Temomide - instructions for use, dose, side effects, contraindications

silicon colloidal dioxide 0.4 mg / 0.5 mg, tartaric acid 4.2 mg / 5.4 mg, sodium carboxymethyl starch 21 mg / 27 mg, lactose anhydrous 171 mg / 121.3 mg, stearic acid 8.4 mg / 10.8 mg;

capsule shell for dosing 140 mg (mean weight 75 mg ± 10%):

gelatin 83.58%, methyl parahydroxybenzoate 0.1%, propyl parahydroxybenzoate 0.1%, sodium lauryl sulfate 0.1%, purified water 14.4%, titanium dioxide 1.68%, colorant diamond blue (FD & C Blue # 1) 0,712%; capsule capsule for a dosage of 180 mg (average weight 75 mg ± 10%):

gelatin 83.42%, methyl parahydroxybenzoate 0.1%, propyl parahydroxybenzoate 0.1%, sodium lauryl sulfate 0.1%, purified water 14.4%, titanium dioxide 1.4%, dye brown No. 1 (D & C Brown # 1) 0,625%.

Description:

Dosage of 140 mg: hard gelatin capsules number "1" in blue.

Dosage of 180 mg: hard gelatin capsules number "1" brown.

The contents of capsules are white or almost white powder.

Pharmacotherapeutic group:An antitumour agent, an alkylating compound.

ATX: & nbsp

L.01.A.X.03 Temozolomide

Pharmacodynamics:Temomide is an imidazotetrazine alkylating drug with antitumor activity. When entering the systemic bloodstream, 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 in position O and additional alkylation in the N . Apparently, cytotoxic lesions resulting from this include (trigger) the mechanism of aberrant reduction of the methyl residue.

Pharmacokinetics:

Suction

After oral administration temozolomide quickly absorbed. The maximum concentration of active substance C_max in plasma is achieved on average 0.5-1.5 hours (the earliest - after 20 minutes) after taking the drug. Taking Temomide along with food causes a decrease FROM_max by 33% and a decrease in the area under the pharmacokinetic curve AUC on 9%. After oral ingestion Temomid average degree of elimination in the feces within 7 days was 0.8%, which indicates complete absorption of the drug. Distribution

The active substance of Temomide - temozolomide quickly penetrates the blood-brain barrier and enters the cerebrospinal fluid. Volume of distribution Vd does not depend on the dose. Temozolomide weakly binds to proteins (12-16%).

Excretion

Quickly excreted from the body by the kidneys. The half-life of the active substance T1 / 2 is about 1.8 hours. After 24 hours after ingestion, approximately 5-10 % dose is determined unchanged in the urine; the rest is derived as 4-amino-5-imidazole-carboxamide hydrochloride (APC), temozolomidic acid or unidentified polar metabolites. Clearance and T1/2 do not depend on the dose.

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, the indicator AUC higher than in adults. The maximum tolerated dose in children and adults was the same and was 1000 mg / m² for one treatment cycle.

Indications:

- the newly discovered multiform glioblastoma (combined treatment with radiotherapy followed by adjuvant monotherapy);

- malignant glioma (glioblastoma multiforme or anaplastic astrocytoma), with relapse or disease progression after standard therapy;

- a common metastatic malignant melanoma (as a first-line therapeutic agent).

Contraindications:

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

- severe myelosuppression;

- pregnancy;

- lactation period (breastfeeding);

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

Carefully:

- older age (over 70 years);

- marked renal or hepatic insufficiency;

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

Pregnancy and lactation:contraindicated

Dosing and Administration:

Temomide is taken orally, on an empty stomach, at least 1 hour before meals. The prescribed dose should be taken using the lowest possible number of capsules. Capsules can not be opened or chewed, they should be swallowed whole, washed down with a glass of water.

The newly discovered multiform glioblastoma

Treatment of adult patients (over 18 years): primary treatment conduct in combination with radiation therapy. Temomide is applied at a dose of 75 mg / m2 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:

- the absolute number of neutrophils is not lower than 1500 / μl,

- the number of platelets is not less than 100,000 / μl,

- the criterion of general toxicity (according to the scale Common Toxicity Criteria - CTC) is not higher than degree 1 (with the exception of alopecia, nausea and vomiting).

During treatment, a blood test should be performed weekly, counting the number of cells. Recommendations for dose reduction or withdrawal of Temomide during the combined phase of treatment are given in Table 1 (see file).

Adjuvant therapy It is applied 4 weeks after the completion of the combination therapy and is performed in the form of 6 additional cycles.

Cycle 1: Temomide is prescribed in a dose of 150 mg / m "for 5 days followed by a 23-day interruption in treatment.

