ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Thyrogen 0.9 mg powder for solution for injection
2.
Each vial of Thyrogen contains a nominal value of 0.9 mg thyrotropin alfa. Following
reconstitution, each vial of Thyrogen contains 0.9 mg of thyrotropin alfa in 1.0 ml.
For a full list of excipients, see section 6.1.
3.
Powder for solution for injection.
White to off-white lyophilised powder.
4.
Thyrogen is indicated for use with serum thyroglobulin (Tg) testing with or without radioiodine
imaging for the detection of thyroid remnants and well-differentiated thyroid cancer in post-
thyroidectomy patients maintained 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 by assaying rh TSH-stimulated Tg levels.
Thyrogen is indicated for pre-therapeutic stimulation in combination with 100 mCi (3.7 GBq)
radioiodine for 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.
Therapy should be supervised by physicians with expertise in thyroid cancer.
Posology
The recommended dose regimen is two doses of 0.9 mg thyrotropin alfa administered at a 24-
hour interval by intramuscular injection only.
Paediatric population
Due to a lack of data on the use of Thyrogen in children, Thyrogen should be given to children
only in exceptional circumstances.
2
Elderly population
Results 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 the elderly population (see section 4.4).
Renal/hepatic impairment
Information 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 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 administration
After reconstitution with water for injection, 1.0 ml solution (0.9 mg thyrotropin alfa) is
administered by intramuscular injection to the buttock. See section 6.6 for instructions for
handling.
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.
•
Hypersensitivity to bovine or human thyroid stimulating hormone or to any of the excipients.
•
Pregnancy (see section 4.6).
Thyrogen should
not
be administered intravenously.
When used as an alternative to thyroid hormone withdrawal, the combination of the whole body
scintigraphy (WBS) and Tg testing after Thyrogen administration assures the highest sensitivity
for detection of thyroid remnants or cancer. False negative results may occur with Thyrogen. If a
high index of suspicion for metastatic disease persists, a confirmatory withdrawal WBS and Tg
testing should be considered.
3
The presence of Tg autoantibodies can be expected in 18-40% of patients with differentiated
thyroid cancer and may cause false negative serum Tg measurements. Therefore, both TgAb and
Tg assays are needed.
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 artery disease, and prior or current tachyarrhythmia including atrial fibrillation) and
have not undergone thyroidectomy.
Thyrogen is known to cause a transient but significant rise in serum thyroid hormone
concentration when given to patients who have substantial thyroid tissue still
in situ
. Therefore,
careful evaluation of individual risk-benefit is necessary for patients with significant residual
thyroid tissue.
In the pivotal trial of Thyrogen for pre-therapeutic stimulation before radioiodine (
131
I) ablation of
thyroid tissue remnants in patients who have undergone a near-total or total thyroidectomy for
well-differentiated thyroid cancer, an activity of 100 mCi (3.7 GBq) radioactive iodine (
131
I) was
used. Experience of rhTSH in combination with other radioiodine activities, in particular as low
as 1 GBq is very limited. The efficacy of rhTSH for thyroid remnant ablation in combination with
low radioiodine activities has not been demonstrated.
Effect on tumour growth and/or size:
In 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 thyroid stimulating hormone (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 pretreatment with corticosteroids be considered for patients in whom local
tumour expansion may compromise vital anatomic structures.
Important information about some of the ingredients of Thyrogen
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. In clinical trials, no interactions were observed between Thyrogen and the thyroid
hormones triiodothyronine (T
3
) and thyroxine (T
4
) when administered concurrently.
The use of Thyrogen allows for radioiodine imaging while patients are euthyroid on thyroid
hormone suppression treatment. Data on radioiodine kinetics indicate that the clearance of
radioiodine is approximately 50% greater while euthyroid than during the hypothyroid state when
4
renal function is decreased, thus resulting in less radioiodine retention in the body at the time of
imaging. This factor should be considered when selecting the activity of radioiodine for use in
radioiodine imaging although only a 3.7 GBq
131
I activity have been tested in the trial of the pre-
therapeutic stimulation.
