Thyrogen (Lyophilisate) Instructions for Use

Marketing Authorization Holder

Genzyme Europe B.V. (Netherlands)

Manufactured By

Hospira, Inc. (USA)

Or

Genzyme Ireland Limited (Ireland)

Packaging and Quality Control Release

GENZYME, Ltd. (United Kingdom)

Or

GENZYME IRELAND Limited (Ireland)

Contact Information

SANOFI

ATC Code

H01AB01 (Thyrotropin alfa)

Active Substance

Thyrotropin alfa (Rec.INN registered by WHO)

Dosage Form

Thyrogen

Lyophilisate for the preparation of solution for intramuscular administration 0.9 mg: vial 2 pcs.

Dosage Form, Packaging, and Composition

Lyophilisate for the preparation of solution for intramuscular administration in the form of an amorphous powder or porous mass of white or almost white color; reconstituted solution is a clear or slightly opalescent, colorless or light yellow liquid.

Excipients: mannitol – 29 mg + 7 mg*, sodium phosphate heptahydrate – 3 mg + 0.7 mg*, sodium phosphate monohydrate – 1.1 mg + 0.3 mg*, sodium chloride – 1.9 mg + 0.5 mg*.
Mass of vial contents: 35.9 mg + 6.1 mg*.

0.9 mg lyophilisate – glass vials with a capacity of 5 ml (2) – cardboard packs.

* The excess of the active substance (+ 0.2 mg) and excipients is due to the 20% overfill of the vials used during the filling and lyophilization stage of the drug (fill volume 1.2 ml), to ensure the nominal extractable volume (1 ml) of the reconstituted drug.

Clinical-Pharmacological Group

Pituitary hormone

Pharmacotherapeutic Group

Pituitary hormone

Pharmacological Action

Mechanism of action

Thyrotropin alfa (recombinant human thyroid-stimulating hormone) is a heterodimeric glycoprotein produced using recombinant DNA technology. The drug molecule consists of two subunits connected by a non-covalent bond. The cDNA encodes the synthesis of the α-subunit, consisting of 92 amino acid residues with two N-linked glycosylation sites, and the β-subunit, which includes 118 amino acid residues with one N-linked glycosylation site. In its biochemical properties, Thyrotropin alfa is similar to natural human thyroid-stimulating hormone (TSH). Binding of thyrotropin alfa to TSH receptors on the surface of thyroid epithelial cells stimulates them to uptake and organify iodine, as well as to synthesize and release thyroglobulin, triiodothyronine (T3), and thyroxine (T4).

Pharmacodynamics

In patients with differentiated thyroid cancer, subtotal or total thyroidectomy is performed. For effective detection of residual thyroid tissue or thyroid cancer (using radioactive iodine scintigraphy or determination of thyroglobulin concentration) and for optimal destruction of residual thyroid parenchyma with radioactive iodine, it is necessary to achieve a sufficiently high serum TSH concentration that stimulates the uptake of radioactive iodine and/or the release of thyroglobulin. The standard method for increasing TSH concentration is withdrawal of thyroid hormone suppression therapy (THST), which usually leads to the appearance of symptoms and clinical signs of hypothyroidism. When using Thyrogen, the stimulating effect of TSH on radioactive iodine uptake and thyroglobulin release is achieved in a euthyroid state while continuing THST, 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 of Thyrogen (0.9 mg IM at 24-hour intervals and 0.9 mg three times at 72-hour intervals), demonstrated the safety and efficacy of its use in combination with radioactive iodine scintigraphy and determination of thyroglobulin concentration for the detection of residual thyroid tissue or thyroid cancer. The efficacy rates for stimulating radioactive iodine uptake during diagnostic scintigraphy with the described dosing regimens were sufficiently high and did not differ statistically significantly from the corresponding rates under THST withdrawal conditions. Stimulation of thyroglobulin release under the influence of Thyrogen in both dosing regimens contributed to an increase in the sensitivity, accuracy, and predictive value of a negative thyroglobulin concentration result, used as a standalone method or in combination with radioactive iodine scintigraphy, compared to the values of these parameters when conducting the study against the background of continued thyroid hormone intake.

