- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe recommended dose regimen is two doses of 0.9 mg thyrotropin alfa administered at a 24-hour interval by intramuscular injection only.
Paediatric populationDue to a lack of data on the use of Thyrogen in children, Thyrogen should be given to children only in exceptional circumstances.
ElderlyResults from controlled trials indicate no difference in the safety and efficacy of Thyrogen between adult patients less than 65 years and those greater than 65 years of age, when Thyrogen is used for diagnostic purposes.No dose adjustment is necessary in elderly (see section 4.4).
Patients with renal/hepatic impairmentInformation from post marketing surveillance, as well as published information, suggests that elimination of Thyrogen is significantly slower in dialysis-dependent end stage renal disease (ESRD) patients, resulting in prolonged elevation of thyroid stimulating hormone (TSH) levels for several days after treatment. This may lead to increased risk of headache and nausea. There are no studies of alternative dose schedules of Thyrogen in patients with ESRD to guide dose reduction in this population.In patients with significant renal impairment the activity of radioiodine should be carefully selected by the nuclear medicine physician.The use of Thyrogen in patients with reduced liver function does not warrant special considerations.
Method of administrationAfter reconstitution with water for injection, 1.0 ml solution (0.9 mg thyrotropin alfa) is administered by intramuscular injection to the buttock. For instructions on reconstitution of the medicinal product before administration, see section 6.6.For radioiodine imaging or ablation, radioiodine administration should be given 24 hours following the final Thyrogen injection. Diagnostic scintigraphy should be performed 48 to 72 hours following radioiodine administration, whereas post-ablation scintigraphy may be delayed additional days to allow background activity to decline.For diagnostic follow-up serum thyroglobulin (Tg) testing, the serum sample should be obtained 72 hours after the final injection of Thyrogen. Use of Thyrogen with Tg testing in follow up of post-thyroidectomy well differentiated thyroid cancer patients should be in accordance with official guidelines.
Effect on tumour growth and/or sizeIn patients with thyroid cancer, several cases of stimulated tumour growth have been reported during withdrawal of thyroid hormones for diagnostic procedures which have been attributed to the associated prolonged elevation of TSH levels.There is a theoretical possibility that Thyrogen, like thyroid hormone withdrawal, may lead to stimulated tumour growth. In clinical trials with thyrotropin alfa, which produces a short-term increase in serum TSH levels, no case of tumour growth has been reported. Due to elevation of TSH levels after Thyrogen administration patients with metastatic thyroid cancer particularly in confined spaces such as the brain, spinal cord and orbit or disease infiltrating the neck, may experience local oedema or focal haemorrhage at the site of these metastases resulting in increased tumour size. This may lead to acute symptoms, which depend on the anatomical location of the tissue e.g. hemiplegia, hemiparesis, 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 after Thyrogen administration. It is recommended that pre-treatment with corticosteroids be considered for patients in whom local tumour expansion may compromise vital anatomic structures.
SodiumThis medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially 'sodium- free'.
PregnancyAnimal reproduction studies have not been conducted with Thyrogen. It is not known whether Thyrogen can cause foetal harm when administered to a pregnant woman or whether Thyrogen can affect reproductive capacity.Thyrogen in combination with diagnostic radioiodine whole body scintigraphy is contra-indicated in pregnancy (see section 4.3), because of the consequent exposure of the foetus to a high dose of radioactive material.
Breast-feedingIt is unknown whether thyrotropin alfa /metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Thyrogen should not be used during breast-feeding.
FertilityIt is not known whether Thyrogen can affect fertility in humans.
Summary of the safety profileThe most commonly reported adverse reactions are nausea and headache, occurring in approximately 11%, and 6% of patients, respectively.
