Clinical Pharmacology

Characteristics and Actions of Thyrogen

Thyrotropin alfa is a heterodimeric glycoprotein comprised of 2 non-covalently linked subunits, an alpha subunit of 92 amino acid residues containing 2 N-linked glycosylation sites, and a beta subunit of 118 residues containing 1 N-linked glycosylation site. The amino acid sequence of thyrotropin alfa [rhTSH, recombinant human thyroid stimulating hormone (TSH)] is identical to that of human pituitary TSH.1

Human pituitary TSH and rhTSH1

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Binding of thyrotropin alfa to TSH receptors on normal thyroid epithelial cells or on well-differentiated thyroid cancer tissue stimulates iodine uptake and organification and synthesis and secretion of thyroglobulin (Tg), thyroxine (T4), and triiodothyronine (T3).1

Prior to radioiodine remnant ablation, serum TSH elevation is used to promote uptake of radioiodine by thyroid cells or thyroid cancer cells. Elevation of TSH may be achieved by withholding synthetic thyroid hormone medication after thyroidectomy, with subsequent rise of endogenous pituitary TSH. 

However, withdrawal of T4 and T3 results in hypothyrodism.2

Normal thyroid physiology3

Thyroid hormone withdrawal results in a slow rise in TSH levels over several weeks.4

Alternatively, rhTSH can be administered to promote uptake of radioiodine without withdrawal of T4 and T3.1

TSH stimulation is necessary for some methods of follow-up testing, including whole-body scans and serum Tg. This may be achieved through administration of rhTSH or thyroid hormone withdrawal, as shown above.5

rhTSH Produces a Rapid Increase in TSH

The pharmacokinetics of rhTSH were studied in 16 patients with well-differentiated thyroid cancer given a single intramuscular dose of 0.9 mg. Mean peak concentrations of 116 ± 38 mU/L were reached between 3 and 24 hours after injection (median of 10 hours). The mean apparent elimination half-life was 25 ± 10 hours. The organ(s) of TSH clearance in humans have not been identified, but studies of pituitary-derived TSH suggest involvement of the liver and kidneys.1

Serum TSH concentration6

References

  1. Thyrogen (thyrotropin alfa for injection) Package Insert. Cambridge, MA. Genzyme Corp. 2014.
  2. Carballo M, Quiros RM. To treat or not to treat: the role of adjuvant radioiodine therapy in thyroid cancer patients. J Oncol. 2012; doi:10.1155/2012/707156.
  3. Mariotti S. Physiology of the Hypothalamic-Pituitary Thyroidal System. Thyroid Disease Manager. 2011. Available at: http://www.thyroidmanager.org/chapter/physiology-of-the-hypothalmic-pituitary-thyroidal-system/. Accessed Nov 6, 2015.
  4. Rosario PW, Salles DS, Purisch S. Area under the curve of TSH after levothyroxine withdrawal versus administration of recombinant human TSH (rhTSH): possible implications for tumor growth. Arq Bras Endocrinol Metabol. 2009;53:767-770.
  5. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2015; doi: 10.1089/thy.2015.0020.
  6. Data on file, Sanofi Genzyme.

INDICATIONS AND USAGE
Thyrogen is a thyroid stimulating hormone indicated for:

Diagnostic: Use as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy.

Limitations of Use:
Thyrogen-stimulated Tg levels are generally lower than, and do not correlate with Tg levels after thyroid hormone withdrawal. Even when Thyrogen-Tg testing is performed in combination with radioiodine imaging, there remains a risk of missing a diagnosis of thyroid cancer or underestimating the extent of the disease. Anti-Tg Antibodies may confound the Tg assay and render Tg levels uninterpretable.

Ablation
: Use as an adjunctive treatment for radioiodine 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.

Limitations of Use:
The effect of Thyrogen on long term thyroid cancer outcomes has not been determined.

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Thyrogen® (thyrotropin alfa for injection) 0.9 mg/mL after reconstitution

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS

There have been reports of death in non-thyroidectomized patients and in patients with distant metastatic thyroid cancer in which events leading to death occurred within 24 hours after administration of Thyrogen.

There are post marketing reports of stroke in young women with risk factors for stroke, and neurological findings suggestive of stroke (e.g., unilateral weakness) occurring within 72 hours of Thyrogen administration in patients without known central nervous system metastases.

Sudden, rapid and painful enlargement of residual thyroid tissue or distant metastases can occur following treatment with Thyrogen.

Pretreatment with glucocorticoids should be considered for patients in whom tumor expansion may compromise vital anatomic structures.

Patients should be well-hydrated prior to treatment with Thyrogen.

Caution should be exercised in patients who have substantial thyroid tissue still in situ or functional thyroid cancer metastases, specifically in the elderly and those with a known history of heart disease.

Hospitalization for administration of Thyrogen and post-administration observation in patients at risk should be considered.

ADVERSE REACTIONS

The most common adverse reactions reported in clinical trials were nausea and headache.

USE IN SPECIFIC POPULATIONS

Pregnancy Category C: Animal reproduction studies have not been conducted with Thyrogen. It is also not known whether Thyrogen can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Thyrogen should be given to a pregnant woman only if clearly needed.

Nursing Mothers: It is not known whether the drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Thyrogen is administered to a nursing woman.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Results from controlled trials do not indicate a difference in the safety and efficacy of Thyrogen between adult patients less than 65 years and those over 65 years of age.

Renal Impairment: Elimination of Thyrogen is significantly slower in dialysis-dependent end stage renal disease patients, resulting in prolonged elevation of TSH levels.

INDICATIONS AND USAGE

Thyrogen is a thyroid stimulating hormone indicated for:

Diagnostic: Use as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy.

Limitations of Use:

  • Thyrogen -stimulated Tg levels are generally lower than, and do not correlate with Tg levels after thyroid hormone withdrawal.
  • Even when Thyrogen -Tg testing is performed in combination with radioiodine imaging, there remains a risk of missing a diagnosis of thyroid cancer or underestimating the extent of the disease.
  • Anti-Tg Antibodies may confound the Tg assay and render Tg levels uninterpretable.

Ablation: Use as an adjunctive treatment for radioiodine 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.

Limitations of Use:

  • The effect of Thyrogen on long term thyroid cancer outcomes has not been determined.

See full Prescribing Information for more details.