4.1. Therapeutic indications

Thyrogen is indicated for use with serum thyroglobulin (Tg) testing with or without radioiodine imaging for the detection of thyroid remnants and well-differentiated thyroid cancer in post-thyroidectomy patients maintained on hormone suppression therapy (THST).

Low risk patients with well-differentiated thyroid carcinoma who have undetectable serum Tg levels on THST and no rh (recombinant human) TSH-stimulated increase of Tg levels may be followed-up by assaying rhTSH-stimulated Tg levels.

Thyrogen is indicated for pre-therapeutic stimulation in combination with a range of 30 mCi (1.1 GBq) to 100 mCi (3.7 GBq) radioiodine for ablation of thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for well-differentiated thyroid cancer and who do not have evidence of distant metastatic thyroid cancer (see section 4.4).

4.2. Posology and method of administration

Therapy should be supervised by physicians with expertise in thyroid cancer.

Posology

The recommended dose regimen is two doses of 0.9 mg thyrotropin alfa administered at a 24-hour interval by intramuscular injection only.

Paediatric population

Due to a lack of data on the use of Thyrogen in children, Thyrogen should be given to children only in exceptional circumstances.

Elderly

Results from controlled trials indicate no difference in the safety and efficacy of Thyrogen between adult patients less than 65 years and those greater than 65 years of age, when Thyrogen is used for diagnostic purposes.

No dose adjustment is necessary in elderly (see section 4.4).

Patients with renal/hepatic impairment

Information from post marketing surveillance, as well as published information, suggests that elimination of Thyrogen is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of thyroid stimulating hormone (TSH) levels for several days after treatment. This may lead to increased risk of headache and nausea. There are no studies of alternative dose schedules of Thyrogen in patients with ESRD to guide dose reduction in this population.

In patients with significant renal impairment the activity of radioiodine should be carefully selected by the nuclear medicine physician.

The use of Thyrogen in patients with reduced liver function does not warrant special considerations.

Method of administration

After reconstitution with water for injection, 1.0 ml solution (0.9 mg thyrotropin alfa) is administered by intramuscular injection to the buttock. For instructions on reconstitution of the medicinal product before administration, see section 6.6.

For radioiodine imaging or ablation, radioiodine administration should be given 24 hours following the final Thyrogen injection. Diagnostic scintigraphy should be performed 48 to 72 hours following radioiodine administration, whereas post-ablation scintigraphy may be delayed additional days to allow background activity to decline.

For diagnostic follow-up serum thyroglobulin (Tg) testing, the serum sample should be obtained 72 hours after the final injection of Thyrogen. Use of Thyrogen with Tg testing in follow up of post-thyroidectomy well differentiated thyroid cancer patients should be in accordance with official guidelines.

4.3. Contraindications

• Hypersensitivity to bovine or human thyroid stimulating hormone or to any of the excipients listed in section 6.1.

• Pregnancy (see section 4.6).

4.4. Special warnings and precautions for use

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Thyrogen should not be administered intravenously.

When used as an alternative to thyroid hormone withdrawal, the combination of the whole body scintigraphy (WBS) and Tg testing after Thyrogen administration assures the highest sensitivity for detection of thyroid remnants or cancer. False negative results may occur with Thyrogen. If a high index of suspicion for metastatic disease persists, a confirmatory withdrawal WBS and Tg testing should be considered.

The presence of Tg autoantibodies can be expected in 18-40% of patients with differentiated thyroid cancer and may cause false negative serum Tg measurements. Therefore, both TgAb and Tg assays are needed.

Careful evaluation of benefit-risk relationships should be assessed for Thyrogen administration in high risk elderly patients who have heart disease (e.g. valvular heart disease, cardiomyopathy, coronary artery disease, and prior or current tachyarrhythmia including atrial fibrillation) and have not undergone thyroidectomy.

Thyrogen is known to cause a transient but significant rise in serum thyroid hormone concentration when given to patients who have substantial thyroid tissue still in situ. Therefore, careful evaluation of individual risk-benefit is necessary for patients with significant residual thyroid tissue.

Effect on tumour growth and/or size

In patients with thyroid cancer, several cases of stimulated tumour growth have been reported during withdrawal of thyroid hormones for diagnostic procedures which have been attributed to the associated prolonged elevation of TSH levels.

There is a theoretical possibility that Thyrogen, like thyroid hormone withdrawal, may lead to stimulated tumour growth. In clinical trials with thyrotropin alfa, which produces a short-term increase in serum TSH levels, no case of tumour growth has been reported.

Due to elevation of TSH levels after Thyrogen administration patients with metastatic thyroid cancer particularly in confined spaces such as the brain, spinal cord and orbit or disease infiltrating the neck, may experience local oedema or focal haemorrhage at the site of these metastases resulting in increased tumour size. This may lead to acute symptoms, which depend on the anatomical location of the tissue e.g. hemiplegia, hemiparesis, loss of vision have occurred in patients with CNS metastases. Laryngeal oedema, respiratory distress requiring tracheotomy, and pain at the site of metastasis have also been reported after Thyrogen administration. It is recommended that pre-treatment with corticosteroids be considered for patients in whom local tumour expansion may compromise vital anatomic structures.

