Composition, form of production and packaging
Capsules hard gelatinous, size 1, with opaque case and a cap of white color; the contents of the capsules are white or white powder with a pink or creamy hue of color.
1 caps.
temozolomide 20 mg
[PRING] mannitol, sodium carboxymethyl starch, silicon dioxide colloid, tartaric acid, stearic acid.
The composition of the capsule shell: gelatin, titanium dioxide.
5 pieces. - polyethylene bottles (1) - cardboard packs.
Capsules hard gelatinous, size в„–0, with opaque case and a cap of white color; the contents of the capsules are white or almost white powder with a pink or creamy hue of color.
1 caps.
temozolomide 100 mg
[PRING] mannitol, sodium carboxymethyl starch, tartaric acid, stearic acid.
The composition of the capsule shell: gelatin, titanium dioxide.
5 pieces. - polyethylene bottles (1) - cardboard packs.
Capsules hard gelatinous, size в„–00, with opaque case and a cap of white color; the contents of the capsules are white or almost white powder with a pink or creamy hue of color.
1 caps.
temozolomide 250 mg
[PRING] mannitol, sodium carboxymethyl starch, silicon dioxide colloid, tartaric acid, stearic acid.
The composition of the capsule shell: gelatin, titanium dioxide.
5 pieces. - polyethylene bottles (1) - cardboard packs.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
PHARMACHOLOGIC EFFECT
Antineoplastic, triazene, alkylating drug. Temozolomide undergoes a rapid chemical transformation when entering the systemic blood stream, at physiological pH values, 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
After ingestion, temozolomide is rapidly absorbed and is rapidly excreted from the body with urine. Temozolomide quickly penetrates the blood-brain barrier and enters the cerebrospinal fluid. C max in plasma is achieved in an average of 0.5-1.5 h (the earliest - in 20 min) after taking the drug. T 1/2 from plasma is approximately 1.8 hours. Clearance, V d in plasma and T 1/2 are dose independent. Temozolomide weakly binds to blood plasma proteins (10-20%). After oral administration, the average excretion rate with feces for 7 days was 0.8%, indicating complete absorption of the drug. The main way of excretion is through the kidneys. At 24 hours after oral administration, approximately 5-10% of the dose is determined unchanged in the urine; the remainder is in the form of 4-amino-5-imidazole-carboxamide hydrochloride (AIC) or unidentified polar metabolites. Taking temozolomide together with food causes a decrease in C max by 33% and a decrease in AUC by 9%.
The clearance of the drug in plasma does not depend on age, kidney function or tobacco consumption. 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 tolerable dose (MTD) in children and adults was the same and amounted to 1000 mg / m 2 per 1 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.
DOSING MODE
Temcital В® is taken orally, on an empty stomach, at least 1 h before meals. The prescribed dose should be taken using the lowest possible number of capsules. Capsules can not be opened or chewed, but should be swallowed whole, washed down with a glass of water.
The newly discovered multiform glioblastoma
The drug is prescribed for adults (over 18 years).
Primary treatment is carried out in combination with radiotherapy. TemcitalВ® is administered at a dose of 75 mg / m 2 daily 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: absolute neutrophil count not lower than 1500 / ОјL, platelet count not less than 100,000 / ОјL, general toxicity criterion (developed by the National Cancer Institute of Canada, 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 Temcital В® during the combined phase of treatment are given in Table 1.
Table 1. Recommendations for dose reduction or withdrawal of the drug Temcital В® during the combined phase of treatment with radiotherapy
Toxicity criterion Interruption in admission Temcital В® Discontinuation of Temmatal В®
The absolute number of neutrophils is 500 / Ојl, but <1500 / ОјL <500 / ОјL
The number of platelets is 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
Adjuvant therapy is prescribed 4 weeks after the completion of the combination therapy and is performed in the form of 6 additional cycles.
Cycle 1: TemcitalВ® is administered at a dose of 150 mg / m 2 for 5 days followed by a 23-day interruption in treatment.
