THYROGEN

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

)תוחיטב )תוחיטב ןולעב ןולעב

אפורל אפורל

:ךיראת

5.8.2014

םש

רישכת

:תילגנאב

Thyrogen

רפסמ

:םושיר

117

91

29910

00

םש

לעב

:םושירה

sanofi aventis Israel Ltd

.

ספוט

הז

דעוימ

טוריפל

תורמחה

!דבלב תורמחהה

תושקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

WARNINGS AND

PRECAUTIONS

Stroke

There are postmarketing reports of radiologically-

confirmed stroke and neurological findings

suggestive of stroke unconfirmed radiologically

(e.g., unilateral weakness) occurring within 72

hours (range 20 minutes to three days) of

THYROGEN administration in patients without

known central nervous system metastases. The

majority of such patients were young women

taking oral contraceptives at the time of their

event or had other risk factors for stroke, such as

smoking or a history of migraine headaches. The

relationship between THYROGEN administration

and stroke is unknown. Patients should be well-

hydrated prior to treatment with THYROGEN.

6.Adverse

Reactions

6.1Clinical Trials

Experience

Table 4

Preferred

Term

THYROGE

N

(N=481)

n %)

Thyroid Hormone

Withdrawal

(N=418)

n (%)

Nausea

57 (11.9)

13 (3.1)

Headache

35 (7.3)

5 (1.2)

Fatigue

16 (3.3)

4 (1.0)

Hyperchole

sterolemia

0 (0.0)

13 (3.1)

Vomiting

14 (2.9)

3 (0.7)

Dizziness

12 (2.5)

0 (0.0)

Paraesthesi

8 (1.7)

0 (0.0)

Asthenia

7 (1.5)

0 (0.0)

Insomnia

7 (1.5)

0 (0.0)

Blood

Cholesterol

Abnormal

0 (0.0)

6 (1.4)

Diarrhea

6 (1.2)

0 (0.0)

Nasophary

ngitis

5 (1.0)

0 (0.0)

Thyroglob

ulin

Present

5 (1.0)

0 (0.0)

Table 1

Preferred Term

THYROGEN

(N=481)

n (%)

Thyroid Hormone

Withdrawal

(N=418)

n (%)

Nausea

53 (11)

2 (<1)

Headache

29 (6)

Fatigue

11 (2)

2 (<1)

Vomiting

11 (2)

Dizziness

9 (2)

0 (0.0)

Asthenia

5 (1)

1 (<1)

Tabulated list of adverse events

The most commonly reported adverse events are nausea and

headache, occurring in approximately 12%, and 7% of patients,

respectively.

The adverse events mentioned in the table, combine adverse events

in the six prospective clinical trials (N=481) and adverse events 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).

Neoplasm benign, malignant and unspecified (incl. cysts and

polyps)

Not known: neoplasm swelling, metastatic pain

Nervous system disorders

Common: dizziness, headache

Uncommon ; paraesthesia

Not known: tremor, stroke

Cardiac disorders

Not known: palpitation

Vascular disorders

Uncommon: feeling hot

Not known: flushing

Respiratory, thoracic and mediastinal disorder

Not known: dyspnoea

Gastrointestinal disorders

Very common: nausea

Common: vomiting

Uncommon ; diarrhoea

Skin and subcutaneous tissue disorders

Uncommon: urticaria, rash

Not known: pruritus, hyperhidrosis

Musculoskeletal and connective tissue disorder

Not known: arthralgia, myalgia

General disorders and administration site conditions

Common: fatigue, asthenia

Uncommon: influenza-like illness, pyrexia, rigors, back pain

Not known: discomfort, pain, pruritus, rash and urticaria at the site of intramuscular injection

Investigations

Not known: TSH decreased

Description of selected adverse events

Atrial fibrillation have been observed in patients receiving Thyrogen

with presence of either partial or entire thyroid gland.

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.

ב"צמ

ןולעה

ובש

תונמוסמ

תורמחהה

תושקובמה

לע

עקר

בוהצ

םייוניש

םניאש

רדגב

תורמחה

ונמוס

עבצב )ןולעב(

הנוש

שי

ןמסל

קר

ןכות

יתוהמ

אלו

םייוניש

םוקימב

טסקטה

748725

748725

Thyrogen®

Thyrotropin alfa for injection.

FULL PRESCRIBING INFORMATION

1.