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially 'sodium- free'.

4.5. Interaction with other medicinal products and other forms of interaction

Formal interaction studies between Thyrogen and other medicinal products have not been performed. In clinical trials, no interactions were observed between Thyrogen and the thyroid hormones triiodothyronine (T3) and thyroxine (T4) when administered concurrently.

The use of Thyrogen allows for radioiodine imaging while patients are euthyroid on thyroid hormone suppression treatment. Data on radioiodine kinetics indicate that the clearance of radioiodine is approximately 50% greater while euthyroid than during the hypothyroid state when renal function is decreased, thus resulting in less radioiodine retention in the body at the time of imaging. This factor should be considered when selecting the activity of radioiodine for use in radioiodine imaging.

4.6. Fertility, pregnancy and lactation

Pregnancy

Animal reproduction studies have not been conducted with Thyrogen.

It is not known whether Thyrogen can cause foetal harm when administered to a pregnant woman or whether Thyrogen can affect reproductive capacity.

Thyrogen in combination with diagnostic radioiodine whole body scintigraphy is contra-indicated in pregnancy (see section 4.3), because of the consequent exposure of the foetus to a high dose of radioactive material.

Breast-feeding

It is unknown whether thyrotropin alfa /metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Thyrogen should not be used during breast-feeding.

Fertility

It is not known whether Thyrogen can affect fertility in humans.

4.7. Effects on ability to drive and use machines

Thyrogen may reduce the ability to drive or use machines, since dizziness and headaches have been reported.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are nausea and headache, occurring in approximately 11%, and 6% of patients, respectively.

Tabulated list of adverse reactions

The adverse reactions mentioned in the table, combine adverse reactions in the six prospective clinical trials (N=481) and undesirable effects that have been reported to Sanofi after licensure of Thyrogen.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).

MedDRA System Organ Class

Very Common

Common

Uncommon

Not known

Infections and infestations

influenza

Neoplasm benign, malignant and unspecified (incl. cysts and polyps)

neoplasm swelling, metastatic pain

Nervous system disorders

dizziness, headache

ageusia, dysgeusia, paraesthesia

stroke, tremor

Cardiac disorders

palpitations

Vascular disorders

flushing

Respiratory, thoracic and mediastinal disorder

dyspnoea

Gastrointestinal disorders

nausea

vomiting

diarrhoea

Skin and subcutaneous tissue disorders

urticaria, rash

pruritus, hyperhidrosis

Musculoskeletal and connective tissue disorder

neck pain, back pain

arthralgia, myalgia

General disorders and administration site conditions

fatigue, asthenia

influenza like illness, pyrexia, chills, feeling hot

discomfort, pain, pruritus, rash and urticaria at the site of injection

Investigations

TSH decreased

Description of selected adverse reactions

Very rare cases of hyperthyroidism or atrial fibrillation have been observed when Thyrogen 0.9 mg has been administered in patients with presence of either partial or entire thyroid gland.

Manifestations of hypersensitivity have been reported uncommonly in both clinical and post-marketing settings. These reactions consisted of urticaria, rash, pruritus, flushing and respiratory signs and symptoms.

In clinical trials involving 481 patients, no patients have developed antibodies to thyrotropin alfa either after single or repeated limited (27 patients) use of the product. It is not recommended to perform TSH assays after Thyrogen administration. The occurrence of antibodies which could interfere with endogenous TSH assays performed during regular follow-ups cannot be excluded.

Enlargement of residual thyroid tissue or metastases can occur following treatment with Thyrogen. This may lead to acute symptoms, which depend on the anatomical location of the tissue. For example, hemiplegia, hemiparesis or loss of vision have occurred in patients with CNS metastases. Laryngeal oedema, respiratory distress requiring tracheotomy, and pain at the site of metastasis have also been reported after Thyrogen administration. It is recommended that pre-treatment with corticosteroids be considered for patients in whom local tumour expansion may compromise vital anatomic structures.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system below.

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

Data on exposure above the recommended dose is limited to clinical studies and a special treatment program. Three patients in clinical trials and one patient in the special treatment program experienced symptoms after receiving Thyrogen doses higher than those recommended. Two patients had nausea after 2.7 mg IM dose, and in one of these patients nausea was also accompanied by weakness, dizziness and headache. The third patient experienced nausea, vomiting and hot flushes after 3.6 mg IM dose. In the special treatment program, a 77 year-old patient with metastatic thyroid cancer who had not been thyroidectomised received 4 doses of Thyrogen 0.9 mg over 6 days, developed atrial fibrillation, cardiac decompensation and terminal myocardial infarction 2 days later.

One additional patient enrolled in a clinical trial experienced symptoms after receiving Thyrogen intravenously. This patient received 0.3 mg of Thyrogen as a single intravenous (IV) bolus and, 15 minutes later experienced severe nausea, vomiting, diaphoresis, hypotension and tachycardia.

A suggested treatment in case of overdose would be the reestablishment of fluid balance and administration of an antiemetic may also be considered.