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

Active substanceTemsirolimusTemsirolimus

Similar drugsTo uncover

Torizel®

concentrate d / infusion

Pfizer Inc. USA

Dosage form: & nbspconcentrate for solution for infusion

Composition:

Concentrate

1 ml of concentrate contains:

Active substance: tamsirolimus - 25.00 mg.

Excipients: alpha-tocopherol - 0.75 mg, ethanol - 394.60 mg, citric acid - 0.025 mg, propylene glycol - 503.325 mg.

Solvent: polysorbate-80 - 400.00 mg, macrogol-400 - 427.73 mg, ethanol - 199.09 mg.

Description:

Concentrate: a clear, colorless or light yellow solution.

Solvent: transparent or almost transparent solution from light yellow to yellow.

Pharmacotherapeutic group:antitumor agent - protein tyrosine kinase inhibitor

ATX: & nbsp

L.01.X.E.09 Temsirolimus

Pharmacodynamics:

Temsirolimus is a selective inhibitor of the enzyme mTOR(targets of mammalian rapamycin). Temsirolimus binds to intracellular protein FKBP-12, forming a complex protein-tessirolimus, which, in turn, is associated with mTOR-kinase inhibits the activity of this enzyme and indirectly controls cell division.

Inhibition of activity mTOR-Kinase leads to the termination of growth of tumor cells in G1 phase, resulting in a selective disruption of translation of the cell-cycle-regulating proteins, such as cyclins D-type, c-mic and ornithine decarboxylase. When tying mTOR-Kinase inhibits its ability to phosphorylation and, as a consequence, the ability to control the activity of protein translation factors, in particular, 4E-BP1 and S6K (both "obey" mTOR in the P13-kinase / ACT pathway), which, in turn, controls the cell division.

In addition to proteins that regulate the cell cycle, mTOR-Kinase can regulate the translation of factors induced by hypoxia (HIF): HIF-1 and HIF-2 alpha. These transcription factors determine the ability of tumors to adapt to the hypoxic microenvironment and produce the angiogenic factor of vascular endothelial growth factor (VEGF). Thus, the antitumor effect of tessirolimus can also be explained by its ability to reduce levels HIF and VEGF in a tumor or tumor microenvironment, which leads to inhibition of the development of blood vessels.

Data on the efficacy and safety of the Toryzel® preparation were obtained during randomized trials in patients with advanced renal cell carcinoma and in patients with lymphoma from the cells of the mantle zone.

Pharmacokinetics:

Absorption

After a single administration of tamsirolimus intravenously at a dose of 25 mg in patients with renal cell carcinoma, the mean maximum concentration of temsirolimus (C_max) in whole blood was about 585 ng / ml, and the average area under the concentration-time curve (AUC) was 1627 ng-hour / ml. When tamsirolimus was administered at a dose of 175 mg per week for 3 weeks, followed by 75 mg of temsirolimus weekly, the mean C_shah in whole blood at the end of the infusion was 2457 ng / ml during the first week and 2574 ng / ml during the third week.

Distribution

The observed polyexponential decrease in the concentration and distribution of temsirolimus in whole blood can be explained by its preferred binding to the protein FKBP-12 in the blood cells. The average value of the dissociation constant of binding (Kd) was 5.1 (3.0) ng / ml, which reflects the concentration at which 50% binding to ligands of blood cells occurs. The distribution of temsirolimus depends on the dose, with an average maximum specific binding in blood cells of about 1.4 mg (0.47 mg to 2.5 mg) of the drug. After a single intravenous administration of temsirolimus in a dose of 25 mg, the average value of the equilibrium volume of distribution in whole blood was 172 liters.

Metabolism

With intravenous administration, the main metabolite of temsirolimus is sirolimus, which has the same therapeutic efficacy.

Research in vitro have also shown the presence of other metabolites of tessirolimus: secomosyrolimus and seco-sirolimus; Additional ways of metabolism are the processes of hydroxylation, reduction and demethylation. After a single intravenous administration of temsirolimus in a dose of 25 mg AUC sirolimus was 2.7 times greater than AUC tamsirolimus, mainly due to a longer half-life of sirolimus.

