Thyrotropin alfa is an injectable thyroid-stimulating hormone (TSH) indicated as an adjunctive diagnostic tool for serum thyroglobulin testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy and as adjunctive therapy 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. Thyrotropin alfa is synthesized in a genetically modified Chinese hamster ovary cell line. Use of thyrotropin alfa before whole-body scanning avoids the need to withdraw the patient's exogenous thyroid supplements 2 weeks or more before scanning and placing the patient in a hypothyroid state. The utility of thyrotropin alfa in scanning for thyroid cancer was compared to standard scanning with withdrawal of thyroid hormone; thyrotropin alfa stimulated radioiodine uptake and resulted in positive scans that were as sensitive as those obtained after withdrawal of thyroid hormone in 71% of cases. In cases where thyrotropin alfa scans were not as sensitive, 6% of patients had more advanced tumor staging and 13% required radioiodine treatment. Patients given thyrotropin alfa appear to have improved quality of life compared to patients who discontinue their thyroid hormone therapy. Thyrotropin alfa also stimulates the production of thyroglobulin by residual thyroid tissue, which may increase the usefulness of thyroglobulin as a tumor marker in patients who have had thyroid ablation and are being treated with thyroid hormone. The effect of thryotropin alfa on thyroid cancer recurrence more than 5 years post-remnant ablation has not been evaluated.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-Consider pretreatment with glucocorticoids for patients in whom tumor expansion may compromise vital anatomic structures.
-Routine measurement of thyroid-stimulating hormone (TSH) concentrations is not recommended after thyrotropin alfa use.
Route-Specific Administration
Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intramuscular Administration
-For intramuscular injection only. Do not administer intravenously.
-Thyrotropin alfa use requires a physician knowledgeable in the management of thyroid cancer.
Reconstitution
-Reconstitute the vial with 1.2 mL of Sterile Water for Injection, USP to yield a single-dose solution containing 0.9 mg/mL of thyrotropin alfa that delivers 1 mL (0.9 mg).
-Gently swirl the contents of the vial until all the material is dissolved. Do not shake the solution.
-Storage: The reconstituted solution must be injected within 3 hours unless refrigerated. If necessary, the reconstituted solution may be stored refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours.
Intramuscular injection
-Withdraw 1 mL (0.9 mg) of the reconstituted solution and inject intramuscularly into the outer region of the gluteus maximus.
-Do not mix with other substances.
Thyrotropin alfa may cause a transient but significant increase in thyroid hormones (7 to 14 days) leading to transient symptoms of hyperthyroidism. Among 481 thyrotropin alfa recipients, nausea (11%), headache (6%), fatigue (2%), vomiting (2%), dizziness (2%), and asthenia (1%) were reported. An increased risk of both nausea and headache may occur in patients with dialysis-dependent end stage renal disease, as the elimination of thyrotropin alfa is significantly slower and, thus, results in prolonged elevation of TSH concentrations. Patients who received thyrotropin alfa at doses higher than recommended (2.7 to 3.6 mg IM) experienced weakness, dizziness, headache, nausea, vomiting, and hot flashes. Headache may also be part of transient (less than 48 hours) influenza-like symptoms, which may also include fever, chills, shivering, myalgia, arthralgia, fatigue, asthenia, and malaise.
Sudden, rapid and painful enlargement of residual thyroid tissue or distant metastases can occur following treatment with thyrotropin alfa. This may lead to acute symptoms, which depend on the anatomical location of the tissue. Such symptoms include acute hemiplegia, hemiparesis (paresis on one side of the body), and loss of vision (visual impairment) 1 to 3 days (24 to 72 hours) after thyrotropin alfa administration. Laryngeal edema, pain at the site of distant metastasis, and respiratory distress (dyspnea) requiring tracheotomy have also been reported after thyrotropin alfa administration. Premedication with corticosteroids should be considered for patients in whom local tumor expansion may compromise vital anatomic structures.