Cycle 2: the dose of Temomide can be increased to 200 mg / m / 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 neutrophils was not lower than 1500 / μl,and the number of platelets is not lower than 100,000 / μl.

If the dose of Temomide was not increased in cycle 2, it should not be increased in the following cycles. If the dose was 200 mg / m 2 in cycle 2, the drug is administered at the same daily dose in the following cycles (in the absence of toxicity) .Timomide is administered for 5 consecutive days with a subsequent 23-day break in each cycle.

Recommendations for dose reduction in the adjuvant phase of treatment are given in Tables 2 and 3. (see the file)

On the 22nd day of treatment (the 21st day after taking the first dose of the drug) it is necessary to conduct a general blood test with the calculation of the formula and the number of platelets. Cancellation or reduction of the dose of Temomide should be carried out according to Table 3 (see the file)

Table 2. Dosage levels of Temomide with adjuvant therapy (see the file)

Table 3. Recommendations for dose reduction or withdrawal of Temomide preparation with adjuvant therapy (see the file)

Progressive or recurrent malignant glioma in the form of multiform glioblastoma or anaplastic astrocytoma (treatment of adults and children over 3 years old). Common metastatic malignant melanoma (treatment of adults)

Patients who have not previously undergone chemotherapy, Temomide is prescribed at a dose of 200 mg / m²1 time per 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 1 once a day; in the second cycle, the dose may be increased to 200 mg / m per day for 5 days, provided that on the first day of the next cycle the absolute number of neutrophils is not lower than 1500 / μl, and the platelet count is not lower than 100,000 / μl.

Recommendations for modifying the dose of Temomide in the treatment of progressive or recurrent malignant glioma or malignant melanoma Start treatment with Temomide is possible only with an absolute number of neutrophils> 1500 / μL and platelets> 100,000 / μL. A complete clinical blood test should be performed on the 22nd day (the 21st day after taking the first dose), but no later than 48 hours after that day; further - weekly, until the absolute number of neutrophils is higher than 1500 / 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, drug treatment should be discontinued.

Side effects:

The following undesirable phenomena described in the literature and marked with the administration of Temomide are distributed according to the frequency of occurrence according to the following gradation: very often (> 10%), often (> 1%, <10%), infrequently (> 0.1% , <1%), rarely (> 0.01%, <0.1%) and very rarely (<0.01%).

The first identified multiform glioblastoma (adults).

Combined phase of treatment (with radiotherapy)

From the side of the blood and lymphatic system:

often - neutropenia, leukopenia, lymphopenia, thrombocytopenia;

infrequently - anemia, febrile neutropenia.

From the heart:

often - swelling, incl. swelling of the legs;

infrequently - palpitations.

From the side of the vessels: often - hemorrhage;

infrequently - increased blood pressure, cerebral hemorrhage.

From the gastrointestinal tract: very often - anorexia, constipation, nausea, vomiting;

often - hyperglycemia, weight loss, abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis, a taste disorder;

infrequently hyperglycemia, weight gain, color change of the tongue.

From the liver and gallbladder: often - increased activity of alanine aminotransferase (ALT);

infrequently - increased activity of alkaline phosphatase, increased activity of gamma-glutamyltransferase, aspartate aminotransferase (ACT), liver enzymes.

From the respiratory system and chest organs: often - cough, shortness of breath;

infrequently - pneumonia, infection of the upper respiratory tract, nasal congestion; rarely - pneumonitis, interstitial pneumonitis, pulmonary fibrosis.

From the immune system (including hypersensitivity reactions): often - hypersensitivity reactions (skin rash, itching);

very rarely - urticaria, exanthema, erythroderma, anaphylaxis, angioedema, toxic epidermal necrolysis (Lyell syndrome), malignant exudative erythema (Stevens-Johnson syndrome).

Infectious diseases:

often - candidiasis of the oral cavity, herpes simplex, pharyngitis, wound infection, other infection. From the osteomuscular system and connective tissue: often - arthralgia, muscle weakness;

infrequently - back pain, musculoskeletal pain, myalgia, myopathy.

From the nervous system (including mental disorders): very often - headache;

often - anxiety, emotional lability, insomnia, dizziness, impaired concentration, confusion, convulsions, memory impairment, peripheral neuropathy, paresthesia, aphasia, agitation, drowsiness, speech disorder, tremor;

infarction, apathy, behavioral disorders, depression, hallucinations, impaired perception, extrapyramidal disorders, dysphasia, amnesia, ataxia, gait disturbance, coordination disruption hemiparesis, hemipeliasis, hyperesthesia, hyposthenia, neurological disorders (unspecified), epileptic status, paresthesia, parosmia, thirst .

From the organ of hearing and the vestibular system: often - hearing impairment;

infrequently - pain in the ear, hyperacusis, ringing in the ears, otitis media.

