Composition, form of production and packaging
Capsules hard gelatin в„–1, blue.
1 caps.
temozolomide 140 mg
[PRING] silicon dioxide colloid 0.4 mg, tartaric acid 4.2 mg, sodium carboxymethyl starch 21 mg, anhydrous anhydrous 171 mg, stearic acid 8.4 mg.
The composition of the capsule shell (average weight 75 mg В± 10%): gelatin 83.58%, methylparahydroxybenzoate 0.1%, propylparahydroxybenzoate 0.1%, sodium lauryl sulfate 0.1%, purified water 14.4%, titanium dioxide 1.68%, dye diamond 0.712%).
5 pieces. - plastic bottles (1) - packs of cardboard.
20 pcs. - plastic bottles (1) - packs of cardboard.
Capsules hard gelatin в„–1, brown.
1 caps.
temozolomide 180 mg
[PRING] silicon colloidal dioxide 0.5 mg, tartaric acid 5.4 mg, sodium carboxymethyl starch 27 mg, anhydrous lactose 121.3 mg, stearic acid 10.8 mg.
The composition of the capsule shell (average weight 75 mg В± 10%): gelatin 83.42%, methylparahydroxybenzoate 0.1%, propylparahydroxybenzoate 0.1%, sodium lauryl sulfate 0.1%, purified water 14.4%, titanium dioxide 1.4%, dye brown No. 1 0.625%).
5 pieces. - plastic bottles (1) - packs of cardboard.
20 pcs. - plastic bottles (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2014.
PHARMACHOLOGIC EFFECT
Temomide is an imidazotetrazine alkylating drug with antitumor activity. When entering the systemic blood stream, at physiological values, the pH undergoes a rapid chemical transformation to form the active compound - monomethyltriazenoimidazolecarboxamide (MTIK).
It is believed that the cytotoxicity of MTIC is due primarily to the alkylation of guanine at the O 6 position and additional alkylation at the N 7 position. Apparently, cytotoxic lesions resulting from this include (trigger) the mechanism of aberrant reduction of the methyl residue.
PHARMACOKINETICS
Suction
After oral administration, temozolomide is rapidly absorbed. C max of the active substance in plasma is achieved on average 0.5-1.5 h (the earliest - in 20 min) after taking the drug. The administration of Temomide along with food causes a decrease in C max by 33% and a decrease in area under the pharmacokinetic curve (AUC) by 9%. After oral administration of Temomide, the average excretion rate with feces for 7 days was 0.8%, indicating complete absorption of the drug.
Distribution
The active substance of Temomide - temozolomide rapidly penetrates the blood-brain barrier and enters the cerebrospinal fluid. The volume of distribution (V d ) is dose independent. Temozolomide weakly binds to proteins (12-16%).
Excretion
Quickly excreted from the body by the kidneys. T 1/2 active substance is approximately 1.8 hours. After 24 hours after ingestion, approximately 5-10% of the dose is determined unchanged in the urine; the remainder is derived as 4-amino-5-imidazole-carboxamide hydrochloride (APC), temozolomidic acid or unidentified polar metabolites. Clearance and T 1/2 are dose independent.
Pharmacokinetics in special clinical cases
The clearance of the drug in plasma does not depend on age, kidney function or smoking. Pharmacokinetic profile of the drug in patients with impaired liver function of mild or moderate degree is the same as in persons with normal liver function. In children, AUC is higher than in adults. The maximum tolerated dose in children and adults was the same and amounted to 1000 mg / m 2 per treatment cycle.
INDICATIONS
- newly diagnosed multiform glioblastoma (combined treatment with radiotherapy followed by adjuvant monotherapy):
- malignant glioma (glioblastoma multiforme or anaplastic astrocytoma), if there is a relapse or progression of the disease after standard therapy;
- a common metastasizing malignant melanoma (as a therapeutic tool of the first series).
