Tirojin (Thyrogen)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceThyrotropin alfaThyrotropin alfa
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  • Tirojin
    lyophilizate w / m 
    Genzyme Europe BV     Netherlands
    • Dosage form: & nbsplyophilizate for the preparation of a solution for intramuscular injection
    Composition:

    Per one vial:

    Component

    Nominal

    amount + excess1

    Active substance

    Thyrotropin alfa

    0.9 mg + 0.2 mg

    Excipients

    Mannitol

    29.0 mg + 7.0 mg

    Sodium hydrogen phosphate heptahydrate

    3.0 mg + 0.7 mg

    Sodium dihydrogen phosphate monohydrate

    1.1 mg + 0.3 mg

    Sodium chloride

    1.9 mg + 0.5 mg

    Weight of the contents of the bottle:

    35.9 mg + 6.1 mg

    1) The excess of active and auxiliary substances is due to the one used in step filling and lyophilization of the preparation with a 20% excess of vial filling (filling volume 1.2 ml), to provide the nominal recoverable volume (1.0 ml) of the reconstituted preparation.

    Description:

    Amorphous powder or porous mass of white or almost white color.

    Description of reconstituted solution: transparent or slightly opalescent, colorless or pale yellow liquid.

    Pharmacotherapeutic group:The pituitary hormone
    ATX: & nbsp

    H.01.A.B   Thyrotropin

    Pharmacodynamics:

    Mechanism of action

    Thyrotropin alfa (recombinant human thyrotropic hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. The molecule of the preparation consists of two subunits, connected by a non-covalent bond.cDNA encodes the synthesis of an α-subunit consisting of 92 amino acid residues with two N-linked glycosylation sites, and a β-subunit that includes 118 amino acid residues with one N-linked site of glycosylation. By biochemical properties tiotropin-alpha is similar to the natural human thyrotropic hormone (TSH). Binding of tirotropin alfa with TSH receptors on the surface of epithelial cells of the thyroid stimulates them to capture and organize iodine, as well as to the synthesis and release of thyroglobulin, triiodothyronine (T3) and thyroxine (T4).

    Pharmacodynamics

    In patients with highly differentiated thyroid cancer, subtotal or total thyroidectomy is performed. For effective detection of residual thyroid tissue or thyroid cancer (using scintigraphy with radioactive iodine or determination of thyroglobulin concentration) and for optimal destruction of the residual thyroid parenchyma with radioactive iodine, it is necessary to achieve a sufficiently high concentration of serum TSH, which stimulates the seizure of radioactive iodine and / or release of thyroglobulin.The standard method of increasing the concentration of TSH is the abolition of suppressive therapy with thyroid hormones (CTGT), which, as a rule, leads to the appearance of symptoms and clinical signs of hypothyroidism. With the use of the drug Tyrodzhin, the stimulating effect of TSH on the seizure of radioactive iodine and the release of thyroglobulin is achieved in the state of euthyroidism against the background of the continuation of STTG, which avoids the clinical manifestations of hypothyroidism.

    Use of the drug for diagnostic purposes

    The results of two studies, one of which evaluated two dosing regimens (0.9 mg intramuscularly at intervals of 24 hours and 0.9 mg 3 times at 72-hour intervals) demonstrated safety and efficacy of its use in combination with scintigraphy with radioactive iodine and determination of thyroglobulin concentration in the detection of residual thyroid tissue or thyroid cancer. The effectiveness of stimulation of radioactive iodine capture during diagnostic scintigraphy against the background of the described dosage regimens was quite high and did not have statistically significant differences from the corresponding indices in the conditions of STTG abolition.The stimulation of the release of thyroglobulin under the influence of the Tyrozhin preparation in both dosing regimens contributed to an increase in the sensitivity, accuracy and prognostic value of the negative result of the determination of the thyroglobulin concentration used as an independent method or in combination with scintigraphy with radioactive iodine, in comparison with the values ​​of these parameters when conducting a study against a background continued reception of thyroid hormone.

