TEMODAL®
Active material: Temozolomide
When ATH: L01AX03
CCF: Anticancer drug
ICD-10 codes (testimony): C43, C71
When CSF: 22.01.07
Manufacturer: SCHERING-PLOUGH LABO N. V. (Belgium)
PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING
Capsules hard gelatin, size №3, with opaque green cap and the White, black ink on capsules marked with the inscription: of krыshechke – “Temodal”, on the body – “5 mg “, trade mark in the form of stylized letters “SP” and two strips; contents of capsules – powder from white to light pink or light yellow-brown.
| 1 caps. | |
| temozolomid | 5 mg |
Excipients: lactose bezvodnaya, colloidal silicon dioxide, sodium carboxymethyl, tartaric acid, stearic acid.
Ingredients of the capsule shell: Titanium dioxide, sodium lauryl, gelatin.
5 PC. – vials of dark glass (1) – cardboard boxes.
20 PC. – vials of dark glass (1) – cardboard boxes.
Capsules hard gelatin, size №2, with opaque yellow CAP and Shell white, black ink on capsules marked with the inscription: of krыshechke – “Temodal”, on the body – “20 mg “, trade mark in the form of stylized letters “SP” and two strips; contents of capsules – powder from white to light pink or light yellow-brown.
| 1 caps. | |
| temozolomid | 20 mg |
Excipients: lactose bezvodnaya, colloidal silicon dioxide, sodium carboxymethyl, tartaric acid, stearic acid.
Ingredients of the capsule shell: Titanium dioxide, sodium lauryl, gelatin.
5 PC. – vials of dark glass (1) – cardboard boxes.
20 PC. – vials of dark glass (1) – cardboard boxes.
Capsules hard gelatin, size №1, with opaque lid pink and white, black ink on capsules marked with the inscription: of krыshechke – “Temodal”, on the body – “100 mg “, trade mark in the form of stylized letters “SP” and two strips; contents of capsules – powder from white to light pink or light yellow-brown.
| 1 caps. | |
| temozolomid | 100 mg |
Excipients: lactose bezvodnaya, colloidal silicon dioxide, sodium carboxymethyl, tartaric acid, stearic acid.
Ingredients of the capsule shell: Titanium dioxide, sodium lauryl, gelatin.
5 PC. – vials of dark glass (1) – cardboard boxes.
20 PC. – vials of dark glass (1) – cardboard boxes.
Capsules hard gelatin, size №0, with opaque lid blue and white hull, black ink on capsules marked with the inscription: of krыshechke – “Temodal”, on the body – “140 mg “, trade mark in the form of stylized letters “SP” and two strips; contents of capsules – powder from white to light pink or light yellow-brown.
| 1 caps. | |
| temozolomid | 140 mg |
Excipients: lactose, sodium carboxymethyl starch, colloidal silicon dioxide, tartaric acid, stearic acid.
Ingredients of the capsule shell: Titanium dioxide, indigokarmin, sodium lauryl, gelatin.
Ink composition for applying labels on Shell capsules: black dye (shellac, ethanol, isopropanol, Butanol, propylene glycol, Purified water, ammonia water, potassium hydroxide, dye iron oxide black).
5 PC. – vials of dark glass (1) – cardboard boxes.
20 PC. – vials of dark glass (1) – cardboard boxes.
Capsules hard gelatin, size №0, with opaque orange cap and Shell white, black ink on capsules marked with the inscription: of krыshechke – “Temodal”, on the body – “180 mg “, trade mark in the form of stylized letters “SP” and two strips; contents of capsules – powder from white to light pink or light yellow-brown.
| 1 caps. | |
| temozolomid | 180 mg |
Excipients: lactose, sodium carboxymethyl starch, colloidal silicon dioxide, tartaric acid, stearic acid.
Ingredients of the capsule shell: Titanium dioxide, dye iron oxide yellow, iron oxide red dye, sodium lauryl, gelatin.
Ink composition for applying labels on Shell capsules: black dye (shellac, ethanol, isopropanol, Butanol, propylene glycol, Purified water, ammonia water, potassium hydroxide, dye iron oxide black).