Excretion

After a single intravenous administration of temsirolimus in a dose of 25 mg, the mean systemic clearance of tamsirolimus was 11.4 ± 2.4 l / hr. Mean values of the half-life (T1/₂) tamsirolimus and sirolimus were 17.7 hours and 73.3 hours, respectively. Excretion, mainly occurs through the intestine (78%). The excretion of the active substance and metabolites by the kidneys was 4.6% of the administered dose.

Temsirolimus and sirolimus are substrates of P-glycoprotein in vitro. Effect of inhibition of P-glycoprotein on the elimination of tamsirolimus and sirolimus in vivo not investigated.

The race, sex and body weight of the patient do not significantly affect the pharmacokinetics of tamsirolimus and sirolimus.

A study of the pharmacokinetics of tamsirolimus and sirolimus in patients under the age of 79 years has shown,that age does not significantly affect the pharmacokinetics of tamsirolimus and sirolimus.

The pharmacokinetics of temsirolimus and sirolimus in children have not been studied.

Indications:

Common renal cell carcinoma.

Recurrent and / or refractory lymphoma from cells of the mantle zone.

Contraindications:

- Hypersensitivity to tessirolimus, its metabolites (including sirolimus), polysorbate-80 or any other auxiliary substance that is part of the drug Torizel®.

- Violation of liver function of moderate and severe severity with a concentration of bilirubin in blood plasma is 1.5 times or more exceeding the upper limit of the norm.

- Age under 18 years (the safety and efficacy of the drug has not been adequately studied).

- Pregnancy and the period of breastfeeding.

Carefully:

Disorders of liver function of mild severity.

Severe kidney failure.

Hypersensitivity to antihistamines in the history or in patients to whom antihistamines are contraindicated for other reasons.

Alcoholism (the drug contains ethanol).

Craniocerebral injury or brain disease (epilepsy). The perioperative period.

Tumor damage to the brain (primary, secondary) and / or concomitant therapy with anticoagulants (increased risk of intracerebral bleeding).

Diabetes.

Pregnancy and lactation:

Adequate controlled studies of the use of tamsirolimus in women during pregnancy have not been carried out, therefore the drug Toryzel® is contraindicated in pregnant women. Women of childbearing age and their partners should use reliable methods of contraception during therapy with the drug Terezel and within three months after its termination.

It is not known whether tessirolimus in breast milk. In this regard, during therapy with the drug Toryzel®, it is recommended to stop breastfeeding.

Dosing and Administration:

Approximately 30 minutes before each dose of TORIZEL®, patients should be assigned diphenhydramine (intravenously in a dose of 25-50 mg) or another antihistamine.

Common renal cell carcinoma

Intravenously drip 25 mg for 30-60 minutes once a week.

Treatment of possible adverse reactions may require a temporary discontinuation therapy and / or reduce the dose of Thorizel® by 5 mg / week.To do this, use the following scheme: at a neutrophil level < 1,000/mm3, thrombocytes < 75,000/mm3, or with development of toxicity of 3-4 degrees by NCI OCEEA (general evaluation criteria toxicity of undesirable phenomena) treatment with Thorizel ® should be suspended.

If the toxicity is reduced to 2 degrees and lower, treatment with Toryzel® can be continued at a lower dose (the dose should not be less than 15 mg / week).

2. Recurrent and / or refractory lymphoma from cells of the mantle zone

Intravenous drip 175 mg for 30-60 minutes once a week for three weeks, then 75 mg intravenously drip for 30-60 minutes also once a week. The occurrence of possible side effects may require a temporary discontinuation of the drug and / or a reduction in the dose of tessirolimus. The dose should be reduced according to the following scheme: if the reaction develops against the background of taking the drug at a dose of 175 mg, the dose should be reduced to 75 mg per week. After that, the dose can be reduced by 25 mg per week to a minimum of 25 mg per week.