In clinical studies for the detection of residual thyroid tissue or thyroid cancer after ablation using thyroglobulin concentration determination, it was shown that determining thyroglobulin concentration in combination with Thyrogen administration is a more sensitive diagnostic method than determining thyroglobulin concentration against the background of THST.

Use of the drug for pre-therapeutic stimulation

In a comparative study of 60 adult patients who underwent thyroidectomy for thyroid cancer, the effectiveness of ablation of residual thyroid tissue by administering radioactive iodine at a dose of 100 mCi/3.7 GBq (±10%) was similar after THST withdrawal and after Thyrogen administration. The success of ablation of residual thyroid tissue was assessed based on the results of radioactive iodine scintigraphy and determination of serum thyroglobulin concentration 8±1 months after treatment. The quality of life of patients significantly decreased after THST withdrawal, but when Thyrogen was administered in both dosing regimens and for both indications, it remained at the same level.

After completing participation in the first study, patients could participate in its continuation. The additional study evaluated data obtained from 51 patients. The main goal of the additional study was to confirm the results of ablation of residual thyroid tissue by static scintigraphy of the neck area against the background of stimulation with Thyrogen. The median time after radioactive iodine ablation was 3.7 years.

The study also included determination of thyroglobulin concentration under conditions of stimulation with Thyrogen.

Overall, the key study and its continuation demonstrated comparable effectiveness of Thyrogen compared to THST withdrawal in terms of the degree of TSH concentration increase as part of preparation for post-surgical ablation of residual thyroid tissue with radioactive iodine.

In two large prospective, randomized studies – HiLo (Mallick) and ESTIMABL (Schlumberger) – different methods of ablating residual thyroid tissue in patients with differentiated thyroid cancer who underwent thyroidectomy were compared. Treatment effectiveness was assessed approximately 8 months later. The results of radioactive iodine scintigraphy and determination of stimulated thyroglobulin concentration (n=421) in the HiLo (Mallick) study showed that ablation was successful in approximately 86% of patients; in the ESTIMABL (Schlumberger) study, the overall rate of successful ablation (based on neck ultrasound and stimulated thyroglobulin concentration) was 92%.

Considering the design of each of these two studies, it should be noted that long-term data (over 9 months) on the use of low doses of radioactive iodine are not yet available. The described study results indicate that the administration of radioactive iodine in a low dose in combination with the use of thyrotropin alfa is an effective treatment method that reduces the level of radiation exposure to the body. Furthermore, it has been shown that the administration of Thyrogen for pre-therapeutic stimulation of the thyroid gland before post-surgical ablation of residual thyroid tissue with radioactive iodine is not inferior to the THST withdrawal method.

Pharmacokinetics

The pharmacokinetics of Thyrogen were studied in patients with differentiated thyroid cancer who received single IM injections of the drug at a dose of 0.9 mg.

After injection, the mean C_max of thyrotropin alfa was 116±38 mIU/L and was reached approximately 13±8 hours after drug administration.

T_1/2 was 22±9 hours. It is believed that Thyrotropin alfa is eliminated from the body mainly by the kidneys and to a lesser extent through the intestines.

Indications

• For determining serum thyroglobulin concentration in combination with or without radioactive iodine scintigraphy to detect residual thyroid tissue or differentiated thyroid cancer in patients who have undergone thyroidectomy and are receiving thyroid hormone suppression therapy (THST).

In patients with differentiated thyroid cancer whose serum thyroglobulin concentration does not reach the detection threshold against the background of THST and does not increase upon stimulation with recombinant human TSH (rhTSH), determination of rhTSH-stimulated thyroglobulin concentration may be used to monitor treatment outcomes.

• For stimulation of 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 differentiated thyroid cancer after subtotal or total thyroidectomy, who have no signs of distant metastases.

ICD codes

Dosage Regimen

The drug should be used under the supervision of a treating physician experienced in the treatment of thyroid cancer.

The recommended regimen for thyrotropin alfa is two IM injections of 0.9 mg at a 24-hour interval.

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

Results from controlled studies using Thyrogen for diagnostic purposes have shown that its safety and efficacy profiles did not differ between patient groups under 65 years of age and those 65 years of age and older. Dose adjustment in elderly patients is not required.

