Temcital® (Temcital®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Dosage form: & nbspcapsules
Composition:

1 capsule contains

Active substance: temozolomide 140 mg

Excipients: mannitol 114,408 mg, sodium carboxymethyl starch 12,600 mg, silicon dioxide colloid 0,392 mg, tartaric acid 5,040 mg, stearic acid 7,560 mg.

Capsule wall composition: gelatin 71.923 mg, iron oxide yellow 0.368 mg, titanium dioxide 3.709 mg.

Active substance: temozolomide 180 mg

Excipients: mannitol 147.096 mg, sodium carboxymethyl starch 16,200 mg, silicon colloidal dioxide 0.504 mg, tartaric acid 6.480 mg, stearic acid 9.720 mg.

The composition of the capsule wall: gelatin 90.339 mg, iron oxide yellow 0.254 mg, iron oxide red 1.698 mg, iron oxide black 0.068 mg, titanium dioxide 3.641 mg.




Description:

Capsules 140 mg

Hard gelatin capsules No. 1 with an opaque casing and a yellow cap containing white or white powder with a pink or cream shade.

Capsules 180 mg

Hard gelatin capsules No. 0 with an opaque white body and an opaque cap of red color, containing white or white with a pink or cream shade powder.

Pharmacotherapeutic group:triazene alkylating drug
Pharmacodynamics:

Temozolomide is a triazene alkylating drug with antitumor activity. If it enters the systemic circulation, at physiological pH values ​​it is exposed rapid chemical conversion to form the active compound monomethyltriazenoimidazolecarboxamide (MTIC). It is believed that the cytotoxicity of MTIC is due primarily to the alkylation of guanine at position 06 and additional alkylation in the N7. Apparently, cytotoxic lesions resulting from this include (trigger) a mechanism aberrant reduction of the methyl radical.

Pharmacokinetics:

Temozolomide after ingestion is rapidly absorbed and is also rapidly excreted from the body with urine. Temozolomide quickly penetrates the blood-brain barrier and enters the cerebrospinal fluid. The maximum concentration (Cmax) in plasma is achieved on average 0.5-1.5 hours (the earliest - in 20 minutes) after taking the drug. The half-life of plasma is approximately 1.8 hours. Clearance, the volume of distribution in the plasma and the half-life do not depend on the dose. Temozolomide weakly binds to proteins (10-20%). After oral administration of temozolomide, the average excretion rate with faeces for 7 days was 0.8%, indicating complete absorption of the drug.The main way of excretion is through the kidneys. 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 (APC) or unidentified polar metabolites.

Taking temozolomide together with food causes a decrease in Cmax by 33% and a decrease in the area under the "concentration-time" curve (AUC) on 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, the indicator AUC higher than in adults. The maximum tolerable dose (MTD) in children and adults was the same and was 1000 mg / m2 for one treatment cycle.

Indications:

- the newly discovered multiform glioblastoma is a 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 first-line therapeutic agent.

Contraindications:

- hypersensitivity to temozolomide or other components of the drug, as well as to dacarbazine.

- expressed myelosuppression.

- pregnancy.

- lactation period.

- children's age - up to 3 years (recurrent or progressive malignant glioma) or up to 18 years (newly diagnosed glioblastoma multiforme or malignant melanoma).

- Rare hereditary diseases, such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption.

Carefully:

- old age (over 70 years).

- marked renal or hepatic insufficiency.

Pregnancy and lactation:contraindicated
Dosing and Administration:

Temcital® is taken orally, on an empty stomach, at least one hour before a meal. 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. Treatment of adult patients (over 18 years). Primary treatment conduct in combination with radiotherapy. Temcital® is given in a dose of 75 mg / m2 daily for 42 days at the same time as 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 / μL, platelet count - not lower than 100,000 / μl, 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® during the combined phase of treatment are given in Table 1.

Table 1. Recommendations for dose reduction or withdrawal of the drug Temcital® at combined treatment with radiotherapy.