Dose reduction:

Level of dose reduction	The initial dose of 175 mg	Maintenance dose of 75 mg^a
-1	75 mg	50 mg
-2	50 mg	25 mg

In studies of patients with lymphoma from the cells of the mantle zone, a dose reduction to the second level was allowed.

Correction of the dose of tasyirolimus depending on the absolute number of neutrophils (AChN) and the number of platelets:

ASC

amount

platelets

The dose of Temsirolimus

> 1.0x10⁹/ l

> 50x 10⁹ / l

100% of the planned dose

<1.0х10⁹/ l

<50x 10⁹ / l

Pause^a

^a After the restoration of the ASC until >1,0x 10⁹ (1000 cells / mm3) and the number of platelets to >50x 10⁹ (50,000 cells / mm3, the dose should be reduced to the next one in turn in accordance with the recommendations above.If the ACN values and the platelet count can not be maintained at the level >=1,0x 10⁹ / l and >=50x 10⁹ / l, respectively, it should once again reduce the dose of the drug to the next recommended after the recovery of ACN and the number of platelets to the level >1,0x 10⁹ and >50x 10⁹ , respectively.

Treatment with Toryzel® should be continued until clinical efficacy is confirmed or an unacceptable toxicity is recorded.

Children

The experience of using the drug in children is limited. Safety and efficacy of the drug in children are not established.

Floor

Correction of the dose is not required.

Elderly patients Correction of the dose is not required.

Impaired renal function Correction of the dose is not required.

Impaired liver function

If it is necessary to use Toryzel® in patients with mild liver function disorder (bilirubin concentration exceeds the upper limit of the norm by no more than 1.5 times, or the activity of aspartate aminotransferase (ACT) above the upper limit of the norm, and the concentration of bilirubin does not exceed the upper limit of the norm), Torizel® should be used with caution.

The use of the drug Toryzel® is contraindicated in patients with a concentration of bilirubin in the blood plasma that exceeds the upper limit of the norm by 1.5 times or more.

Instructions for preparing a solution for intravenous administration

Preparation of all solutions of the Toryzel® preparation should be carried out in a room protected from direct sunlight.

a) Preparation of the stock solution

To prepare a solution for injection for patients with lymphoma from the cells of the mantle zone, several vials with a drug for each dose of more than 25 mg will be needed. In this case, the drug in each vial should be diluted, following the technique described below.

The contents of the solvent vial (1.8 ml) are added to a vial of concentrate (30 mg / 1.2 ml). The bottle is carefully turned (Do not shake!) Until a homogeneous solution is obtained without air bubbles. The solution should be clear or slightly unclear, colorless, light yellow or yellow, free from visible mechanical inclusions. The concentration of temsirolimus in the resulting solution is 10 mg / ml. The resulting stock solution should be used to prepare a solution for infusion.

The prepared stock solution remains stable for 24 hours if stored at a temperature of no higher than 25 ° C in a dark place.

b) Preparation of a solution for infusions

2.5 ml of the initial solution of the preparation Torizel® (contains 25 mg of temsirolimus) is added to 250 ml of 0.9% sodium chloride solution. For patients with lymphoma from the cells of the mantle zone, the required amount of the drug is taken from the vials into a single syringe and added to the infusion solution - 250 ml of 0.9% sodium chloride for injection. The resulting infusion solution should be mixed by turning the plastic container for infusion or vial, avoiding excessive shaking, as this can cause the formation of vesicles.The resulting solution should be used within 6 hours (including an infusion time of 30-60 minutes). For infusion, it is preferable to use an infusion pump to ensure the exact flow of the drug.

The solution for infusions before administration should be carefully examined: in the presence of foreign inclusions, the solution should be destroyed.

When preparing, storing and administering the Toryzel® preparation, you should use equipment that does not contain PVC parts: glass, polyolefin, polyethylene, since polysorbate-80 contained in the solution of the Toryzel® preparation can cause an increase in the extraction of diethylhexaphthalate from polyvinyl chloride.

