Thyrotropin Alfa

Thyrotropin alfa is recombinant human thyroid-stimulating hormone (rhTSH), a heterodimeric glycoprotein made by recombinant DNA technology. It has two subunits that are not covalently linked: an alpha subunit of 92 amino acid residues with two N-linked glycosylation sites, and a beta subunit of 118 residues with one. Its biochemical properties are comparable with those of natural human TSH.

Mechanism of Action

• Receptor binding: thyrotropin alfa binds to TSH receptors on thyroid epithelial cells, including well-differentiated thyroid cancer tissue. This stimulates iodine uptake and organification, and the synthesis and release of thyroglobulin, triiodothyronine (T3) and thyroxine (T4).
• Why stimulation is needed: after a near-total or total thyroidectomy for well-differentiated thyroid cancer, a high serum TSH is needed to drive radioiodine uptake and thyroglobulin release, both for diagnosis (radioiodine imaging or thyroglobulin testing) and for radioiodine therapy of remnants.
• Instead of hormone withdrawal: the usual way to raise TSH is to withdraw thyroid hormone suppression therapy (THST), which brings on the signs and symptoms of hypothyroidism. With thyrotropin alfa the TSH stimulation is achieved while patients stay euthyroid on THST.

Pharmacokinetics

• Absorption: after a single 0.9 mg intramuscular injection in patients with well-differentiated thyroid cancer, the mean peak level was 116 ± 38 mU/L, reached about 13 ± 8 hours after the injection.
• Elimination: the half-life is 22 ± 9 hours. The main route of elimination is believed to be renal, and to a lesser extent hepatic.
• Special populations: elimination is significantly slower in dialysis-dependent end-stage renal disease, with TSH raised for several days. Reduced liver function needs no special consideration.

• Diagnostic 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 thyroid hormone suppression therapy (THST).
• Follow-up of low-risk patients: patients with well-differentiated thyroid carcinoma who have undetectable serum Tg levels on THST and no rhTSH-stimulated increase of Tg may be followed up by assaying rhTSH-stimulated Tg levels.
• Pre-therapeutic stimulation: in combination with 30 mCi (1.1 GBq) to 100 mCi (3.7 GBq) of radioiodine for ablation of thyroid tissue remnants in patients who have had a near-total or total thyroidectomy for well-differentiated thyroid cancer and who have no evidence of distant metastatic thyroid cancer.

• Hypersensitivity to bovine or human thyroid-stimulating hormone, or to any of the excipients.
• Pregnancy. In particular, Thyrogen with diagnostic radioiodine whole-body scintigraphy is contraindicated in pregnancy because the foetus would be exposed to a high dose of radioactive material.

The most commonly reported reactions are nausea (about 11% of patients) and headache (about 6%). The SmPC table combines reactions from six prospective clinical trials (481 patients) with reports received after marketing.

Very common (≥1/10): nausea.

Common (≥1/100 to <1/10): dizziness, headache, vomiting, fatigue, asthenia.

Uncommon (≥1/1,000 to <1/100): influenza, ageusia, dysgeusia, paraesthesia, diarrhoea, urticaria, rash, neck pain, back pain, influenza-like illness, pyrexia, chills, feeling hot.

Not known: swelling of the tumour, metastatic pain, stroke, tremor, palpitations, flushing, dyspnoea, pruritus, hyperhidrosis, arthralgia, myalgia, discomfort, pain, pruritus, rash and urticaria at the injection site, decreased TSH.

Further points from the SmPC:

• Very rare cases of hyperthyroidism or atrial fibrillation have been seen with 0.9 mg Thyrogen in patients with part or all of the thyroid gland still present.
• Hypersensitivity reactions (urticaria, rash, pruritus, flushing, and respiratory signs and symptoms) have been reported uncommonly.
• Enlargement of residual thyroid tissue or metastases can follow treatment and may cause acute symptoms, depending on where the tissue lies (see Special Instructions).
• No antibodies to thyrotropin alfa developed in 481 trial patients, including 27 who had repeated use.

• No formal interaction studies have been performed. In clinical trials no interaction was seen between Thyrogen and the thyroid hormones T3 and T4 given at the same time.
• Radioiodine: radioiodine clearance is about 50% greater while the patient is euthyroid than in the hypothyroid state, when renal function is decreased, so less radioiodine is retained at the time of imaging. This should be considered when choosing the radioiodine activity for imaging.
• Significant renal impairment: the nuclear medicine physician should select the radioiodine activity carefully.

Treatment should be supervised by physicians with expertise in thyroid cancer. Thyrogen is given by healthcare staff, by intramuscular injection only, and never into a vein.