5 PC. – vials of dark glass (1) – cardboard boxes.
20 PC. – vials of dark glass (1) – cardboard boxes.
Capsules hard gelatin, size №0, with opaque lid and casing of white color, black ink on capsules marked with the inscription: of krыshechke – “Temodal”, on the body – “250 mg “, trade mark in the form of stylized letters “SP” and two strips; contents of capsules – powder from white to light pink or light yellow-brown.
| 1 caps. | |
| temozolomid | 250 mg |
Excipients: lactose bezvodnaya, colloidal silicon dioxide, sodium carboxymethylcellulose, tartaric acid, stearic acid.
Ingredients of the capsule shell: Titanium dioxide, sodium lauryl, gelatin.
5 PC. – vials of dark glass (1) – cardboard boxes.
20 PC. – vials of dark glass (1) – cardboard boxes.
Pharmacological action
Temodal® – This drug is an alkylating imidazotetrazinovyj, with antitumor activity. When released into the bloodstream, at physiological pH is the rapid chemical transformation with the formation of the active connection – monometiltriazenoimidazolkarboksamida (MTIC). It is believed, that the cytotoxicity of MTIC due primarily due to the molecular guanine at position on6 and additional due to the molecular in position N7. Apparently, cytotoxic damage, arising out of this, include (run) mechanism of methyl restore balance aberrant.
Pharmacokinetics
Absorption
After intake of rapidly absorbed temozolomid. FROMmax plasma is on average 0.5-1.5 no (the earliest – through 20 m) After taking the drug. Admission drug Temodal® along with the food causes decreased withmax on 33% and reducing AUC by 9%. After oral dose Temodal® the average degree of excretion from faeces during 7 days was 0.8%, indicating a full intake of the drug.
Distribution
Temozolomid quickly penetrates the Geb and enters into the cerebrospinal fluid.
Vd not dose. Temozolomid weakly binds to proteins (12-16%).
Deduction
Rapidly excreted with urine. T1/2 from plasma is approximately 1.8 no. The main way of deducing temosolomida – kidneys. Through 24 hours after intake of approximately 5-10% the dose is determined by the unaltered in urine; the rest of the place in the form of 4-amino-imidazole-5-carbaxamide hydrochloride (AIK), temozolomidovoj acid or unidentified polar metabolites. Clearance and T1/2 not dose dependent.
Pharmacokinetics in special clinical situations
Clearance of the drug in plasma is not dependent on age, kidney or smoking.
Farmakokineticeski profile of the drug in patients with impaired liver weak or moderate extent the same, as in those with normal liver function.
Children rate higher AUC, than in adults.
Maximum portable dose in children and adults turned out to be the same and amounted to 1000 mg / m2 for one cycle of treatment.
Testimony
for the first time identified glioblastoma Multiforme – combined treatment with radiation therapy with subsequent adjuvant alone;
-malignant glioma (glioblastoma Multiforme or anaplastic Astrocytoma), if recurrence or progression after standard therapy;
— common metastezirutaya malignant melanoma – as a therapeutic means the first row.
Dosage regimen
Temodal® is inwards, fasting, no less, than 1 hours before the meal. Assigned dose should be taken with using the minimum possible number of capsules. You cannot open capsules or chew, they should be swallowed whole, with a glass of water.
For the first time identified multiform glioblastoma (treatment Adult older patients 18 years).
Primary treatment conduct in combination with radiation therapy. Temodal® assigned dose 75 mg / m2 daily for 42 days in conjunction with radiotherapy (30 factions in total dose 60 GR). Dose reduction is not recommended, However, the admission of the drug may be interrupted depending on portability. Resume taking the drug may throughout the 42-day period, the combined treatment and up to 49 days, but only if all the following conditions: the absolute number of neutrophils is not below 1500/MKL, the number of platelets is not below 100 000/l, the general criterion of toxicity (STS) no higher degree 1 (except for alopecia, nausea and vomiting). During treatment should be the study of blood with a weekly count of the number of cells. Recommendations for reducing the dose or eliminate the medication Temodal® during the combination phase of treatment are given in table 1.