The Toryzel® preparation is recommended to be introduced through a system with an integrated membrane filter made of polyethersulfone with a pore size of not more than 5 microns to prevent the entry of larger particles. In the absence of a built-in membrane filter, an additional filter should be used, which is connected to the end of the system tube, located upstream of the solution in the patient's vein. It is possible to use end filters with pores of different diameters (from 0.2 μm to 5 μm).It is not recommended to use the end filter and the filter installed inside the system at the same time.

Side effects:

In clinical trials, the following serious adverse events have been reported, the relationship of which with Toryzel therapy can not be ruled out: hypersensitivity reactions and / or infusion reactions (including undesirable events that are life threatening and, in rare cases, fatal), hyperglycemia and / or intolerance to glucose, infections, interstitial lung diseases, hyperlipidemia, intracranial hemorrhage, renal failure, intestinal perforation and complicated wound healing, thrombotic cytopenia, neutropenia (including febrile neutropenia), thromboembolism of the pulmonary artery.

The most frequent adverse events are at least 20% of cases: anemia, nausea, rash (including an itchy rash, patchy-papular rash, pustular rash), anorexia, edema (including facial edema, peripheral edema), asthenia , weakness, thrombocytopenia, diarrhea, fever, nasal bleeding, inflammation of the mucous membranes, stomatitis, vomiting, hyperglycemia, hypercholesterolemia, perversion of taste sensations, itchy skin, cough, infection, pneumonia, dyspnea.

The development of cataracts was noted in some patients who received a combination of the drug Toryzel® and interferon alfa.

The following adverse reactions were identified during studies with the use of Toryzel® in patients with renal cell carcinoma, but were not detected in patients with lymphoma from the cells of the mantle zone: anaphylaxis, wound healing failure, renal failure with lethal outcome, pericardial effusion (including cases, requiring interventions), convulsions and thromboembolism of the pulmonary artery. The following adverse reactions were identified in studies using the Toryzel® drug in patients with lymphoma from the cells of the mantle zone, but were not detected in patients with renal cell carcinoma: thrombocytopenia and neutropenia (including febrile neutropenia).

The development of adverse reactions after administration of temsyrolimus at a dose of 175 mg per week in patients with lymphoma from cells in the mantle zone (such as infections or thrombocytopenia of grade 3 or 4) is more common than in patients receiving tessirolimus in a dose of 75 mg per week under normal conditions.

Undesired reactions are distributed according to the frequency in accordance with the following gradation: very frequent - more than 1/10; frequent - more than 1/100, but less than 1/10; infrequent - more than 1/1000, but less than 1/100.

From the hemopoietic system and lymphatic system: very frequent - thrombocytopenia **, neutropenia, anemia; frequent - Lakopenia **, lymphopenia.

From the nervous system: very frequent - perversion of taste sensations, insomnia, headache; frequent - Lack of taste sensations, drowsiness, paresthesia, dizziness, depression, anxiety; infrequent - intracranial hemorrhage, convulsions.

From the side of the organ of vision: frequent - conjunctivitis, violation of lacrimation; infrequent - hemorrhage in the eyeball ***.

From the cardiovascular system: frequent - venous thromboembolic complications (including deep vein thrombosis, pulmonary embolism, in some cases with fatal outcome), increased blood pressure, thrombophlebitis; infrequent - pericardial effusion, including severe cases of hemodynamic disorders requiring intervention.

From the respiratory system, thorax and mediastinum: very frequent - shortness of breath, nosebleeds **, cough, bronchitis *, pharyngitis, rhinitis, sinusitis, folliculitis, pneumonia (including interstitial pneumonia); frequent - pneumonitis, pleural effusion (including fatal cases), upper respiratory tract infections, interstitial lung diseases; infrequent - laryngitis.

From the gastrointestinal tract: very frequent - abdominal pain, nausea, vomiting, stomatitis (including aphthous stomatitis, ulceration of the oral mucosa, glossitis, pain in the mouth), mucositis, diarrhea, anorexia, constipation; frequent - bloating, gingivitis, gastritis **, dysphagia, pain in the oral cavity, bleeding from the gastrointestinal tract (including anal, rectal, hemorrhoidal bleeding, bleeding from the lips, into the mouth, bleeding from the gums); infrequent

- intestinal perforation (there is a report of one fatal outcome).