Cycle 2: The dose of Temmatital В® can be increased to 200 mg / m 2 / day, provided that during the first treatment cycle, the severity of non-hematologic toxicity (according to the STS toxicity scale) did not exceed the grade 2 (with the exception of alopecia, nausea and vomiting) , while the absolute number of neutrophils was not lower than 1500 / Ојl, and the number of platelets was not lower than 100,000 / ОјL. If, in cycle 2, the dose of Temmatital В® has not been increased, it should not be increased in the following cycles. If the dose in the cycle 2 was 200 mg / m 2 , then in the same daily dose the drug is prescribed in the following cycles (in the absence of toxicity). In each cycle, TemcitalВ® should be taken 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 (21 days after taking the first dose of Temcital В® ), a blood test should be performed to count the number of cells. The abolition or reduction of the dose of Temcital В® should be carried out according to Table 3.
Table 2. Dosage regimen of the drug Temicital В® with adjuvant therapy
Step Dose (mg / m 2 / day)
- 1 100 Decrease dose in view of previous toxicity
0 150 Dose during cycle 1
1 200 Dose during cycles 2-6 (in the absence of toxicity)
Table 3. Recommendations for reducing the dose or withdrawal of the drug Temicital В® with adjuvant therapy.
Toxicity criterion To reduce the dose of Temcital В® by 1 step (see Table 2) The discontinuation of Temcital В®
Absolute number of neutrophils <1000 / ОјL *
The number of platelets <50 000 / ОјL *
STS of non-hematological toxicity (except for alopecia, nausea and vomiting) Degree 3 Degree 4 *
* Temmatital В® should be discontinued if a dose reduction of <100 mg / m 2 is required, as well as in 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 a multiform glioblastoma or anaplastic astrocytoma
The drug is prescribed for adults and children over 3 years of age . Patients who had not previously received chemotherapy, TemcitalВ® , were given a dose of 200 mg / m 2 1 times / 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 received chemotherapy earlier , the initial dose is 150 mg / m 2 1 time / day; in the second cycle, the dose can be increased to 200 mg / m 2 / day, provided that on the 1st day of the next cycle the absolute number of neutrophils is not lower than 1500 / Ојl, and the number of platelets is not lower than 100,000 / Ојl.
Recommendations for correcting the dose of Temcital В® in the treatment of progressive or recurrent malignant glioma
Start treatment with Temmatital В® is only possible with an absolute neutrophil count of? 1500 / ОјL and platelets? 100,000 / ОјL. A complete clinical blood test should be performed on day 22 (21 days after 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, treatment with TemcitalВ® should be discontinued.
SIDE EFFECT
The newly discovered multiform glioblastoma (adult patients)
Table 4 shows the side effects noted in the treatment of patients with newly diagnosed multiform glioblastoma during the combined and adjuvant phases of treatment.Determination of the frequency of side effects: very often (> 10%), often (> 1% and <10%), infrequently (> 0.1% and <1%).
Table 4.
Reaction frequency Response pattern
combined treatment phase (with radiation therapy) n = 288 adjuvant treatment phase n = 224
Infections and invasions
often candidiasis of the oral mucosa, herpes simplex, pharyngitis, wound infection, other infection candidiasis of the oral mucosa, another infection
infrequent herpes simplex, herpes zoster, influenza-like syndrome
On the part of the hematopoiesis system
often leukopenia, lymphopenia, neutropenia, thrombocytopenia anemia, febrile neutropenia, leukopenia, thrombocytopenia
infrequently anemia, febrile neutropenia of lymphopenia, petechiae
From the side of the cardiovascular system
often swelling, incl. swelling of the legs, hemorrhage, edema of the legs, hemorrhage, deep vein thrombosis
infrequent heartbeat, increased blood pressure, hemorrhagic stroke swelling, incl. peripheral edema, pulmonary embolism
From the respiratory system
often cough, dyspnea cough, dyspnea
infrequently pneumonia, upper respiratory tract infection, nasal congestion of pneumonia, upper respiratory tract infection, sinusitis, bronchitis
From the endocrine system
infrequently Syndrome Itenko-Cushing syndrome Itenko-Cushing