Criterion of toxicity

Break in admission Temcitala®

Termination of Temmatital®

Absolute number of neutrophils

> 500 / μL, but <1500 / μl

<500 / μL

Platelet count

> 10000 / μL, but <100,000 / μL

<10000 / μL

CTC non-hematological toxicity (with the exception of alopecia, nausea and vomiting)

Degree 2

Degree 3 or 4



Adjuvant therapy is appointed 4 weeks after the completion of the combination therapy and is performed in the form of 6 additional cycles.
Cycle 1: Temcital® is administered at a dose of 150 mg / m2 for 5 days followed by a 23-day interruption in treatment. Cycle 2: The dose of Temcital® can be increased to 200 mg / m2 per day, provided that during the first treatment cycle the severity of non-hematologic toxicity (according to the STS toxicity scale) did not exceed 2 degrees (except for alopecia, nausea and vomiting), while the absolute number of neutrophils was not lower than 1500 / μl, and the number platelets - not lower than 100000 / mkl. If the dose of Temcital® has not been increased in cycle 2, it should not be increased in the following cycles. If in cycle 2 the dose was 200 mg / m2, in the same daily dose the drug is prescribed and in the following cycles (in the absence of toxicity). In each cycle, Temcital® is administered for 5 consecutive days, followed by a 23-day break. Recommendations for dose reduction in the adjuvant phase of treatment are given in Tables 2 and 3.On day 22 of treatment (21 days after taking the first dose of Temcital®), a study
blood counting the number of cells. The abolition or reduction of the dose of Temcital® should be carried out in accordance with Table 3.

Table 2. Dosage regimen of Temcital® with adjuvant therapy.

Step


Dose (mg / m2 / day)

Note

-1

100

Reduction of dose taking into account previous toxicity (see Table 3)

0

150

Dose during cycle 1

1

200

The dose during cycles 2-6 (in the absence of toxicity)


Table 3. Recommendations for dose reduction or elimination of Temcital® with adjuvant therapy.

Criterion of toxicity

Reduce the dose of Temcital® by 1 step (see Table 2)

Termination of Temmatital®

Absolute number of neutrophils

<1000 / μL

*

Platelet count

<50000 / μL

*

CTC non-hematological toxicity (with the exception of alopecia, nausea and vomiting)

Degree 3

Degree 4 *
* Temcital® should be discontinued if a dose reduction of <100 mg / m2, and also in case of recurrence of non-hematological toxicity degree 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).A common metastasis of malignant melanoma (treatment of adults). Patients who had not previously undergone chemotherapy, Temcital® is prescribed at a dose of 200 mg / m2 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 / m2 once a day; in the second cycle, the dose can be increased to 200 mg / m2 per day, provided that on the first day of the next cycle the absolute number of neutrophils is not lower than 1500 / μl, and the number of platelets is not lower than 100,000 / μl.

Recommendations for correcting the dose of Temcital® in the treatment of progressive or rettiiviruyuschey malignant glioma or malignant melanoma.

Begin treatment with Temcital ® is only possible with an absolute number of neutrophils> 1500 / μL and platelets> 100,000 / μL. 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; then - weekly until the absolute number of neutrophils is above 1500 / μL, and the number of platelets does not exceed 100,000 / μl.With an absolute number of neutrophils below 1000 / μL or platelets below 50,000 / μL during any treatment cycle, the dose in the next cycle should be reduced by one step. Possible doses: 100 mg / m2, 150 mg / m2 and 200 mg / m2. The minimum recommended dose is 100 mg / m2.

Duration of treatment is maximum 2 years. If signs of disease progression appear, treatment with Temzital should be discontinued.
Side effects:

Glioblastoma multiforme (adult patients) was first detected. AT -

The table below shows the side effects noted in the treatment of patients with newly diagnosed multiform glioblastoma at the time of the combined and adjuvant phases of treatment. The frequency distribution of side effects was made in accordance with the following gradation: very often> 10%, often> 1% and <10%, infrequently> 0.1% and <1%.

Table 4.

System

organism

Frequency

reactions

The nature of the reaction

combined treatment phase (with radiotherapy) n = 288

adjuvant treatment phase n = 224

Infections and invasions

often infrequently

candidiasis of the oral mucosa, herpes simplex, pharyngitis, wound infection, other infection

Candidiasis of the oral mucosa, another infection

herpes simplex, herpes zoster, influenza-like syndrome

Blood and

lymphatic

system

often infrequently

leukopenia, lymphopenia, neutropenia, thrombocytopenia anemia, febrile neutropenia

anemia, febrile neutropenia, leukopenia, thrombocytopenia of lymphopenia, petechiae

The cardiovascular system

often infrequently

edema, incl. swelling of the feet, hemorrhage of the heartbeat, increased blood pressure, hemorrhagic stroke

swelling of the legs, hemorrhage, deep vein thrombosis? edema, incl. peripheral edema, pulmonary embolism