From the genitourinary system: very frequent - urinary tract infections (including cystitis), dysuria, hematuria, increased frequency of urination; frequent - Renal insufficiency (including cases with fatal outcome).

From the skin and subcutaneous tissues: very frequent - rash (including pustistopapuleznaya, pustular rash, eczema, itching rash, generalized rash, macular rash, papular rash), urticaria (including generalized urticaria), skin itching, acne, a violation of the structure of the nail plate, dry skin; frequent - exfoliative dermatitis, ecchymosis ***, petechiae ***.

From the side of the musculoskeletal system and connective tissue: very frequent

- back pain, arthralgia; frequent - myalgia (including cramps of the muscles of the lower extremities).

From the immune system: frequent - allergic reactions, reactions hypersensitivity.

Metabolic and nutritional disorders: very frequent - hypokalemia, hyperglycemia, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, decreased appetite; frequent - hypophosphatemia, diabetes mellitus, dehydration, hypocalcemia. Laboratory indicators: very frequent - increase in the concentration of creatinine in the blood plasma; frequent - increased activity ACT and alanine aminotransferase (ALT). Other: very frequent - pain in the chest, swelling (including generalized edema, peripheral edema, face swelling, swelling of the scrotum, swelling of the genitals), fever,fatigue, asthenia (there is a report of one fatal outcome), the attachment of secondary bacterial or viral infections (including cellulitis, herpes zoster, herpes mucosa of the oral cavity, herpes of the eye, herpes simplex, abscess, influenza, wound infections (including postoperative wounds) ); frequent - delayed healing of wounds, chills, sepsis * (including septic shock), candidiasis of skin and mucous membranes, fungal infections / fungal dermatitis, pain of different localization.
* adverse reactions 3 or more in accordance with the criteria for assessing the severity of the most frequent adverse events of the National Cancer Institute of the United States (NCI Common Terminology Criteria for Adverse Events) In most cases, clinical trials of thresirolimus were used to treat lymphoma from the cells of the mantle zone.
** adverse reactions at all levels in accordance with the criteria for assessing the severity of the most frequent adverse events of the National Cancer Institute of the United States (NCI Common Terminology Criteria for Adverse Events) In most cases, clinical trials of thresirolimus were used to treat lymphoma from the cells of the mantle zone.
*** all unwanted reactions of 1 and 2 degrees in accordance with the criteria for assessing the severity of the most frequent adverse events of the National Cancer Institute of the United States (NCI Common Terminology Criteria for Adverse Events) were observed during clinical studies of the use of temsirolimus for the treatment of lymphoma from cells of the mantle zone.
During post-marketing studies of the use of the Toryzel® drug, there were cases of the development of Stevens-Johnson syndrome, rhabdomyolysis, angioedema-type edema, pneumonia caused by Pneumocystis jiroveci.

Overdose:

Specific recommendations for an overdose of Toryzel® are not available. Application of Thorizel ® in the form of repeated intravenous administration in a dose of 220 mg / m was not accompanied by undesirable phenomena.

The administration of Torizela® at a dose of 330 mg twice per week in one patient resulted in rectal bleeding III degree and diarrhea II degree.

Interaction:

Pharmaceutical incompatibility

The drug Toryzel® should not be mixed with other medicines, except for 0.9% sodium chloride solution.

Due to the danger of precipitation, concentrate of the preparation Thorizel ® Do not add directly to aqueous solutions for infusions, but you must first dilute the applied solvent!

The Toryzel® preparation contains polysorbate-80, which, when present in solution, increases the rate of extraction of diethylhexaphthalate from polyvinyl chloride, which should be taken into account when preparing and introducing the drug solution.