    In clinical studies with residual thyroid tissue or thyroid cancer after ablation with the determination of thyroglobulin concentration, it has been shown that the determination of thyroglobulin concentration in combination with the administration of Tyrodzhin is a more sensitive diagnostic method than the determination of thyroglobulin concentration against CTH.

    The use of the drug for the purpose of pre-healing stimulation

    In a comparative study in 60 adult patients who underwent thyroidectomy due to thyroid cancer, the ablation efficiency of residual thyroid tissue by administration of radioactive iodine at a dose of 100 mCi / 3.7 GBq (± 10%) was similar after the withdrawal of STTG and after administration of the Tyrozhin drug .The success of ablation of residual thyroid tissue was assessed by scintigraphy with radioactive iodine and determination of serum thyroglobulin concentration 8 ± 1 months after treatment. The quality of life of patients was significantly reduced after the abolition of CTHT, but when Tyrozin was administered in both dosing regimens and for both indications it was maintained at the same level.

    After completing participation in the first study, patients could take part in its continuation. In a further study, data from 51 patients were evaluated. The main purpose of the additional study was to confirm the results of ablation of residual thyroid tissue by static neck scintigraphy on the background of stimulation with Tyrodzhin. The median duration of the time after ablation with radioactive iodine was 3.7 years.

    In the course of the study, the thyroid globulin concentration was also determined under stimulation conditions with the Tyrodzhin preparation.

    In general, the key study and its continuation demonstrated a comparable efficacy of Tyrodzhin in comparison with the abolition of STTG in the degree of increase in concentrationTTG in preparation for post-surgical ablation of residual thyroid tissue with radioactive iodine.

    In two large-scale prospective, randomized trials - HiLo (Mallick) and ESTIMABL (Schlumberger) - Different methods of ablation of residual thyroid tissue were compared in patients with differentiated thyroid cancer who underwent thyroidectomy. The effectiveness of treatment was estimated after about 8 months. Results of scintigraphy with radioactive iodine and determination of the concentration of stimulated thyroglobulin (n= 421) in the study HiLo (Mallick) showed that ablation was successful in approximately 86% of patients, in the study ESTIMABL (Schlumberger) - the total frequency of successful ablation (based on the results of ultrasound examination of the neck and determination of the concentration of stimulated thyroglobulin) was 92%.

    Given the design of each of these two studies, it should be noted that long-term data (over a period of more than 9 months) on the use of low doses of radioactive iodine have not yet been obtained. The described research results indicate that the introduction of radioactive iodine in low dose combined with the use of tirotropine alpha is an effective method of treatment,which allows you to reduce the level of radiation exposure to the body. In addition, it was shown that the administration of Tyrodzhin on the effectiveness of pre-healing thyroid stimulation before performing post-surgical ablation of residual thyroid tissue with radioactive iodine is not inferior to the CTGT abolition technique.

    Pharmacokinetics:

    The pharmacokinetics of the Tyrozhin preparation was studied in patients with highly differentiated thyroid cancer receiving single intramuscular injection of the drug at a dose of 0.9 mg. After injection, the mean maximum concentration (CmOh) of tirotropine alpha was 116 ± 38 mIU / L and was achieved approximately 13 ± 8 hours after the administration of the drug. The half-life was 22 ± 9 hours. It is believed that tiotropin-alpha is excreted from the body, mainly by the kidneys and to a lesser extent - through the intestine.

    Indications:

    The drug Tyrodzhin is used in the determination of serum thyroglobulin concentration in combination with scintigraphy with or without radioactive iodine in order to identify residual thyroid tissue or highly differentiated thyroid cancer in patients undergoing thyroidectomy and receiving suppressive thyroid hormone (STTG) therapy.