INDICATIONS AND USAGE

1.1

Adjunctive Diagnostic Tool for Serum Thyroglobulin Testing

in Well Differentiated Thyroid Cancer

THYROGEN

is indicated for use as an adjunctive diagnostic

tool for serum thyroglobulin (Tg) testing with or without

radioiodine imaging in the follow-up of patients with well-

differentiated thyroid cancer who have previously undergone

thyroidectomy.

Limitations of Use:

THYROGEN-stimulated Tg levels are generally lower

than, and do not correlate with, Tg levels after thyroid

hormone withdrawal [

see

Clinical Studies

14.1

Even when THYROGEN-stimulated Tg testing is

performed in combination with radioiodine imaging, there

remains a risk of missing a diagnosis of thyroid cancer or

of underestimating the extent of disease.

Anti-Tg antibodies may confound the Tg assay and render

Tg levels uninterpretable [

see Clinical Studies

14.1

Therefore, in such cases, even with a negative or low-stage

THYROGEN radioiodine scan, consideration should

be given to further evaluating patients.

1.2

Adjunct to Treatment for Ablation in Well

Differentiated Thyroid Cancer

THYROGEN is indicated for use as an adjunctive

treatment for radioiodine ablation of thyroid tissue

remnants in patients who have undergone a near-total or

total thyroidectomy for well-differentiated thyroid cancer

and who do not have evidence of distant metastatic

thyroid cancer.

Limitations of Use:

The effect of THYROGEN on long-term thyroid cancer

outcomes has not been determined. Due to the relatively

small clinical experience with THYROGEN in remnant

ablation, it is not possible to conclude whether long-term

thyroid cancer outcomes would be equivalent after use

of THYROGEN or use of thyroid hormone withholding

for TSH elevation prior to remnant ablation.

2

DOSAGE AND ADMINISTRATION

2.1

Recommended Dosage

THYROGEN should be used by physicians knowledgeable in

the management of patients with thyroid cancer.

THYROGEN is indicated as a two-injection regimen. The

recommended dosage of THYROGEN is a 0.9 mg intramuscular

injection to the buttock followed by a second 0.9 mg

intramuscular injection to the buttock 24 hours later.

THYROGEN should be administered intramuscularly only.

THYROGEN should not be administered intravenously.

Pretreatment with glucocorticoids should be considered for

patients in whom tumor expansion may compromise vital

anatomic structures [

see Warnings and Precautions

5.3

Routine measurement of serum TSH levels is not recommended

after THYROGEN use.

2.2

Reconstitution, Preparation, and Administration of

THYROGEN

The supplied lyophilized powder must be reconstituted with

Sterile Water for Injection. THYROGEN should be prepared,

and administered in the following manner:

Add 1.2 mL of Sterile Water for Injection to the vial

containing the THYROGEN lyophilized powder.

Swirl the contents of the vial until all the material is

dissolved. Do not shake the solution. The reconstituted

THYROGEN solution has a concentration of 0.9 mg of

thyrotropin alfa per mL.

Visually inspect the reconstituted solution for particulate

matter and discoloration prior to administration. The

reconstituted THYROGEN solution should be clear and

colorless. Do not use if the solution has particulate matter

or is cloudy or discolored.

Withdraw 1 mL of the reconstituted THYROGEN

solution (0.9 mg of thyrotropin alfa) and inject

intramuscularly in the buttocks.

The reconstituted THYROGEN solution must be injected

within 3 hours unless refrigerated; if refrigerated, the

reconstituted solution may be kept for up to 24 hours.

Discard unused portions. Do not mix with other

substances.

2.3

Timing of Serum Thyroglobulin Testing Following

THYROGEN Administration

For serum thyroglobulin testing, the serum sample should be

obtained 72 hours after the final injection of THYROGEN [

see

Clinical Studies (14.1)

2.4

Timing for Remnant Ablation and Diagnostic Scanning

Following THYROGEN Administration

Oral radioiodine should be given 24 hours after the second

injection of THYROGEN in both remnant ablation and

diagnostic scanning. The activity of

I is carefully selected at

the discretion of the nuclear medicine physician.

Diagnostic scanning should be performed 48 hours after the

radioiodine administration whereas post-therapy scanning may

be delayed additional days to allow background activity to

decline.