DOSING MODE
Temomide is taken orally, on an empty stomach, at least 1 hour before meals. The prescribed dose should be taken using the lowest possible number of capsules.Capsules can not be opened or chewed, they should be swallowed whole, washed down with a glass of water.
The newly discovered multiform glioblastoma
Treatment of adult patients (over 18 years of age): primary treatment is carried out in combination with radiotherapy. Temomide is applied at a dose of 75 mg / m 2daily for 42 days concurrently with radiotherapy (30 fractions in a total dose of 60 Gy). Dose reduction is not recommended, but the drug may be interrupted depending on the tolerability.
Renewal of the drug is possible during the entire 42-day period of combined treatment and up to 49 days, but only if all of the following conditions are met:
- the absolute number of neutrophils - not lower than 1500 / Ојl,
- the number of platelets - not less than 100 000 / mkl,
- the criterion of general toxicity (on the scale of Common Toxicity Criteria - STS) is not higher than degree 1 (except for alopecia, nausea and vomiting).
During treatment, a blood test should be performed weekly, counting the number of cells. Recommendations for dose reduction or withdrawal of Temomide during the combined phase of treatment are given in Table 1.
Table 1. Recommendations for dose reduction or withdrawal of Temomide in combination treatment with radiotherapy
Criterion of toxicity Break in taking the drug Temomide Termination of the drug Temomide
absolute number of neutrophils> 500 / ОјL, but <1500 / ОјL <500 / ОјL
platelet count> 10,000 / ОјL, but <100,000 / ОјL <10,000 / ОјL
STS of non-hematological toxicity (except for alopecia, nausea and vomiting) Degree 2 Degree 3 or 4
Renewal of Temomide preparation is possible if all the conditions listed below are met: the absolute number of neutrophils is not lower than 1500 / Ојl, the platelet count is not lower than 100,000 / Ојl, the criterion of general toxicity (STS) is not higher than degree 1 (except for alopecia, nausea and vomiting) .
Adjuvant therapy is used 4 weeks after the completion of the combination therapy and is performed in the form of 6 additional cycles.
Cycle 1: Temomide is administered at a dose of 150 mg / m for 5 days followed by a 23-day interruption in treatment.
Cycle 2 : The dose of Temomide can be increased to 200 mg / m 2 / day, provided that during the first cycle, the severity of non-hematologic toxicity (according to the STS toxicity scale) did not exceed degree 2 (except for alopecia, nausea and vomiting); the absolute number of neutrophils was not lower than 1500 / Ојl, and the number of platelets was not lower than 100,000 / ОјL.
If the dose of Temomide was not increased in cycle 2, it should not be increased in the following cycles. If, in cycle 2, the dose was 200 mg / m 2 , in the same daily dose the drug is used in the following cycles (in the absence of toxicity). In each cycle, Temomide is administered for 5 consecutive days with a subsequent 23-day break.
Recommendations for dose reduction in the adjuvant phase of treatment are given in Tables 2 and 3.
On the 22nd day of treatment (the 21st day after taking the first dose of the drug), it is necessary to conduct a general anesthetic of the blood with the calculation of the formula and the number of platelets. Cancellation or reduction of the dose of Temomide should be carried out according to Table 3.
Table 2. Dosage levels of Temomide with adjuvant therapy
Step Dose (mg / m 2 / day)
-1 100 Reduction of dose taking into account previous toxicity (see Table 3)
0 150 Dose during cycle 1
1 200 Dose during cycles 2-6 (in the absence of toxicity)
Table 3. Recommendations for dose reduction or withdrawal of Temomide with adjuvant therapy
Toxicity criterion Reduce the dose of Temomide preparation by 1 step (see Table 2) Stop taking the preparation Temomide
absolute number of neutrophils <1000 / ОјL *
number of platelets <50 000 / ОјL *
STS of non-hematological toxicity (except for alopecia, nausea and vomiting) Degree 3 Degree 4 *
* Temomide should be discontinued if a dose reduction of <100 mg / m 2 is required, as well as in the case of recurrence of non-hematologic toxicity grade 3 (except for alopecia, nausea and vomiting) after dose reduction.
