your doctor.   

How Temodar Works:

Cancerous tumors are characterized by cell division, which is no longer controlled as it is in normal tissue.   "Normal" cells stop dividing when they come into contact with like cells, a mechanism known as contact inhibition.  Cancerous cells lose this ability.  Cancer cells no longer have the normal checks and balances in place that control and limit cell division.  The process of cell division, whether normal or cancerous cells, is through the cell cycle.  The cell cycle goes from the resting phase, through active growing phases, and then to mitosis (division).

The ability of chemotherapy to kill cancer cells depends on its ability to halt cell division.  Usually, the drugs work by damaging the RNA or DNA that tells the cell how to copy itself in division.  If the cells are unable to divide, they die.  The faster the cells are dividing, the more likely it is that chemotherapy will kill the cells, causing the tumor to shrink.  They also induce cell suicide (self-death or apoptosis).

Chemotherapy drugs that affect cells only when they are dividing are called cell-cycle specific.  Chemotherapy drugs that affect cells when they are at rest are called cell-cycle non-specific.  The scheduling of chemotherapy is set based on the type of cells, rate at which they divide, and the time at which a given drug is likely to be effective.  This is why chemotherapy is typically given in cycles.

Chemotherapy is most effective at killing cells that are rapidly dividing.  Unfortunately, chemotherapy does not know the difference between the cancerous cells and the normal cells. The "normal" cells will grow back and be healthy but in the meantime, side effects occur.  The "normal" cells most commonly affected by chemotherapy are the blood cells, the cells in the mouth, stomach and bowel, and the hair follicles; resulting in low blood counts, mouth sores, nausea, diarrhea, and/or hair loss.  Different drugs may affect different parts of the body.

Chemotherapy (anti-neoplastic drugs) is divided into five classes based on how they work to kill cancer.  Although these drugs are divided into groups, there is some overlap among some of the specific drugs.  The following are the types of chemotherapy:

Temodar is classified as an alkylating agent.  Alkylating agents are most active in the resting phase of the cell.  These drugs are cell-cycle non-specific.  There are several types of alkylating agents.

·         Mustard gas derivatives:  Mechlorethamine, Cyclophosphamide, Chlorambucil, Melphalan, and Ifosfamide. 

·         Ethylenimines:  Thiotepa and Hexamethylmelamine.

·         Alkylsulfonates:  Busulfan.

·         Hydrazines and Triazines: Altretamine, Procarbazine, Dacarbazine and Temodar. 

·         Nitrosureas:  Carmustine, Lomustine and Streptozocin.  Nitrosureas are unique because, unlike most chemotherapy, they can cross the blood-brain barrier.  They can be useful in treating brain tumors.

·         Metal salts:  Carboplatin, Cisplatin, and Oxaliplatin.

Temodar is similar to the drug dacarbazine.  It acts as a "pro-drug" meaning it needs to be transformed to its active (cancer fighting) form by the body's metabolism.

Note:  We strongly encourage you to talk with your health care professional about your specific medical condition and treatments. The information contained in this website is meant to be helpful and educational, but is not a substitute for medical advice.

Temozolomide information from DrugsUpdate

See Available Brands of Temozolomide in India

P - Contraindicated in pregnancy
L - Caution when used during lactation

Temozolomide (brand names Temodar and Temodal Schering-Plough Corporation) is an oral alkylating agent which can be used for the treatment of Grade IV astrocytoma -- an aggressive brain tumor, also known as glioblastoma multiforme. The agent was developed by Malcolm Stevens and his team at Aston University in Birmingham, A derivative of imidazotetrazine, temozolomide is the prodrug of MTIC (3-methyl-(triazen-1-yl)imidazole-4-carboxamide).

Pharmacodynamics

Pharmacokinetics

Temozolomide, a triazene, is an inactive prodrug. It is chemically hydrolysed to 3-methyl-(triazen-1-yl) imidazole-4-carboxamide (MTIC), the active metabolite of dacarbazine. The cytotoxicity of MTIC is believed to be due alkylation of DNA, mainly at the O6 and N7 positions of guanine.

Absorption
Rapidly and completely absorbed from GI tract. Peak plasma concentration: 0.5-1.5 hours. Rate and extent of absorption decreased by food.

Distribution
Protein binding: 15%. Cross blood-brain barrier.

Metabolism
Undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound MTIC and to temozolomide acid metabolite. MTIC is further hydrolysed to 5-amino-imidazole-4-carboxamide (AIC) and methylhydrazine.

Excretion
Excreted mainly in urine as unchanged drug, AIC, temozolomide acid metabolite and unidentified polar metabolites. Plasma half life: 1.8 hours.

Temozolomide Indications / Temozolomide Uses

Information Not Available

Temozolomide Adverse Reactions / Temozolomide Side Effects

Nausea, vomiting, taste perversion, constipation, diarrhoea, abdominal pain, stomatitis, anorexia, headache, fatigue, convulsions, dizziness, memory impairment, impaired concentration, tremors, blurred vision, hearing impairment, speech disorder, rash, infection, oral candidiasis, dyspnoea, coughing, neutropenia, thrombocytopenia, leucopenia, anaemia, hyperglycemia, decreased wt, insomnia, anxiety, alopecia, muscle weakness, urinary incontinence, increased alanine aminotransferase. Rarely, myelodysplastic syndrome and secondary malignancies.