Tabulated list of adverse reactionsThe adverse reactions mentioned in the table, combine adverse reactions in the six prospective clinical trials (N=481) and undesirable effects that have been reported to Genzyme after licensure of Thyrogen.Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The reporting rate is classified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
|MedDRA System Organ Class||Very Common||Common||Uncommon||Not known|
|Infections and infestations||influenza|
|Neoplasm benign, malignant and unspecified (incl. cysts and polyps)||neoplasm swelling, metastatic pain|
|Nervous system disorders||dizziness, headache||ageusia, dysgeusia, paraesthesia||stroke, tremor|
|Respiratory, thoracic and mediastinal disorder||dyspnoea|
|Skin and subcutaneous tissue disorders||urticaria, rash||pruritus, hyperhidrosis|
|Musculoskeletal and connective tissue disorder||neck pain, back pain||arthralgia, myalgia|
|General disorders and administration site conditions||fatigue, asthenia||influenza like illness, pyrexia, chills, feeling hot||discomfort, pain, pruritus, rash and urticaria at the site of injection|
Description of selected adverse reactionsVery rare cases of hyperthyroidism or atrial fibrillation have been observed when Thyrogen 0.9 mg has been administered in patients with presence of either partial or entire thyroid gland. Manifestations of hypersensitivity have been reported uncommonly in both clinical and post-marketing settings. These reactions consisted of urticaria, rash, pruritus, flushing and respiratory signs and symptoms. In clinical trials involving 481 patients, no patients have developed antibodies to thyrotropin alfa either after single or repeated limited (27 patients) use of the product. It is not recommended to perform TSH assays after Thyrogen administration. The occurrence of antibodies which could interfere with endogenous TSH assays performed during regular follow-ups cannot be excluded.Enlargement of residual thyroid tissue or metastases can occur following treatment with Thyrogen. This may lead to acute symptoms, which depend on the anatomical location of the tissue. For example, hemiplegia, hemiparesis or 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 after Thyrogen administration. It is recommended that pre-treatment with corticosteroids be considered for patients in whom local tumour expansion may compromise vital anatomic structures.Very rare cases of stroke have been reported from world-wide post marketing experience in female patients. The relationship to Thyrogen administration is unknown.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system below.United Kingdom Yellow Card SchemeWebsite: www.mhra.gov.uk/yellowcardIrelandHPRA PharmacovigilanceEarlsfort Terrace IRL - Dublin 2Tel: +353 1 6764971Fax: +353 1 6762517Website: www.hpra.iee-mail: firstname.lastname@example.orgMaltaADR ReportingWebsite: www.medicinesauthority.gov.mt/adrportal
Mechanism of actionThyrotropin alfa (recombinant human thyroid stimulating hormone) is a heterodimeric glycoprotein produced by recombinant DNA technology. It is comprised of two non-covalently linked subunits. The cDNAs encode for 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. It has comparable biochemical properties to natural human Thyroid Stimulating Hormone (TSH). Binding of thyrotropin alfa to TSH receptors on thyroid epithelial cells stimulates iodine uptake and organification, and synthesis and release of thyroglobulin, triiodothyronine (T3) and thyroxine (T4).In patients with well-differentiated thyroid cancer, a near total or total thyroidectomy is performed. For optimal diagnosis of thyroid remnants or cancer via either radioiodine imaging or thyroglobulin testing and for radioiodine therapy of thyroid remnants, a high serum level of TSH is needed to stimulate either radioiodine uptake and/or thyroglobulin release. The standard approach to achieve elevated TSH levels has been to withdraw patients from thyroid hormone suppression therapy (THST), which usually causes patients to experience the signs and symptoms of hypothyroidism. With the use of Thyrogen, the TSH stimulation necessary for radioiodine uptake and thyroglobulin release is achieved while patients are maintained euthyroid on THST, thus avoiding the morbidity associated with hypothyroidism.
Clinical efficacy and safety
Diagnostic useThe efficacy and safety of Thyrogen for use with radioiodine imaging together with serum thyroglobulin testing for the diagnosis of thyroid remnants and cancer was demonstrated in two studies. In one of the studies, two dose regimens were examined: 0.9 mg intramuscular every 24 hours for two doses (0.9 mg x 2) and 0.9 mg intramuscular every 72 hours for three doses (0.9 mg x 3). Both dose regimens were effective and not statistically different from thyroid hormone withdrawal in stimulating radioiodine uptake for diagnostic imaging. Both dose regimens improved the sensitivity, accuracy and negative predictive value of Thyrogen-stimulated thyroglobulin alone or in combination with radioiodine imaging as compared to testing performed while patients remained on thyroid hormones. In clinical trials, for the detection of thyroid remnants or cancer in ablated patients using a thyroglobulin assay with a lower limit of detection of 0.5 ng/ml, Thyrogen-stimulated thyroglobulin levels of 3 ng/ml, 2 ng/ml and 1 ng/ml corresponded with thyroglobulin levels after withdrawal of thyroid hormone of 10 ng/ml, 5 ng/ml and 2 ng/ml, respectively. In these studies the use of thyroglobulin testing on Thyrogen was found to be more sensitive than thyroglobulin testing on TSHT. Specifically in a Phase III study involving 164 patients the detection rate of tissue of thyroid origin after a Thyrogen thyroglobulin test ranged from 73-87%, whereas, by using thyroglobulin on TSHT it was 42-62% for the same cut-off values and comparable reference standards. Metastatic disease was confirmed by a post-treatment scan or by lymph node biopsy in 35 patients. Thyrogen-stimulated thyroglobulin levels were above 2 ng/ml in all 35 patients, whereas, thyroglobulin on THST was above 2 ng/ml in 79% of these patients.