Hypersensitivity reactions, including urticaria, rash (unspecified), pruritus, flushing, and respiratory signs and symptoms (such as dyspnea or wheezing), have been reported with thyrotropin alfa use in postmarketing surveillance.
Cases of radiologically-confirmed stroke and neurological findings suggestive of stroke unconfirmed radiologically (e.g., unilateral weakness) occurring within 72 hours (range, 20 minutes to 3 days) of thyrotropin alfa administration have been reported postmarketing in patients without known CNS metastases. Most cases involved young women taking oral contraceptives at the time of their event or had other risk factors for stroke, such as smoking or a history of migraine headaches. The relationship between thyrotropin alfa administration and stroke is unknown. Patients should be well-hydrated prior to treatment with thyrotropin alfa.
An injection site reaction, including erythema, pruritus, hematoma, or pain, has been reported with use of thyrotropin alfa during postmarketing surveillance.
Thyrotropin alfa therapy requires an experienced clinician to guide the diagnostic or treatment course. The drug should be used by physicians knowledgeable in the management of patients with thyroid cancer. Sudden, rapid and painful enlargement of residual thyroid tumor or distant metastases can occur following treatment with thyrotropin alfa. This may lead to acute symptoms, including hemiplegia, hemiparesis, and loss of vision one to three days after thyrotropin alfa administration, depending on the anatomical location of the tissue. Laryngeal edema, pain at the site of distant metastasis, and respiratory distress requiring tracheotomy have also been reported after thyrotropin alfa administration. Premedication with corticosteroids should be considered for patients in whom local tumor expansion may compromise vital anatomic structures. When thyrotropin alfa-stimulated thyroglobulin (Tg) testing is performed in combination with radioiodine imaging, there is still a risk of missing a diagnosis of thyroid cancer or underestimating the extent of disease. Thyrotropin alfa-stimulated Tg levels are generally lower than, and do not correlate with Tg levels after thyroid hormone withdrawal. Furthermore, antibodies to thyroglobulin may confound the assay and render the thyroglobulin concentrations non-interpretable. In these instances, patients should also be evaluated further, even with a negative or low-stage thyrotropin radioiodine scan.
When given to patients who have substantial thyroid tissue still in situ or functional thyroid cancer metastases, thyrotropin alfa is known to cause a transient (over 7 to 14 days) but significant rise in serum thyroid hormone concentration. 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 thyrotropin alfa. Patients with residual thyroid tissue at risk for thyrotropin alfa-induced hyperthyroidism include geriatric patients and those with a known history of cardiac disease. Consider hospitalization for administration of thyrotropin alfa and postadministration observation in patients at risk.
There are postmarketing reports of radiologically-confirmed stroke and neurological findings suggestive of stroke unconfirmed radiologically (e.g., unilateral weakness) occurring within 72 hours (range, 20 minutes to 3 days) of thyrotropin alfa administration in patients without known CNS metastases. The majority of such patients were young females taking oral contraceptives at the time of their event or had other risk factors for stroke, such as tobacco smoking or a history of migraine headaches. The relationship between thyrotropin alfa administration and stroke is unknown. Ensure patients are well-hydrated before treatment with thyrotropin alfa.
Thyrotropin alfa elimination is significantly reduced in patients with end-stage renal failure on dialysis; elevated TSH concentrations which occur with thyrotropin alfa therapy are prolonged in these patients.
The combination of thyrotropin alfa and radioiodine in pregnant women is contraindicated because fetal exposure of radioiodine can lead to neonatal hypothyroidism, which in some cases is severe and irreversible. Available data with thyrotropin alfa use in human pregnancy are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal reproduction studies have not been conducted with thyrotropin alfa.
The combination of thyrotropin alfa and radioiodine in lactating women is contraindicated because radioiodine concentrates in the breast tissue and increases the risk of radiation breast toxicity. There are no data available on the presence of thyrotropin alfa in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for thyrotropin alfa and any potential adverse effects on the breast-fed infant from thyrotropin alfa or the underlying maternal condition.