3

DOSAGE FORMS AND STRENGTHS

THYROGEN is a lyophilized powder containing 1.1 mg of

thyrotropin alfa for single use after reconstitution with Sterile

Water for Injection.

Supplied as:

Two vial kit (two vials of lyophilized thyrotropin alfa)

4

CONTRAINDICATIONS

None

5

WARNINGS AND PRECAUTIONS

5.1

THYROGEN-induced Hyperthyroidism

When given to patients who have substantial thyroid tissue still

in situ

or functional thyroid cancer metastases, THYROGEN

is known to cause a transient (over 7 to 14 days) but significant

rise in serum thyroid hormone concentration. There have

been reports of death in non-thyroidectomized patients and in

patients with distant metastatic thyroid cancer in which events

leading to death occurred within 24 hours after administration

of THYROGEN. Patients with residual thyroid tissue at risk

for THYROGEN-induced hyperthyroidism include the elderly

and those with a known history of heart disease. Hospitalization

for administration of THYROGEN and post-administration

observation in patients at risk should be considered.

5.2

Stroke

There are postmarketing reports of radiologically-confirmed

stroke and neurological findings suggestive of stroke

unconfirmed radiologically (e.g., unilateral weakness)

occurring within 72 hours (range 20 minutes to three days) of

THYROGEN administration in patients without known central

nervous system metastases. The majority of such patients were

young women taking oral contraceptives at the time of their

event or had other risk factors for stroke, such as smoking or

a history of migraine headaches. The relationship between

THYROGEN administration and stroke is unknown. Patients

should be well-hydrated prior to treatment with THYROGEN.

5.3

Sudden Rapid Tumor Enlargement

Sudden, rapid and painful enlargement of residual thyroid

tissue or distant metastases can occur following treatment with

THYROGEN. This may lead to acute symptoms, which depend

on the anatomical location of the tissue. Such symptoms include

acute hemiplegia, hemiparesis, and loss of vision one to three

days after THYROGEN administration. Laryngeal edema, pain

at the site of distant metastasis, and respiratory distress requiring

tracheotomy have also been reported after THYROGEN

administration.

Pretreatment with glucocorticoids should be considered for

patients in whom tumor expansion may compromise vital

anatomic structures.

6

ADVERSE REACTIONS

6.1

Clinical Trials Experience

Because clinical trials are conducted under widely varying

conditions, adverse reaction rates observed in the clinical trials

of a drug cannot be directly compared to rates in the clinical

trials of another drug and may not reflect the rates observed in

practice.

The data described below reflect exposure to THYROGEN

in 481 thyroid cancer patients who participated in a total of 6

clinical trials of THYROGEN: 4 trials for diagnostic use and 2

trials for ablation. In clinical trials, patients had undergone near-

total thyroidectomy and had a mean age of 46.1 years. Thyroid

cancer diagnosis was as follows: papillary (69.2%), follicular

(12.9%), Hurthle cell (2.3%) and papillary/follicular 15.6%.

Most patients received 2 intramuscular

0.9 mg of thyrotropin

alfa injections given 24 hours apart [

see Clinical Studies (14.1)

(14.2)

The safety profile of patients who have undergone

thyroidectomy and received THYROGEN as adjunctive

treatment for radioiodine ablation of thyroid tissue remnants

for well-differentiated thyroid cancer did not differ from that of

patients who received THYROGEN for diagnostic purposes.

Reactions reported in ≥ 1% of patients in the combined trials

are summarized in Table 1. In some studies, an individual

patient may have participated in both THYROGEN and thyroid

hormone withdrawal [

see Clinical Studies (14.1) (14.2)

Table 1: Summary of Adverse Reactions by THYROGEN and

Thyroid Hormone Withdrawal in Pooled Clinical Trials (≥1% of

Patients in any Phase)

Preferred Term

THYROGEN

(N=481)

n (%)

Thyroid Hormone

Withdrawal

(N=418)

n (%)

Nausea

53 (11)

2 (<1)

Headache

29 (6)

Fatigue

11 (2)

2 (<1)

Vomiting

11 (2)

Dizziness

9 (2)

0 (0.0)

Asthenia

5 (1)

1 (<1)

6.2

Postmarketing Experience

The following adverse reactions have been identified during

post-approval use of THYROGEN. Because these reactions are

reported voluntarily from a population of uncertain size, it is not

always possible to reliably estimate their frequency or establish a

causal relationship to drug exposure.