Respiratory system

often infrequently

cough, shortness of breath pneumonia, upper respiratory tract infection, nasal congestion

cough, shortness of breath pneumonia, upper respiratory tract infection, sinusitis, bronchitis

Endocrine

system

infrequently

Isenko-Cushing syndrome

Isenko-Cushing syndrome

Skin and subcutaneous cellulose

mammary gland

very often



infrequently

alopecia, rash dermatitis, dry skin, erythema, skin itching, swelling face, photosensitivity reaction, pigmentation disorder, skin detachment

alopecia, rash, dryness, itching of the skin

erythema, impaired pigmentation, excessive sweating, pain in the mammary gland, swelling of the face




Nervous system

Often

headache

headache, convulsions


often

anxiety,

anxiety, depression,



emotional

emotional lability,



lability, insomnia,

insomnia, dizziness,



dizziness,

disturbance of balance,



balance disorder,

concentration disorder



concentration disorder

attention, confusion



attention, confusion and

consciousness, speech disorder,

\


oppression of consciousness,

hemiparesis, memory impairment,



convulsions, worsening

neurological disorders



memory, neuropathy,

(unspecified), neuropathy,



paresthesia, drowsiness,

paresthesia, drowsiness,



speech disorder, tremor

tremor


infrequently

apathy, behavioral

hallucinations, amnesia,



disorders, depression,

violation of gait,



hallucinations, violation

hemiplegia, hyperesthesia,



perception,

violation of



extrapyramidal

sensitivity, sensory



disorders of gait, hemiparesis, hyperesthesia, hypoesthesia, neurological disorders (unspecified), epileptic status, parosmia, thirst

violations

Oporno-

often

arthralgia, muscular

arthralgia, muscular-

motor


weakness

skeletal pain, myalgia,

staff

infrequently

pain in the back, musculoskeletal pain, myalgia,

muscle weakness in back pain, myopathy



myopathy


Body of sight

often

blurred vision

blurred vision, diplopia, visual field limitation


infrequently

pain in the eye, hemianopsia,

pain in the eye, dry eyes,



visual impairment, visual acuity, visual field limitation

visual acuity reduction

Genitourinary

often

frequent urination,

urinary incontinence

system

infrequently

incontinence

dysuria, amenorrhea, menorrhagia, vaginal bleeding, vaginitis

The organ of hearing and

often

hearing impairment

hearing impairment, ringing in the ears

equilibria

infrequently

pain in the ear, hyperacia,

deafness, pain in the ear,



ringing in the ears, otitis media

dizziness




Digestive

system

very often

infrequently

anorexia, constipation, nausea, vomiting

increased activity of alanine transaminase (ALT), abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis, hypokalemia, increased alkaline phosphatase activity, discoloration of the tongue, increased activity

gamma-glutamyltranspeptase (Gamma-GT), aspartic transaminase (ACT), liver enzymes

anorexia, constipation, nausea, vomiting

increased activity of alanine transaminase (ALT), diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, abnormality of bloating, fecal incontinence, hemorrhoids, gastroenteritis, dental diseases

Organism as a whole

Often

fatigue

fatigue


often

fever, pain syndrome,

fever, painful



radiation damage,

syndrome, radiation



allergic reaction,

defeat, allergic



weight loss

reaction, weight loss




bodies


infrequently

"hot flashes" of heat to the body,

asthenia, worsening



asthenia, worsening

condition, chills,



condition, chills,

weight gain



weight gain



Laboratory indicators.
Myelosuppression (neutropenia and thrombocytopenia) is a dose-limiting side effect. Among patients in both groups (combined and adjuvant therapy), neutrophil toxicity reactions, 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.

Progressive or recurrent malignant glioma (adults and children over 3 years old) or malignant melanoma (adults).

The following adverse events noted with the administration of the drug Temcital® are distributed. according to the frequency of occurrence in accordance with the following gradation: very often (> 10% of cases), often (> 1% <10%), infrequently (> 0.1% <1%), rarely (> 0.01% <0.1%) and very rare (<0.01%).

On the part of the system - hematopoiesis: very often - thrombocytopenia, neutropenia, lymphopenia; infrequently - pancytopenia, leukopenia, 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 Temcitala was required in 8% and 4% of cases, respectively, in glioma and in 3% and 1.3% in melanoma. 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.

On the part 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.