Dermatological reactions
very often alopecia, rash, alopecia, rash
often dermatitis, dry skin, erythema, skin itching, face swelling dryness, itching of the skin
infrequently photosensitization reactions, pigmentation disorder, erythema skin detachment, pigmentation disorder, increased sweating, facial edema
From the nervous system
very often headache headache, cramps
anxiety, emotional lability, insomnia, dizziness, balance disorder, impaired concentration, confusion and decreased oppression, convulsions, memory impairment, neuropathy, paresthesia, drowsiness, speech disorder, tremor anxiety, depression, emotional lability, insomnia, dizziness, disturbance balance, impaired concentration, confusion, speech disorder, hemiparesis, memory impairment, neurological disorders (unspecified), neuropathy, paresthesia , Somnolence, tremor
infrequent apathy, behavioral disorders, depression, hallucinations, impaired perception, extrapyramidal disorders, gait disorders, hemiparesis, hyperesthesia, hypoesthesia, neurological disorders (unspecified), epileptic status, parosmia, thirst for hallucinations, amnesia, gait disturbance, hemiplegia, hyperesthesia, / sensory disorders
From the musculoskeletal system
often arthralgia, muscular weakness arthralgia, musculoskeletal pain, myalgia, muscle weakness
infrequently back pain, musculoskeletal pain, myalgia, myopathy, back pain, myopathy
From the side of the organ of vision
often blurred vision, blurred vision, diplopia, visual field limitation
infrequently pain in the eye, hemiapopsia, visual impairment, decreased visual acuity, limitation of visual fields, pain in the eye, dry eyes, decreased visual acuity
From the side of the organ of hearing and balance
often hearing impairment hearing impairment, ringing in the ears
infrequently pain in the ear, hyperacusis, ringing in the ears, otitis media, otitis media, earache, dizziness
From the urinary system
frequent urination, incontinence, urinary incontinence
infrequently dysuria
On the part of the reproductive system
infrequent impotence of amenorrhea, menorrhagia, vaginal bleeding, vaginitis, pain in the mammary gland
From the digestive system
very often anorexia, constipation, nausea, vomiting of anorexia, constipation, nausea, vomiting
often increased ALT activity, abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis, impaired taste, increased ALT activity, diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, impaired taste
infrequent increase in activity of alkaline phosphatase, changes in color of the tongue, increased activity of GGT, ACT, liver enzymes bloating, fecal incontinence, hemorrhoids, gastroenteritis, dental diseases
From the body as a whole
very often fatigue fatigue
often fever, pain syndrome, radiation damage, allergic reaction, weight loss fever, pain syndrome, radiation damage, allergic reaction, weight loss
infrequent hot flashes to the body, asthenia, worsening of the condition, chills, weight gain of asthenia, worsening of the condition, chills, weight gain
On the part of laboratory indicators: myelosuppression (neutropenia and thrombocytopenia) is a dose-limiting side effect. Among patients in both groups (combined and adjuvant therapy), neutrophil changes, including neutropenia, were noted in 8% of cases, and platelet counts, including thrombocytopenia, in 14% of cases.Hyperglycemia was noted in less than 10% of cases with combined therapy and less than 1% with adjuvant therapy; hypokalemia was noted in less than 1% of cases with combined therapy.
Progressing or recurrent malignant glioma (adults and children over 3 years old)
Determination of the incidence of side effects: very often (? 10% of cases), often (? 1% <10%), infrequently (? 0.1% <1%), rarely (≤0.01% <0.1%) and very rarely (<0.01% ).
From the hemopoietic system: very often - thrombocytopenia, neutropenia, lymphopenia; infrequently - pancytopenia, leukopenia, anemia. In the treatment of patients with glioma, thrombocytopenia and grade 3 or 4 neutropenia were noted in 19% and 17%. Hospitalization of the patient and / or withdrawal of the drug Temcital was required in 8% and 4% of cases. Oppression of the bone marrow developed usually during the first few cycles of treatment, with a maximum between 21 and 28 days;recovery occurred, usually within 1-2 weeks. No evidence of cumulative myelosuppression was noted.
