Temodal - instructions for use, doses, side effects, contraindications

Capsule shell composition: titanium dioxide 1,921 mg, iron oxide dye yellow 0.115 mg, iron oxide red oxide 0.402 mg, sodium lauryl sulfate 0.137 mg, gelatin q.s. The composition of the ink for inscribing the capsule shell: black dye contains shellac, ethanol *, isopropanol *, butanol *, propylene glycol, purified water *, ammonia water *, potassium hydroxide and iron dye oxide black.

* Removed during production.

Description:

Capsules 140 mg

Capsules of size No. 0, with a transparent lid of blue color and an opaque white body.

On the capsules black ink is inscribed: on the lid- "TEMODAL", on the case - "140 mg & quot ;, trademark in the form of stylized letters "SP" and two strips. Capsules contain powder from white to light pink or light yellow-brown color. Capsules 180 mg

Capsules of size No. 0, with an opaque lid of red-brown color and a white body.On the capsules black ink is inscribed: on the lid - "TEMODAL", on the body - "180 mg & quot ;, trademark in the form of stylized letters "SP" and two strips. Capsules contain powder from white to light pink or light yellow-brown in color.

Pharmacotherapeutic group:antitumor agent, alkylating compound.

ATX: & nbsp

L.01.A.X.03 Temozolomide

Pharmacodynamics:

A drug temozolomide is an imidazotetrazine alkylating drug with antitumor activity. When it enters the systemic circulation at physiological pH values, it 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 O⁶ and additional alkylation in the N⁷. Apparently, the resulting cytotoxic lesions include (trigger) the mechanism of aberrant reduction of the methyl residue.

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 (C_max) 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 (12-16%). 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 of the drug temozolomide is through the kidneys.

At 24 hours after oral administration, approximately 5-10% of the dose is determined unchanged in the urine; the remainder is derived as 4-amino-5-imidazolecarboxamide hydrochloride (AIC), temozolomidic acid or unidentified polar metabolites.

Taking temozolomide together with food causes a decrease FROM_max 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.The pharmacokinetic profile of the drug in patients with impaired liver function of a mild to moderate degree is the same as in patients 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 myoherapy.

- Malignant glioma (glioblastoma multiforme or anaplastic astrocytoma), if there is a relapse or progression of the disease after standard therapy. -Distributed metastasis and malignant melanoma-as a first-line therapeutic.

Contraindications:

- Hypersensitivity to temozolomide or other components of the drug, as well as to dacarbazip (DTIK).

- Expressive mission.

- Pregnancy.

- Breastfeeding period.

- Child age - up to 3 years (recurrent or progressing malignant glioma) or up to 18 years (newly diagnosed glioblastoma multiforme or malignant melanoma).

Carefully:

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

- Elderly age (over 70 years).

- Violation of the function of the kidney or liver of severe severity.

Pregnancy and lactation:

The drug Temodal® is contraindicated in pregnant women. Patients using the drug should be aware of the potential hazard to the fetus if the pregnancy occurs during treatment with Temodal®.

It is not known whether Temodal® penetrates into breast milk, therefore it is necessary to stop either feeding the pile or therapy with Temodal®.

Dosing and Administration:

The drug Temodal ® 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. The drug Temodal ® applied at 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) followed by 6 cycles of adjuvant therapy.

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 (1.5 * 10⁹/ l), the number of platelets is below 100,000 / μl (100 * 10⁹/ l), the 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 the drug Temodal during the combined phase of treatment are given in Table 1.

Table 1. Recommendations for dose reduction or withdrawal of the drug Temodal in combination treatment with radiation therapy

Criterion is toxicthe	A break in taking the drug Temodal ® *	Termination of the reception of Tematal ®
Absolute number of neutrophils	> 500 / μL (> 0.5 * 10⁹/ l), but <1500 / μL (<1.5 * 10⁹/ l)	<500 / μL (<0.5 * 10⁹/ l )

* The resumption of Temodal® is possible if all of the following conditions are met: absolute neutrophil count, not lower than 1500 / μL (1.5x 10⁹/ l ), the number of platelets is not lower than 100,000 / μL (100x 10⁹/ l ), the toxicity criterion (CTC) is not higher than degree 1 (except for alopecia, nausea and vomiting).