Analysis of data obtained in the post-registration period showed that in patients with end-stage chronic kidney disease (ES CKD) on dialysis, there is a significant slowdown in the elimination of Thyrogen, leading to a prolongation of the increase in TSH concentration for several days after drug administration. This may increase the likelihood of headache and nausea. Formulating recommendations for reducing the dose of Thyrogen in patients with ES CKD is not possible, as studies of alternative dosing regimens in these patients have not been conducted. In patients with impaired renal function, careful calculation of the radioactive iodine dose by a radiologist is required.

There are no special instructions for the use of Thyrogen in patients with reduced liver function.

Method of administration

After reconstituting the lyophilisate with water for injections, 1 ml of the resulting solution (0.9 mg thyrotropin alfa) is injected into the gluteal muscle. Administration of radioactive iodine as part of scintigraphy or ablation procedures should be performed 24 hours after the final injection of Thyrogen. Diagnostic scintigraphy should be performed 48-72 hours after radioactive iodine administration, and post-ablation scintigraphy may be delayed for several more days until background radioactivity decreases.

Blood sampling for control determination of serum thyroglobulin concentration for diagnostic purposes should be performed 72 hours after the final injection of Thyrogen. The use of Thyrogen in combination with thyroglobulin concentration determination as part of clinical monitoring of patients with differentiated thyroid cancer who have undergone thyroidectomy should be carried out in accordance with clinical guidelines.

Instructions for preparing the drug solution

Water for injections should be used to dissolve the powder for the preparation of the injection solution. Only one vial of Thyrogen is required for one injection. Each vial is intended for single use only.

Administration of the drug is carried out in compliance with aseptic rules.

Add 1.2 ml of water for injections to the Thyrogen powder in the vial. Gently mix the vial contents until the powder is completely dissolved. Do not shake. The total volume of the drug in the vial after powder dissolution is 1.2 ml. The pH of the Thyrogen solution is approximately 7.0.

The resulting solution must be inspected for foreign particles or unusual coloration. The drug solution should be clear and colorless. If foreign particles, cloudiness, or coloration of the solution are detected, its use is not permitted.

Draw 1 ml of the Thyrogen solution from the vial into a syringe. This volume of injection solution contains 0.9 mg of thyrotropin alfa.

Thyrogen does not contain preservative agents. All unused solution residues must be disposed of. There are no special requirements for drug disposal.

The Thyrogen solution should be administered to the patient no later than 3 hours after reconstitution, but may remain chemically stable for up to 24 hours when stored in a refrigerator (at a temperature of 2-8°C (35.6-46.4°F)).

Aseptic rules must be observed when preparing the solution.

Adverse Reactions

The most frequent adverse reactions were nausea and headache, which occurred in approximately 11% and 6% of patients, respectively.

The adverse reactions listed below include adverse reactions recorded during 6 prospective clinical studies (n=481) and adverse effects identified in the post-registration period.

Within each frequency category, adverse reactions are presented in order of decreasing severity. For each adverse reaction, a frequency category was determined according to the following gradation: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (frequency cannot be estimated from the available data).

Infections and infestations uncommon – influenza.

Benign, malignant and unspecified neoplasms (including cysts and polyps) frequency not known – tumor tissue swelling, pain at the site of metastases.

Nervous system disorders common – dizziness, headache; uncommon – ageusia, dysgeusia, paresthesia; frequency not known – tremor, stroke.

Cardiac disorders frequency not known – palpitations, flushing.

Respiratory, thoracic and mediastinal disorders frequency not known – dyspnea.

Gastrointestinal disorders very common – nausea; common – vomiting; uncommon – diarrhea.

Skin and subcutaneous tissue disorders uncommon – urticaria, rash; frequency not known – pruritus, hyperhidrosis.

Musculoskeletal and connective tissue disorders uncommon – neck pain, back pain; frequency not known – arthralgia, myalgia.

General disorders and administration site conditions common – fatigue, asthenia; uncommon – flu-like syndrome, pyrexia, chills, feeling hot; frequency not known – discomfort, pain, injection site pruritus, rash and urticaria.