Transient (<48 hours) influenza-like symptoms, including

fever (>100°F/38°C), chills/shivering, myalgia/arthralgia,

fatigue/asthenia/malaise, headache, and chills.

Hypersensitivity including urticaria, rash, pruritus,

flushing, and respiratory signs and symptoms.

Tabulated list of adverse events

:

The most commonly reported adverse events are nausea and headache,

occurring in approximately 12%, and 7% of patients, respectively.

The adverse events 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 events 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).

Neoplasm benign, malignant and unspecified (incl. cysts and polyps)

Not known:

neoplasm swelling, metastatic pain

Nervous system disorders

Common

: dizziness, headache,

Uncommon:

paraesthesia

Not known:

tremor, stroke

Cardiac disorders

Not known:

palpitation

Vascular disorders

Uncommon:

feeling hot

Not known:

flushing

Respiratory, thoracic and mediastinal disorder

Not known:

dyspnoea

Gastrointestinal disorders

Very common:

nausea

Common:

vomiting

Uncommon:

diarrhoea

Skin and subcutaneous tissue disorders

Uncommon:

urticaria, rash

Not known:

pruritus, hyperhidrosis

Musculoskeletal and connective tissue disorder

Not known:

arthralgia, myalgia

General disorders and administration site conditions

Common:

fatigue, asthenia

Uncommon:

influenza-like illness, pyrexia, rigors, back pain

Not known:

discomfort, pain, pruritus, rash and urticaria at the site of

intramuscular injection

Investigations

Not known:

TSH decreased

Description of selected adverse

events

Atrial fibrillation have been observed in patients receiving Thyrogen with

presence of either partial or entire thyroid gland.

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.

7

USE IN SPECIFIC POPULATIONS

7.1

Pregnancy

Pregnancy Category C

Animal reproduction studies have not been conducted with

THYROGEN.

It is also not known whether THYROGEN can cause fetal

harm when administered to a pregnant woman or can affect

reproductive capacity. THYROGEN should be given to a

pregnant woman only if clearly needed.

7.2

Nursing Mothers

It is not known whether the drug is excreted in human milk.

Because many drugs are excreted in human milk, caution should

be exercised when THYROGEN is administered to a nursing

woman.

7.3

Pediatric Use

Safety and effectiveness in pediatric patients have not been

established.

7.4

Geriatric Use

In pooled clinical studies of THYROGEN, 60 patients (12%)

were >65 years, and 421 (88%) were ≤ 65 years of age. Results

from controlled trials do not indicate a difference in the safety

and efficacy of THYROGEN between adult patients less than

65 years and those over 65 years of age [

see Warnings and

Precautions

5.1

7.5

Renal Impairment

Elimination of THYROGEN is significantly slower in dialysis-

dependent end stage renal disease (ESRD) patients, resulting in

prolonged elevation of TSH levels. This may lead to increased

risk of headache and nausea.

8

OVERDOSAGE

In clinical trials of THYROGEN, three patients experienced

symptoms after receiving THYROGEN doses higher than

those recommended. Two patients had nausea after a 2.7 mg

IM dose (3 times the recommended dose), and in one of these

patients, the event was accompanied by weakness, dizziness and

headache. Another patient experienced nausea, vomiting and

hot flashes after a 3.6 mg IM dose (4 times the recommended

dose). There is no specific therapy for THYROGEN overdose.

Supportive care is recommended.

In addition, one patient experienced symptoms after receiving

Thyrogen intravenously. This patient received 0.3 mg Thyrogen

as a single intravenous bolus and, 15 minutes later experienced

severe nausea, vomiting, diaphoresis, hypotension (BP decreased

from 115/66 mm Hg to 81/44 mm Hg) and tachycardia (pulse

increased from 75 to 117 bpm).

9

DESCRIPTION

Each vial of THYROGEN contains 1.1 mg thyrotropin alfa,

Mannitol 36 mg, Sodium phosphate monobasic, monohydrate

1.4 mg, Sodium phosphate dibasic, heptahydrate 3.7 mg,

Sodium chloride 2.4 mg

THYROGEN (thyrotropin alfa for injection) contains

recombinant human thyroid stimulating hormone (TSH).

Thyrotropin alfa is synthesized in a genetically modified Chinese

hamster ovary cell line.