    In patients with highly differentiated thyroid cancer, in which the serum thyroglobulin concentration does not reach the threshold of detection against the CTG and does not increase with stimulation with recombinant human TSH (rchTTG), the determination of the concentration of thyroglobulin stimulated with rhTTH is acceptable.

    Tyrozhin is used to stimulate the thyroid gland before the procedure of ablation of residual thyroid tissue with radioactive iodine in doses from 30 mCi (1.1 GBq) to 100 mCi (3.7 GBq) in patients with highly differentiated thyroid cancer after subtotal or total thyroidectomy, in whom there are no signs of distant metastases (see section "Special instructions").

    Contraindications:

    - Hypersensitivity reactions to bovine or human thyroid-stimulating hormone or to any of the excipients of the drug.

    - Pregnancy and the period of breastfeeding.

    - Age under 18 years (due to the lack of data on the effectiveness and safety of the drug in children and adolescents).

    Carefully:

    - In patients at high risk, particularly in elderly patients with heart disease (with heart valves, cardiomyopathy, coronary artery disease, coronary heart disease, tachyarrhythmias, including atrial fibrillation, at the time of the examination and in the anamnesis) who did not undergo thyroidectomy (a careful assessment of the benefit / risk ratio is required, see section "Specific guidance").

    - In patients with a significant mass of residual thyroid parenchyma (a careful assessment of the benefit-risk ratio is required, see the "Specific guidance" section).

    - In patients with metastasis of thyroid cancer in organs in closed anatomical formations (preliminary treatment with glucocorticosteroids is recommended, see section "Special instructions").

    Pregnancy and lactation:

    Pregnancy

    Studies of reproductive toxicity of tiotropin alfa in laboratory animals have not been conducted.

    Information on the potential damaging effect of tirotropin alpha on the fetus during its use during pregnancy, as well as on the effect of the drug on reproductive function, has not been obtained.

    The use of Tyrodzhin in combination with diagnostic whole body scintigraphy is contraindicated during pregnancy (see "Contraindications") due to the risk of exposure to high doses of radioactive material on the fetus.

    Breastfeeding period

    Information on the penetration of tirotropin alpha or its metabolites into human breast milk is not available. It is impossible to exclude the risk with regard to the infant who is breastfed. The use of the drug Tyrodzhin during breastfeeding is contraindicated.

    Dosing and Administration:

    The drug should be administered under the supervision of a physician with experience in the treatment of thyroid cancer.

    Dosing regimen

    The recommended regimen for the use of tirotropine alpha- double intramuscular injection of 0.9 mg at intervals of 24 hours.

    Pediatric population

    Due to the lack of data on efficacy and safety in children and adolescents under the age of 18, the use of the Tyrodzhin drug in this category of patients is contraindicated.

    The use of the drug in elderly patients

    The results of controlled trials using the Tyrodzhin drug for diagnostic purposes demonstrated that the indices of its safety and efficacy did not differ between groups of patients younger and older than 65 years. Correction of the dose of the drug in elderly patients is not required (see section "Special instructions").

    Use of the drug in cases of impaired renal / hepatic function

    The analysis of the data obtained during the post-marketing period showed that in patients with chronic kidney diseases in the terminal stage (CCHTS) in dialysis, there is a significant delay in the excretion of the Tyrodzhin preparation, which leads to the prolongation of the increase in the TSH concentration up to several days after the drug administration. This can increase the likelihood of a headache and nausea. The formulation of recommendations to reduce the dose of the drug Tyrodzhin in patients with CKDPTS is not possible, because studies of alternative dosage regimens in these patients have not been conducted.

    In patients with impaired renal function, a careful calculation of the dose of radioactive iodine by a radiologist is required.

    Special instructions for the use of Tyrozhin in patients with a decrease in liver function are absent.

