The following drugs and medications are in some way related to, or used in the treatment of Burns, Nitrogen Retention. This service should be used as a supplement to, and NOT a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners.
Medical Encyclopedia:
Treating certain types of moderate to severe acne. It may also be used for other conditions as determined by your doctor.
Minocycline Extended-Release Tablets are a tetracycline antibiotic. It works by slowing the growth of certain bacteria, which allows the body's immune system to kill them.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Minocycline Extended-Release Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Minocycline Extended-Release Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Minocycline Extended-Release Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Minocycline Extended-Release Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Minocycline Extended-Release Tablets.
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:
Dizziness; lightheadedness; mild headache or diarrhea; nausea; tiredness.
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); black, tarry, or bloody stool; blurred vision; change in amount of urine produced; changes in color of skin, teeth, or gums; dark urine; decreased hearing; fever; joint aches or pain; muscle pain or weakness; red, swollen, blistered, or peeling skin; severe or persistent headache, diarrhea, or tiredness; stomach cramps or pain; symptoms of pancreatitis (eg, severe stomach or back pain with or without nausea or vomiting); unusual bruising or bleeding; unusual tiredness or weakness; vaginal irritation or discharge; vision changes; yellowing of the eyes or skin.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately.
Store Minocycline Extended-Release Tablets at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Minocycline Extended-Release Tablets out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Minocycline Extended-Release Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Severe and sometimes fatal liver problems have occurred in patients taking Viramune XR Extended-Release Tablets. This may occur in men and women, but the risk may be greater in women and in patients with a high CD4 cell count at the start of treatment. Certain pregnant women and women with a CD4 cell count higher than 250 have the greatest risk. Liver function tests and CD4 cell counts may be performed while you use Viramune XR Extended-Release Tablets. Contact your doctor right away if you develop a rash, dark urine, yellowing of the eyes or skin, pale stools, stomach pain, nausea, loss of appetite, or unusual tiredness.
Viramune XR Extended-Release Tablets should only be used in patients who have been diagnosed with HIV. Do not use Viramune XR Extended-Release Tablets to prevent HIV infection if you have been exposed to the virus.
Viramune XR Extended-Release Tablets may cause serious and sometimes fatal skin reactions. Contact your doctor immediately if you develop a rash or red, swollen, blistered, or peeling skin.
The risk of liver and skin problems is greatest during the first 18 weeks of therapy, but these problems may occur at any time during treatment. Your doctor will check for side effects frequently during the first several months after you start Viramune XR Extended-Release Tablets. Be sure to keep all doctor and lab appointments. Take Viramune XR Extended-Release Tablets exactly as prescribed by your doctor. If you develop a liver or skin problem or if you have a severe allergic reaction to Viramune XR Extended-Release Tablets, you must not take it again.
Treating HIV infection. It must be used along with other HIV medicines.
Viramune XR Extended-Release Tablets are a nonnucleoside reverse transcriptase inhibitor (NNRTI). It works by blocking the growth of HIV.
Contact your doctor or health care provider right away if any of these apply to you.
Some medical conditions may interact with Viramune XR Extended-Release Tablets. Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:
Some MEDICINES MAY INTERACT with Viramune XR Extended-Release Tablets. Tell your health care provider if you are taking any other medicines, especially any of the following:
This may not be a complete list of all interactions that may occur. Ask your health care provider if Viramune XR Extended-Release Tablets may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.
Use Viramune XR Extended-Release Tablets as directed by your doctor. Check the label on the medicine for exact dosing instructions.
Ask your health care provider any questions you may have about how to use Viramune XR Extended-Release Tablets.
All medicines may cause side effects, but many people have no, or minor, side effects. No COMMON side effects have been reported with Viramune XR Extended-Release Tablets. Seek medical attention right away if any of these SEVERE side effects occur:
Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); change in the amount of urine produced; eye irritation, pain, redness, or swelling; fever, chills, or sore throat; general feeling of being unwell; mouth sores; muscle or joint aches or pain; red, swollen, peeling, or blistered skin (with or without fever); swollen lymph glands; symptoms of liver problems (eg, yellowing of the skin or eyes; dark urine; loss of appetite; pale stools; severe, persistent, or unusual nausea or stomach pain); unusual tiredness or weakness.
This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.