Progressive or recurrent malignant glioma in the form of multiform glioblastoma or anaplastic astrocytoma (treatment of adults and children over 3 years old).Common metastatic malignant melanoma (treatment of adults)
Patients who had not previously received chemotherapy were prescribed Temomide at a dose of 200 mg / m 2 once a day for 5 consecutive days, followed by a break in taking the drug for 23 days (the total duration of one treatment cycle is 28 days). For patients who had previously undergone chemotherapy, the initial dose is 150 mg / m 2 once a day; in the second cycle, the dose may be increased to 200 mg / m 2 per day for 5 days, provided that on the first day of the next cycle the absolute number of neutrophils is not lower than 1500 / Ојl, and the platelet count is not lower than 100,000 / Ојl.
Recommendations for modifying the dose of Temomide in the treatment of progressive or recurrent malignant glioma or malignant melanoma
To start treatment with Temomide is possible only with an absolute number of neutrophils> 1500 / ОјL and platelets> 100,000 / Ојl. A complete clinical blood test should be performed on the 22nd day (the 21st day after taking the first dose), but no later than 48 hours after that day; further - weekly, until the absolute number of neutrophils is higher than 1500 / ОјL, and the number of platelets does not exceed 100,000 / Ојl. With an absolute number of neutrophils below 1000 / ОјL or platelets below 50,000 / ОјL during any treatment cycle, the dose in the next cycle should be reduced by one step. Possible doses: 100 mg / m 2 , 150 mg / m 2 and 200 mg / m 2. The minimum recommended dose is 100 mg / m 2 . Duration of treatment is maximum 2 years. If signs of disease progression appear, drug treatment should be discontinued.
SIDE EFFECT
The following undesirable phenomena described in the literature and marked with Temomide are distributed according to the frequency of occurrence in accordance with the following gradation: very often (> 10%), often (> 1%, <10%). infrequently (> 0.1%, <1%), rarely (> 0.01%, <0.1%) and very rarely (<0.01%).
For the first time, multiform glioblastoma (adults) was identified.
Combined phase of treatment (with radiotherapy)
On the part of the blood and lymphatic system: often - neutropenia, leukopenia, lymphopneumonia, thrombocytopenia; infrequently - anemia, febrile neutropenia.
From the heart: often - swelling, incl. swelling of the legs; infrequently - palpitations.
From the side of the vessels: often - hemorrhage; infrequently - increased blood pressure, cerebral hemorrhage.
From the digestive tract: very often - anorexia, constipation, nausea, vomiting; often - hyperglycemia, weight loss, abdominal pain, diarrhea, dyspepsia, dysphagia.stomatitis, a taste disorder; infrequently hyperglycemia, weight gain, color change of the tongue.
From the liver and gallbladder: often - increased ALT activity; infrequently - increased activity of alkaline phosphatase, increased activity of gamma-glutamyltransferase, ACT, liver enzymes.
From the respiratory system and chest organs: often - cough, shortness of breath; infrequently - pneumonia, infection of the upper respiratory tract, nasal congestion;rarely - pneumonitis, interstitial pneumonitis, pulmonary fibrosis.
On the part of the immune system (including hypersensitivity reactions): often - hypersensitivity reactions (skin rash, itching); very rarely - urticaria, exanthema, erythroderma, anaphylaxis, angioedema, toxic epidermal necrolysis (Lyell syndrome), malignant exudative erythema (Stevens-Johnson syndrome).
Infectious diseases: often - candidiasis of the mouth, infection caused by Herpes simplex, pharyngitis, wound infection, other infection.
From the osteomuscular system and connective tissue: often - arthralgia, muscle weakness; infrequently - back pain, musculoskeletal pain, myalgia, myopathy.