Thyrotropin alfa is a heterodimeric glycoprotein comprised

of two non-covalently linked subunits, an alpha subunit of 92

amino acid residues containing two N-linked glycosylation

sites and a beta subunit of 118 residues containing one N-linked

glycosylation site. The amino acid sequence of thyrotropin alfa

is identical to that of human pituitary TSH.

Both thyrotropin alfa and naturally occurring human pituitary

TSH are synthesized as a mixture of glycosylation variants.

Unlike pituitary TSH, which is secreted as a mixture of

sialylated and sulfated forms, thyrotropin alfa is sialylated

but not sulfated. The biological activity of thyrotropin alfa

is determined by a cell-based bioassay. In this assay, cells

expressing a functional TSH receptor and a cAMP-responsive

element coupled to a heterologous reporter gene, luciferase,

enable the measurement of thyrotropin alfa activity by

measuring the luciferase response. The specific activity of

thyrotropin alfa is determined relative to an internal Genzyme

reference standard that was calibrated against the World Health

Organization (WHO) human TSH reference standard.

10

CLINICAL PHARMACOLOGY

10.1

Mechanism of Action

Thyrotropin (TSH) is a pituitary hormone that stimulates

the thyroid gland to produce thyroid hormone. Binding of

thyrotropin alfa to TSH receptors on normal thyroid epithelial

cells or on well-differentiated thyroid cancer tissue stimulates

iodine uptake and organification, and synthesis and secretion of

thyroglobulin (Tg), triiodothyronine (T3) and thyroxine (T4).

The effect of thyroid stimulating hormone activation of thyroid

cells is to increase uptake of radioiodine to allow scan detection

or radioiodine killing of thyroid cells. TSH activation also leads

to the release of thyroglobulin by thyroid cells. Thyroglobulin

functions as a tumor marker which is detected in blood

specimens.

10.2

Pharmacokinetics

The pharmacokinetics of THYROGEN were studied in 16

patients with well-differentiated thyroid cancer given a single

0.9 mg IM dose. Mean peak serum TSH concentrations of 116

± 38 mU/L were reached between 3 and 24 hours after injection

(median of 10 hours). The mean apparent elimination half-life

was 25 ± 10 hours. The organ(s) of TSH clearance in man have

not been identified, but studies of pituitary-derived TSH suggest

the involvement of the liver and kidneys.

11

NONCLINICAL TOXICOLOGY

11.1

Carcinogenesis, Mutagenesis, Impairment of Fertility

Long-term toxicity studies in animals have not been performed

with THYROGEN to evaluate the carcinogenic potential of

the drug. THYROGEN was not mutagenic in the bacterial

reverse mutation assay. Studies have not been performed with

THYROGEN to evaluate the effects on fertility.

11.2

Animal Pharmacology and/or Toxicology

Four toxicology studies, two in rodents and two in primates,

have been conducted using both single and repeated daily

injections of thyrotropin alfa. In a single-dose study utilizing

male and female rats bolus injections were given at levels up to

7.14 IU/kg (equivalent to 50 times the expected single human

dose). There were no effects, either gross or microscopic, in

this study which could be attributed to the administration of

thyrotropin alfa. In a repeated-dose study, rats were given

thyrotropin alfa in the form of 5 daily intramuscular injections

at levels up to 1.43 IU/kg (equivalent to 10 times the expected

single human dose) without dose-related toxic effects observed.

A single-dose study in male and female cynomolgus monkeys

used single intramuscular injections of thyrotropin alfa at

levels equivalent to the expected dose and 0.25 and 4 times

the expected single human dose. There were no changes that

were regarded as indicative of an adverse or toxic response to

thyrotropin alfa. Cynomolgus monkeys were also administered

thyrotropin alfa as three consecutive daily bolus intramuscular

injections at levels extending to 4 times the dose in humans.

There were no changes that are considered to indicate an adverse

or toxic response to thyrotropin alfa.

12

CLINICAL STUDIES

12.1

Clinical Trials of THYROGEN as an Adjunctive Diagnostic

Tool

Two prospective, randomized phase 3 clinical trials were

conducted in patients with well-differentiated thyroid cancer

to compare

I whole body scans obtained after THYROGEN

injection to

I whole body scans after thyroid hormone

withdrawal. A cross-over, non-blinded design was used in both

trials. Oral radioiodine was given 24 hours after the second

injection of THYROGEN, and scanning was done 48 hours after

the radioiodine administration. Each patient was scanned first

following THYROGEN and then scanned after thyroid hormone

withdrawal. In both studies, the primary endpoint was the rate

of concordant scans (scan findings in agreement in a given

patient using each preparation method).