Preparations, inducing isozyme metabolism CYP3A4 and CYP3A5

Joint use of the drug Thorizel® with rifampicin, a powerful inducer isozymes CYP3A4 and CYP3A5, did not significantly affect C_max and AUC tessirolimus after its intravenous administration, but reduced C_max sirolimus by 65% and AUC by 56% compared with monotherapy with TORIZEL®. Thus, simultaneous use of drugs that potentially induce isoenzyme metabolism CYP3A4 and CYP3A5, in particular, carbamazepine, phenobarbital, phenytoin, rifampicin, rifabutin, rifapentin and preparations of St. John's wort perfumed. If simultaneous use of these drugs is necessary, consider increasing the dose of Thorizel® up to 50 mg per week.Patients with lymphoma from the cells of the mantle zone should avoid simultaneous application of isoenzyme inducers CYP3A4/5 in view of the need for high doses of tessirolimus.

Drugs that inhibit the metabolism of isoenzymes CYP3A4 and CYP2D6 Joint use of the Thorizel® 5 mg preparation with ketoconazole, a potent inhibitor of the isoenzyme CYP3A4, does not significantly affect the FROM_max and AUC tessirolimus; but AUC The sirolimus increases approximately 3.1 times, and the total AUC (tessirolimus + sirolimus) increases approximately 2.3-fold compared with monotherapy with Toryzel®. Medicines that are potent inhibitors of isoenzyme activity CYP3A4, for example, protease inhibitors (in t.ch. indinavir, nelfinavir, ritonavir), antifungal drugs (at t.ch. itraconazole, ketoconazole, voriconazole), macrolide antibiotics (incl. clarithromycin, erythromycin), nefazodone increase the concentration of sirolimus in the blood. It should avoid simultaneous use of the drug Thorizel ® with drugs that can significantly inhibit the isoenzyme CYP3A4. In combination with moderate inhibitors of isoenzyme CYP3A4, for example, blockers of "slow" calcium channels (including diltiazem, verapamil), selective serotonin reuptake inhibitors (aprepitant), cimetidine, fluvoxamine, fluconazole and grapefruit juice, Thorizel ® should be used with caution in patients receiving tessirolimus in a dose of 25 mg, and this combination should be avoided in patients receiving tessirolimus in a dose above 25 mg. Consider the possibility of using other drugs that do not have an inhibitory effect on the isoenzyme CYP3A4.

Caution should be exercised during the simultaneous use of the drug Thorizel "at a dose of 175 mg with drugs that are metabolized by the isoenzyme CYP2D6 and have a narrow therapeutic index. The use of TORIZEL® does not affect the concentration of desipramine, the substrate of the isoenzyme CYP2D6. It is not expected significant clinical impact in the joint use of the drug Torysel "with drugs that are metabolized by isoenzyme CYP2D6.

In studies in vitro tamsirolimus inhibited the transport of digoxin (P-glycoprotein substrate), the inhibitory concentration (IC50) was about 2 μmol.

Study of inhibition of P-glycoprotein in vivo not carried out. FROM_max In patients with lymphoma from cells of the mantle zone, tessirolimus intravenously at a dose of 175 mg, was 2.6 μmol. In this regard, with the joint appointment of tessirolimus with substrates of P-glycoprotein (including digoxin, vincristine, colchicine, paclitaxel), careful monitoring of adverse reactions is necessary. The clinical significance of simultaneous application of substrates of P-glycoprotein and tamsirolimus is unknown.

It is possible that the joint use of tamsirolimus with amphiphilic drugs, such as amiodarone or statins, may increase the risk of developing amphiphilic toxicity in relation to the lungs.

Simultaneous use of tamsirolimus and sunitinib leads to the development of toxicity, which limits the dose of drugs. This side effect may be manifested by maculopapular rash, gout and / or cellulitis requiring hospitalization.

Special instructions:

Treatment with the drug Thorizel "must be conducted under the supervision of an oncologist.

Older patients are more likely to develop unwanted reactions such as face swelling, pneumonia, pleural effusion, anxiety, depression, dyspnea,leukopenia, lymphopenia, myalgia, loss of taste and upper respiratory tract infections, rhinitis, pleurisy, insomnia, dizziness, arthralgia, mucositis.