For use in patients with thyroid cancer:
-for use as an adjunctive diagnostic tool for serum thyroglobulin testing (with or without radioiodine imaging) in the follow-up of patients with well-differentiated thyroid cancer who have undergone thyroidectomy:
NOTE: Thyrotropin has been designated an orphan drug by the FDA for this indication.
Intramuscular dosage:
Adults: 0.9 mg (1 mL) IM once every 24 hours for 2 doses. For radioiodine imaging, radioiodine administration should be given 24 hours following the final thyrotropin alfa injection. Diagnostic scanning should be performed 48 hours after administration of the radioiodine (72 hours after the last thyrotropin alfa injection). For serum thyroglobulin testing, the serum sample should be obtained 72 hours after the final injection of thyrotropin alfa.
-for adjunctive treatment in 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 metastatic thyroid disease:
Intramuscular dosage:
Adults: 0.9 mg (1 mL) IM once every 24 hours for 2 doses. Radioiodine should be given 24 hours after the final dose of thyrotropin alfa. Diagnostic scanning should be performed 48 hours after radioiodine administration. The activity of 131I should be carefully selected at the discretion of the nuclear medicine physician. Studies using thyrotropin alfa used 30 to 100 mCi +/- 10% of 131I.
Maximum Dosage Limits:
-Adults
0.9 mg/day IM for 2 doses.
-Geriatric
0.9 mg/day IM for 2 doses.
-Adolescents
Safety and efficacy have not been established.
-Children
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed. However, patients requiring dialysis may experience prolonged elevated TSH concentrations; caution is advised, and patients should be monitored for increased toxicity.
*non-FDA-approved indication
There are no drug interactions associated with Thyrotropin Alfa products.
Thyrotropin alfa acts similarly to native thyroid stimulating hormone (TSH). Binding of thyrotropin alfa to TSH receptors on normal thyroid tissue or on well differentiated thyroid cancer tissue stimulates iodine uptake and organification, and the synthesis and release of thyroglobulin (Tg), triiodothyronine (T3), and thyroxine (T4). The effect of TSH activation on thyroid cells is to increase uptake of radioiodine to allow scan detection or radioiodine killing of thyroid cells. TSH activation also leads to the release of thyroglobulin by thyroid cells, which functions as a tumor marker and is detected in blood specimens.
Thyrotropin alfa is administered by intramuscular injection. Following thyrotropin alfa administration, serum Tg concentrations rose from a baseline of 0.2 +/- 0.3 milliunits/L to 101 +/- 60 and 132 +/- 89 milliunits/L 24 hours after the first and second doses of thyrotropin. On the day of radioiodine administration (72 hours after the second dose of thyrotropin), the mean serum Tg level was 16 +/- 12 milliunits/L as compared to a mean Tg level of 101 +/- 77 milliunits/L on the day of radioiodine administration following thyroid hormone withdrawal. The mean elimination half-life of thyrotropin is 25 +/- 10 hours. The elimination organs for thyrotropin is not known; however, it appears that clearance of TSH occurs through the kidneys and the liver.
-Route-Specific Pharmacokinetics
Intramuscular Route
Following a single 0.9 mg intramuscular (IM) dose in 16 patients, the mean peak serum concentration of thyrotropin was 116 +/- 38 milliunits/L occurring at a median of 10 hours (range, 3 to 24 hours) following administration.
-Special Populations
Hepatic Impairment
Studies of pituitary-derived TSH suggest the involvement of the liver in the elimination of the drug; however, studies with thyrotropin alfa in hepatic impairment are not available.
Renal Impairment
Elimination of thyroptropin alfa is significantly longer in patients with end-stage renal disease on dialysis, resulting in prolonged elevation of TSH levels.