THYROGEN 0.9mg powder for injection medication leaflet

Thyrogen 0.9 mg powder for solution for injection

Each vial of Thyrogen contains a nominal value of 0.9 mg thyrotropin alfa. Following reconstitution, eachvial of Thyrogen contains 0.9 mg of thyrotropin alfa in 1.0 ml.

For the full list of excipients, see section 6.1.

Powder for solution for injection.

White to off-white lyophilised powder.

Thyrogen is indicated for use with serum thyroglobulin (Tg) testing with or without radioiodine imagingfor the detection of thyroid remnants and well-differentiated thyroid cancer in post-thyroidectomy patientsmaintained on hormone suppression therapy (THST).

Low risk patients with well-differentiated thyroid carcinoma who have undetectable serum Tg levels on

THST and no rh (recombinant human) TSH-stimulated increase of Tg levels may be followed-up byassaying rhTSH-stimulated Tg levels.

Thyrogen is indicated for pre-therapeutic stimulation in combination with a range of 30 mCi (1.1 GBq) to100 mCi (3.7 GBq) radioiodine for ablation of thyroid tissue remnants in patients who have undergone anear-total or total thyroidectomy for well-differentiated thyroid cancer and who do not have evidence ofdistant metastatic thyroid cancer (see section 4.4).

Therapy should be supervised by physicians with expertise in thyroid cancer.

The recommended dose regimen is two doses of 0.9 mg thyrotropin alfa administered at a 24-hour intervalby intramuscular injection only.

Due to a lack of data on the use of Thyrogen in children, Thyrogen should be given to children only inexceptional circumstances.

Results from controlled trials indicate no difference in the safety and efficacy of Thyrogen between adultpatients less than 65 years and those greater than 65 years of age, when Thyrogen is used for diagnosticpurposes.

No dose adjustment is necessary in elderly (see section 4.4).

Patients with renal/hepatic impairment

Information from post marketing surveillance, as well as published information, suggests that eliminationof 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 aftertreatment. This may lead to increased risk of headache and nausea. There are no studies of alternative doseschedules 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 thenuclear medicine physician.

The use of Thyrogen in patients with reduced liver function does not warrant special considerations.

After reconstitution with water for injection, 1.0 ml solution (0.9 mg thyrotropin alfa) is administered byintramuscular injection to the buttock. For instructions on reconstitution of the medicinal product beforeadministration, see section 6.6.

For radioiodine imaging or ablation, radioiodine administration should be given 24 hours following thefinal Thyrogen injection. Diagnostic scintigraphy should be performed 48 to 72 hours followingradioiodine administration, whereas post-ablation scintigraphy may be delayed additional days to allowbackground activity to decline.

For diagnostic follow-up serum thyroglobulin (Tg) testing, the serum sample should be obtained 72 hoursafter the final injection of Thyrogen. Use of Thyrogen with Tg testing in follow up of post-thyroidectomywell differentiated thyroid cancer patients should be in accordance with official guidelines.

* Hypersensitivity to bovine or human thyroid stimulating hormone or to any of the excipients listed insection 6.1.

* Pregnancy (see section 4.6).

In order to improve the traceability of biological medicinal products, the name and the batch number ofthe administered product should be clearly recorded.

Thyrogen should not be administered intravenously.

When used as an alternative to thyroid hormone withdrawal, the combination of the whole-bodyscintigraphy (WBS) and Tg testing after Thyrogen administration assures the highest sensitivity fordetection of thyroid remnants or cancer. False negative results may occur with Thyrogen. If a high indexof suspicion for metastatic disease persists, a confirmatory withdrawal WBS and Tg testing should beconsidered.

The presence of Tg autoantibodies can be expected in 18-40% of patients with differentiated thyroidcancer and may cause false negative serum Tg measurements. Therefore, both TgAb and Tg assays areneeded.

Careful evaluation of benefit-risk relationships should be assessed for Thyrogen administration in high-risk elderly patients who have heart disease (e.g. valvular heart disease, cardiomyopathy, coronary arterydisease, and prior or current tachyarrhythmia including atrial fibrillation) and have not undergonethyroidectomy.