Table 1. Recommendations for reducing the dose or eliminate the medication Temodal® in the combined treatment with radiation therapy
| The criterion of toxicity | A break in the employment drug Temodal®* | Discontinuations Temodal® |
| absolute neutrophil count | ≥ 500/μl, but <1500/l | ≤ 500/μl |
| the number of platelets | ≥ 10000/µl, but <100 000/l | <10 000/l |
| STS negematologičeskoj toxicity (except for alopecia, nausea and vomiting) | Power 2 | Power 3 or 4 |
*Resumption of dose Temodal® Maybe if all the following conditions: the absolute number of neutrophils is not below 1500/MKL, the number of platelets is not below 100 000/l, the general criterion of toxicity (STS) no higher degree 1 (except for alopecia, nausea and vomiting).
Adjuvant therapy assigned through 4 weeks after the combination therapy and is held in the form of 6 additional cycles.
Cikl1: Temodal® administered at a dose of 150 mg / m2 during 5 days, followed by a 23-day break in the treatment.
Cycle 2: dose Temodal® It can be increased to 200 mg / m2/d, provided, the first cycle of the severity of toxicity negematologičeskoj (in accordance with the scale of toxicity of STS) does not exceed the degree 2 (except for alopecia, nausea and vomiting), While the absolute number of neutrophils was not below 1500/MKL, and the number of platelets – not below 100 000/l. If the cycle 2 dose Temodal® was not increased, It should not increase and the following cycles. If the cycle 2 the dose was 200 mg / m2, in the same daily dose of the drug is indicated in the following cycles (in the absence of toxicity). In each cycle taking drugs Temodal® exercise for 5 consecutive days followed by 23-day break. Recommendations to reduce dose adjuvant treatment phase are given in tables 2 and 3. The 22-day treatment (21-the 10th day after the first dose of the drug) a study should be undertaken with a count of the number of blood cells. Lifting or lowering the dose should be, guided by the table 3.
Table 2. Stage Temodal doses® in adjuvant therapy
| Stage | Dose (mg / m2/d) | Note |
| -1 | 100 | Reducing the dose, taking into account the previous toxicity (cm. Table. 3) |
| 0 | 150 | Dose during the cycle 1 |
| 1 | 200 | Dose during cycles 2-6 (in the absence of toxicity) |
Table 3. Recommendations for reducing the dose or eliminate the medication Temodal® in adjuvant therapy
| The criterion of toxicity | Reduce dose Temodal® on 1 stage (cm. Table. 2) | Discontinuations Temodal® |
| absolute neutrophil count | <1000/l | * |
| the number of platelets | <50 000/l | * |
| STS negematologičeskoj toxicity (except for alopecia, nausea and vomiting) | Power 3 | Power 4* |
* Temodal® should be abolished, If you want to reduce the dose to <100 mg / m2, and also in case of recurrence of negematologičeskoj toxicity degree 3 (except for alopecia, nausea and vomiting) After dose reduction.
Progressive or relapsing malignant glioma, glioblastoma Multiforme in the form or anaplastičeskoj astrocytomas (treatment adults and children over 3 years). Common metastezirutaya malignant melanoma (treatment Adult).
Patients, previously subjected to chemotherapy, Temodal® administered at a dose of 200 mg / m2 1 times/day for 5 consecutive days, followed by a break in the employment drug during 23 days (the total duration of one cycle of treatment is 28 days).
For patients, before undergoing chemotherapy, starting dose is 150 mg / m2 1 time / day; in the second cycle, the dose can be increased to 200 mg / m2/SUT provided, that on the first day of the next cycle of the absolute number of neutrophils is not below 1500/MKL, and the number of platelets is not below 100 000/l.
Recommendations for dose modification Temodal® in the treatment of recurrent malignant glioma or progressive or malignant melanoma
Starting treatment with Temodal® only if the absolute number of neutrophils ≥ 1500/MKL and platelets ≥ 100 000000/µl, Full blood test must be performed on the 22nd day (21-the 10th day after the first dose), but no later than 48 hours after this day; further – weekly, While the absolute number of neutrophils will not above 1500/MKL, and the number of platelets will not exceed 100 000/l. If the absolute number of neutrophils below 1000/µl or platelets below 50000/l during any cycle treatment, dose next cycle should be reduced by one step. Possible dose: 100 mg / m2, 150 mg / m2 and 200 mg / m2. The minimum recommended dose is 100 mg / m2.