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
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.
It 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.
No studies on the effects on the ability to drive and use machines have been performed.
Thyrogen may reduce the ability to drive or use machines, since dizziness and headaches have been
reported.
The most commonly reported adverse reactions are nausea and headache, occurring in approximately
12%, and 7% of patients, respectively.
The 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. Due to unknown frequency of
adverse reactions
reported in the post-marketing
period they are presented in a separate column
Within each frequency grouping, adverse reactions are presented in order of decreasing
seriousness.
5
System Organ Class Very common
Common
Uncommon
Not known
(≥1/10)
(≥1/100 to <1/10)
(≥1/1,000 to
<1/100)
(cannot be
estimated from the
available data)
Neoplasm benign,
malignant and
unspecified (incl.
cysts and polyps)
neoplasm,
swelling,
metastatic pain
Nervous system
disorders
dizziness,
headache
paraesthesia
tremor
Cardiac disorders
p
alpitation
Vascular disorders
feeling hot
flushing
Respiratory,
thoracic and
mediastinal disorder
dyspnoea
Gastrointestinal
disorders
nausea
vomiting
diarrhoea
Skin and
subcutaneous tissue
disorders
urticaria, rash
pruritus,
hyperhydrosis
Musculoskeletal and
connective tissue
disorder
arthralgia,
myalgia
General disorders
and administration
site conditions
fatigue
asthenia
influenza-like
illness, pyrexia,
rigors, back pain
discomfort, pain,
pruritus, rash and
urticaria at the
site of
intramuscular
injection
Investigations
TSH decreased
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. The occurrence of
antibodies which could interfere with endogenous TSH assays 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
6
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
pretreatment with corticosteroids be considered for patients in whom local tumour expansion may
compromise vital anatomic structures.
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
5.1 Pharmacodynamic 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
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 (T
3
) and thyroxine (T
4
).
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.
7
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
r
adioiodine. 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. There is evidence from the
literature of lower efficacy of Thyrogen administration compared with withdrawal of THST when
using 30 mCi. Data regarding the efficacy of Thyrogen with activities of
131
I <100 mCi is very
limited.
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
8
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 this 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.
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 (C
max
)
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 to man from use of Thyrogen.
6.
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, Thyrogen should 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.
9
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 of the reconstituted medicinal product, see section 6.3.
6.5 Nature and content 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 and two vials of Thyrogen 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. Throw away any unused solution immediately.
There are 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.
10
7.
Genzyme Europe B.V., Gooimeer 10, 1411 DD Naarden, The Netherlands
8.
EU/1/99/122/001
EU/1/99/122/002
9.
Date of first authorisation: 9 March 2000
Date of last renewal: 9 March 2010
Detailed information on this product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu
11
ANNEX II
A.
MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING
AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
12
A.
MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) of the biological active substance
Genzyme Corp.
45,51,74,76 and 80 New York Avenue
Framingham, MA 01701-9322
USA
Name and address of the manufacturer(s) responsible for batch release
Genzyme Ltd
37 Hollands Road
Haverhill
Suffolk CB9 8PU
United Kingdom
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, section 4.2).
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities
detailed in the Pharmacovigilance Plan, as agreed in version 5 of the Risk Management Plan
(RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates
of the RMP agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any
updated RMP should be submitted at the same time as the following Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted:
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
13
•
At the request of the EMEA
PSUR
The MAH will submit yearly PSURs, unless otherwise specified by the CHMP.
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
{OUTER CARTON (PACK OF 1 VIAL)}
1.
THYROGEN 0.9 mg powder for solution for injection.
thyrotropin alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 0.9 mg/ml of thyrotropin alfa when reconstituted with 1.2 ml water for injection.
3.
LIST OF EXCIPIENTS
Excipients:
Mannitol
Sodium phosphate monobasic, monohydrate
Sodium phosphate dibasic, heptahydrate
Sodium chloride
See leaflet for further information.
4.
1 vial of powder for solution for injection.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intramuscular injection only.