    Mode of application

    After dilution with water for injection, 1.0 ml of the resulting solution (0.9 mg tirotropin alfa) is introduced into the gluteus muscle. The introduction of radioactive iodine in the scintigraphy or ablation procedures should be performed 24 hours after the final injection of the Tyrodzhin preparation.Diagnostic scintigraphy should be performed 48-72 hours after the administration of radioactive iodine, and scintigraphy after Ablation can be delayed for a few more days before the background radioactivity decreases.

    Sampling a serum sample for the control determination of serum thyroglobulin concentration for diagnostic purposes should be performed 72 hours after the final injection of the Tyrodzhin preparation. The use of Tyrodzhin in combination with the determination of thyroglobulin concentration within the clinical observation of patients with highly differentiated thyroid cancer who underwent thyroidectomy should be carried out in accordance with clinical recommendations.

    Instructions for preparing the drug solution

    To dissolve the powder for the injection solution, use water for injection. For one injection, only one bottle of Tyrodzhin is required. Each bottle is for single use only.

    The administration of the drug is carried out in accordance with the rules of asepsis.

    Add 1.2 ml of water for injection to the powder of the drug Tyrodzhin in the vial.Carefully mix the contents of the vial until the powder is completely dissolved. Do not shake. The total volume of the drug in the vial after dissolving the powder is 1.2 ml. The pH of the solution of the Tyrodzhin preparation is approximately 7.0.

    The resulting solution must be inspected to detect foreign particles or uncharacteristic color. The drug solution should be clear and colorless. When detecting foreign particles, clouding or coloring the solution, its use is not allowed.

    Draw in a syringe 1.0 ml of the solution of the drug Tyrodzhin from the bottle. In this volume of the injection solution, 0.9 mg tirotropine alpha is contained.

    The composition of the preparation Tyrozhin does not include preserving agents. All unused remnants of the solution must be disposed of. Special requirements for the disposal of the drug are absent.

    The drug Tyrozhin solution should be administered to the patient not later than 3 hours after dilution, but can remain chemically stable for up to 24 hours when stored in a refrigerated chamber (at a temperature of 2-8 ° C).

    When preparing the mortar, you must follow the rules of asepsis.

    Side effects:

    Undesirable reactions, presented in the form of a table

    The most frequent adverse reactions were nausea and headache, which occurred in approximately 12% and 7% of patients, respectively.

    The undesirable reactions listed in the following table include unwanted reactions recorded during 6 prospective clinical trials (n= 481), and adverse effects that were identified in the post-marketing period.

    Within each frequency category, adverse reactions are presented in descending order of severity. For each unwanted reaction, the frequency category was determined according to the following gradation: very often (≥1/10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10,000 to <1/1000), very rarely (<1/10 000), the frequency is unknown (the frequency can not be determined from the available data).

    Benign, malignant and unspecified neoplasms (including cysts and polyps)

    Frequency unknown: edema of the tumor tissue, pain in the localization of metastases.

    Disturbances from the nervous system

    Often: dizziness, headache, paresthesia.

    Frequency unknown: tremor, stroke.

    Heart Disease

    Frequency unknown: a feeling of palpitations.

    Vascular disorders

    Infrequently: feeling of heat.

    Frequency unknown: "tides".

    Disturbances from the respiratory system, chest and mediastinal organs

    Frequency unknown: dyspnea.

    Disorders from the gastrointestinal tract

    Often: nausea.

    Often: vomiting, diarrhea.

    Disturbances from the skin and subcutaneous tissues

    Infrequently: urticaria, rash.

    Frequency unknown: itching, hyperhidrosis.

    Disturbances from musculoskeletal system and connective tissue

    Frequency unknown: arthralgia, myalgia.

    General disorders and disorders at the site of administration

    Often: fatigue, asthenia.

    Infrequently: flu-like syndrome, fever, chills, back pain.

    Frequency unknown: discomfort, pain, itching, rash and hives in intramuscular injection.

    Laboratory and instrumental data

    Frequency unknown: decrease in the concentration of TSH.