Investigations frequency not known – decreased TSH concentration.

Description of selected adverse reactions

Administration of Thyrogen at a dose of 0.9 mg to patients with an intact thyroid gland or part of it has very rarely been accompanied by the development of hyperthyroidism or atrial fibrillation.

Hypersensitivity reactions were reported uncommonly (both in clinical studies and in the post-registration period). These reactions included urticaria, rash, pruritus, flushing, as well as clinical signs and symptoms of respiratory system involvement.

In clinical studies involving 481 patients, there were no cases of antibody formation to thyrotropin alfa either after single or repeated (27 patients) administration of the drug.

Determination of TSH concentration is not recommended after administration of Thyrogen. The formation of antibodies cannot be ruled out, which may affect the results of endogenous TSH determination performed during regular monitoring.

Administration of Thyrogen may cause an increase in the volume of residual thyroid tissue or metastases. This may lead to the sudden appearance of various symptoms depending on the anatomical location of the tumor foci. For example, patients with brain metastases may develop hemiplegia, hemiparesis, or loss of vision.

Cases of laryngeal edema, respiratory distress syndrome requiring tracheotomy, as well as pain at the sites of metastases have been reported during the use of Thyrogen. In case of risk of compression of vital anatomical structures due to tumor enlargement, preliminary treatment with corticosteroids is recommended.

Within the framework of international post-registration surveillance, very rare cases of stroke in females have been registered. The connection of these clinical cases with the use of Thyrogen has not been established.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after registration of the drug is important. This allows continuous monitoring of the benefit/risk ratio of the drug. Healthcare professionals are requested to report any suspected adverse reactions.

Contraindications

• Pregnancy;
• Period of lactation (breastfeeding);
• Age under 18 years (due to the lack of data on the efficacy and safety of the drug use in children and adolescents);
• Hypersensitivity reactions to bovine or human thyrotropin or to any of the excipients of the drug.

With caution

• In high-risk category patients, particularly in elderly patients with heart disease (with valvular heart disease, cardiomyopathy, coronary artery disease, tachyarrhythmias, including atrial fibrillation, at the time of examination and in history) who have not undergone thyroidectomy (a thorough benefit-risk assessment is required);
• In patients with a significant mass of residual thyroid parenchyma (a thorough benefit-risk assessment is required);
• In patients with metastases of thyroid cancer in organs, especially those located in confined anatomical spaces, such as the brain, spinal cord, and organ of vision, as well as with infiltration of neck tissues (prior treatment with glucocorticosteroids is recommended).

Use in Pregnancy and Lactation

Reproductive toxicity studies of thyrotropin alfa in laboratory animals have not been conducted. Data on the potential damaging effect of thyrotropin alfa on the fetus when used during pregnancy, as well as on the effect of the drug on reproductive function, have not been obtained. The use of the drug Thyrogen in combination with diagnostic whole-body scintigraphy is contraindicated during pregnancy due to the risk of exposure to high doses of radioactive material on the fetus.

Data on the penetration of thyrotropin alfa or its metabolites into human breast milk are not available. The risk to the breastfed infant cannot be ruled out. The use of the drug Thyrogen during breastfeeding is contraindicated.

Use in Hepatic Impairment

There are no special instructions for the use of the drug Thyrogen in patients with impaired liver function.

Use in Renal Impairment

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

Pediatric Use

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

Geriatric Use

Dose adjustment of the drug in elderly patients is not required.

Special Precautions

The drug Thyrogen is not intended for intravenous administration.

The use of the drug Thyrogen as an alternative to thyroid hormone withdrawal before whole-body scintigraphy (WBS) and determination of thyroglobulin concentration allows to maximize the sensitivity of these methods in detecting residual thyroid tissue or thyroid cancer. Examination using the drug Thyrogen may yield false-negative results. If there is a high degree of suspicion of a metastatic process, to confirm the obtained results, it is recommended to perform WBS and determine the serum thyroglobulin concentration against the background of thyroid hormone withdrawal.