See also: Viramune XR side effects (in more detail)
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center, or emergency room immediately. Symptoms may include dizziness; fever; nausea; rash; severe or persistent headache; swelling; trouble breathing; trouble sleeping; unexplained weight loss; unusual tiredness; vomiting.
Store Viramune XR Extended-Release Tablets at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store in a tightly closed container. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Viramune XR Extended-Release Tablets out of the reach of children and away from pets.
This information is a summary only. It does not contain all information about Viramune XR Extended-Release Tablets. If you have questions about the medicine you are taking or would like more information, check with your doctor, pharmacist, or other health care provider.
Generic Name: quinidine (Oral route, Injection route, Intramuscular route)
KWIN-i-deen
Many trials of antiarrhythmic therapy for non-life threatening arrhythmias, has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease. In the case of quinidine used to prevent or defer recurrence of atrial flutter/fibrillation, meta-analysis data has shown that the mortality associated with the use of quinidine was more than three times greater than placebo. Another meta-analysis showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of quinidine was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics .
Many trials of antiarrhythmic therapy for non-life threatening arrhythmias, has resulted in increased mortality; the risk of active therapy is probably greatest in patients with structural heart disease. In the case of quinidine used to prevent or defer recurrence of atrial flutter/fibrillation, meta-analysis data has shown that the mortality associated with the use of quinidine was more than three times greater than placebo. Another meta-analysis showed that in patients with various non-life-threatening ventricular arrhythmias, the mortality associated with the use of quinidine was consistently greater than that associated with the use of any of a variety of alternative antiarrhythmics .
In the U.S.
Available Dosage Forms:
Therapeutic Class: Antiarrhythmic, Group IA
Chemical Class: Cinchona Alkaloid
Quinidine is used to treat abnormal heart rhythms. It is also used to treat malaria.
Do not confuse this medicine with quinine, which, although related, has different medical uses.
Quinidine is available only with your doctor's prescription.
In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:
Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.
Quinidine has not been widely studied in children; however, it is used in children to treat abnormal heart rhythms and to treat malaria. Children may be able to take higher doses than adults and may have fewer side effects (such as vomiting, loss of appetite, and diarrhea) than adults.
Many medicines have not been studied specifically in older people. Therefore, it may not be known whether they work exactly the same way they do in younger adults. Although there is no specific information comparing use of quinidine in the elderly with use in other age groups, this medicine is not expected to cause different side effects or problems in older people than it does in younger adults. However, quinidine may remain in the bodies of older adults longer than it does in younger adults, which may increase the risk of side effects and which may require lower doses.
| Pregnancy Category | Explanation | |
|---|---|---|
| All Trimesters | C | Animal studies have shown an adverse effect and there are no adequate studies in pregnant women OR no animal studies have been conducted and there are no adequate studies in pregnant women. |
Studies in women suggest that this medication poses minimal risk to the infant when used during breastfeeding.
Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.
Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.
Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.
Using this medicine with any of the following may cause an increased risk of certain side effects but may be unavoidable in some cases. If used together, your doctor may change the dose or how often you use this medicine, or give you special instructions about the use of food, alcohol, or tobacco.
The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:
This section provides information on the proper use of a number of products that contain quinidine. It may not be specific to Quinalan. Please read with care.
Take this medicine exactly as directed. Do not take more of this medicine and do not take it more often than your doctor ordered. Do not miss any doses.
Taking quinidine with food may help lessen stomach upset.
For patients taking the extended-release tablet form of this medicine:
The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.
The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.
If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.
Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.
Keep out of the reach of children.
Do not keep outdated medicine or medicine no longer needed.
It is very important that your doctor check your progress at regular visits to make sure that the quinidine is working properly and does not cause unwanted effects.
Do not stop taking this medicine without first checking with your doctor, to avoid possible worsening of your condition.
Before having any kind of surgery (including dental surgery) or emergency treatment, tell the medical doctor or dentist in charge that you are taking this medicine.
Dizziness or lightheadedness may occur with this medicine, especially when you get up from a lying or sitting position. Getting up slowly may help.
Fainting may occur with this medicine. Do not drive or do anything else that could be dangerous if fainting occurs.
. Check with your doctor immediately if you faint or experience other side effects with this medicine.
Your doctor may want you to carry a medical identification card or bracelet stating that you are using this medicine.
Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.
Check with your doctor immediately if any of the following side effects occur:
Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.
Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.
See also: Quinalan side effects (in more detail)
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The use of the Thomson Reuters Healthcare products is at your sole risk. These products are provided "AS IS" and "as available" for use, without warranties of any kind, either express or implied. Thomson Reuters Healthcare and Drugs.com make no representation or warranty as to the accuracy, reliability, timeliness, usefulness or completeness of any of the information contained in the products. Additionally, THOMSON REUTERS HEALTHCARE MAKES NO REPRESENTATION OR WARRANTIES AS TO THE OPINIONS OR OTHER SERVICE OR DATA YOU MAY ACCESS, DOWNLOAD OR USE AS A RESULT OF USE OF THE THOMSON REUTERS HEALTHCARE PRODUCTS. ALL IMPLIED WARRANTIES OF MERCHANTABILITY AND FITNESS FOR A PARTICULAR PURPOSE OR USE ARE HEREBY EXCLUDED. Thomson Reuters Healthcare does not assume any responsibility or risk for your use of the Thomson Reuters Healthcare products.
Temomedac 140 mg hard capsules
Each hard capsule contains 140 mg temozolomide.
Excipient: Each hard capsule contains 117 mg of anhydrous lactose.
For a full list of excipients, see section 6.1.
Hard capsule
The hard capsules have a white body and cap with two stripes in blue ink on the cap and with “T 140 mg” in blue ink on the body.
Temomedac hard capsules is 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.
Temomedac hard capsules 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
Temomedac hard capsules 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/m² daily for 42 days concomitant with focal radiotherapy (60 Gy administered in 30 fractions). No dose reductionsare 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) 9/l
- thrombocyte count 9/l
- common toxicity criteria (CTC) non-haematological toxicity
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.
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a: Treatment with concomitant TMZ can be continued when all of the following conditions are met: absolute neutrophil count 9/l; thrombocyte count 9/l; CTC non-haematological toxicity
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/m² once daily for 5 days followed by 23 days without treatment. At the start of Cycle 2, the dose is escalated to 200 mg/m² if the CTC nonhaematological toxicity for Cycle 1 is Grade 9/l, and the thrombocyte count is 9/l. If the dose was not escalated at Cycle 2, escalation should not be done in subsequent cycles. Once escalated, the dose remains at 200 mg/m² per day for the first 5 days of each subsequent cycle except if toxicity occurs.
Dose reductions and discontinuations during the 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.
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a: TMZ dose levels are listed in Table 2.
b: TMZ is to be discontinued if:
• dose level -1 (100 mg/m²) 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
A treatment cycle comprises 28 days. In patients previously untreated with chemotherapy, TMZ is administered orally at a dose of 200 mg/m² 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/m² once daily, to be increased in the second cycle to 200 mg/m² once daily, for 5 days if there is no haematological toxicity (see section 4.4)
Special populations
Paediatric patients
In patients 3 years of age or older, TMZ is only to be used in recurrent or progressive malignant glioma. There is no clinical experience with use of TMZ in children under the age of 3 years. Experience in older children is very limited (see sections 4.4 and 5.1).
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
Temomedac hard 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.
Hypersensitivity to the active substanceor to any of the excipients.
Hypersensitivity to dacarbazine (DTIC).
Severe myelosuppression (see section 4.4).
Pneumocystis carinii 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 carinii 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
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.
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
Prior to dosing, the following laboratory parameters must be met: ANC 9/l and platelet count 9/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 109/l and platelet count> 100 x109 /l. If ANC falls to < 1.0 x 109/l or the platelet count is < 50 x 109/l during any cycle, the next cycle should be reduced one dose level (see section 4.2). Dose levels include 100 mg/m², 150 mg/m², and 200 mg/m². The lowest recommended dose is 100 mg/m².
Paediatric use
There is no clinical experience with use of TMZ in children under the age of 3 years. 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 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.
Interaction studies have only been performed in adults.
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 Cmax and a 9 % decrease in area under the curve (AUC).
As it cannot be excluded that the change in Cmax is clinically significant, Temomedac should be administered without food.
Based on an analysis of population pharmacokinetics in phase II trials, co-administration of dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H2 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 (seesection 5.2).
Use of TMZ in combination with other myelosuppressive agents may increase the likelihood of myelosuppression.