Thyrogen is known to cause a transient but significant rise in serum thyroid hormone concentration whengiven to patients who have substantial thyroid tissue still in situ. Therefore, careful evaluation ofindividual risk-benefit is necessary for patients with significant residual thyroid tissue.

Effect on tumour growth and/or size

In patients with thyroid cancer, several cases of stimulated tumour growth have been reported duringwithdrawal of thyroid hormones for diagnostic procedures which have been attributed to the associatedprolonged elevation of TSH levels.

There is a theoretical possibility that Thyrogen, like thyroid hormone withdrawal, may lead to stimulatedtumour growth. In clinical trials with thyrotropin alfa, which produces a short-term increase in serum TSHlevels, no case of tumour growth has been reported.

Due to elevation of TSH levels after Thyrogen administration patients with metastatic thyroid cancerparticularly in confined spaces such as the brain, spinal cord and orbit or disease infiltrating the neck, mayexperience local oedema or focal haemorrhage at the site of these metastases resulting in increased tumoursize. 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 forpatients in whom local tumour expansion may compromise vital anatomic structures.

This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially ‘sodium-free’.

Formal interaction studies between Thyrogen and other medicinal products have not been performed. Inclinical trials, no interactions were observed between Thyrogen and the thyroid hormones triiodothyronine(T3) and thyroxine (T4) when administered concurrently.

The use of Thyrogen allows for radioiodine imaging while patients are euthyroid on thyroid hormonesuppression treatment. Data on radioiodine kinetics indicate that the clearance of radioiodine isapproximately 50% greater while euthyroid than during the hypothyroid state when renal function isdecreased, thus resulting in less radioiodine retention in the body at the time of imaging. This factorshould be considered when selecting the activity of radioiodine for use in radioiodine imaging.

Animal reproduction studies have not been conducted with Thyrogen.

It is not known whether Thyrogen can cause foetal harm when administered to a pregnant woman orwhether Thyrogen can affect reproductive capacity.

Thyrogen in combination with diagnostic radioiodine whole body scintigraphy is contra-indicated inpregnancy (see section 4.3), because of the consequent exposure of the foetus to a high dose of radioactivematerial.

It is unknown whether thyrotropin alfa /metabolites are excreted in human milk. A risk to the sucklingchild cannot be excluded. Thyrogen should not be used during breast-feeding.

It is not known whether Thyrogen can affect fertility in humans.

Thyrogen may reduce the ability to drive or use machines, since dizziness and headaches have beenreported.

The most commonly reported adverse reactions are nausea and headache, occurring in approximately11%, and 6% of patients, respectively.

The adverse reactions mentioned in the table, combine adverse reactions in the six prospective clinicaltrials (N=481) and undesirable effects that have been reported to Sanofi after licensure of Thyrogen.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Thereporting 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 theavailable data).

MedDRA System Very Common Uncommon Not known

Organ Class Common

Infections and influenzainfestations

Neoplasm benign, neoplasm swelling,malignant and metastatic painunspecified (incl.

cysts and polyps)

Nervous system dizziness, headache ageusia, stroke, tremordisorders dysgeusia,paraesthesia

Cardiac disorders palpitations

Vascular disorders flushing

Respiratory, dyspnoeathoracic andmediastinaldisorder

Gastrointestinal nausea vomiting diarrhoeadisorders

Skin and urticaria, rash pruritus,subcutaneous hyperhidrosistissue disorders

Musculoskeletal neck pain, back arthralgia, myalgiaand connective paintissue disorder

MedDRA System Very Common Uncommon Not known

Organ Class Common

General disorders fatigue, asthenia influenza like discomfort, pain,and administration illness, pyrexia, pruritus, rash andsite conditions chills, feeling urticaria at the site ofhot injection

Investigations TSH decreased

Very rare cases of hyperthyroidism or atrial fibrillation have been observed when Thyrogen 0.9 mg hasbeen administered in patients with presence of either partial or entire thyroid gland.