Duration of treatment is maximum 2 year. When you see the progression of the disease drug treatment should be discontinued.
Side effect
For the first time identified multiform glioblastoma (adult patients)
The following table lists the side effects, marked in the treatment of patients with newly diagnosed glioblastomoj Multiforme during combined and adjuvant treatment phases in clinical trials (causal link between taking the drug and the side effects has not been installed). The distribution of the frequency of side effects was in accordance with the following gradation: Often (>10%), often (>1%,<10%), infrequently (>0.1%, <1%).
| Frequency response | The nature of the reactions | |
| combined phase treatment (with radiation therapy) n = 288 | adjuvant treatment phase n = 224 | |
| Mechanisms of resistance to infection | ||
| often | oral candidiasis, herpes simplex, pharyngitis, wound infection, Another infection | oral candidiasis, Another infection |
| infrequently | – | herpes simplex, herpes zoster, flu-like symptoms |
| On the part of the blood and lymphatic system | ||
| often | leukopenia, lymphopenia, neutropenia, thrombocytopenia | anemia, febrile neutropenia, leukopenia, thrombocytopenia |
| infrequently | anemia, febrile neutropenia | lymphopenia, petechiae |
| Cardio-vascular system | ||
| often | swelling, t. h. swelling of the feet, hemorrhage | swelling of the feet, hemorrhage, deep vein thrombosis |
| infrequently | heartbeat, arterial hypertension, cerebral hemorrhage | swelling, t. h. peripheral edema, pulmonary embolism |
| The respiratory system | ||
| often | cough, breathlessness | cough, breathlessness |
| infrequently | pneumonia, infection of the upper respiratory tract, nasal congestion | pneumonia, infection of the upper respiratory tract, sinusitis, bronchitis |
| On the part of the endocrine system | ||
| infrequently | kušingoid | kušingoid |
| From the nervous system | ||
| Often | headache | headache, convulsions |
| often | anxiety, emotional lability, insomnia, dizziness, balance disorder, violation of concentration, confusion and reduced consciousness, convulsions, memory impairment, Neuropathy, paresthesia, drowsiness, speech disorder, tremor | anxiety, depression, emotional lability, insomnia, dizziness, balance disorder, violation of concentration, confusion, speech disorder, gemiparez, memory impairment, neurological disorders (unspecified), Neuropathy, paresthesia, drowsiness, tremor |
| infrequently | apathy, behavioral disorders, depression, hallucinations, the perception, extrapyramidal disorder, gait disturbance, gemiparez, giperesteziya, gipesteziya, neurological disorders (unspecified), status epilepticus, parosmija, thirst | hallucinations, amnesia, gait disturbance, hemiplegia, giperesteziya, disorders of the senses |
| Skin and subcutaneous tissue, Breast | ||
| Often | alopecia, rash | alopecia, rash |
| often | dermatitis, xerosis, эritema, itching, swelling of the face | xerosis, itching |
| infrequently | photosensitivity, pigmentation disorders, exfoliation | эritema, pigmentation disorders, increased perspiration, pain in the breast, swelling of the face |
| On the part of the musculoskeletal system | ||
| often | arthralgia, muscular weakness | arthralgia, muscular weakness, myalgia, musculo-skeletal pain |
| infrequently | backache, musculo-skeletal pain, myalgia, myopathy | backache, myopathy |
| On the part of the organ of vision | ||
| often | blurred vision | blurred vision, diplopia, limiting fields of view |
| infrequently | eye pain, hemianopsia, blurred vision, reduced visual acuity, limiting fields of view | eye pain, dry eyes, reduced visual acuity |
| By hearing and vestibular system | ||
| often | amblyacousia | amblyacousia, tinnitus |
| infrequently | earache, hyperacusis, otitis media, tinnitus | deafness, earache, dizziness |
| From the digestive system | ||
| Often | anorexia, constipation, nausea, vomiting | anorexia, constipation, nausea, vomiting |
| often | increased ALT, giperglikemiâ, weight loss, abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis, taste disturbance | increased ALT, weight loss, diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, taste disturbance |
| infrequently | kaliopenia, increased activity of alkaline phosphatase, weight gain, color change language, increased activity of GGT, ACT, liver enzymes | giperglikemiâ, weight gain, abdominal distention, scatacratia, hemorrhoids, gastroenteritis, dental disease |
| With the genitourinary system | ||
| often | frequent urination, urinary incontinence | urinary incontinence |
| infrequently | impotence | dizurija, amenorrhea, menorragija, vaginal bleeding, vaginitis |
| From the body as a whole | ||
| Often | fatigue | fatigue |
| often | fever, pain syndrome, radiation syndrome, allergic reaction | fever, pain syndrome, radiation syndrome, allergic reaction |
| infrequently | tides, asthenia, the deterioration of the, chills | asthenia, the deterioration of the, chills |
Laboratory findings: mielosuprescia (neutropenia and thrombocytopenia), is dozolimitiruûŝim side effect. Among the patients of both groups (When combined and adjuvant therapy) changes 3 and 4 degree by Klebsiella, including neutropenia, marked in 8% cases, and by platelets, including thrombocytopenia, – in 14% cases.
Progressive or relapsing malignant glioma (adults and children over 3 years) or malignant melanoma (adults)
The following adverse events, marked with the admission Temodala, distributed incidence according to the following gradation: Often (≥10%), often (≥1%, <10%), infrequently (≥0.1%, <1%), rarely (≥0.01%, <0.1%) and very rare (<0.01%).
From the hematopoietic system: often – thrombocytopenia, neutropenia, lymphopenia; infrequently – pancytopenia, leukopenia, anemia. In the treatment of patients with metastatic melanoma and gliomoj there were cases of thrombocytopenia and neutropenia 3 or 4 degree in 19% and 17% respectively – with the gliome and 20% and 22% Consequently, when you smile. Hospitalization of the patient or/and cancel Temodala in doing so required in 8% and 4% cases and gliome respectively 3% and 1.3% – melanoma. Oppression bone marrow developed normally for the first few cycles of treatment, with a maximum between 21 and 28 recently; restore occurred, usually, during 1-2 weeks. Signs of cumulative mielosupression not noted.
From the digestive system: Often – nausea, vomiting, anorexia, constipation; often – diarrhea, abdominal pain, dyspepsia, taste perversion. The most common were nausea and vomiting. In most cases, these phenomena were 1-2 (from mild to moderate) degree and have passed on their own or are easily controlled using the standard protivorvotnoj therapy. Frequency expressed nausea and vomiting – 4%.
From the nervous system: often – headache; often – drowsiness, dizziness, paresthesia, asthenia.
Dermatological reactions: often – rash, itch, alopecia, petechiae; rarely – hives, rash, erythroderma, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.
On the part of the immune system: rarely – allergic reactions, including anaphylaxis.
Other: often – fatigue; often – weight loss, breathlessness, fever, chills, general malaise; seldom-opportunistic infections, including pneumonia, caused by Pneumocystis carinii; very rarely mentioned development mielodisplastičeskogo syndrome and secondary malignant processes, including leukemia, as well as long it has evolved with the risk of aplastic anemia and irreversible infertility.
Contraindications
— expressed mielosuprescia;
- Pregnancy;
- Lactation (breast-feeding);
- Children up to age 3 years (recurrent or progressive malignant glioma) or to 18 years (for the first time revealed Erythema glioblastoma or malignant melanoma);
is a rare hereditary diseases, such as Galactose intolerance, lactase deficiency or glucose-galaktoznaâ malabsorption;
-hypersensitivity to temozolomidu or other components of the drug, as well as dacarbazino.
FROM caution should appoint drug patients over 70 years, When expressed kidney or liver failure.
Pregnancy and lactation
Study of application of Temodal® in pregnant women has not been. When conducting preclinical studies in rats and rabbits, receiving Temodal® dose 150 mg / m2, It was observed teratogenic effects and toxic effects of the drug on fruit. In this regard, Temodal® not recommended to appoint during pregnancy.
Men and women of childbearing age during drug treatment Temodal®, and, least, during 6 months after the end must use reliable methods of contraception.