Pregnancy
There are no data in pregnant women. In preclinical studies in rats and rabbits receiving 150 mg/m²
TMZ, teratogenicity and/or foetal toxicity were demonstrated (see section 5.3). Temomedac hard capsules should not be administered to pregnant women. If use during pregnancy must be considered, the patient should be apprised of the potential risk to the foetus. Women of childbearing potential should be advised to use effective contraception to avoid pregnancy while they are receiving TMZ.
Lactation
It is not known whether TMZ is excreted in human milk; thus, breast-feeding should be discontinued while receiving treatment with 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.
No studies on the effects on the ability to drive and use machines have been performed. The ability to drive and use machines may be impaired in patients treated with TMZ due to fatigue and somnolence.
Clinical trial experience
In patients treated with TMZ, whether used in combination with RT or as monotherapy following RT for newly-diagnosed glioblastoma multiforme, or as monotherapy in patients with recurrent or progressive glioma, the reported very common adverse reactions were similar: nausea, vomiting, constipation, anorexia, headache and fatigue. Convulsions were reported very commonly in the newly-diagnosed glioblastoma multiforme patients receiving monotherapy, and rash was reported very commonly in newly-diagnosed glioblastoma multiforme patients receiving TMZ concurrent with RT and also as monotherapy, and commonly in recurrent glioma. Most haematologic adverse reactions were reported commonly or very commonly in both indications (Tables 4 and 5);the frequency of grade 3-4 laboratory findings is presented after each table.
In the tables undesirable effects are classified according to System Organ Class and frequency.
Frequency groupings are defined according to the following convention: Very common (
Newly-diagnosed glioblastoma multiforme
Table 4 provides treatment-emergent adverse events in patients with newly-diagnosed glioblastoma multiforme during the concomitant and monotherapy phases of treatment.
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*A patient who was randomised to the RT arm only, received TMZ + RT.
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 neutrophilabnormalities 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
In clinical trials, the most frequently occurring treatment-related undesirable effects were gastrointestinal disorders, specifically nausea (43 %) and vomiting (36 %). These reactions 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 %.
Table 5 includes adverse reactions reported during clinical trials for recurrent or progressive malignant glioma and following the marketing of TMZ.
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Laboratory results
Grade 3 or 4 thrombocytopenia and neutropenia occurred in 19 % and 17 % respectively, of patients treated for malignant glioma. This led to hospitalisation and/or discontinuation of TMZ in 8 % and 4 %, respectively. 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. 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 109/l), 12 % vs 5 %, and thrombocytopenia (< 20 x 109/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.
Post-marketing experience
Antineoplastic agents, and notably alkylating agents, have been associated with a potential risk of myelodysplastic syndrome (MDS) and secondary malignancies, including leukaemia. Very rare cases of MDS and secondary malignancies, including myeloid leukaemia have been reported in patients treated with regimens that included TMZ. Prolonged pancytopenia, which may result in aplastic anaemia has been reported very rarely.
Cases of toxic epidermal necrolysis and Stevens-Johnson syndrome have been reported very rarely.
Cases of interstitial pneumonitis/pneumonitis have been reported very rarely.
Doses of 500, 750, 1,000, and 1,250 mg/m² (total dose per cycle over 5 days) have been evaluated clinically in patients. Dose-limiting toxicity was haematological and was reported 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, multiorgan failure and death. There are reports of patients who have taken the recommended dose for more than 5 days of treatment (up to 64 days) with adverse events reported including bone marrow suppression, with or without infection, in some cases severe and prolonged and resulting in death. In the event of an overdose, haematological evaluation is needed. Supportive measures should be provided as necessary.
Pharmacotherapeutic group: Other alkylating agents, ATC code: L01A X03
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 O6 position of guanine with additional alkylation also occurring at the N7 position. Cytotoxic lesions that develop subsequently are thought to involve aberrant repair of the methyl adduct.
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/m²) once daily, starting the first day of RT until the last day of RT, for 42 days (with a maximum of 49 days). This was followed by monotherapy TMZ (150 - 200 mg/m²) on Days 1 - 5 of every 28-day cycle for up to 6 cycles, starting 4 weeks after the end of RT. Patients in the control arm received RT only. Pneumocystis carinii pneumonia (PCP) prophylaxis was required during RT and combined TMZ therapy.
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 TMZmonotherapy 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).
Figure 1 Kaplan-Meier curves for overall