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

The use of the drug Thyrogen in patients from the high-risk category, particularly in elderly patients with heart disease (valvular heart disease, cardiomyopathy, coronary artery disease, tachyarrhythmias, including atrial fibrillation, at the time of examination and in history) who have not undergone thyroidectomy, requires a thorough benefit-risk assessment.

The drug Thyrogen is known to cause a transient but significant increase in serum thyroid hormone concentrations in patients with a sufficient mass of preserved thyroid tissue. In this regard, in patients with a significant mass of residual thyroid parenchyma, the use of the drug requires a thorough benefit-risk assessment.

Long-term data on the use of low doses of radioactive iodine have not yet been obtained.

Influence on tumor growth and/or size

In patients with thyroid cancer, several cases of tumor growth stimulation during thyroid hormone withdrawal for diagnostic purposes have been registered, which could be associated with a prolonged increase in TSH concentration.

The use of the drug Thyrogen, as well as thyroid hormone withdrawal, may theoretically cause stimulation of tumor growth. In clinical studies, the use of thyrotropin alfa, accompanied by a short-term increase in serum TSH concentration, did not lead to the activation of tumor growth.

Due to an increase in TSH concentration after the administration of the drug Thyrogen, local edema or focal hemorrhages may occur in patients with metastases of thyroid cancer at the sites of metastasis (especially in organs located in confined anatomical spaces, such as the brain, spinal cord, and organ of vision, as well as with infiltration of neck tissues), which is manifested by an increase in tumor size. This can lead to the sudden appearance of various symptoms depending on the anatomical location of the tumor foci (for example, in patients with brain metastases, hemiplegia, hemiparesis, or loss of vision may develop).

Cases of laryngeal edema, respiratory distress syndrome requiring tracheotomy, as well as pain at the sites of metastasis have been reported during the use of the drug Thyrogen. In case of risk of compression of vital anatomical structures due to an increase in tumor size, prior treatment with glucocorticosteroids is recommended.

Important information about some excipients

The drug Thyrogen contains 1 mmol of sodium (23 mg) in one injection dose, i.e., it can be considered sodium-free.

Influence on the ability to drive vehicles and mechanisms

The use of the drug Thyrogen may reduce the ability to drive vehicles and mechanisms, as the development of dizziness and headache after its administration has been reported.

Overdose

Symptoms

Data on exceeding the recommended dosages of the drug were obtained only during clinical studies and a special treatment program. In three clinical study participants and one patient from the special treatment program, the use of the drug Thyrogen in an increased dose led to the development of a number of clinical symptoms. In two patients, intramuscular administration 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 the third patient, intramuscular administration 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 administration of 4 doses of the drug Thyrogen of 0.9 mg each over 6 days to a 77-year-old patient with metastatic thyroid cancer who had not undergone thyroidectomy was registered. After 2 days, the patient developed atrial fibrillation, decompensated heart failure with fatal myocardial infarction.

In another clinical study participant, clinical symptoms occurred after intravenous administration of the drug Thyrogen. Fifteen minutes after a single bolus injection of the drug Thyrogen at a dose of 0.3 mg, the patient developed severe nausea, vomiting, increased sweating, arterial hypotension, and tachycardia.

Treatment

In case of an overdose of the drug Thyrogen, measures aimed at restoring water balance are recommended. If necessary, the administration of antiemetics is indicated.

Drug Interactions

Special studies of the interaction of the drug Thyrogen with other medicinal products have not been conducted. During clinical studies, no cases of interaction between the drug Thyrogen and thyroid hormones – T3 and T4 – were registered.

The use of the drug Thyrogen allows performing scintigraphy with radioactive iodine in a euthyroid state during suppressive therapy with thyroid hormones. Analysis of radioactive iodine kinetics indicates that its clearance in a euthyroid state is approximately 50% higher than in hypothyroidism, which is characterized by reduced renal function. An increase in radioactive iodine clearance contributes to a reduction in its retention time in the body during scintigraphy. This factor must be taken into account when choosing the dose of radioactive iodine for scintigraphy.

Storage Conditions

The drug should be stored out of the reach of children at a temperature from 2°C (35.6°F) to 8°C (46.4°F).

Shelf Life

Shelf life – 3 years. Do not use after the expiration date.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.