Precautions

Monitor
Prior to administration, patient must have an ANC of at least 1,500 mcL and platelet count of at least 100,000 mcL. Observe all patients for development of PCP. Obtain CBC weekly during concomitant treatment phase with radiotherapy. For 28day treatment cycles, obtain CBC on day 22 (21 days after first dose) or within 48 hours of that day; perform CBC weekly until ANC is above 1,500/mcL and the platelet count is above 100,000/mcL.

Special Precautions

Severe hepatic and renal impairment. Elderly >70 years, children. Women of child bearing potential should avoid becoming pregnant during therapy. Males should be advised not to father a child up to 6 months after treatment and to consider cryoconservation of sperms due to possibility of irreversible infertility. Unknown if distributed into breastmilk, discontinue nursing due to potential risk. May impair ability to drive or operate machinery. Swallow capsules whole with a full glass of water on an empty stomach or at bedtime. Do not take a 2nd dose if capsules are vomited. Monitor CBC wkly during concomitant therapy and on day 22 of each 28 day treatment cycle, followed by wkly blood count until recovery. Hepatitis screening and prophylactic therapy with antiviral agents as clinically indicated to be considered. Prophylaxis for Pneumocystis jiroveci (or Pneumocystis carinii) pneumonia (PCP) needed for all patients receiving concomitant temozolomide and radiation therapy for the 42-day regimen; if patients experience lymphocytopenia during the concomitant phase of therapy, PCP prophylaxis should be continued until recovery from lymphocytopenia. Monitor closely for PCP development in all patients. Anti-emetic prophylaxis recommended.

Other Drug Interactions

Reduced effectiveness of vaccines and generalised infection may occur in patients immunised with live vaccines. Decreased temozolomide clearance with valproic acid.

Potentially Fatal: Increased risk of myelosupression with other myelosuppressive agents. Increased risk of myelosuppression with colony stimulating factors (e.g. filgrastim, molgramostim and lenograstim) if given at the same time, colony stimulating factors to be used 24 hours before or until 24 hours after chemotherapy.

Other Interactions

Information Not Available

Dosage

Oral
Glioblastoma Multiforme
Adult: 75 mg/m2 once daily for 42 days with focal radiotherapy (concomitant phase). Do not reduce dose during concomitant phrase but interrupt or discontinue therapy depending on toxicity. Continue if absolute neutrophil count (ANC)≥ 1.5x109/L, thrombocyte count ≥100x109/L and Common Toxicity Criteria (CTC) non-haematological toxicity ≤ Grade 1 (except for alopecia, nausea and vomiting). Initiate monotherapy 4 weeks after completing concomitant phase: 150 mg/m2 once daily for 5 days followed by a 23 day break (1 cycle). In cycle 2, increase dose to 200 mg/m2 once daily for 5 days, if ANC ≥1.5x109/L, thrombocyte count ≥100x109/L and CTC non-haematological toxicity for cycle 1 is ≤ Grade 2 (except for alopecia, nausea and vomiting). If dose cannot be increased in cycle 2, do not increase dose in subsequent cycles. Dose used in cycle 2 is given for the rest of the cycles, toxicity allowing, up to 6 cycles.

Oral
Recurrent or Progressive Malignant Gliomas
Adult: Previously untreated with chemotherapy: 200 mg/m2 once daily for 5 days, followed by a 23 day break (1 cycle). Previously treated with chemotherapy: 150 mg/m2 daily for 5 days followed by 23 day break (1 cycle) increased to 200 mg/m2 daily for the 2nd cycle if there is no haematological toxicity.
Child: >3 years: Previously untreated with chemotherapy: 200 mg/m2 once daily for 5 days, followed by a 23 day break (1 cycle). Previously treated with chemotherapy: 150 mg/m2 daily for 5 days followed by 23 day break (1 cycle) increased to 200 mg/m2 for the 2nd cycle if there is no haematological toxicity.

Oral
Metastatic Melanoma
Adult: 200 mg/m2 daily for 5 days every 28 days.

Food(before/after)

Should be taken on an empty stomach. (Take on an empty stomach at least 1 hour before meals.)

List of Contraindications

Temozolomide and Pregnancy

Contraindicated in pregnancy

Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Temozolomide and Lactation

Caution when used during lactation

Temozolomide and Children

Safety and efficacy have not been established.

Temozolomide and Geriatic

Elderly patients at least 70 years of age had a higher incidence of grade 4 neutropenia and grade 4 thrombocytopenia in the first cycle of therapy; exercise caution when treating.

Temozolomide and Other Contraindications

Hypersensitivity to dacarbazine. Severe myelosupression. Pregnancy.

Storage

Oral
Store at 15-30°C.

Lab interference

Information Not Available

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