Number of platelets	> 10000 / μL (> 10x 10⁹/ l ), but <100,000 / μL (<100 × 10⁹/ l )	<10000 / μL (<10 × 10⁹/ l )
CTC (non-hematologic toxicity, except for alopecia, nausea and vomiting)	Degree 2	Degree 3 or 4

Adjuvant therapy It is prescribed after 4 pedules after the completion of the combination therapy and is performed in the form of 6 additional cycles. Cycle 1: Temodal® is given at a dose of 150 mg / m for 5 days followed by a 23-day interruption in treatment. Cycle 2: the dose of Temodal® can be increased to 200 mg / m² per day, provided that during the first treatment cycle, the severity of nonhematological toxicity (in accordance with the STS toxicity scale) was higher than grade 2 (except for alopecia, nausea and vomiting), with an absolute neutrophil count of at least 1500 / μL (1.5x 10⁹/ l ), and the number of platelets is not lower than 100,000 / μL (100x 10⁹/ l ). If the dose of Temodal® 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, in the same daily dose the drug is administered in the following cycles (in the absence of toxicity). In each cycle, Temodal® 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 (21 days after taking the first dose of Temodal®), a blood test should be performed to count the number of cells. Cancellation or reduction of the dose of Temodal® should be carried out according to Table 3.

Table 2. Dosage levels of Temodal® 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 reducing the dose or canceling the drug Temodal '¹ with adjuvant therapy

Criterion of toxicity	Reduction of the dose of the drug Temodal ® by 1 step (see Table 2)	Termination Temodal ®
Absolute number of neutrophils	<1000 / μL (< 1.0x 10⁹/ l )	*
Number of platelets	<50000 / μL (<50 х 10⁹/ l )	*
S'GS (non-hematologic toxicity, except for alopecia, nausea and vomiting)	Degree 3	Degree 4 *

* The drug Temodal ® should be abolished if a dose reduction of <100 mg / m 2 is required, and also 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 previously treated with chemotherapy, Temodal ® is prescribed in 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 for 5 days, provided that on the first day of the next cycle the absolute amount of neutrophils is not lower than 1500 / μL (1.5x 10⁹/ l ), and the number of platelets is not lower than 100,000 / μl (<100 × 10⁹/ l ).

Special patient groups

Children

The drug Temodal ® in children 3 years and older should be used only with recurrent or progressive malignant glioma. The experience of using the drug in children of this age group is very limited. Data on the use of the drug in children younger than 3 years are absent.

Patients with hepatic or renal insufficiency

The pharmacokinetic data of temozolomide in patients with normal liver function were comparable to those in patients with mild to moderate hepatic impairment. Data on the dosage regimen of the preparation Temodal ® in patients with severe hepatic insufficiency (class C) and renal insufficiency are absent. Based on pharmacokinetics data, it is unlikely that a dose reduction in patients with severe hepatic insufficiency and any degree of renal failure is required. However, care should be taken when using the drug in these patient groups.

Elderly patients

Based on the data obtained by pharmacokinetic analysis in patients aged 19-78 years, the clearance of temozolomide does not depend on age.However, in elderly patients (from 70 years old), the risk of neutropenia and thrombocytopenia increases. Recommendations for modifying the dose of Tsmodal in the treatment of progressive or recurrent malignant glioma or malignant melanoma

In patients taking Temodal ® may develop myelosunpression, including prolonged pancytopenia. Perhaps the development of aplastic anemia, which in a few 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, therefore, with the simultaneous use of the preparation of 1 modal and these drugs, it is difficult to establish the cause of the development of aplastic anemia. Initiate treatment with Temodal ® it is possible only with an absolute number of neutrophils> = 1500 / μL (> = 1.5 × 10⁹/ l) and platelets> = 100000 / μL (> = 100х10⁹/ l). 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 and then on until the absolute number of neutrophils is above 1500 / μl (1.5x 10⁹/ l ), and the number of platelets does not exceed 100,000 / μL (100 × 10⁹/ l ). With an absolute neutrophil count below 1000 / μL (1.0x 10⁹/ l ) or platelets below 50,000 / μL (50x 10⁹/ l ) during any cycle of treatment, the dose in the next cycle should be reduced by one step. Possible doses: 100 mg / m², 150 mg / m and 200 mg / m. The minimum recommended dose is 100 mg / m. Duration of treatment is maximum 2 years. If signs of disease progression appear, treatment with Temodal ® should be discontinued.