From the side of the digestive system: very often - nausea, vomiting, constipation, anorexia; often diarrhea, abdominal pain, indigestion, taste perversion. The most frequent were nausea and vomiting. In most cases, these events were 1-2 (from mild to moderate) severity and were treated independently or were easily controlled with standard antiemetic therapy. The frequency of severe nausea and vomiting is 4%.
From the nervous system: very often - headache; often - drowsiness, dizziness, paresthesia, asthenia.
Dermatological reactions: often - rash, itching, alopecia, petechiae; very rarely - hives, exanthema, erythroderma, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.
Allergic reactions: very rarely - manifestations of allergic reactions, including anaphylaxis.
Other: very often - increased fatigue; often - weight loss, shortness of breath, fever, chills, general malaise; rarely opportunistic infections, including pneumonia caused by Pneumocystis carinii; very rarely observed the development of myelodysplastic syndrome (MDS) and secondary malignant processes, including leukemia, as well as the development of prolonged pancytopenia with a risk of developing aplastic anemia.
CONTRAINDICATIONS
- expressed myelosuppression;
- Pregnancy;
- lactation period;
- Children under 3 years of age (recurrent or progressive malignant glioma) or up to 18 years (newly diagnosed glioblastoma multiforme);
- hypersensitivity to the components of the drug;
- hypersensitivity to dacarbazine.
With caution should be used in elderly patients (over 70 years), with severe renal or hepatic insufficiency.
PREGNANCY AND LACTATION
The drug is contraindicated in pregnancy and lactation (breastfeeding).
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution: severe renal failure.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution: severe hepatic impairment.
APPLICATION FOR CHILDREN
Contraindicated in childhood to 3 years (recurrent or progressive malignant glioma) or up to 18 years (newly diagnosed glioblastoma multiforme).
APPLICATION IN ELDERLY PATIENTS
With caution: advanced age (over 70 years).
SPECIAL INSTRUCTIONS
Before the start of the combined treatment (radiation therapy) is recommended to carry out the preventive antiemetic therapy and is highly recommended during adjuvant therapy in newly diagnosed glioblastoma multiforme. If during the treatment preparation Temtsital В® nausea or vomiting on subsequent receptions recommended antiemetic therapy. Antiemetics may be taken both before and after taking the drug Temtsital В® . Even if vomiting developed in the first 2 hours after administration of the drug Temtsital В® , repeating 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 Temtsital В® , increased vigilance in regard to the possible development of PCP should be exercised in respect of all patients receiving the drug Temtsital В® , particularly in combination with corticosteroids.
Pharmacokinetic parameters of the drug Temtsital В®in subjects with normal hepatic function and in patients with impaired hepatic function or mild to moderate in severity, comparable. Data on the use Temtsital drug В® patients with severe hepatic impairment (class C Child-Pugh classification) or impaired renal function is not available. Based on the pharmacokinetic properties of the drug study data Temtsital В® it is unlikely that even patients with severe liver or kidney function may require a reduction in dose, however when assigning Temtsital preparation В® such patients should be cautious.
Men and women of childbearing age during treatment with Temtsital В®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, on the background of treatment Temtsital В® , 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 membranes they must be rinsed with water.
Impact on the ability to drive vehicles and manage mechanisms
During the treatment period, care must be taken when driving vehicles and engaging in other potentially hazardous activities that require increased concentration and speed of psychomotor reactions.
OVERDOSE
Symptoms: when using the drug in doses of 500, 750, 1000 and 1250 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. Described overdose case (receiving a dose of 2000 mg / 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 symptoms overdose mentioned inhibition of hematopoiesis, complicated or not complicated by infection, in some cases, long and expressed, with a fatal outcome.
Treatment:antidote to temozolomide is not known. Haematological monitoring is recommended, and if necessary - symptomatic therapy
DRUG INTERACTION
Receiving temozolomide conjunction with ranitidine 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 entails weakly pronounced 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 plasma protein, its effect on the pharmacokinetics of other drugs are unlikely.
The use of temozolomide in conjunction with other substances depressing the bone marrow may increase the likelihood of myelosuppression.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
The drug is stored in reach of children, dry, dark place at a temperature of from 2 В° to 25 В° C. Shelf life - 2 years.