Recommended Dose

• Two doses of 0.9 mg of thyrotropin alfa, given 24 hours apart by intramuscular injection only.
• The powder is reconstituted with water for injection (1.2 mL per vial). 1.0 mL of the solution, equal to 0.9 mg, is withdrawn and injected into the buttock. The SmPC gives the reconstitution instructions in section 6.6.

Timing with Radioiodine and Testing

• Radioiodine imaging or ablation: radioiodine is given 24 hours after the final Thyrogen injection. Diagnostic scintigraphy follows 48 to 72 hours after the radioiodine. Post-ablation scintigraphy may be delayed by additional days so that background activity can fall.
• Thyroglobulin testing: the serum sample is taken 72 hours after the final Thyrogen injection. Use of Thyrogen with Tg testing in the follow-up of post-thyroidectomy well-differentiated thyroid cancer should follow official guidelines.

Special Populations

• Children: because data are lacking, Thyrogen is given to children only in exceptional circumstances.
• Elderly: in controlled trials there was no difference in safety and efficacy between patients under and over 65 years when Thyrogen was used for diagnosis. No dose adjustment is needed.
• Renal impairment: elimination is significantly slower in dialysis-dependent end-stage renal disease, leaving TSH raised for several days, which may increase the risk of headache and nausea. No alternative dose schedules have been studied. In significant renal impairment the nuclear medicine physician selects the radioiodine activity carefully.
• Hepatic impairment: reduced liver function needs no special consideration.

Traceability

The name and batch number of the administered product should be clearly recorded, to improve the traceability of this biological medicine.

Not for Intravenous Use

Thyrogen must not be given intravenously.

False Negative Results and Thyroglobulin Antibodies

• Used as an alternative to thyroid hormone withdrawal, whole-body scintigraphy (WBS) combined with Tg testing after Thyrogen gives the highest sensitivity for detecting thyroid remnants or cancer. False negative results may still occur. If suspicion of metastatic disease stays high, a confirmatory WBS and Tg test after hormone withdrawal should be considered.
• Tg autoantibodies are expected in 18–40% of patients with differentiated thyroid cancer and can cause false negative Tg results, so both TgAb and Tg assays are needed.
• TSH assays are not recommended after Thyrogen administration, because antibodies that could interfere with endogenous TSH assays cannot be excluded.

Heart Disease and Residual Thyroid Tissue

• The benefit–risk balance needs careful evaluation in high-risk elderly patients with heart disease (valvular disease, cardiomyopathy, coronary artery disease, or past or current tachyarrhythmia including atrial fibrillation) who have not had a thyroidectomy.
• Thyrogen causes a transient but significant rise in serum thyroid hormone when substantial thyroid tissue remains in place, so individual risk and benefit must be weighed in patients with significant residual thyroid tissue.

Tumour Growth and Metastases

• Stimulated tumour growth has been reported during thyroid hormone withdrawal, attributed to the prolonged rise in TSH. There is a theoretical possibility that Thyrogen could do the same; in clinical trials, which involve a short-term rise in TSH, no case of tumour growth was reported.
• In patients with metastatic thyroid cancer, especially in confined spaces such as the brain, spinal cord and orbit, or disease infiltrating the neck, the rise in TSH may cause local oedema or focal haemorrhage and an increase in tumour size. Hemiplegia, hemiparesis and 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.
• Pre-treatment with corticosteroids should be considered in patients in whom local tumour expansion may compromise vital anatomical structures.

Sodium

Each injection contains less than 1 mmol sodium (23 mg), so the medicine is essentially sodium-free.

Pregnancy, Breastfeeding and Fertility

• Pregnancy: contraindicated. Animal reproduction studies have not been conducted, and it is not known whether Thyrogen can cause foetal harm. With diagnostic radioiodine whole-body scintigraphy it would expose the foetus to a high dose of radioactive material.
• Breastfeeding: it is unknown whether thyrotropin alfa or its metabolites pass into breast milk, and a risk to the suckling child cannot be excluded. Thyrogen should not be used during breastfeeding.
• Fertility: it is not known whether Thyrogen affects fertility in humans.

Effect on Driving

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

Store the vials in a refrigerator at 2–8 °C, in the outer carton to protect them from light. Keep the cold chain unbroken during transport and handling. For storage after reconstitution, see Shelf Life.

3 years for unopened vials. After reconstitution it is recommended to inject the solution within 3 hours. The reconstituted solution can be kept for up to 24 hours in a refrigerator (2–8 °C), protected from light, while avoiding microbial contamination.

Prescription only (Rx), under restricted medical prescription (Annex II B). Treatment is supervised by a physician with expertise in thyroid cancer. Thyrogen is injected by healthcare staff, so it is supplied to the hospital or clinic that administers it, with cold-chain delivery at 2–8 °C.