As tessirolimus almost not excreted by the kidneys, studies involving patients with renal insufficiency of varying severity, including those on hemodialysis, were not conducted.

Concentrations of temsirolimus and its metabolite sirolimus increase in patients with increased activity ACT or bilirubin concentration. In this regard, prior to the initiation of therapy with temsirolimus and periodically throughout the therapy, it is recommended to determine the concentration ACT and bilirubin.

In the clinical study, thrombocytopenia of grade 3, 4 and / or grade 3 and 4 neutropenia were observed (see the "Side effect" section)

In patients with central nervous system (CNS) tumors (primary tumors or metastases in the CNS) and / or those receiving anticoagulant therapy, the risk of developing intracranial hemorrhage (including fatal outcome) with the use of temsirolimus is increased.

In patients who received the Toryzel® preparation for advanced renal cell carcinoma and / or with previousexisting kidney failure, there were cases of kidney failure (including, with a lethal outcome).

In some patients who received combination therapy with tamsirolimus and interferon alpha, cataract development was noted.

Treatment with Thorizel ® can be complicated by the development of hypersensitivity reactions or infusion reactions, including life-threatening, in rare cases, fatal. These reactions can develop at the very beginning of the infusion of the drug, but may also occur during subsequent injections. During intravenous infusion of Toryzel®, patients should be under constant medical supervision. In the development of severe toxic reactions, the introduction of Toryzel® should be suspended and appropriate therapy should be carried out. The decision to continue treatment should be made on the basis of an assessment of the relationship between benefit and risk.

If the patient develops a hypersensitivity reaction during the administration of the Toryzel®, stop the infusion immediately and observe the patient for at least 30-60 minutes, depending on the severity of the reaction. At the doctor's discretion, treatment can be resumed.In this case, 30 min before the infusion of the Toryzel drug, "a H1-histamine receptor blocker should be administered (eg, diphenhydramine), if this drug was not previously administered, and / or the H2-histamine receptor blocker (eg, famotidine in a dose of 20 mg intravenously or ranitidine in a dose of 50 mg intravenously). The effectiveness of glucocorticosteroids in these situations has not been shown. Then you can resume the infusion at a lower rate (up to 60 minutes) and complete it within 6 hours after the addition of 0.9% sodium chloride solution.

In connection with the recommendation of the use of antihistamines before the infusion, caution should be used in the preparation of Thorizel® in patients with a history of hypersensitivity to antihistamines or in patients who have antihistamines contraindicated for other reasons.

Patients, in the first place, patients suffering from diabetes, should be informed about the possibility of increasing the concentration of glucose in the blood on the background of therapy with the drug Thorizel ®. This may require the appointment or increase in the dose of insulin and / or hypoglycemic therapy.Patients should be informed to the attending physician about cases of excessive thirst, increase in the volume of urine or frequency of urination.

In connection with the fact that against the background of therapy with Tirizel, "cases of development of nonspecific interstitial pneumonitis, which in rare cases lead to death, are observed, patients should be monitored in order to timely identify the symptoms of respiratory diseases." In some cases, the course of nonspecific interstitial pneumonitis was asymptomatic or with minimal clinical manifestations, which were detected during CT or chest X-ray examination. It is also possible the appearance of cough, dyspnea and fever. For some patients, it is necessary to cancel therapy with Toryzel® or to additionally prescribe glucocorticosteroids and / or antibiotics, while for other patients treatment can be continued without additional intervention.

Prior to the initiation of therapy with the Toryzel® drug, an X-ray examination or computed tomography of the chest is recommended.A similar examination should be carried out periodically also during treatment with Toryzel® even if there are no signs of respiratory illness. In case of signs of respiratory disease, therapy with Toryzel® should be suspended until the symptomatology is resolved and the x-ray signs of pneumonitis disappear, if any. When conducting differential diagnosis, one should consider the possibility of developing opportunistic infections, such as pneumocystis pneumonia, caused by Pneumocystis jiroveci. In addition, the use of glucocorticosteroids and / or antibiotics should be considered. It is necessary to assess the feasibility of preventing pneumocystic pneumonia caused by Pneumocystis jiroveci, in patients who require simultaneous treatment with glucocorticosteroids.