Manifestations of hypersensitivity have been reported uncommonly in both clinical and post-marketingsettings. These reactions consisted of urticaria, rash, pruritus, flushing and respiratory signs andsymptoms.

In clinical trials involving 481 patients, no patients have developed antibodies to thyrotropin alfa eitherafter single or repeated limited (27 patients) use of the product. It is not recommended to perform TSHassays after Thyrogen administration. The occurrence of antibodies which could interfere withendogenous TSH assays performed during regular follow-ups cannot be excluded.

Enlargement of residual thyroid tissue or metastases can occur following treatment with Thyrogen. Thismay 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. Laryngealoedema, respiratory distress requiring tracheotomy, and pain at the site of metastasis have also beenreported after Thyrogen administration. It is recommended that pre-treatment with corticosteroids beconsidered for patients in whom local tumour expansion may compromise vital anatomic structures.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals areasked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Data on exposure above the recommended dose is limited to clinical studies and a special treatmentprogram. Three patients in clinical trials and one patient in the special treatment program experiencedsymptoms after receiving Thyrogen doses higher than those recommended. Two patients had nausea after2.7 mg IM dose, and in one of these patients’ nausea was also accompanied by weakness, dizziness andheadache. The third patient experienced nausea, vomiting and hot flushes after 3.6 mg IM dose. In thespecial treatment program, a 77-year-old patient with metastatic thyroid cancer who had not beenthyroidectomised received 4 doses of Thyrogen 0.9 mg over 6 days, developed atrial fibrillation, cardiacdecompensation and terminal myocardial infarction 2 days later.

One additional patient enrolled in a clinical trial experienced symptoms after receiving Thyrogenintravenously. 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 andadministration of an antiemetic may also be considered.

5 PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Pituitary and Hypothalamic Hormones and Analogues, Anterior Pituitary

Lobe Hormones and Analogues. ATC code for thyrotropin alfa: H01AB01

Thyrotropin alfa (recombinant human thyroid stimulating hormone) is a heterodimeric glycoproteinproduced by recombinant DNA technology. It is comprised of two non-covalently linked subunits. ThecDNAs encode for an alpha subunit of 92 amino acid residues containing two N-linked glycosylationsites, and a beta subunit of 118 residues containing one N-linked glycosylation site. It has comparablebiochemical properties to natural human Thyroid Stimulating Hormone (TSH). Binding of thyrotropin alfato TSH receptors on thyroid epithelial cells stimulates iodine uptake and organification, and synthesis andrelease of thyroglobulin, triiodothyronine (T3) and thyroxine (T4).

In patients with well-differentiated thyroid cancer, a near total or total thyroidectomy is performed. Foroptimal diagnosis of thyroid remnants or cancer via either radioiodine imaging or thyroglobulin testingand for radioiodine therapy of thyroid remnants, a high serum level of TSH is needed to stimulate eitherradioiodine uptake and/or thyroglobulin release. The standard approach to achieve elevated TSH levelshas been to withdraw patients from thyroid hormone suppression therapy (THST), which usually causespatients to experience the signs and symptoms of hypothyroidism. With the use of Thyrogen, the TSHstimulation necessary for radioiodine uptake and thyroglobulin release is achieved while patients aremaintained euthyroid on THST, thus avoiding the morbidity associated with hypothyroidism.