Pre-therapeutic stimulationIn a comparator study involving 60 evaluable patients, the rates of successful ablation of thyroid remnants with 100 mCi/3.7 GBq (± 10%) radioiodine in post-thyroidectomy patients with thyroid cancer, were comparable for patients treated after thyroid hormone withdrawal versus patients treated after Thyrogen administration. Patients studied were adults (>18 years), with newly diagnosed differentiated papillary or follicular thyroid carcinoma, including papillary-follicular variant, characterised, principally (54 of 60), as T1-T2, N0-N1, M0 (TNM classification). Success of remnant ablation was assessed with radioiodine imaging and with serum thyroglobulin testing at 8 ± 1 months after treatment. All 28 patients (100%) treated after withdrawal of THST and all 32 patients (100%) treated after Thyrogen administration had either no visible uptake of radioiodine in the thyroid bed or, if visible, thyroid bed uptake <0.1% of the administered activity of radioiodine. The success of thyroid remnant ablation also was assessed by the criterion of Thyrogen-stimulated serum Tg level < 2 ng/ml eight months after ablation, but only in patients who were negative for interfering anti-Tg antibodies. Using this Tg criterion, 18/21 patients (86%) and 23/24 patients (96%) had thyroid remnants successfully ablated in the THST withdrawal group and the Thyrogen treatment group, respectively. Quality of life was significantly reduced following thyroid hormone withdrawal, but maintained following either dosage regimen of Thyrogen in both indications. A follow-up study was conducted on patients who previously completed the initial study, and data is available for 51 patients. The main objective of the follow-up study was to confirm the status of thyroid remnant ablation by using Thyrogen-stimulated radioiodine static neck imaging after a median follow-up of 3.7 years (range 3.4 to 4.4 years) following radioiodine ablation. Thyrogen-stimulated thyroglobulin testing was also performed. Patients were still considered to be successfully ablated if there was no visible thyroid bed uptake on the scan, or if visible, uptake was less than 0.1%. All patients considered ablated in the initial study were confirmed to be ablated in the follow-up study. In addition, no patient had a definitive recurrence during the 3.7 years of follow-up. Overall, 48/51 patients (94%) had no evidence of cancer recurrence, 1 patient had possible cancer recurrence (although it was not clear whether this patient had a true recurrence or persistent tumour from the regional disease noted at the start of the original study), and 2 patients could not be assessed.In summary, in the pivotal study and its follow-up study, Thyrogen was non-inferior to thyroid hormone withdrawal for elevation of TSH levels for pre-therapeutic stimulation in combination with radioiodine for post-surgical ablation of remnant thyroid tissue.Two large prospective randomised studies, the HiLo study (Mallick) and the ESTIMABL study (Schlumberger), compared methods of thyroid remnant ablation in patients with differentiated thyroid cancer who had been thyroidectomised. In both studies, patients were randomised to 1 of 4 treatment groups: Thyrogen + 30 mCi 131-I, Thyrogen + 100 mCi 131-I, thyroid hormone withdrawal + 30 mCi 131-I, or thyroid hormone withdrawal + 100 mCi 131-I, and patients were assessed about 8 months later. The HiLo study randomised 438 patients (tumour stages T1-T3, Nx, N0 and N1, M0) at 29 centres. As assessed by radioiodine imaging and stimulated Tg levels (n = 421), ablation success rates were approximately 86% in all four treatment groups. All 95% confidence intervals for the differences were within ±10 percentage points, indicating in particular non-inferiority of the low to the high radioiodine dose. Analyses of T3 patients and N1 patients showed that these subgroups had equally good ablation success rates as did lower-risk patients. The ESTIMABL study randomised 752 patients with low-risk thyroid cancer (tumour stages pT1 < 1 cm and N1 or Nx, pT1 >1-2 cm and any N stage, or pT2 N0, all patients M0) at 24 centres. Based on 684 evaluable patients, the overall ablation success rate assessed by neck ultrasounds and stimulated Tg levels was 92%, without any statistically significant difference among the four groups. Considering the design of each of these two studies, it should be noted that long term data (beyond approximately 9 months) in relation to use of the lower dose of radioiodine are not yet available. In summary, these studies suggest that low dose radioiodine plus thyrotropin alpha is an effective treatment (with reduced radiation exposure) and Thyrogen was non-inferior to thyroid hormone withdrawal for pre-therapeutic stimulation in combination with radioiodine for post-surgical ablation of thyroid remnant tissue.
Unopened vials3 years.
Shelf-life after reconstitutionIt is recommended that the Thyrogen solution be injected within three hours.The reconstituted solution can be stored for up to 24 hours in a refrigerator (2°C - 8°C) under protection from light, while avoiding microbial contamination.
Use aseptic techniqueAdd 1.2 ml water for injection to the Thyrogen powder in the vial. Swirl the contents of the vial gently until all material is dissolved. Do not shake the solution. When the powder is dissolved the total volume in the vial is 1.2 ml. The pH of the Thyrogen solution is approximately 7.0.Visually inspect the Thyrogen solution in the vial for foreign particles and discoloration. The Thyrogen solution should be a clear, colourless solution. Do not use vials exhibiting foreign particles, cloudiness or discoloration.Withdraw 1.0 ml of the Thyrogen solution from the product vial. This equals 0.9 mg thyrotropin alfa to be injected.Thyrogen does not contain preservatives. Dispose of any unused solution immediately. No special requirements for disposal.The Thyrogen solution should be injected within three hours, however the Thyrogen solution will stay chemically stable for up to 24 hours, if kept in a refrigerator (between 2°C and 8°C). It is important to note that the microbiological safety depends on the aseptic conditions during the preparation of the solution.
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