THYROGEN- thyrotropin alfa injection, powder, for solution
THYROGEN- thyrotropin alfa
Genzyme Corporation
1 INDICATIONS AND USAGE
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.
Limitations of Use:
THYROGEN-stimulated Tg levels are generally lower than, and do not correlate with, Tg levels after thyroid hormone withdrawal [seeClinical Studies (14.1)].
Even when THYROGEN-stimulated Tg testing is performed in combination with radioiodine imaging, there remains a risk of missing a diagnosis of thyroid cancer or of underestimating the extent of disease.
Anti-Tg antibodies may confound the Tg assay and render Tg levels uninterpretable [see Clinical Studies(14.1)]. Therefore, in such cases, even with a negative or low-stage THYROGEN radioiodine scan, consideration should be given to further evaluating patients.
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.
Limitations of Use:
The effect of THYROGEN on long-term thyroid cancer outcomes has not been determined. Due to the relatively small clinical experience with THYROGEN in remnant ablation, it is not possible to conclude whether long-term thyroid cancer outcomes would be equivalent after use of THYROGEN or use of thyroid hormone withholding for TSH elevation prior to remnant ablation.
2 DOSAGE AND ADMINISTRATION
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 131 I is carefully selected at the discretion of the nuclear medicine physician.
Diagnostic scanning should be performed 48 hours after the radioiodine administration.
3 DOSAGE FORMS AND STRENGTHS
THYROGEN is a lyophilized powder containing 1.1 mg of thyrotropin alfa for single use after reconstitution with Sterile Water for Injection.
Supplied as:
Two vial kit (two vials of lyophilized thyrotropin alfa).
4 CONTRAINDICATIONS
None
5 WARNINGS AND PRECAUTIONS
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 ADVERSE REACTIONS
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)].
Table 1: Summary of Adverse Reactions by THYROGEN and Thyroid Hormone Withdrawal in Pooled Clinical Trials (≥1% of Patients in any Phase)
Preferred Term
THYROGEN
(N=481)
n (%)
Thyroid Hormone Withdrawal
(N=418)
n (%)
Nausea
53 (11)
2 (<1)
Headache
29 (6)
0
Fatigue
11 (2)
2 (<1)
Vomiting
11 (2)
0
Dizziness
9 (2)
0 (0.0)
Asthenia
5 (1)
1 (<1)
In addition, uncommon adverse reactions (≥0.1% and <1%) reported in at least 2 patients in clinical trials included influenza, paresthesia, feeling hot, ageusia, diarrhea, dysgeusia, and neck pain.
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 (e.g., discomfort, pain, and pruritus at the injection site).
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
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.
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.
10 OVERDOSAGE
In clinical trials of THYROGEN, three patients experienced symptoms after receiving THYROGEN doses higher than those recommended. Two patients had nausea after a 2.7 mg IM dose (3 times the recommended dose), and in one of these patients, the event was accompanied by weakness, dizziness and headache. Another patient experienced nausea, vomiting and hot flashes after a 3.6 mg IM dose (4 times the recommended dose). There is no specific therapy for THYROGEN overdose. Supportive care is recommended.
11 DESCRIPTION
Each vial of THYROGEN contains 1.1 mg thyrotropin alfa, 36 mg Mannitol, 5.1 mg Sodium Phosphate, and 2.4 mg Sodium Chloride.
THYROGEN (thyrotropin alfa for injection) contains recombinant human thyroid stimulating hormone (TSH). Thyrotropin alfa is synthesized in a genetically modified Chinese hamster ovary cell line.
Thyrotropin alfa is a heterodimeric glycoprotein comprised of two non-covalently linked subunits, an alpha subunit of 92 amino acid residues containing two N-linked glycosylation sites and a beta subunit of 118 residues containing one N-linked glycosylation site. The amino acid sequence of thyrotropin alfa is identical to that of human pituitary TSH.
Both thyrotropin alfa and naturally occurring human pituitary TSH are synthesized as a mixture of glycosylation variants. Unlike pituitary TSH, which is secreted as a mixture of sialylated and sulfated forms, thyrotropin alfa is sialylated but not sulfated. The biological activity of thyrotropin alfa is determined by a cell-based bioassay. In this assay, cells expressing a functional TSH receptor and a cAMP-responsive element coupled to a heterologous reporter gene, luciferase, enable the measurement of thyrotropin alfa activity by measuring the luciferase response. The specific activity of thyrotropin alfa is determined relative to an internal Genzyme reference standard that was calibrated against the World Health Organization (WHO) human TSH reference standard.
12 CLINICAL PHARMACOLOGY
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).
HOW SUPPLIED/STORAGE AND HANDLING
THYROGEN (thyrotropin alfa for injection) is supplied as a sterile, non-pyrogenic, lyophilized product. It is available as a two-vial kit. containing 1.1 mg of THYROGEN. .
NDC 58468-0030-2 (2-vial kit)
THYROGEN is for intramuscular injection to the buttock. The lyophilized powder should be reconstituted immediately prior to use with 1.2 mL of Sterile Water for Injection, USP [see Dosage and Administration (2.2)]. Each vial of THYROGEN and each vial of diluent, if provided, is intended for single use.
THYROGEN should be stored at 2-8�C (36-46�F)
If necessary, the reconstituted solution can be stored for up to 24 hours at a temperature between 2�C and 8�C, while avoiding microbial contamination.
Protect from light.
17 PATIENT COUNSELING INFORMATION
Adverse Reactions
Inform patients that the most common adverse events from clinical experience were nausea and headache.
Advise patients to seek immediate medical attention should they experience severe symptoms.
Important Information
Prior to THYROGEN administration, counsel patients to seek care immediately for any neurologic symptoms occurring after administration of the drug.
Inform patients for whom THYROGEN induced hyperthyroidism could have serious consequences, hospitalization for administration of THYROGEN and post-administrative observation should be considered.
Dosing and Administration
Patients should be instructed that THYROGEN is for intramuscular administration into the buttock only. THYROGEN should not be administered intravenously.
Inform patients the treatment regimen is two doses of THYROGEN administered at a 24 hour interval.
Encourage patients to remain hydrated prior to treatment with THYROGEN.
Schedule of Procedures
Inform patients that if diagnostic scanning will be performed, radioiodine will be given 24 hours after the second injection of THYROGEN, and patients should return for the scan 48 hours after radioiodine administration.
Inform patients that if serum Tg testing is performed, blood will be drawn 72 hours or later after the second injection of THYROGEN.
Inform patients that if remnant ablation is performed radioiodine will be administered 24 hours after the second injection of THYROGEN.
THYROGEN is manufactured and distributed by:
Genzyme Corporation
500 Kendall Street
Cambridge, MA, U.S.A. 02142
(800) 745-4447
THYROGEN is a registered trademark of Genzyme Corporation.
Package Label - Principal Display Panel � 4 vial Carton
NDC 58468-1849-4
Thyrogen�
thyrotropin alfa for injection
0.9 mg/mL after reconstitution
For intramuscular injection only
Carton contains 2 vials of Thyrogen�
and 2 vials of diluent.
genzyme