Diagnostic use

The efficacy and safety of Thyrogen for use with radioiodine imaging together with serum thyroglobulintesting for the diagnosis of thyroid remnants and cancer was demonstrated in two studies. In one of thestudies, two dose regimens were examined: 0.9 mg intramuscular every 24 hours for two doses (0.9 mg x2) and 0.9 mg intramuscular every 72 hours for three doses (0.9 mg x 3). Both dose regimens wereeffective and not statistically different from thyroid hormone withdrawal in stimulating radioiodine uptakefor diagnostic imaging. Both dose regimens improved the sensitivity, accuracy and negative predictivevalue of Thyrogen-stimulated thyroglobulin alone or in combination with radioiodine imaging ascompared 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 thyroglobulinassay 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 of10 ng/ml, 5 ng/ml and 2 ng/ml, respectively. In these studies, the use of thyroglobulin testing on Thyrogenwas found to be more sensitive than thyroglobulin testing on TSHT. Specifically in a Phase III studyinvolving 164 patients the detection rate of tissue of thyroid origin after a Thyrogen thyroglobulin testranged from 73-87%, whereas, by using thyroglobulin on TSHT it was 42-62% for the same cut-off valuesand 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 remnantswith 100 mCi/3.7 GBq (± 10%) radioiodine in post-thyroidectomy patients with thyroid cancer, werecomparable for patients treated after thyroid hormone withdrawal versus patients treated after Thyrogenadministration. Patients studied were adults (>18 years), with newly diagnosed differentiated papillary orfollicular 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 radioiodineimaging 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 hadeither no visible uptake of radioiodine in the thyroid bed or, if visible, thyroid bed uptake <0.1% of theadministered activity of radioiodine. The success of thyroid remnant ablation also was assessed by thecriterion of Thyrogen-stimulated serum Tg level <2 ng/ml eight months after ablation, but only in patientswho were negative for interfering anti-Tg antibodies. Using this Tg criterion, 18/21 patients (86%) and23/24 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 followingeither dosage regimen of Thyrogen in both indications.

A follow-up study was conducted on patients who previously completed the initial study, and data isavailable for 51 patients. The main objective of the follow-up study was to confirm the status of thyroidremnant ablation by using Thyrogen-stimulated radioiodine static neck imaging after a median follow-upof 3.7 years (range 3.4 to 4.4 years) following radioiodine ablation. Thyrogen-stimulated thyroglobulintesting was also performed.

Patients were still considered to be successfully ablated if there was no visible thyroid bed uptake on thescan, or if visible, uptake was less than 0.1%. All patients considered ablated in the initial study wereconfirmed to be ablated in the follow-up study. In addition, no patient had a definitive recurrence duringthe 3.7 years of follow-up. Overall, 48/51 patients (94%) had no evidence of cancer recurrence, 1 patienthad possible cancer recurrence (although it was not clear whether this patient had a true recurrence orpersistent tumour from the regional disease noted at the start of the original study), and 2 patients couldnot be assessed.

In summary, in the pivotal study and its follow-up study, Thyrogen was non-inferior to thyroid hormonewithdrawal for elevation of TSH levels for pre-therapeutic stimulation in combination with radioiodine forpost-surgical ablation of remnant thyroid tissue.

Two large prospective randomised studies, the HiLo study (Mallick) and the ESTIMABL1 study(Schlumberger), compared methods of thyroid remnant ablation in patients with differentiated thyroidcancer who had been thyroidectomised. In both studies, patients were randomised to 1 of 4 treatmentgroups: Thyrogen + 30 mCi 131I, Thyrogen + 100 mCi 131I, thyroid hormone withdrawal + 30 mCi 131I, orthyroid hormone withdrawal + 100 mCi 131I, and patients were assessed about 8 months later. The HiLostudy randomised 438 patients (tumour stages T1-T3, Nx, N0 and N1, M0) at 29 centres. As assessed byradioiodine imaging and stimulated Tg levels (n = 421), ablation success rates were approximately 86% inall four treatment groups. All 95% confidence intervals for the differences were within ±10 percentagepoints, indicating in particular non-inferiority of the low to the high radioiodine activity. Analyses of T3patients and N1 patients showed that these subgroups had equally good ablation success rates as didlower-risk patients. The ESTIMABL1 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 24centres. Based on 684 evaluable patients, the overall ablation success rate assessed by neck ultrasoundsand stimulated Tg levels was 92%, without any statistically significant difference among the four groups.

For the ESTIMABL1 study, 726 (97%) of the original 752 patients were followed up for diseaserecurrence. The median follow-up was 5.4 years (0.5 to 9.2 years).