From the side of the organ of vision:

infrequent - blurred vision, pain in the eyes, hemianopsia, impaired vision, reduced visual acuity.

From the endocrine system: infrequently - Itenko-Cushing syndrome.

From the side of the kidneys and urinary tract: frequent urination, incontinence.

From the side of the reproductive system (including diseases of the mammary glands): infrequently - impotence.

From the skin and subcutaneous tissues:

very often - alopecia, rash;

often - dermatitis, dry skin, swelling of the face;

infrequently, reactions of photosensitization, pigmentation disorders, exfoliation.

General disorders and disorders at the site of administration: very often fatigue;

often - fever, pain syndrome, radiation damage;

infrequent - hot flushes to the body, asthenia, worsening of the condition, chills.

Adjuvant phase of treatment

From the side of the blood and lymphatic system:

often - anemia, febrile neutropenia, leukopenia, thrombocytopenia; infrequently - lymphopenia, petechiae.

From the heart: often swelling of the feet; infrequently - palpitations.

From the side of the vessels:

often - hemorrhage, deep vein thrombosis;

infrequently - swelling, incl. peripheral edema, pulmonary embolism.

From the gastrointestinal tract: very often - anorexia, constipation, nausea, vomiting;

often - increased ALT activity, weight loss, diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, taste disorder, hyperkalemia;

infrequently hyperglycemia, hypokalemia, weight gain, bloating, fecal incontinence, hemorrhoids, gastroenteritis, dental diseases.

From the liver and gallbladder: often - increased ALT activity.

From the respiratory system and chest organs: often - cough, shortness of breath;

infrequently - pneumonia, upper respiratory tract infection, sinusitis, bronchitis; rarely - pneumonitis, interstitial pneumonitis, pulmonary fibrosis.

From the immune system (including hypersensitivity reactions): often - hypersensitivity reactions (skin rash, itching);

very rarely - urticaria, exanthema, erythroderma, anaphylaxis, angioedema, toxic epidermal necrolysis (Lyell syndrome), malignant exudative erythema (Stevens-Johnson syndrome).

Infectious diseases:

often - candidiasis of the oral mucosa;

infrequently - herpes simplex, herpes zoster, flu-like syndrome, another infection.

From the osteomuscular system and connective tissue:

infrequently - arthralgia, musculoskeletal pain, myalgia, muscle weakness, back pain, myopathy.

From the nervous system (including mental disorders): very often - headache, convulsions;

often - anxiety, emotional lability, insomnia, depression, dizziness, imbalance, coordination disorder, ataxia, impaired concentration, confusion,aphasia, dysphasia, hemiparesis, memory impairment, neurological disorders (unspecified), peripheral neuropathy, paresthesia, agitation, drowsiness, tremor, hallucinations, amnesia, hemiplegia, hyperesthesia.

From the organ of hearing and the vestibular system: often - hearing impairment, ringing in the ears; infrequently - deafness, pain in the ear, dizziness.

From the side of the organ of vision: infrequent - blurred vision, diplopia, limited field of vision, pain in the eyes, dry eyes, reduced visual acuity.

From the endocrine system: infrequently - Itenko-Cushing syndrome.

From the side of the kidneys and urinary tract: often - urinary incontinence; infrequently - dysuria.

From the side of the reproductive system (including diseases of the mammary glands): infrequently - impotence, amenorrhea, menorrhagia, vaginal bleeding, vaginitis, pain in the mammary gland.

From the skin and subcutaneous tissues: very often - alopecia, rash; often - dry skin, itching of the skin;

infrequently - erythema, a violation of pigmentation, excessive sweating, swelling of the face.

General disorders and disorders at the site of administration: very often fatigue;

often - fever, chills, pain syndrome, radiation damage, asthenia, worsening of the condition.

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

From the side of the blood and lymphatic system: very often - thrombocytopenia, neutropenia, lymphopenia; infrequently - pancytopenia, leukopenia, anemia; rarely - myelodysplastic syndrome;

very rarely - prolonged pancytopenia with a risk of developing aplastic anemia.

In patients with glioma and metastatic melanoma, thrombocytopenia and grade 3 or 4 neutropenia were noted in 19% and 17%, respectively, in glioma and 20% and 22%, respectively, in melanoma. Hospitalization of the patient and / or removal of temozolomide was required in 8% and 4% of cases, respectively, with glioma and 3 % and 1.3 % - with melanoma. Oppression of the bone marrow developed usually during the first few cycles of treatment, with a maximum between 21 and 28 days; the recovery occurred, as a rule, within 1 -2 weeks. No evidence of cumulative myelosuppression was noted.

From the heart: often swelling of the feet; infrequently - palpitations.

From the side of the vessels:

often - hemorrhage, deep vein thrombosis;

infrequently - swelling, incl.peripheral edema, pulmonary embolism.

From the gastrointestinal tract:

very often - nausea, vomiting, anorexia, constipation;

often - diarrhea, abdominal pain, indigestion, taste perversion.

From the liver and gallbladder:

often - to raisewthe activity of ALT, alkaline phosphatase;

infrequently - hypokalemia.

From the immune system (including hypersensitivity reactions):

very rarely, hypersensitivity reactions, including anaphylaxis, angioedema, exanthema, erythroderma, toxic epidermal necrolysis (Lyell syndrome), malignant exudative erythema (Stevens-Johnson syndrome).

Infectious diseases:

rarely opportunistic infections, including pneumonia caused by Pneumocystis carinii.

From the nervous system (including mental disorders): very often - headache;

often - drowsiness, dizziness, paresthesia, asthenia.

From the side of the reproductive system (including diseases of the mammary glands): very rarely - irreversible infertility.

From the skin and subcutaneous tissues: often - a rash, itchy skin, alopecia, petechiae.

Malignant neoplasms:

very rarely - secondary malignant processes, including leukemia.

General disorders and disorders at the site of administration: very often - increased fatigue;

often - weight loss, shortness of breath, fever, chills, general malaise;

infrequently - an increase in body weight.

Overdose:

When using the drug at doses of 500 mg / m, 750 mg / m, 1000 mg / m and 1250 mg / m (total dose obtained for a 5-day treatment cycle), the hematologic toxicity was observed with dose-limiting toxicity, which was noted for any dose but more pronounced - at higher doses. The case of overdose (taking a dose of 2 g / 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 side effects, hematopoietic suppression was complicated, complicated or uncomplicated by the infection, in some cases prolonged and severe, with a fatal outcome.

Treatment: antidote is unknown. Hematologic control is also recommended. necessary - symptomatic therapy.

Interaction:

The administration of Temomide 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, histamine H2 receptor blockers or phenobarbital does not change the clearance of temozolomide.

Joint administration with valproic acid causes a mild 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 proteins, its effect on the pharmacokinetics of other drugs is unlikely.

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

Special instructions:

Prophylactic antiemetic therapy is recommended before the beginning of combined treatment (with radiotherapy) and is strongly recommended during adjuvant therapy for newly diagnosed multiform glioblastoma. If against the background of treatment with Temomide, nausea or vomiting occurs, it is recommended to perform antiemetic therapy in subsequent doses.Antiemetic drugs can be taken both before and after taking Temomide. Even if vomiting has developed in the first 2 hours after taking Temomide, the same day should not be repeated.

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 periods of treatment with Temomide, increased alertness to the possible development of PCP should be shown for all patients receiving Temomide, especially in combination with glucocorticosteroids. Pharmacokinetic indices of Temomide in persons with normal liver function and in patients with impaired liver function of mild or moderate severity are comparable. Data on the use of Temomide in patients with severe liver function disorder (class C on the Child-Pugh scale) or renal dysfunction are not available.Based on the data on the pharmacokinetic properties of temozolomide, it seems unlikely that patients with even a severe degree of impaired liver or kidney function may need to reduce the dose of the drug. However, when prescribing Temomide, such patients should be cautious.

In elderly patients (over 70 years), the risk of developing neutropenia and thrombocytopenia is higher than in younger patients. Therefore, patients of advanced age Temomide should be administered with caution.

Men and women of childbearing age during treatment with Temomide, and at least 6 months after graduation should use reliable methods of contraception. Because of the risk of irreversible infertility during treatment Temomidom, male patients before treatment, if necessary, it is recommended to discuss the possibility of sperm cryopreservation.

If the contents of the capsule (powder) get on the skin or mucous membranes, rinse them with plenty of water.

Effect on the ability to drive transp. cf. and fur:Some side effects of the drug, such as drowsiness and fatigue,can adversely affect the ability to drive vehicles or perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

Form release / dosage:

Capsules 140 mg, 180 mg

For 5 or 20 capsules in a plastic bottle with a screwed plastic lid. 1 bottle with instructions for use in a cardboard box.

Packaging:(20) - plastic bottles (1) - packs cardboard
(5) - plastic bottles (1) - packs cardboard

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration of the yearindicated on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-002108

Date of registration:18.06.2013

The owner of the registration certificate:Sunrise, LLCSunrise, LLC

Manufacturer: & nbsp

NOVALEK PHARMACEITICAL, Pvt. Ltd. India

Representation: & nbspSunrise, LLCSunrise, LLC

Information update date: & nbsp14.09.2015

Illustrated instructions

Instructions

Temomide (Temomid)