From the nervous system (including mental disorders): very often - headache, often - anxiety, emotional lability, insomnia, dizziness, impaired concentration, confusion, convulsions, memory impairment, peripheral neuropathy, paresthesia, aphasia, agitation, drowsiness, speech disorder, tremor; infarction, apathy, behavioral disorders, depression, hallucinations, impaired perception, extrapyramidal disorders, dysphasia, amnesia, ataxia, gait disturbance, coordination disorder, hemiparesis, hemiplegia, hyperesthesia, hypoesthesia, neurological disorders (unspecified), epileptic status, paresthesia, parasymia, thirst.
From the organ of hearing and the vestibular system: often - deterioration of hearing; infrequently - pain in the ear, hyperacusis, ringing in the ears, otitis media.
From the side of the organ of vision: infrequently - blurred vision, pain in the eyes, hemianopsia, impaired vision, reduced visual acuity.
From the endocrine system: infrequently - Syndrome Itenko-Cushing.
From the side of the kidneys and urinary tract: often - frequent urination, urinary incontinence.
From the part of the reproductive system (including diseases of the mammary glands): infrequently - impotence.
From the skin and subcutaneous tissues: very often - alopecia, rash; often - dermatitis, dry skin, swelling of the face; infrequently, reactions of photosensitization, pigmentation disorders, exfoliation.
General disorders and disorders at the injection site: very often - fatigue; often - fever, pain syndrome, radiation damage; infrequent - hot flushes to the body, asthenia, worsening of the condition, chills.
Adjuvant phase of treatment
On the part of the blood and lymphatic system: often - anemia, febrile neutropenia, leukopenia, thrombocytopenia; infrequently - lymphopenia, petechiae.
From the heart: often - swelling of the legs; infrequently - palpitations.
From the side of the vessels: often - hemorrhages, deep vein thrombosis; infrequently - swelling, incl. peripheral edema, pulmonary embolism.
From the digestive tract: very often - anorexia. constipation, nausea, vomiting; often - increased ALT activity, weight loss, diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, taste disorder, hyperkalemia; infrequently hyperglycemia, hypokalemia, weight gain, bloating, fecal incontinence, hemorrhoids, gastroenteritis, dental diseases.
From the liver and gallbladder: often - increased ALT activity.
From the respiratory system and chest organs: often - cough, shortness of breath; infrequently - pneumonia, upper respiratory tract infection, sinusitis, bronchitis;rarely - pneumonitis, intrststitsialny pneumonitis, pulmonary fibrosis.
On the part of the immune system (including hypersensitivity reactions): often - hypersensitivity reactions (skin rash, itching); very rarely - urticaria, exanthema, erythroderma, anaphylaxis, angioedema, toxic epidermal necrolysis (Lyell syndrome), malignant exudative erythema (Stevens-Johnson syndrome).
Infectious diseases: often - candidiasis of the oral mucosa; infrequently - diseases caused by Herpes simplex, Herpes zoster, influenza-like syndrome, another infection.
From the osteomuscular system and connective tissue: infrequently - arthralgia, musculoskeletal pain, myalgia. muscle weakness, back pain, myopathy.
From the nervous system (including mental disorders): very often - headache, convulsions; anxiety, emotional lability, insomnia, depression, dizziness, imbalance, coordination disorder, ataxia, impaired concentration, confusion, aphasia, dysphasia, hemiparesis, memory impairment, neurological disorders (unspecified), peripheral neuropathy, paresthesia, agitation, drowsiness, tremor, hallucinations, amnesia, hemiplegia, hyperesthesia.
From the organ of hearing and the vestibular system: often - deterioration of hearing, ringing in the ears; infrequently - deafness, pain in the ear, dizziness.
From the side of the organ of vision: infrequent - blurred vision, diplopia, limited field of vision, eye pain, dry eyes, reduced visual acuity.