Side effects:

The following undesirable phenomena noted with the use of the drug Temodal ®, are distributed according to the frequency of occurrence according to the following classification: very often (> 10% of cases), often (> 1% to <10%), infrequently (>> 0.1% to <1%), rarely (> 0.01% to <0.1%) and very rarely (<0.01%).

The newly discovered multiform glioblastoma (adult patients) Combined phase of treatment (with radiotherapy)

On the part of mechanisms of resistance to infections

Often: candidiasis of the oral cavity, herpes simplex, pharyngitis, wound infection, other infection.

On the part of the blood and lymphatic system

Often: leukopenia, lymphopenia, no ripsniya, thrombocytopaedic.

Infrequently: anemia, febrile neutropenia.

From the side of the cardiovascular system Often: edema, including legs, hemorrhage.

Infrequently: a feeling of heartbeat, an increase in blood pressure, a hemorrhage into the brain.

On the part of the respiratory system Often: cough, shortness of breath.

Infrequently: pneumonia, upper respiratory tract infection, nasal congestion.

From the side endocrine systems Infrequently: syndrome Itenko-Kushipga.

From the skin side and subcutaneous fat cellulose, nursing glands Often: alopecia, rash.

Often: dermatitis, dry skin, erythema, skin itching, face swelling.

Infrequently: photosensitivity reaction, pigmentation disorder, exfoliation.

From the nervous system Often: headache.

Often: anxiety, emotional lability, insomnia, dizziness, aphasia, balance disorder, impaired concentration, confusion and decreased consciousness, convulsions, memory impairment, neuropathy, paresthesia, drowsiness, speech disorder, tremor.

Infrequently: agitation, apathy, behavioral disorders, depression, hallucinations, impaired perception, extrapyramidal disorders, dysphasia, ataxia, gait disorders, hemiparesis, hyperesthesia, hypoesthesia, neurological disorders (unspecified),epileptic status, peripheral neuropathies, a paromyemia, thirst.

From the side of the musculoskeletal system Often: arthralgia, muscle weakness.

Infrequently: pain in the back, musculoskeletal pain, myalgia, myopathy.

From the side of the organ of vision Often: blurred vision.

Infrequently: pain in the eyes, hemianopsia, visual impairment, decreased visual acuity, and limited vision.

From the genitourinary system

Often: frequent urination, urinary incontinence.

Infrequently: impotence.

From the organs of hearing and vestibular system Often: worsening of hearing.

Infrequently: pain in the ears, hyperacia, ringing in the ears, otitis media.

From the digestive system Often: anorexia, constipation, nausea, vomiting.

Often: increased activity of alanine aminotransferase, hyperglycemia, weight loss, abdominal pain, diarrhea, dyspepsia, dysphagia, stomatitis, impaired taste.

Infrequently: hypokalemia, increased activity of alkaline phosphatase, weight gain, discoloration of the tongue, increased activity of gamma-glutamyltransfsrase, aspartate aminotransferase, liver enzymes.

From the body as a whole

Often: increased fatigue.

Often: fever, pain syndrome, radiation damage, allergic reaction.

Infrequently: "hot flushes" to the body, asthenia, worsening of the condition, chills.

Adjuvant phase of treatment

On the part of mechanisms of resistance to infections

Often: Candidiasis of the oral mucosa, another infection.

Infrequently: herpes simplex, herpes zoster, influenza-like syndrome.

On the part of the blood and lymphatic system

Often: anemia, febrile neutropsy, leukopenia, thrombocytopenia.

Infrequently: lymphopenia, petechin.

From the side of the cardiovascular system

Often: edema of the legs, hemorrhage, deep vein thrombosis.

Infrequently: edema, including peripheral, pulmonary embolism.

On the part of the respiratory system Often: cough, shortness of breath.

Infrequently: pneumonia, upper respiratory tract infection, sinusitis, bronchitis.

From the endocrine system Infrequently: Istsnko-Cushing syndrome.

From the skin and subcutaneous fat, nursing glands Often: alopecia, rash.

Often: dryness, itching of the skin.

Infrequently: erythema, impaired pigmentation, excessive sweating, pain in the breast, swelling of the face.

From the nervous system Often: headache, convulsions.