Unknown, does temozolomid stands out with breast milk. During lactation should abandon breastfeeding, or from taking the drug.
Due to the risk of irreversible infertility treatment drug Temodal® male patients before treatment in case of need, it is recommended to discuss the possibility of cryoconservation of a sperm.
Cautions
Protivorvotnoj preventive therapy is recommended before starting the combination therapy (with radiation therapy) and strongly recommended during adjuvant therapy of newly diagnosed glioblastoma Multiforme. If the background of Temodal treatment® nausea or vomiting occurs on subsequent techniques recommended protivorvotnuû therapy. Antiemetic medications can be taken to, and after taking the drug Temodal®. Even if the vomiting has developed into the first 2 h after administration of the drug Temodal® to repeat the dose on the same day, should not be.
In connection with the increased risk of developing pneumonia, caused by Pneumocystis carinii, patients, receiving combined treatment with radiation therapy for 42 days (up to 49 days), such patients are advised to conduct preventive treatment against the pathogen Pneumocystis carinii. Although more frequent development of pneumonia, caused by Pneumocystis carinii, associated with a more lengthy periods of Temodal treatment®, increased alertness with regard to the possible development of Pneumocystis pneumonia should be in respect of all patients, receiving Temodal®, especially in combination with glucocorticosteroids it.
Pharmacokinetic drug Temodal indicators® in patients with normal liver function, and in patients with impaired liver weak or moderate severity nearly comparable. Data on the use of drugs Temodal® patients expressed impaired liver (class C Child-Pugh) or impairment of renal function is not available. On the basis of the data of the study of Pharmacokinetic properties of Temodala® it seems unlikely, that even patients expressed impaired liver or kidney disease may need lower doses of the drug. Nonetheless, in appointing the drug Temodal® such patients should exercise caution.
Elderly patients (senior 70 years) the risk of neutropenia and thrombocytopenia above, than in younger. Therefore, patients older Temodal® It should be administered with caution.
When ingested the contents of capsules (powder) on the skin or mucous membranes must be washed them plenty of water.
Use in Pediatrics
Clinical experience of application of Temodal® If you have glioblastome Multiforme Children up to 3 years and in malignant smile at children and adolescents under the age of 18 years missing. There is limited experience with the application of Temodala® with the gliome u older children 3 years.
Impact on the ability to drive vehicles and driving
Some side effects of the drug, such as drowsiness and fatigue, may adversely affect the ability to drive vehicles or perform potentially hazardous activities, require high concentration and speed of psychomotor reactions.
Overdose
If you are using the drug in doses 500 mg / m2, 750 mg / m2, 1000 mg / m2 and 1250 mg / m2 (total dose, received for 5-day treatment cycle) dozolimitiruûŝej toxicity hematological toxicity was, that occurred when taking any dose, but it was more – at higher doses. Describes the case of an overdose (welcome dose 2 g / day for 5 days), as a result of which have developed pancytopenia, pyrexia, multiple organ failure and death. Before the drug more 5 days (up to 64 days), among other side effects noted oppression blood, complicated or not complicated infection, in some cases, prolonged and pronounced, fatal.
Treatment: the antidote is unknown. Recommended haematological control and, if necessary, – simptomaticheskaya therapy.
Drug Interactions
Admission drug Temodal® together with ranitidine do not result in clinically important change in the degree of suction Temodala.
Joint reception with dexamethasone, prohlorperazinom, phenytoin, karʙamazepinom, ondansetronom, blokatorami gistaminovykh n2-receptors or phenobarbital does not alter the ground temosolomida.
Joint reception valproeva acid with causes weakly expressed, but statistically significant decrease in clearance temosolomida.
Research, aimed at clarifying the effects of temosolomida on metabolism and excretion of other drugs, not performed. Because, that temozolomid not metabolised in the liver and weakly binds to proteins, its effect on farmakokinetiku other medicines it is unlikely.
Application of drug Temodal® together with other substances, depressing the bone marrow, can increase the likelihood mielosupression.
Conditions of supply of pharmacies
The drug is released under the prescription.
Conditions and terms
The drug should be kept out of the reach of children at a temperature from 2° to 30° c. Shelf life – 2 year.