Only 1 ml should be withdrawn equal to 0.9 mg of thyrotropin alfa.
Administration within 3 hours after reconstitution.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
17
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C - 8°C).
Keep the vial in the outer carton.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only.
Any unused solution should be discarded.
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/99/122/001
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
18
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
{OUTER CARTON (PACK OF 2 VIALS)}
1.
THYROGEN 0.9 mg powder for solution for injection.
thyrotropin alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each vial contains 0.9 mg/ml of thyrotropin alfa when reconstituted with 1.2 ml water for injection.
3.
LIST OF EXCIPIENTS
Excipients:
Mannitol
Sodium phosphate monobasic, monohydrate
Sodium phosphate dibasic, heptahydrate
Sodium chloride
See leaflet for further information.
4.
2 vials of powder for solution for injection equal to 2 doses to be administered at a 24-hour interval.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Intramuscular injection only.
Only 1 ml should be withdrawn equal to 0.9 mg of thyrotropin alfa.
Administration within 3 hours after reconstitution.
Read package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
19
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2°C - 8°C).
Keep the vial in the outer carton.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
For single use only.
Any unused solution should be discarded.
Genzyme Europe B.V.
Gooimeer 10
1411 DD Naarden
The Netherlands
EU/1/99/122/002
13. BATCH NUMBER
Batch
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted
20
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
{LABEL (VIAL )}
1.
THYROGEN 0.9 mg powder for solution for injection.
thyrotropin alfa
Intramuscular use.
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Batch
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
Store in a refrigerator (2°C - 8°C).
Genzyme Europe B.V.- NL
21
B. PACKAGE LEAFLET
22
PACKAGE LEAFLET: INFORMATION FOR THE USER
THYROGEN 0.9 mg powder for solution for injection.
thyrotropin alfa
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet:
1. What Thyrogen is and what it is used for
2. Before you use Thyrogen
3. How to use Thyrogen
4. Possible Side Effects
5. How to store Thyrogen
6. Further Information
1.
WHAT THYROGEN IS AND WHAT IT IS USED FOR
Thyrogen is a human thyroid stimulating hormone (TSH) manufactured using biotechnology processes.
Thyrogen is used to detect certain types of thyroid cancer in patients who have had their thyroid gland
removed and who are taking thyroid hormones. One of the effects is that it stimulates any remaining
thyroid tissue to take up iodine which is important for radioiodine imaging. It also stimulates the
production of thyroglobulin and thyroid hormones if there is any thyroid tissue left. These hormones
can be measured in your blood.
Thyrogen is also used with radioiodine treatment to eliminate (ablate) the thyroid tissue left over after
surgical removal of the thyroid gland (remnant) in patients who do not have secondaries (metastases)
and who are taking thyroid hormone.
2.
BEFORE YOU USE THYROGEN
Do not use Thyrogen
Tell your doctor:
•
if have ever had an
allergic reaction
(for example, rash or itchiness) to bovine or human thyroid
stimulating hormone (TSH).
•
if you are
allergic
to any of the other ingredients before you take this medicine (these are listed
in Section 6; see also at the end of Section 2).
•
if you are
pregnant.
Take special care with Thyrogen
Thyrogen should never be injected into a vein.
23
-
If you have any further questions, ask your doctor or your pharmacist.
Tell your doctor if you have:
•
kidney disease that require dialysis and he/she will decide how much Thyrogen to give to you as
you may have more chance of experiencing headache and nausea.
•
reduced kidney function and he/she will decide how much radioiodine to give you.
•
reduced liver function; you should still be able to receive Thyrogen.
Elderly patients
No special precautions for elderly patients are necessary. However if your thyroid gland has not been
removed completely and you are also suffering from heart disease, your doctor will help you decide if
Thyrogen should be given to you.
Effect on tumour growth
In patients with thyroid cancer, tumour growth has been reported during withdrawal of thyroid
hormones for diagnostic procedures. This was thought to be related to the elevated thyroid stimulating
hormone (TSH) levels over a longer period. It is possible that Thyrogen may also cause tumour
growth. In clinical trials this was not seen.