    Description of individual adverse reactions

    The administration of the drug Tyrozhin in a dose of 0.9 mg to patients with a preserved thyroid gland or a part of it in very rare cases was accompanied by the development of hyperthyroidism or atrial fibrillation.

    Hypersensitivity reactions were recorded infrequently (both during clinical trials and post-marketing period).These reactions included hives, rashes, itchy skin, "hot flashes", as well as clinical signs and symptoms of the respiratory system.

    In clinical studies involving 481 patients, cases of antibody production to tirotropin alpha were absent both after a single and after repeated (27 patients) administration of the drug. The possibility of antibodies that neutralize endogenous TSH can not be ruled out.

    The administration of the Tyrozhin preparation can cause an increase in the volume of residual thyroid tissue or metastasis. This can lead to a sudden appearance of various symptoms, depending on the anatomical location of the tumor. For example, in patients with metastases in the brain, hemiplegia, hemiparesis, or loss of vision can develop. Against the backdrop of the use of the drug Tyrodzhin, cases of laryngeal edema, respiratory distress syndrome, requiring tracheotomy, as well as pain in the localization of metastases were recorded. In the event of a risk of compression of vital anatomical structures as a result of an increase in the size of the tumor, preliminary treatment with glucocorticosteroids is recommended.

    Within the framework of international post-registration surveillance, very rare cases of stroke in female patients have been registered. The association of these clinical cases with the use of Tyrozhin is not established.

    Overdose:

    Data on the excess of recommended dosages of the drug were obtained only in the course of clinical studies and a special treatment program. In three participants in clinical trials and one patient from a special treatment program, the use of Tyrozhin in an increased dose led to the development of a number of clinical symptoms. In two patients, intramuscular injection of the drug at a dose of 2.7 mg caused nausea, which in one of them was accompanied by general weakness, dizziness and headache. In a third patient, intramuscular injection of the drug at a dose of 3.6 mg caused nausea, vomiting and "hot flashes". During the special treatment program, a clinical case of administering 4 doses of Tyrozhin 0.9 mg for 6 days to a 77-year-old patient with metastatic thyroid cancer who did not undergo thyroidectomy was recorded. After 2 days, the patient developed atrial fibrillation, decompensated heart failure with a lethal myocardial infarction.

    Another clinical trial participant had clinical symptoms after the administration of Tyrozhin in an intravenous way. After 15 minutes after a single bolus administration of the drug Tyrodzhin at a dose of 0.3 mg, the patient developed severe nausea, vomiting, increased sweating, hypotension and tachycardia.

    In case of an overdose of the drug Tyrodzhin, it is recommended to carry out measures aimed at restoring the water balance. If necessary, the administration of antiemetics is indicated.

    Interaction:

    Special studies of the interaction of the drug Tyrodzhin with other drugs have not been conducted. In the course of clinical studies, there were no cases of interaction between the Tyrodzhin preparation and thyroid hormones - triiodothyronine (T3) and thyroxine (T4).

    The use of the drug Tyrodzhin allows you to perform scintigraphy with radioactive iodine in a state of euthyroidism on the background of suppressive therapy with thyroid hormones. Analysis of the kinetics of radioactive iodine indicates that its clearance in the state of euthyroidism is approximately 50% higher than in hypothyroidism, which is characterized by a decrease in kidney function. The increase in the clearance of radioactive iodine contributes to reduction of the time of its retention in the body during scintigraphy. This factor should be taken into account when choosing a dose of radioactive iodine for scintigraphy.

    Special instructions:

    The drug Tyrodzhin is not intended for intravenous administration.

    The use of Tyrodzhin as an alternative to the abolition of CTG before whole-body scintigraphy (CBT) and the determination of thyroglobulin concentration makes it possible to maximize the sensitivity of these methods in detecting residual thyroid tissue or thyroid cancer. Examination with the use of the drug Tyrodzhin can give false-negative results. If it is impossible to exclude the metastatic process to confirm the results, it is recommended that an SVT be performed and the serum thyroglobulin concentration is determined against the background of STTG abolition.

    The production of autoantibodies to thyroglobulin may occur in 18-40% of patients with differentiated thyroid cancer and may cause false negative results in determining the serum thyroglobulin concentration. In this regard, it is necessary to conduct a combined determination of thyroglobulin concentration and antibodies to it.

    The use of Tyrodzhin in patients at high risk, particularly in elderly patients with heart disease (heart valve disease, cardiomyopathy, coronary heart disease, tachyarrhythmias, including atrial fibrillation, at the time of examination and in the history), who did not undergo thyroidectomy, requires a thorough assessment of the relationship between benefit and risk.

    It is known that the drug Tyrodzhin is able to cause a transient but significant increase in serum concentrations of thyroid hormones in patients with a sufficient mass of preserved thyroid tissue. In this connection, in patients with a significant mass of residual thyroid parenchyma, the use of the drug requires a careful evaluation of the relationship between benefit and risk.

    Data on the long-term use of low doses of radioactive iodine have not yet been received.

    Effect on tumor growth and / or size

    In patients with thyroid cancer, several cases of stimulation of tumor growth during the abolition of CTG for diagnostic purposes were registered, which could be associated with a prolonged increase in the thyroid-stimulating hormone (TSH) concentration.

    The use of the Tyrozin preparation, as well as the abolition of CTGT, can theoretically stimulate tumor growth. In clinical trials, the use of thyrotropin alfa, accompanied by a brief increase in serum TSH, did not lead to activation of tumor growth.

    Due to the increase in TSH concentration after administration of the Tyrodzhin preparation in patients with thyroid cancer metastases, local edema or focal hemorrhages can occur in the localization of metastases (especially in organs in closed anatomical formations such as the brain, spinal cord and the organ of vision, and also with the infiltration of the tissues of the neck region), which is manifested by an increase in the size of the tumor. This can lead to the sudden appearance of various symptoms, depending on the anatomical localization of tumor foci (for example, in patients with brain metastases, hemiplegia, hemiparesis, or loss of vision may develop). Against the backdrop of the use of Tyrozhin, cases of laryngeal edema, respiratory distress syndrome requiring tracheotomy, as well as pain in the localization of metastases have been reported.In the event of a risk of compression of vital anatomical structures as a result of an increase in the size of the tumor, preliminary treatment with glucocorticosteroids is recommended.

    Important information about some of Tygestin's excipients

    This drug contains 1 mmol sodium (23 mg) in one injection dose, that is, it can be considered as non-nutrient.

    Effect on the ability to drive transp. cf. and fur:

    Studies of the effect of the drug on the ability to drive vehicles and mechanisms were not conducted. The use of the drug Tyrodzhin requires caution in the management of vehicles and mechanisms, since it is possible to develop unwanted reactions such as dizziness and headache, which can reduce the ability to drive vehicles and mechanisms.

    Form release / dosage:

    Lyophilizate for the preparation of solution for intramuscular injection 0.9 mg.

    Packaging:

    The amount of the drug equivalent to 0.9 mg of active ingredient is placed in a vial of glass I of hydrolytic class, with a capacity of 5.0 ml,sealed with 20 mm siliconized chlorine or bromine butyl stopper and 20 mm aluminum 6-strip cap for running in, with a plastic cap.

    Two bottles together with instructions for use in a cardboard box.

    Storage conditions:

    At a temperature of 2 to 8 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004339
    Date of registration:13.06.2017
    Expiration Date:13.06.2022
    The owner of the registration certificate:Genzyme Europe BVGenzyme Europe BV Netherlands
    Manufacturer: & nbsp
    Representation: & nbspSanofi Russia, JSCSanofi Russia, JSCRussia
    Information update date: & nbsp12.08.2017
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