1.1 Adjunctive Diagnostic Tool for Serum Thyroglobulin Testing in Well Differentiated Thyroid Cancer

THYROGEN® is indicated for 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.

1.2 Adjunct to Treatment for Ablation in Well Differentiated Thyroid Cancer

THYROGEN is indicated for 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.

2.1 Recommended Dosage

THYROGEN should be used by physicians knowledgeable in the management of patients with thyroid cancer.

THYROGEN is indicated as a two-injection regimen. The recommended dosage of THYROGEN is a 0.9 mg intramuscular injection to the buttock followed by a second 0.9 mg intramuscular injection to the buttock 24 hours later.

THYROGEN should be administered intramuscularly only. THYROGEN should not be administered intravenously.

Pretreatment with glucocorticoids should be considered for patients in whom tumor expansion may compromise vital anatomic structures [see Warnings and Precautions (5.3)].

Routine measurement of serum TSH levels is not recommended after THYROGEN use.

2.2 Reconstitution, Preparation, and Administration of THYROGEN

The supplied lyophilized powder must be reconstituted with Sterile Water for Injection. THYROGEN should be prepared, and administered in the following manner:

• Add 1.2 mL of Sterile Water for Injection to the vial containing the THYROGEN lyophilized powder.
• Swirl the contents of the vial until all the material is dissolved. Do not shake the solution. The reconstituted THYROGEN solution has a concentration of 0.9 mg of thyrotropin alfa per mL.
• Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration. The reconstituted THYROGEN solution should be clear and colorless. Do not use if the solution has particulate matter or is cloudy or discolored.
• Withdraw 1 mL of the reconstituted THYROGEN solution (0.9 mg of thyrotropin alfa) and inject intramuscularly in the buttocks.
• The reconstituted THYROGEN solution must be injected within 3 hours unless refrigerated; if refrigerated, the reconstituted solution may be kept for up to 24 hours.
• Discard unused portions. Do not mix with other substances.

2.3 Timing of Serum Thyroglobulin Testing Following THYROGEN Administration

For serum thyroglobulin testing, the serum sample should be obtained 72 hours after the final injection of THYROGEN [see Clinical Studies (14.1)].

2.4 Timing for Remnant Ablation and Diagnostic Scanning Following THYROGEN Administration

Oral radioiodine should be given 24 hours after the second injection of THYROGEN in both remnant ablation and diagnostic scanning. The activity of 131I is carefully selected at the discretion of the nuclear medicine physician.

Diagnostic scanning should be performed 48 hours after the radioiodine administration.

5.1 THYROGEN-induced Hyperthyroidism

When given to patients who have substantial thyroid tissue still in situ or functional thyroid cancer metastases, THYROGEN 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 THYROGEN. Patients with residual thyroid tissue at risk for THYROGEN-induced hyperthyroidism include 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.

5.2 Stroke

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 three days) of THYROGEN administration in patients without known central nervous system metastases. The majority of such patients were 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 THYROGEN administration and stroke is unknown. Patients should be well-hydrated prior to treatment with THYROGEN.

5.3 Sudden Rapid Tumor Enlargement

Sudden, rapid and painful enlargement of residual thyroid tissue or distant metastases can occur following treatment with THYROGEN. This may lead to acute symptoms, which depend on the anatomical location of the tissue. Such symptoms include acute hemiplegia, hemiparesis, and loss of vision one to three days after THYROGEN administration. Laryngeal edema, pain at the site of distant metastasis, and respiratory distress requiring tracheotomy have also been reported after THYROGEN administration.

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

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data described below reflect exposure to THYROGEN in 481 thyroid cancer patients who participated in a total of 6 clinical trials of THYROGEN: 4 trials for diagnostic use and 2 trials for ablation. In clinical trials, patients had undergone near-total thyroidectomy and had a mean age of 46.1 years. Thyroid cancer diagnosis was as follows: papillary (69.2%), follicular (12.9%), Hurthle cell (2.3%) and papillary/follicular (15.6%). Most patients received 2 intramuscular injections of 0.9 mg of THYROGEN injection given 24 hours apart [see Clinical Studies (14.1) (14.2)].

The safety profile of patients who have undergone thyroidectomy and received THYROGEN as adjunctive treatment for radioiodine ablation of thyroid tissue remnants for well-differentiated thyroid cancer did not differ from that of patients who received THYROGEN for diagnostic purposes.

Reactions reported in ≥ 1% of patients in the combined trials are summarized in Table 1. In some studies, an individual patient may have participated in both THYROGEN and thyroid hormone withdrawal [see Clinical Studies (14.1) (14.2)].

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of THYROGEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Transient (<48 hours) influenza-like symptoms, including fever (>100°F/38°C), chills/shivering, myalgia/arthralgia, fatigue/asthenia/malaise, headache, and chills.
• Hypersensitivity including urticaria, rash, pruritus, flushing, and respiratory signs and symptoms.
• Injection site reactions, including pain, erythema, bruising, and pruritus.

8.1 Pregnancy

8.3 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.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

In pooled clinical studies of THYROGEN, 60 patients (12%) were >65 years, and 421 (88%) were ≤ 65 years of age. 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 [see Warnings and Precautions (5.1)].

8.6 Renal Impairment

Elimination of THYROGEN is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of TSH levels.

12.1 Mechanism of Action

Thyrotropin (TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroid hormone. 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), triiodothyronine (T3) and thyroxine (T4).

The effect of thyroid stimulating hormone activation of 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. Thyroglobulin functions as a tumor marker which is detected in blood specimens.

12.3 Pharmacokinetics

The pharmacokinetics of THYROGEN were studied in 16 patients with well-differentiated thyroid cancer given a single 0.9 mg IM dose. Mean peak serum TSH 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 man have not been identified, but studies of pituitary-derived TSH suggest the involvement of the liver and kidneys.