Due to elevation of TSH levels after Thyrogen, patients with secondary cancer growths (metastases)
can experience local swelling or bleeding at the site of these metastases which may become bigger. If
the metastases are present in narrow spaces e.g. intracerebral (in the brain) or in the spinal cord,
patients could experience rapid symptoms such as partial paralysis affecting one side of the body
(hemiparesis), breathing problems or loss of vision.
Your doctor will decide if you belong to a specific group of patients for which pre-treatment with
corticosteroids is to be considered (for example, if you have secondary cancer growths in your brain or
spinal cord ). Please talk to your doctor about this if you have concerns.
Using other medicines
There are no known drug interactions with Thyrogen and the thyroid hormones you may be taking.
Please tell you doctor if you are taking or have recently taken any other medicines including medicines
obtained without prescription.
Your doctor will determine the exact activity of radioiodine to use for radioiodine imaging, taking into
consideration the fact that you continue to take thyroid hormones.
Pregnancy and breast-feeding
Ask your doctor for advice before taking any medicine.
Do not take Thyrogen if you are pregnant. Please consult your doctor if you are pregnant or think you
may be pregnant.
Thyrogen should not be given to breastfeeding women. Breast-feeding should only be resumed
following advice from your doctor.
Driving and using machines
Some patients may feel dizzy or have headaches after administration of Thyrogen which may affect the
ability to drive and use machines.
24
Important information about some of the ingredients of Thyrogen
This medicinal product contains less than 1 mmol sodium (23 mg) per injection, i.e. essentially
‘sodium- free’.
3.
HOW TO USE THYROGEN
Your doctor, nurse or pharmacist will prepare the injection for you.
Your treatment should be supervised by a doctor who has expertise in thyroid cancer. Thyrogen
powder must be dissolved in water for injection. Only one vial of Thyrogen is required per injection.
The injection must be given intra-muscularly. Thyrogen must not be mixed with other medicines in the
same injection
Use in children
Your child’s doctor will help you decide if Thyrogen should be given to your child.
Dosage:
The recommended dose of Thyrogen is two doses administered 24 hours apart. Your doctor or nurse
will inject 1.0 ml of the Thyrogen solution.
Thyrogen should only be administered into the buttock muscle. Thyrogen solution should never be
injected into a vein.
If you have
•reduced liver function you should still be able to receive Thyrogen.
•kidney disease that require dialysis and your doctor will decide how much Thyrogen to give to
you. You may have more chance of experiencing headache and nausea after receiving Thyrogen.
•
reduced kidney function your doctor will decide how much radioiodine to give you.
When you undergo radioiodine imaging or elimination (ablation), your doctor will give you
radioiodine 24 hours after your final Thyrogen injection.
Diagnostic scanning should be performed 48 to 72 hours after the radioiodine administration (72 to 96
hours after the final injection of Thyrogen).
Post-treatment scanning may be delayed a few days to allow background radioactivity to decline.
For thyroglobulin (Tg) testing, your doctor or nurse will take a serum sample 72 hours after the last
injection of Thyrogen.
If you are given more Thyrogen than you should receive
Patients who accidentally received too much Thyrogen have reported nausea, weakness, dizziness,
headache, vomiting and hot flashes.
If you have any further questions on the use of this product, ask your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Thyrogen can cause side effects although not everybody gets them.
The following effects have been reported with Thyrogen:
25
Very common
(affects more than 1 user in 10):
•
nausea
Common
(affects 1 to 10 users in 100):
•
vomiting
•
fatigue
•
dizziness
•
headache,
•
diarrhoea,
•
weakness,
•
prickling or tingling sensation (paraesthesia).
Uncommon
(affects 1 to 10 users in 1,000):
•
feeling hot
•
hives (urticaria)
•
rash
•
flu symptoms
•
fever
•
chills
•
back pain
Frequency not known
(frequency cannot be estimated from the available data
)
•
swelling of the tumour
•
pain (including pain at the site of metastases (secondary cancer growths))
•
tremor
•
palpitations
•
flushing
•
shortness of breath
•
itching (pruritus)
•
excessive sweating
•
muscle or joint pain
•
injection site reactions (including: redness, discomfort, itching, local pain or stinging, and an
itchy rash)
•
low TSH
•
hypersensitivity (allergic reactions), these reactions include hives (urticaria), itching, flushing,
difficulty in breathing and rash.