12.2

Clinical Trials of THYROGEN as an Adjunct to Radioiodine

Therapy to Achieve Thyroid Remnant Ablation

A randomized prospective clinical trial compared the rates of

thyroid remnant ablation achieved after preparation of patients

with thyroid hormone withdrawal or THYROGEN. Patients

(n = 63) with low-risk, well-differentiated thyroid cancer who

underwent near-total thyroidectomy were made euthyroid after

surgery by receiving thyroid hormone replacement and were

subsequently randomized to a thyroid hormone withdrawal or

THYROGEN. Patients in the THYROGEN group received

THYROGEN 0.9 mg IM daily on 2 consecutive days and

radioiodine 24 hours after the second dose of THYROGEN.

Patients in the thyroid hormone withdrawal group had the

thyroid replacement withheld until they became hypothyroid.

Patients in both groups received 100 mCi

I ± 10% with

the intent to ablate any thyroid remnant tissue. The primary

endpoint of the study, was the rate of successful ablation, and

was assessed 8 months later by a THYROGEN-stimulated

radioiodine scan. Patients were considered successfully ablated

if there was no visible thyroid bed uptake on the scan, or if

visible, if uptake was less than 0.1%. Table 3 summarizes the

results of this evaluation.

Table 3: Remnant Ablation in Clinical Trial of Patients with Well-

Differentiated Thyroid Cancer

Group

a

Mean

Age

(Yr)

Gender

(F:M)

Cancer

Type

(Pap:Fol)

Ablation Criterion

(Measure at 8

Months)

Thyroid

Activity

<0.1%

Visible

Thyroid

Activity

Thyroid

Hormone

Withdrawal

(N=28)

24:6

29:1

28/28

(100%)

24/28

(86%)

THYROGEN

(N=32)

26:7

30:3

32/32

(100%)

24/32

(75%)

60 per protocol patients with interpretable scan data.

95% CI for difference in ablation rates THYROGEN minus Thyroid

Hormone Withdrawal, = 7% to 27%.

Interpretation by 2 of 3 reviewers.

95% CI for difference in ablation rates, THYROGEN minus Thyroid

Hormone Withdrawal, = -31% to 9%.

Abbreviations: fol = follicular, pap = papillary

The mean radiation dose to blood was 0.266±0.061 mGy/MBq

in the THYROGEN group and 0.395±0.135 mGy/MBq in the

thyroid hormone withdrawal group. Radioiodine residence time

in remnant tissue was 0.9±1.3 hours in the THYROGEN group

and 1.4±1.5 hours in the thyroid hormone withdrawal group. It

is not known whether this difference in radiation exposure would

convey a clinical benefit.

Patients who completed were followed up for

a median duration

of 3.7 years (range 3.4 to 4.4 years) following radioiodine

ablation. Tg testing was also performed.

The main objective

of the follow-up study was to evaluate the status of thyroid

remnant ablation by using THYROGEN-stimulated neck

imaging. Of the

fifty-one patients enrolled, forty eight patients

received THYROGEN for remnant neck/whole body imaging

and/or thyroglobulin testing. Only 43 patients had imaging.

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 from both original

treatment groups who had scanning were found to still be

ablated

.

Of 37 patients who were

Tg–antibody negative, 16/17

(94%) of patients in the former thyroid hormone withdrawal

group and 19/20 (95%) of patients in the former THYROGEN

group maintained successful ablation measured as stimulated

serum Tg levels of <2 ng/mL.

No patient had a definitive cancer 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 tumor from the regional disease

noted at the start of the initial study), and 2 patients could not be

assessed.

Two large prospective multi-center randomized studies

compared THYROGEN to thyroid hormone withdrawal using

two different doses of radioactive iodine in patients with

differentiated thyroid cancer who had been thyroidectomized.

In both studies, patients were randomized to 1 of 4 treatment

groups: THYROGEN + 30 mCi

I, THYROGEN + 100 mCi

I, thyroid hormone withdrawal + 30 mCi

I, or thyroid

hormone withdrawal + 100 mCi

I. Patients were assessed for

efficacy (ablation success rates) at approximately 8 months.