Often: anxiety, depression, emotional lability, insomnia, dizziness, aphasia, imbalance, impaired concentration, confusion, dysphasia, speech disorder, hemiparesis, memory impairment, neurological disorders (unspecified), neuropathy, peripheral neuropathy, paresthesia, drowsiness, tremor. Infrequently: hallucinations, ataxia, impaired coordination, amnesia, gait disorders, hemiplegia, hyperesthesia, impaired sensory organs.

From the side of the musculoskeletal system

Often: arthralgia, musculoskeletal pain, myalgia, muscle weakness.

Infrequently: back pain, myopathy.

From the side of the organ of vision

Often: blurred vision, diplopia, limitation of visual fields.

Infrequently: pain in the eyes, dry eyes, decreased visual acuity.

From the genitourinary system Often: urinary incontinence.

Infrequently: dysuria, amenorrhea, msnorrhagia, vaginal bleeding, vaginitis.

From the organ of hearing and vestibular system Often: hearing impairment, ringing in the ears.

Infrequently: deafness, pain in the ears, vertigo.

From the digestive system Often: anorexia, constipation, nausea, vomiting.

Often: increased activity of alapipaminotransferase, weight loss, diarrhea, dyspepsia, dysphagia, stomatitis, dry mouth, perversion of taste.

Infrequently: hyperglycemia, weight gain, bloating, fecal incontinence, hemorrhoids, gastroenteritis, dental diseases, gastrointestinal disturbances.

From the body as a whole

Often: increased fatigue.

Often: fever, pain syndrome, radiation damage, allergic reaction.

Infrequently: asthenia, worsening of the condition, chills.

Laboratory indicators

Myelosuppression (peitropenia and thrombocytopaia) 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)

On the part of the hematopoiesis system

Often: thrombocytopaia, peitropenia, lymphopenia.

Often: 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. Patient hospitalization and / or removal of Temodal® was required in 8% and 4% of cases, respectively, for glioma and 3% and 1.3% for melanoma. Bone marrow depression developed usually during the first few cycles of treatment, with a maximum between 21 and 28 days, the recovery occurred, usually within 1-2 weeks. No evidence of cumulative myelosuppression was noted.

From the side of the digestive system

Often: nausea, vomiting, constipation, anorexia.

Often: diarrhea, abdominal pain, dyspepsia, 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 Often: headache.

Often: drowsiness, dizziness, paresthesia, asthenia, pain syndrome.

From the skin and subcutaneous fat Often: rash, itching, alopecia, pegechia.

Rarely: urticaria, exanthema, erythroderma.

Other

Often: increased fatigue.

Often: weight loss, shortness of breath, fever, chills, general malaise.

Rarely: Opportunistic infections, including pancytopenia.

Rarely: angioedema.

Data from post-research studies

In the course of post-marketing studies, erythema multiforme, toxic epidermal pecrolisis, Stevens-Johnson syndrome, and allergic reactions, including anaphylaxis, were very rare.

There have been reports of hepatotoxicity, including increased activity of liver enzymes, hyperbilirubinemia, cholestasis and hepatitis. Very rarely there were violations of the liver, including cases with a fatal outcome.

Opportunistic infections were rare, including pneumonia caused by Pneumocystis carinii, and cases of reactivation of cntomegalovirus and hepatitis B. Very rarely reported cases of interstitial pneumonitis and pneumonitis, as well as pulmonary fibrosis. Also very rarely was the development of myelodysplastic syndrome (MDS) and secondarymalignant processes, including leukemia; very rarely met the development of prolonged pancytopenia. Perhaps the development of aplastic anemia, which in a few cases led to a fatal outcome. There have also been cases of diabetes insipidus.

Overdose:

Use of the drug in doses of 500, 750, 1000 and 1250 mg / m² (total dose per cycle) was evaluated clinically in patients. Dose-limiting toxicity was hematologic toxicity, which was noted when taking any dose, but more expression, 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, nirexia, multiple organ failure and death. When taking the drug for more than 5 days (up to 64 days), among other side effects, hemopoiesis was complicated, complicated or complicated by the infection, in some cases prolonged and severe, with a fatal outcome.

Treatment. Antidote to the preparation of Temodal ® not known. Recommended hematological control and, if necessary, symptomatic therapy.

Interaction:Taking temozolomide together with raiitidine does not lead to a clinically significant change in the degree of absorption of temozolomide. Joint reception with dexamstasoid, prochlorperazion, phenytoiom, carbamazepine, ondansstron, H2-histamine receptor antagonists or phenobarbital does not change the clearance of temozolomide. Joint administration with valeric 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 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.