Application of Thorizel ® was accompanied by an increase in the concentration of triglycerides and cholesterol in the blood plasma, which may require the appointment or increase in the dose of lipid-lowering drugs. Before the initiation of therapy with Toryzel®, and during treatment, the concentration of cholesterol and triglycerides in blood plasma should be monitored.

The use of the Toryzel® preparation was accompanied by a worsening of wound healing, and therefore it should be used with caution in the perioperative period.

In some patients receiving concomitantly tessirolimus and inhibitors

angiotensin-converting enzyme (ACE), there were reactions similar to

angioedema, including delayed reactions that occur 2 months after initiation of treatment.

The Toryzel® preparation, like other immunosuppressants, can reduce the immunological response to vaccination, so the use of live vaccines should be avoided during treatment with Toryzel®.

Torizel® (concentrate-solvent mixture) contains 35% vol. % ethanol, i.e. up to 693.5 mg of ethanol per dose of 25 mg, equivalent to 17.6 ml of beer or 7.3 ml of wine; the content of ethanol at a dose of 175 mg is up to 4.85 g, which is equivalent to 123 ml of beer or 51 ml of wine. This can be a threat to people with alcoholism.This fact should also be considered when treating patients from high-risk groups, namely: patients with liver disease or epilepsy.

The use of Toryzel® can lead to immunosuppression. In this regard, patients should be carefully monitored for the development of infections. In patients receiving tessirolimus, cases of pneumocystis pneumonia caused by Pneumocystis jiroveci, in some cases with a fatal outcome. Many of these patients also received therapy with glucocorticosteroids or other immunosuppressive drugs. In this regard, consideration should be given to the possibility of preventing pneumocystic pneumonia caused by Pneumocystis jiroveci, in patients who are simultaneously receiving treatment with glucocorticosteroids or other immunosuppressive drugs.

The frequency and severity of side effects depends on the dose. In patients receiving an initial dose of 175 mg per week, monitoring of the condition is required to make a decision to reduce the dose of the drug.

Effect on the ability to drive transp. cf. and fur:Studies of the effect of Toryzel® on the ability to drive and deal with potentially dangerousActivities that require a high concentration of attention and speed of psychomotor reactions have not been carried out. However, when it is necessary to drive and work with complex equipment, it should be taken into account that the preparation contains ethanol, and may also cause dizziness and other side effects from the nervous system.

Form release / dosage:

Concentrate for the preparation of a solution for infusions of 30 mg.

For 30 mg / 1.2 ml in bottles of transparent glass with a nominal capacity of 4 ml, sealed with a rubber butyl rubber stopper coated with fluoropolymer and rolled aluminum cap, equipped plastic detachable cap.

According to 1.8 ml of solvent in bottles of transparent glass with a nominal capacity of 3 ml, sealed with a rubber butyl rubber stopper coated with fluoropolymer and rolled aluminum cap, equipped plastic detachable cap.

For 1 vial of concentrate with a solvent (1 bottle), together with instructions for use in a cardboard pack.

Packaging:vials (1) / complete with a solvent (vials) 1.8 ml / - packs of cardboard

Storage conditions:

In the dark place at a temperature of 2 to 8 ° C. Do not freeze.Keep out of the reach of children.

Shelf life:

Concentrate in vials - 3 years.

Solvent in vials - 3 years.

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

Terms of leave from pharmacies:On prescription

Registration number:LSR-001305/10

Date of registration:24.02.2010

The owner of the registration certificate: Pfizer Inc. Pfizer Inc. USA

Manufacturer: & nbsp

PIERRE FABRE MEDICAMENT PRODUCTION France

Representation: & nbspPfizer H. Si. Pi. CorporationPfizer H. Si. Pi. Corporation

Information update date: & nbsp16.09.2015

Illustrated instructions

Instructions

Torizel® (Torizel®)