The tables below provide long term follow up information for the ESTIMABL1 and HiLo studies

Table 1. ESTIMABL1 study recurrence rates in patients who received low or high dose RAI andthose who prepared with Thyrogen or THW

Thyrogen (N=374) THW (N=378)

Total number of patients with recurrence (5.4 years) 7 (1,9%) 4 (1,1%)

Low activity RAI (1.1 GBq) 5 (1,3%) 1 (0,3%)

High activity RAI (3.7 GBq) 2 (0,5%) 3 (0,8%)

For the HiLo study, 434 (99%) of the original 438 patients were followed up for disease recurrence. Themedian follow-up was 6.5 years (4.5 to 7.6 years).

Table 2. HiLo study recurrence rates in patients who received low or high dose activity RAI

Low activity dose High activity dose RAI (3.7 GBq)

RAI (1.1 GBq)

Total number of patients with recurrence 11 10

Recurrence rate (3 years) 1.5% 2.1%

Recurrence rate (5 years) 2.1% 2.7%

Recurrence rate (7 years) 5.9% 7.3%

HR: 1.10 [95% CI 0.47 - 2.59]; p=0.83

Table 3. HiLo study recurrence rates in patients who prepared for ablation with Thyrogen or

Thyroid Hormone Withdrawal

Thyrogen Thyroid Hormone Withdrawal (THW)

Total number of patients with 13 8recurrence

Recurrence rate (3 years) 1.5% 2.1%

Recurrence rate (5 years) 2.1% 2.7%

Recurrence rate (7 years) 8.3% 5.0%

HR: 1.62 [95% CI 0.67 - 3.91], p=0.28

The long-term follow-up data in ESTIMABL1 and HiLo confirmed similar outcomes for patients in allfour treatment groups.

In summary, these studies support the efficacy of low activity radioiodine plus thyrotropin alpha (withreduced radiation exposure). Thyrotropin alfa was non-inferior to thyroid hormone withdrawal for pre-therapeutic stimulation in combination with radioiodine for post-surgical ablation of thyroid remnanttissue.

The pharmacokinetics of Thyrogen were studied in patients with well-differentiated thyroid cancerfollowing a single 0.9 mg intramuscular injection. After injection, the mean peak (Cmax) level obtainedwas 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 lesserextent hepatic.

Non-clinical data are limited but reveal no special hazard for humans from use of Thyrogen.

Mannitol

Sodium phosphate monobasic, monohydrate

Sodium phosphate dibasic, heptahydrate

Sodium chloride

In the absence of compatibility studies, this medicinal product must not be administered as a mixture withother medicinal products in the same injection.

Unopened vials3 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 protectionfrom light, while avoiding microbial contamination.

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.

Clear Type I glass 5 ml vials. The closure consists of a siliconised butyl stopper with a tamper proofflip-off cap. Each vial contains 1.1 mg thyrotropin alfa. After reconstitution with 1.2 ml water forinjection, 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 containan overfill of 0.2 ml.

Package size: one or two vials per carton.

Not all pack sizes may be marketed.

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 gentlyuntil all material is dissolved. Do not shake the solution. When the powder is dissolved the total volume inthe 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 Thyrogensolution should be a clear, colourless solution. Do not use vials exhibiting foreign particles, cloudiness ordiscoloration.

Withdraw 1.0 ml of the Thyrogen solution from the product vial. This equals 0.9 mg thyrotropin alfa to beinjected.

Thyrogen does not contain preservatives. Dispose of any unused solution immediately. No specialrequirements for disposal.

The Thyrogen solution should be injected within three hours, however the Thyrogen solution will staychemically stable for up to 24 hours, if kept in a refrigerator (between 2°C and 8°C). It is important to notethat the microbiological safety depends on the aseptic conditions during the preparation of the solution.

Sanofi Winthrop Industrie82 Avenue Raspail94250 Gentilly

France

EU/1/99/122/001

EU/1/99/122/002

Date of first authorisation: 9 March 2000

Date of last renewal: 15 January 2010

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu