Composition, form of production and packaging
Liofilizate for the preparation of a solution for white infusions with a pinkish hue of color, not containing mechanical inclusions.
temozolomide 100 mg
[PRING] mannitol - 600 mg, threonine - 160 mg, polysorbate 80 - 120 mg, sodium citrate dihydrate - 235.2 mg, hydrochloric acid concentrated - 160 mg.
Bottles of colorless glass with a capacity of 100 ml (1) - packs of cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2015.
An antineoplastic agent, an imidazotetrazine derivative, is an alkylating agent. 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.
Temozolomide quickly penetrates the BBB and enters the cerebrospinal fluid.
V d does not depend on the dose. Temozolomide weakly binds to proteins (12-16%).
T 1/2 from the plasma is approximately 1.8 hours. The main way of removal of temozolomide is the kidney. At 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 (AIC), 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.
- 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.
The newly discovered multiform glioblastoma
Treatment of adults over 18 years of age
Primary treatment is carried out in combination with radiotherapy . TemodalВ® is prescribed 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 use of the drug may be interrupted depending on 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, total toxicity criterion (CTC) 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 Temodal В® during the combined phase of treatment are given in Table 1.
Table 1. Recommendations for dose reduction or withdrawal of Temodal В® in combination treatment with radiotherapy
Criterion of toxicity Break in taking Temodal В® * Stopping Temodal В®
the absolute number of neutrophils is 500 / Ојl, but <1500 / ОјL <500 / ОјL
the platelet count 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
* The resumption of Temodal В® 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 total toxicity criterion (CTC) is not higher than degree 1 (except for alopecia, nausea and vomiting).
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: Temodal В® 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 Temodal В® 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 the grade 2 (except for 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 the dose of Temodal В® 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 administered in the following cycles (in the absence of toxicity). In each cycle, the preparation Temodal В® 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), a blood test should be performed to count the number of cells. The cancellation or reduction of the dose of the drug should be carried out, guided by Table 3.
Table 2. Dosage levels of TemodalВ® 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 Temodal В® with adjuvant therapy
Toxicity criterion To reduce the dose of Temodal В® by 1 step (see Table 2) Termination of Temodal В®
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 *
* Temodal В® 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.
Progressing or relapsing 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 undergone chemotherapy, Temodal В® were prescribed at a dose of 200 mg / m 2 1 time / 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 / day; in the second cycle, the dose may be increased to 200 mg / m 2 / day, 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 Temodal В® in the treatment of progressive or recurrent malignant glioma or malignant melanoma
In patients receiving Temodal В® , myelosuppression may develop, including prolonged pancytopenia. Possible development of aplastic anemia, which in isolated cases led to a fatal outcome. The development of aplastic anemia can also be associated with the use of a number of drugs, such as carbamazepine, phenytoin or sulfamethoxazole / trimethoprim, so it is difficult to establish the cause of development of aplastic anemia with simultaneous use of Temodal В® and these drugs.
Initiate treatment with Temodal В® is possible only with an absolute number of neutrophils в‰¤ 1500 / ОјL and platelets в‰Ґ 100,000 / ОјL. A complete clinical blood test should be performed on day 22 (the 21st day after taking the first dose), but not 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. When there is a progression of the disease, the drug should be discontinued.
Rules for the preparation of a solution for infusions
Preparation of solution for infusion should be carried out in strictly aseptic conditions.
41 ml of water for injections is added to the vial to dissolve the drug. Dissolve by rotating the vials, not allowing shaking. The concentration of the resulting solution is 2.5 mg / ml of temozolomide.
Vials with a solution containing visible mechanical inclusions can not be used. The reconstituted solution should be used within 14 hours, including the infusion time.
Calculate the volume of solution required for administration. In aseptic conditions, up to 40 ml of solution is transferred from each vial to an empty 250 ml infusion bottle.
The solution must be administered IV for 90 minutes.
The solution is allowed to enter in one infusion system with 0.9 % sodium chloride solution . The drug is not compatible with dextrose solutions. Because studies of the compatibility of temozolomide, lyophilizate for the preparation of a solution for infusions, with other intravenous drugs or auxiliaries have not been carried out, do not simultaneously administer them together using a single system.
The newly discovered multiform glioblastoma (adult patients)
The side effects noted in the treatment of patients with newly diagnosed multiform glioblastoma during the combined and adjuvant phases of treatment during clinical trials are listed below. Determination of the frequency of side effects: very often (? 1/10), often (from? 1/100 to <1/10), infrequently (from? 1/1000 to <1/100).
In the combined phase of treatment (with radiotherapy)
Most side effects are caused by radiation therapy and are not associated with the use of the drug.
Infectious and parasitic diseases: often - candidiasis of the oral cavity, herpes simplex, pharyngitis, wound infection, other infection.
On the part of the hematopoiesis system: often - leukopenia, lymphopenia, neutropenia, thrombocytopenia; infrequently - anemia, febrile neutropenia.
From the endocrine system: infrequently - Cushingoid.
From the side of metabolism: very often - anorexia; often hyperglycemia, weight loss; infrequently - hypokalemia, increased activity of AF, increase in body weight.
From the psyche: often - anxiety, emotional lability, insomnia; infrequently - agitation, apathy, behavioral disorders, depression, hallucinations.
From the nervous system: very often - headache; often - convulsions, depression of consciousness, drowsiness, aphasia, imbalance, dizziness, confusion, memory impairment, concentration disorder, neuropathy, paresthesia, speech disorder, tremor; infrequently - epileptic status, extrapyramidal disorders, hemiparesis, ataxia, impaired perception, dysphasia, gait disorders, hyperesthesia, hypoesthesia, neurological disorders (unspecified), peripheral neuropathy.
From the side of the organ of vision: often - blurred vision; infrequently - hemianopia, decreased visual acuity, visual impairment, limitation of visual fields, pain in the eyes.
From the side of the hearing organ and labyrinthine disorders: often - deterioration of hearing; infrequently - otitis media, ringing in the ears, hyperacusis, pain in the ears.
From the cardiovascular system: often - hemorrhage, swelling, incl. swelling of the legs; infrequently - palpitation, cerebral hemorrhage, arterial hypertension.
On the part of the respiratory system: often - shortness of breath, cough; infrequently - pneumonia, infection of the upper respiratory tract, nasal congestion.
From the side of the digestive system: very often - constipation, nausea, vomiting; often - stomatitis, diarrhea, abdominal pain, indigestion, dysphagia.
From the skin and subcutaneous tissues: very often - a rash, alopecia; often - dermatitis, dry skin, erythema, itching of the skin; infrequently - exfoliation, photosensitization reactions, pigmentation disorder.
From the musculoskeletal system: often - muscle weakness, arthralgia; infrequently - myopathy, back pain, musculoskeletal pain, myalgia.
From the urinary system: often - frequent urination, urinary incontinence.
On the part of the reproductive system: infrequently - impotence.
General disorders: very often fatigue; often - an allergic reaction, fever, radiation damage, facial edema, pain syndrome, perversion of taste; infrequently - asthenia, redness, hot flashes, worsening of the condition, chills, dysentery of the tongue, perversion of smell, thirst.
Laboratory studies: often - increased ALT activity; infrequently - increased activity of liver enzymes, GGT, AST.
In the adjuvant phase of treatment
Infectious and parasitic diseases: often - candidiasis of the oral mucosa, another infection; infrequent - herpes simple, herpes zoster, flu-like symptoms.
From the hemopoietic system : often - febrile neutropenia, thrombocytopenia, anemia, leukopenia; infrequently - lymphopenia, petechiae.
From the endocrine system: infrequently - Cushingoid.
From the side of metabolism: very often - anorexia; often - a decrease in body weight; infrequently hyperglycemia, weight gain.
From the psyche: often - anxiety, depression, emotional lability, insomnia; infrequently hallucinations, amnesia.
From the nervous system: very often - convulsions, headache; often - hemiparesis, aphasia, imbalance, drowsiness, oppression of consciousness, dizziness, confusion, memory impairment, concentration disorders, dysphasia, neurological disorder, neuropathy, peripheral neuropathy, paresthesia, speech disorder, tremor; infrequently - hemiplegia, ataxia, decreased coordination, gait disturbance, hyperesthesia, sensory disturbances.
From the side of the organ of vision: often - restriction of visual fields, blurred vision, diplopia; infrequently - reduced visual acuity, pain in the eyes, dry eyes.
From the side of the hearing organ and labyrinthine disturbances: often - deterioration of hearing, ringing in the ears; infrequently - deafness, vertigo, pain in the ear.
From the cardiovascular system: often - hemorrhage, deep vein thrombosis, swelling of the legs; infrequently - pulmonary embolism, edema, peripheral edema.
On the part of the respiratory system: often - shortness of breath, cough; infrequently - pneumonia, sinusitis, infection of the upper respiratory tract.
From the side of the digestive system: very often - constipation, nausea, vomiting; often - stomatitis, diarrhea, dyspepsia, dysphagia, dryness of the mucous membranes of the oral cavity; infrequent - bloating, fecal incontinence, gastrointestinal upset (unspecified), gastroenteritis, hemorrhoids.
From the skin and subcutaneous tissues: very often - a rash, alopecia; often - dry skin, itching of the skin; infrequently - erythema, a violation of pigmentation, increased sweating.
From the musculoskeletal system: often - muscle weakness, arthralgia, musculoskeletal pain, myalgia; infrequently - myopathy, back pain.
From the urinary system: often - urinary incontinence, infrequently - dysuria.
On the part of the reproductive system: infrequently - vaginal bleeding, menorrhagia, amenorrhea, vaginitis, pain in the mammary glands.
General disorders: very often fatigue; often - an allergic reaction, fever, radiation damage, pain syndrome, perversion of taste; infrequently - asthenia, edema of the face, pain, deterioration, chills, dental disorders, perversion of taste.
Laboratory studies: often - increased ALT activity.
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.