From the endocrine system: infrequently - Syndrome Itenko-Cushing.
From the side of the kidneys and urinary tract: often - urinary incontinence; infrequently - dysuria.
From the side of the reproductive system (including diseases of the mammary glands): infrequently - impotence, amenorrhea, menorrhagia, vaginal bleeding, vaginitis, pain in the mammary gland.
From the skin and subcutaneous tissues: very often - alopecia, rash; often - dry skin, itching of the skin; infrequently - erythema, a violation of pigmentation, excessive sweating, swelling of the face.
General disorders and disorders at the injection site: very often - fatigue; often - fever, chills, pain syndrome, radiation damage, asthenia, worsening of the condition.
Progressive or recurrent malignant glioma (adults and children over 3 years old) or malignant melanoma (adults ).
On the part of the blood and lymphatic system: very often - thrombocytopenia, neutropenia, lymphopenia; infrequently - pancytopenia. leukopenia, anemia; rarely - myelodysplastic syndrome; very rarely - prolonged pancytopenia with a risk of developing aplastic anemia. In patients with glioma and metastatic melanoma, thrombocytopenia and grade 3 or 4 neutropenia were noted in 19% and 17%, respectively, in glioma and 20% and 22%, respectively, in melanoma. Hospitalization of the patient and / or removal of temozolomide was required in 8% and 4% of cases, respectively, for glioma and 3% and 1.3% for melanoma. Bone marrow suppression razvivapos usually within the first few treatment cycles, with a maximum between 21 and 28 days; recovery was usually within 1-2 weeks. Evidence of cumulative myelosuppression was observed.
Of the heart: often - swelling of the feet; Infrequent - palpitation.
On the part of the vessels: often - bleeding, deep vein thrombosis; Infrequent - edema, including peripheral edema, pulmonary embolism.
On the part of the digestive tract: often - nausea, vomiting, anorexia. constipation; often - diarrhea, abdominal pain, dyspepsia, taste perversion.
Of the liver and gallbladder: often - increased ALT, alkaline phosphatase; rarely - hypokalemia.
By the immune system (including hypersensitivity reaction): very rarely - hypersensitivity reactions, including anaphylaxis, angioneurotic edema, exanthema, erythroderma, toxic epidermal necrolysis (Lyell's syndrome), malignant exudative erythema (Stivsnsa-Johnson syndrome).
Infectious diseases: rare - opportunistic infections, including pneumonia caused by Pneumocystis carinii.
From the nervous system (including mental disorders): very often - headache; often - drowsiness, dizziness, paresthesia, asthenia.
Reproductive system (including breast disease) , very rarely - irreversible infertility.
Skin and subcutaneous tissue disorders:often - rash, pruritus, alopecia, petechiae.
Malignancies: very rarely - secondary malignancies, including leukemia.
General disorders and at the injection site: very often - fatigue; often - weight loss, dyspnea, fever, chills, malaise; rarely - weight gain.
CONTRAINDICATIONS
- hypersensitivity to temozolomide or other components of the drug as well as dacarbazine;
- severe myelosuppression;
- Pregnancy;
- the period of lactation (breastfeeding);
- Children up to age 3 years (recurrent or progressive malignant glioma) or 18 years (for the first time revealed glioblastoma multiforme or malignant melanoma).
Carefully
- old age (over 70 years);
- severe renal or hepatic impairment;
- rare hereditary disorders such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.
PREGNANCY AND LACTATION
Contraindicated in pregnancy and lactation.
APPLICATION FOR FUNCTIONS OF THE LIVER
Caution should be used in advanced renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Caution should be used in severe liver disease.
APPLICATION FOR CHILDREN
Is contraindicated in children under 3 years (recurrent or progressive malignant glioma) or 18 years (for the first time revealed glioblastoma multiforme or malignant melanoma).
APPLICATION IN ELDERLY PATIENTS
With care should be prescribed to patients of advanced age (over 70 years).
