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部份中文α-促甲状腺素处方资料（仅供参考）
Very 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 reactions Reporting 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 Scheme Website: www.mhra.gov.uk/yellowcard Ireland HPRA Pharmacovigilance Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.hpra.ie e-mail: medsafety@hpra.ie Malta ADR Reporting Website: www.medicinesauthority.gov.mt/adrportal 4.9 Overdose Data on exposure above the recommended dose is limited to clinical studies and a special treatment program. Three patients in clinical trials and one patient in the special treatment program experienced symptoms after receiving Thyrogen doses higher than those recommended. Two patients had nausea after 2.7 mg IM dose, and in one of these patients nausea was also accompanied by weakness, dizziness and headache. The third patient experienced nausea, vomiting and hot flushes after 3.6 mg IM dose. In the special treatment program, a 77 year-old patient with metastatic thyroid cancer who had not been thyroidectomised received 4 doses of Thyrogen 0.9 mg over 6 days, developed atrial fibrillation, cardiac decompensation and terminal myocardial infarction 2 days later. One additional patient enrolled in a clinical trial experienced symptoms after receiving Thyrogen intravenously. This patient received 0.3 mg of Thyrogen as a single intravenous (IV) bolus and, 15 minutes later experienced severe nausea, vomiting, diaphoresis, hypotension and tachycardia. A suggested treatment in case of overdose would be the reestablishment of fluid balance and administration of an antiemetic may also be considered. 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Pituitary and Hypothalamic Hormones and Analogues, Anterior Pituitary Lobe Hormones and Analogues. ATC code for thyrotropin alfa: H01AB01 Mechanism of action Thyrotropin 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 use The 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 stimulation In 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. 5.2 Pharmacokinetic properties The pharmacokinetics of Thyrogen were studied in patients with well-differentiated thyroid cancer following a single 0.9 mg intramuscular injection. After injection, the mean peak (Cmax) level obtained was 116 ± 38 mU/l and occurred approximately 13 ± 8 hours after administration. The elimination half-life was 22 ± 9 hours. The major elimination route of thyrotropin alfa is believed to be renal and to a lesser extent hepatic. 5.3 Preclinical safety data Non-clinical data are limited, but reveal no special hazard for humans from use of Thyrogen. 6. Pharmaceutical particulars 6.1 List of excipients Mannitol Sodium phosphate monobasic, monohydrate Sodium phosphate dibasic, heptahydrate Sodium chloride 6.2 Incompatibilities In the absence of compatibility studies, this medicinal product must not be administered as a mixture with other medicinal products in the same injection. 6.3 Shelf life Unopened vials 3 years. Shelf-life after reconstitution It 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. 6.4 Special precautions for storage Store in a refrigerator (2°C - 8°C). Keep the vial in the outer carton in order to protect from light. For storage conditions after reconstitution of the medicinal product, see section 6.3. 6.5 Nature and contents of container Clear Type I glass 5 ml vials. The closure consists of a siliconised butyl stopper with a tamper proof flip-off cap. Each vial contains 1.1 mg thyrotropin alfa. After reconstitution with 1.2 ml water for injection, 1.0 ml of solution (equal to 0.9 mg Thyrogen) is withdrawn and administered to the patient. To provide sufficient volume to allow accurate dispensing, each vial of Thyrogen is formulated to contain an overfill of 0.2 ml. Package size: one or two vials per carton. Not all pack sizes may be marketed. 6.6 Special precautions for disposal and other handling The powder for solution for injection has to be reconstituted with water for injection. Only one vial of Thyrogen is required per injection. Each vial of Thyrogen is for single use only. Use aseptic technique Add 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. 7. Marketing authorisation holder Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands 8. Marketing authorisation number(s) EU/1/99/122/001 EU/1/99/122/002 9. Date of first authorisation/renewal of the authorisation Date of first authorisation: 9 March 2000 Date of last renewal: 9 March 2010 10. Date of revision of the text 26/05/2016 Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu ----------------------------------- 产地国家：荷兰 原产地英文商品名: Thyrogen 1.1MG（0.9MG/ML）/vial 2vial/box 原产地英文药品名: Thyrotropin alfa 中文参考商品译名: Thyrogen 1.1毫克（0.9毫克/毫升）/瓶 2瓶/盒 中文参考药品译名: α-促甲状腺素 中文参考厂家译名: 健贊公司 英文参考厂家译名: Genzyme ——注射用促甲状腺素α（thyrotropin alfa，Thyrogen） 近日:美国FDA已批准了Thyrogen（促甲状腺素α 注射剂）与放射疗法联用于除去或破坏已进行甲状腺癌切除手术后患者的残余甲状腺组织，可降低复发风险与更好的监测病情。甲状腺癌术后剩余甲状腺组织去除治疗常用在甲状腺癌治疗中都会进行。 公司官员说道：“这项新适应症扩大了Thyrogen对于那些甲状腺癌初始治疗者的益处，Thyrogen之前在检测癌症是否复发的后继诊断过程中使用。” 美国癌症协估计在2007年，约有33550例患者诊断出甲状腺癌，其中90%的甲状腺癌是完全分化的，这些患者可接受剩余甲状腺组织去除治疗。 Thyrogen于1998年初次在美国获得批准，2001年在欧洲获得批准用于作为诊断试剂，用于检测完全分化型甲状腺癌的复发。2005年欧洲批准了Thyrogen用于剩余甲状腺组织去除过程中。 |