From the skin and skin appendages: often - rash, itching, alopecia, petechiae; very rarely - hives, exanthema, erythroderma, erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome.

From the immune system: very rarely - 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.

Overdose:

When using the drug in doses of 500, 750, 1000 and 1250 mg / m2 (the total dose received for a 5-day treatment cycle). Dose-limiting toxicity was hematologic toxicity, which was noted when taking any dose, but more pronounced - at higher doses. A case of overdose (taking a dose of 2000 mg per day for 5 days), which resulted in the development of pancytopenia, pyrexia, multiple organ failure and death. When taking the drug for more than 5 days (up to 64 days), among other symptoms of an overdose, hematopoiesis was suppressed, complicated or uncomplicated by the infection, in some cases prolonged and severe, with a fatal outcome.

Treatment. The antidote to temozolomide is not known. It is recommended hematological control and, if necessary, symptomatic therapy.

Interaction:

The administration of temozolomide together with ranitidine does not lead to a clinically significant change in the degree of absorption of temozolomide.

Joint reception with dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, blockers of H2-histamine receptors or phenobarbital does not change the clearance of temozolomide.Joint administration with valproic acid results in a weak but statistically significant decrease in the clearance of temozolomide. Studies aimed at elucidating the effects of temozolomide on metabolism and excretion of other drugs have not been conducted. Due to temozolomide It is not metabolized in the liver and weakly binds to plasma proteins, its effect on the pharmacokinetics of other drugs is unlikely.

The use of temozolomide together with other substances that depress the bone marrow may increase the likelihood of myelosuppression.

The use of Temcital® together with other bone marrow suppressors may increase the likelihood of myelosuppression.

Special instructions:

Before the beginning of the combined treatment (with radiotherapy), it is recommended to carry out preventive antiemetic therapy and is strongly recommended during the adjuvant therapy of the newly diagnosed multiform glioblastoma. If against the background of treatment with Temcital®, nausea or vomiting occurs in the subsequent administration, it is recommended that antiemetic therapy be given. Antiemetic drugs can be taken before and after taking Temcital®.Even if vomiting has developed within the first 2 hours after taking Temcital®, it is not necessary to repeat the medication on the same day.

Due to the increased risk of developing pneumonia caused by Pneumocystis carinii, in patients receiving combined treatment with radiotherapy within 42 days (up to 49 days), such patients are recommended to carry out preventive treatment against the pathogen Pneumocystis carinii. Although the more frequent development of pneumonia caused by Pneumocystis carinii, is associated with longer treatment times with Temcital®, increased alertness for the possible development of PCP should be shown for all patients receiving the preparation of Temcital®, especially in combination with glucocorticosteroids.

The pharmacokinetic parameters of Temcital® in individuals with normal liver function and in patients with impaired liver function of mild or moderate severity are comparable. Data on the use of the drug Temcital® in patients with severe hepatic impairment (Child-Pugh class C) or renal dysfunction is not available.

Based on the data on the pharmacokinetic properties of the drug Temcital®, it seems unlikely that patients with even severe impaired liver or kidney function may need to reduce the dose of the drug. Nevertheless, when prescribing Temzital®, such patients should be cautious. Men and women of childbearing age during treatment with Temcital® and how at least 6 months after completion should use reliable methods of contraception.


Because of the risk of developing irreversible infertility, against the background of treatment with Temcital®, male patients before the start of treatment, if necessary, are advised to discuss the possibility of cryopreservation of sperm.

If the contents of the capsule (powder) get on the skin or mucous membranes, they should be washed with a large amount of water.

Effect on the ability to drive transp. cf. and fur: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.
Form release / dosage:Capsules of 140 mg, 180 mg. 5 capsules in a bottle of high density white polyethylene with a screwed plastic cover.1 bottle together with instructions for use in a pack of cardboard.
Packaging:(5) - White high density polyethylene bottle with screwed plastic cover (1) - cardboard pack
Storage conditions:

Store in dry the dark place at a temperature of 2 ° C to 25 ° C.

Keep out of the reach of children.
Shelf life:

2 years

Do not use the product after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription
Registration number:LP-001832
Date of registration:12.09.2012
The owner of the registration certificate:ANSTAR, AG ANSTAR, AG Switzerland
Manufacturer: & nbsp
Representation: & nbspANSTAR AG ANSTAR AG Switzerland
Information update date: & nbsp14.09.2015
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