Progressive or recurrent malignant glioma (adults and children over 3 years old) or malignant melanoma (adults)
Determination of the frequency of side effects: very often (? 1/10), often (from? 1/100 to <1/10), infrequently (from? 1/1000 to <1/100), rarely (<1/1000).
Infectious and parasitic diseases: rarely - infections caused by conditionally pathogenic flora, including pneumocystis pneumonia.
From the hemopoietic system: very often - neutropenia or lymphopenia (3-4 degrees), thrombocytopenia (3-4 degrees); infrequently - pancytopenia, anemia (3-4 degrees), and leukopenia. 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% in melanoma, respectively. Hospitalization of the patient and / or removal of Temodal В® was required in 8% and 4% of cases, respectively, in glioma and in 3% and 1.3% in melanoma. Oppression of bone marrow hematopoiesis developed usually during the first few cycles of treatment, with a maximum between 21 and 28 days; recovery was usually within 1-2 weeks. Evidence of cumulative myelosuppression was observed.
From a metabolism: often - anorexia; often - weight loss.
From the nervous system: very often - headache; often - drowsiness, dizziness, paresthesia.
The respiratory system, organs, thoracic and mediastinal disorders: often - shortness of breath.
On the part of the digestive system:very often - nausea, vomiting, constipation; often - diarrhea, abdominal pain, dyspepsia. The most common are nausea and vomiting. In most cases, these phenomena were 1-2 (mild to moderate) degree and passed alone or easily monitored by standard antiemetic therapy. The frequency of severe nausea and vomiting - 4%.
Skin and skin appendages: often - a rash, itching, alopecia; very rarely - erythema multiforme, erythroderma, urticaria, rash.
General disorders: often - fatigue; often - fever, fatigue, chills, anxiety, pain, taste perversion; very rare - allergic reactions, including anaphylaxis, angioedema.
In the post-marketing period,very rarely reported cases of erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and allergic reactions, including anaphylaxis. They were also received reports of hepatotoxicity, including increased liver enzymes, hyperbilirubinemia, cholestasis and hepatitis.
In rare cases it reported opportunistic infections, including pneumonia caused by Pneumocystis carinii. Very rarely reported cases of interstitial pneumonitis / pneumonitis, myelodysplastic syndrome, metastatic malignancies, including myeloid leukemia. It reported cases of prolonged pancytopenia. May develop aplastic anemia, which is a few cases resulted in death.
- severe myelosuppression;
- 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);
- hypersensitivity to the components of the drug;
- Hypersensitivity to dacarbazine.
With care should be prescribed to patients older than 70 years, with severe renal or hepatic insufficiency.
PREGNANCY AND LACTATION
Application Temodal preparation В® is contraindicated in pregnancy and lactation (breast feeding).
Men and women of childbearing age during treatment with Temodal В® , and at least for 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 with Temodal В® male patients before treatment, if necessary, it is recommended to discuss the possibility of sperm cryopreservation.
APPLICATION FOR FUNCTIONS OF THE LIVER
With care should be prescribed in severe renal insufficiency.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With care should be prescribed in severe liver disease.
APPLICATION FOR CHILDREN
Is contraindicated in children younger than 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 older than 70 years.
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 the treatment preparation Temodal В® nausea or vomiting on subsequent receptions recommended antiemetic therapy.
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 Pneumocystis carinii. Although more frequent development of pneumonia caused by Pneumocystis carinii, is associated with a longer period of treatment with TemodalВ® , increased vigilance in regard to the possible development of PCP should be exercised in respect of all patients receiving Temodal В® , particularly in combination with corticosteroids.
Pharmacokinetic parameters of the drug Temodal В® in subjects with normal hepatic function and in patients with impaired hepatic function or mild to moderate in severity closely comparable. Data on the use of medication Temodal В®in patients with severe hepatic impairment (class C Child-Pugh) or impaired renal function is not available. On the basis of the pharmacokinetic properties Temodal data it seems unlikely that even patients with severe liver or kidney function may require a reduction in dose. Nevertheless, the appointment of the drug Temodal В® in such patients should exercise caution.
After contact with the capsule contents (powder) to the skin or mucous membrane must be washed with plenty of water.
Use in Pediatrics
The clinical experience with the drug Temodal В® with glioblastoma multiforme in children younger than 3 years and in malignant melanoma in children and adolescents under the age of 18 years is missing. There is limited experience with the use of Temodal in glioma in children older than 3 years .
Effects on ability to drive vehicles and management of vehicle
Some of the side effects of the drug such as drowsiness and fatigue, may adversely affect the ability to drive vehicles or perform potentially hazardous activities that require high concentration and psychomotor speed reactions.
Symptoms during clinical studies have examined the use of 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). Toxicity was dose-limiting 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 fatal consequences.
Treatment : Antidote is unknown. Haematological monitoring is recommended, and if necessary - symptomatic therapy.
Joint application with 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 Temodal preparation В® together 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
Drug should be stored out of the reach of children at a temperature of from 2 В° to 8 В° C. Do not freeze shelf life - 3 years.