Very rare cases of
hyperthyroidism
(increased activity of the thyroid gland) or
atrial fibrillation
have
been reported when Thyrogen was administered to patients who had not undergone total or partial
removal of the thyroid gland.
If any of the side effects gets serious, or if any side effects not listed in this leaflet, please tell your
doctor or pharmacist.
5.
HOW TO STORE THYROGEN
Keep out of the reach and sight of children.
26
Do not use after the expiry date which is stated on the label after “EXP”. The expiry date refers to the
last day of that month.
Store in a refrigerator (2°C - 8°C).
Keep the vial in the outer carton in order to protect from light.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Thyrogen contains
The active substance in Thyrogen is thyrotropin alfa.
Each vial contains 0.9 mg/ml of thyrotropin alfa when reconstituted with 1.2 ml water for injection.
Only 1 ml should be withdrawn equal to 0.9 mg of thyrotropin alfa.
The other ingredients are:
•
mannitol
•
sodium phosphate monobasic, monohydrate
•
sodium phosphate dibasic, heptahydrate
•
sodium chloride
(see
at the end
of
Section 2 “Important information about some of the ingredients of Thyrogen”)
What Thyrogen looks like and contents of the pack
Powder for solution for injection. White to off-white lyophilised powder.
Pack sizes: one or two vials of Thyrogen per carton.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder:
Genzyme Europe B.V.,
Gooimeer 10,
1411 DD Naarden,
The Netherlands.
Manufacturing authorisation holder:
Genzyme Ltd.,
37 Hollands Road,
Haverhill, Suffolk CB9 8PU,
United Kingdom
27
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien/
Luxemburg/Luxembourg
Genzyme Belgium N.V.,
Tel/Tél: + 32 2 714 17 11
Ísland
Genzyme A/S,
Tel: +354 535 7000
България
Търговско представителство на Genzyme
CEE GmbH
Тел. +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet
Tel: +36 1 310 7440
Česká Republika/Slovenská Republika/
Slovenija
Genzyme Czech s.r.o.,
Tel: +420 227 133 655
Nederland
Genzyme Europe B.V.,
Tel: +31 35 6991200
Danmark/Norge/Sverige/Suomi/Finland
Genzyme A/S, (Danmark/Tanska)
Tlf/Puh.: + 45 32712600
Österreich
Genzyme Austria GmbH
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska Sp. z o.o.
(Poola/Polija/Lenkija),
Tel: +
48 22 246 0900
Ελλάδα/
Κύπρος
Genzyme Hellas Ltd (Ελλάδα),
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal S.A.,
Tel: +351 21 422 0100
España
Genzyme, S.L.,
Tel: +34 91 6591670
România
Genzyme CEE GmbH- Reprezentanţa pentru
România
Tel: +40 21 243 4228
France
Genzyme S.A.S.,
Tél: +33 (0) 825 825 863
United Kingdom/Ireland
Genzyme Therapeutics (United Kingdom)
Tel: +44 1865 405200
Italia/Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349811
This leaflet was last approved in
28
Detailed information on this medicine is available on the European Medicines Agency (EMEA)
website: http://www.emea.europa.eu.
-----------------------------------------------------------------------------------------------------------------------
The following information is intended for medicinal or healthcare professionals only:
The recommended dose regimen of Thyrogen is two intramuscular injections of 0.9 mg thyrotropin
alfa administered at a 24-hour interval.
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.
After reconstitution, the solution should be injected within three hours, however the Thyrogen solution
will stay chemically stable for up to 24 hours, when stored between 2°C and 8°C protected from light.
It is important to note that the microbiological safety depends on the aseptic conditions during the
preparation of the solution.
29
Source: European Medicines Agency
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