Special instructions:

Due to the increased risk of developing pneumonia caused by Pneumocystis carinii, in patients receiving combined treatment with radiotherapy for 42 days (up to 49 days), it is 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 the drug Temodal ® , caution should be exercised with regard to the possible development of PMSV pneumonia in all patients receiving Temodal ®, especially in combination with glucocorticosteroids.

Antiemetic therapy

Nausea and vomiting are often associated with the administration of the drug Tsmodal ® , in connection with which it is recommended to conduct preventive antiemetic therapy before the beginning of combined treatment (with radiation therapy) and is strongly recommended during adjuvant therapy of the newly diagnosed multiform glioblastoma.

Patients with recurrent or progressive glioma who have experienced severe (grade 3 or 4) vomiting in previous cycles of treatment may require antiemetic therapy.

Effect on kidney function

The kidney function, determined by the magnitude of creatinine clearance, did not affect the clearance of the drug Tsmodal.

Effects on liver function

There are no data on the effect of the preparation Temodal ® on parameters of liver function, such as serum albumin, total protein, as well as liver function indicators such as alkaline phosphatase, alanine aminotransferase (ALT), aspartame aminotransferase (ACT) and bilirubin.

Pharmacokinetic parameters in persons with severe impairment of liver function have not been adequately studied. These pharmacokinetics of tsmozolomide showed that a reduction in the dose of the drug in patients with mild and moderate hepatic insufficiency is not required.

Pharmacokinetic parameters of the preparation Temodal ® in individuals with normal liver function and in patients with impaired liver function of mild or moderate severity (class I-II Child-Pugh), are comparable.

Very rarely in the treatment with the drug Tsmodal ® hepatic insufficiency, including fatal cases, was noted. In connection with this, it is necessary to monitor liver function before starting treatment with Temodal ®. If the indicators exceed the norm, the physician should assess the benefit / risk before the start of therapy, including the risk of developing a fatal liver failure. On the 42nd day of treatment (in the middle of the treatment cycle), it is necessary to repeatedly check the liver function. All patients need to monitor liver function after each treatment cycle. In patients with significant liver function abnormalities, the benefit / risk of continuing therapy should be evaluated.Toxic liver damage can occur after several weeks or more after the end of the use of the drug Temodal ®.

Children

There are no clinical data on the use of the drug Temodal ® in children under 3 years. Elderly patients

In clinical studies, elderly patients (over 70 years of age) experienced an increased risk of developing neutropenia and thrombocytopenia compared to younger patients.

Men and women of childbearing age during the treatment with the drug 1modal and for at least 6 months after the termination should use reliable methods of contraception.

Because of the risk of developing irreversible infertility during the treatment with Temodal, male patients are advised to discuss the possibility of cryopreservation of semen before the treatment if necessary.

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:Some side effects of the drug, such as drowsiness and fatigue, can adversely affect the ability to drive vehicles or perform potentially hazardous activities,requiring increased concentration of attention and speed of psychomotor reactions. In this regard, care should be taken when driving vehicles and working with machinery.

Form release / dosage:

Capsules of 140 mg and 180 mg.

Packaging:

For 5 or 20 capsules in dark glass bottles screwed with a plastic cap that has a waxed soft polyethylene liner and seal and is equipped with a device that prevents the opening of the bottle by children. A wad of cotton wool is put into the bottle.

1 bottle is placed in a pack of cardboard along with instructions for use.

1 capsule in a white sachet made of aluminum foil, covered from the inside with a layer of low-density polyethylene and externally with a layer of no-ethylene terephthalate (PET).

For 1.5 or 20 sachets are placed in a pack of cardboard along with instructions for use.

Storage conditions:

At a temperature of 2 to 30 ° C. Keep out of the reach of children.

Shelf life:

3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-005805/09

Date of registration:17.07.2009

The owner of the registration certificate:Schering-Plau N. Labo.Schering-Plau N. Labo. USA

Manufacturer: & nbsp

ORION CORPORATION ORION PHARMA Finland

Representation: & nbspORTAT, CJSCORTAT, CJSC

Information update date: & nbsp16.09.2015

Illustrated instructions

Instructions

Temodal® (Temodal®)