SPECIAL INSTRUCTIONS
Conducting prophylactic antiemetic therapy is recommended before the start of the combined treatment (radiotherapy) and is strongly recommended during adjuvant therapy in newly diagnosed glioblastoma multiforme. If during treatment with the drug Temomid nausea or vomiting on subsequent receptions recommended antiemetic therapy. Antiemetics may be taken both before and after taking the drug Temomid. Even if vomiting developed in the first 2 hours after administration of the drug Temomid repeat the drug on the same day follows.
Due to an increased risk of pneumonia caused by Pneumocystis carinii, in patients receiving combination therapy with radiation therapy for 42 days (up to 49 days), so patients are advised to conduct preventive treatment against the pathogen Pneumocystis carinii. Although more frequent development of pneumonia caused by Pneumocystis carinii, is associated with a longer period of treatment Temomid, increased vigilance in regard to the possible development of PCP should be exercised in respect of all patients receiving Temomid, particularly in combination with corticosteroids.
Pharmacokinetic parameters of the drug Temomid in subjects with normal hepatic function and in patients with impaired mild or moderate liver function comparable. Temomid data on the use of the drug in patients with severe liver function abnormalities (class C Child-Pugh) or impaired renal function is not available. Based on the data studying pharmacokinetic properties of temozolomide it is unlikely that even patients with severely impaired liver or renal function may require a reduction in dose. Nevertheless, the appointment Temomid drug to such patients should be cautious.
Elderly patients (over 70 years), the risk of neutropenia and thrombocytopenia higher than in younger. Therefore, elderly patients Temomid be used with caution.
Men and women of childbearing age during treatment Temomidom, and for at least 6 months after the end of the need to use reliable methods of contraception. Because of the risk of irreversible infertility during treatment Temomidom, male patients before treatment, if necessary, it is recommended to discuss the possibility of sperm cryopreservation.
After contact with the capsule contents (powder) to the skin or mucous membrane must be washed with plenty of water.
Effects on ability to drive and operate machinery
Some side effects of the drug such as drowsiness and fatigue, may adversely affect the ability to drive a vehicle or perform potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
When using the drug in doses of 500 mg / m 2 , 750 mg / m 2 1000 mg / m 2 and 1,250 mg / m 2 (total dose received over a 5-day treatment cycle) dose-limiting toxicity was hematologic toxicity that was observed when receiving any dose, but more pronounced - at higher doses. A case of an overdose (reception dose of 2 g / day for 5 days) which resulted in the developed pancytopenia, pyrexia, multiple organ failure and death. When receiving the drug for more than 5 days (up to 64 days), among other side effects observed inhibition of hematopoiesis, complicated or not complicated by infection, in some cases, long and expressed, with a fatal outcome.
Treatment:the antidote is not known. Haematological monitoring is recommended, and if necessary - symptomatic therapy.
DRUG INTERACTION
Receiving Temomid conjunction with ranitidine formulation does not lead to clinically meaningful change in the degree of absorption of temozolomide.
Co-administration of dexamethasone, prochlorperazine, phenytoin. carbamazepine, ondansetron, blockers of histamine H 2 -receptors or phenobarbital not alter the clearance of temozolomide.
Co-administration with valproic acid is poorly marked, but statistically significant decrease in clearance of temozolomide.
Research aimed at clarifying the effects of temozolomide on the metabolism and excretion of other drugs have been conducted. Due to the fact that temozolomide is not metabolized in the liver, and weakly binds to the protein, its effect on the pharmacokinetics of other drugs are unlikely.
Application Temomid preparation together with other substances depressing the bone marrow may increase the likelihood of myelosuppression.
TERMS OF RELEASE FROM PHARMACY
On prescription.
TERMS AND CONDITIONS OF STORAGE
In a dry, dark place at a temperature not higher than 25 В° C. Keep out of the reach of children. Shelf life - 2 years.