The first study (Study A) randomized 438 patients (tumor stages

T1-T3, Nx, N0 and N1, M0). Ablation success was defined as

radioiodine uptake of <0.1% in the thyroid bed and stimulated

thyroglobulin levels of < 2.0 ng/mL.

The second study (Study B) randomized 752 patients with

low-risk thyroid cancer (tumor stages pT1 < 1 cm and N1 or

Nx, pT1 >1-2 cm and any N stage, or pT2 N0, all patients M0).

Ablation success was defined by neck ultrasound and stimulated

thyroglobulin of ≤ 1.0 ng/mL.

Results for both trials are summarized below.

Table 4: Successful Remnant Ablation Rates in Study A

THYROGEN

Thyroid Hormone

Withdrawal

Total

Low-dose

radioiodine

91/108

(84.3%)

91/106

(85.8%)

182/214

(85.0%)

High-dose

Radioiodine

92/102

(90.2%)

92/105

(87.6%)

184/207

(88.9%)

Total

183/210

(87.1%)

183/211

(86.7%)

366/421

(86.9%)

95% CI of difference in ablation rate (low-dose minus high dose): -10.2% to

2.6%

95% CI of difference in ablation rate (THYROGEN - Thyroid Hormone

Withdrawal): -6.0% to 6.8%

Table 5: Successful Remnant Ablation Rates in Study B

THYROGEN

Thyroid

Hormone

Withdrawal

Total

Low-dose

radioiodine

160/177

(90.4%)

156/170

(91.8%)

316/347

(91.1%)

High-dose

Radioiodine

159/171

(93.0%)

156/166

(94.0%)

315/337

(93.5%)

Total

319/348

(91.6%)

312/336

(92.9%)

631/684

(92.3%)

95% CI of difference in ablation rate (low-dose minus high dose):

-5.8% to 0.9%

95% CI of difference in ablation rate (THYROGEN minus Thyroid

Hormone Withdrawal): -4.5% to 2.2%

748725

Study 1 (n=127) compared the diagnostic scanning following a

THYROGEN regimen of 0.9 mg IM daily on two consecutive

days to thyroid hormone withdrawal. In addition to body

scans, Study 2 (n=229) also compared thyroglobulin (Tg) levels

obtained after THYROGEN to those at baseline and to those

after thyroid hormone withdrawal. All Tg testing was performed

in a central laboratory using a radioimmunoassay (RIA) with

a functional sensitivity of 2.5 ng/mL. Patients who were

included in the Tg analysis were those who had undergone total

or near-total thyroidectomy with or without

I ablation, had

< 1% uptake in the thyroid bed on a scan after thyroid hormone

withdrawal, and did not have detectable anti-Tg antibodies. The

maximum THYROGEN Tg value was obtained 72 hours after

the final THYROGEN injection, and this value was used in the

analysis.

Diagnostic Radioiodine Whole Body Scan Results

Study 1 enrolled 127 patients, 71% were female and 29% male,

and mean age was 44 years. The study included the following

forms of differentiated thyroid cancer: papillary cancer (88%),

follicular cancer (9%), and Hurthle cell (2%). Study results are

displayed in Table 2.

In Study 2, patients with differentiated thyroid cancer who had

been thyroidectomized (n = 229) were randomized into one of

two THYROGEN treatment regimens: THYROGEN 0.9 mg

IM daily on two consecutive days (n = 117), and THYROGEN

0.9 mg IM daily on days 1, 4 and 7 (n = 112). Each patient was

scanned first using THYROGEN, then scanned using thyroid

hormone withdrawal. The group receiving the THYROGEN

0.9 mg IM x 2 regimen was 63% female/27% male, had a mean

age 44 years, and generally had low-stage papillary or follicular

cancer (AJCC/TNM Stage I 61%, Stage II 19%, Stage III 14%,

Stage IV 5%). The group receiving the THYROGEN 0.9 mg

IM x 3 regimen was 66% female/34% male, had a mean age

50 years, and generally had low-stage papillary or follicular

cancer (AJCC/TNM Stage I 50%, Stage II 20%, Stage III 20%,

Stage IV 9%). The amount of radioiodine used for scanning

was 4 mCi ± 10%, and scanning times were lengthened in some

patients to capture adequate images (30 minute scans, or 140,000

counts). Scan pairs were assessed by blinded readers. Study

results are presented in Table 2.

Table 2: Concordance of Positive Thyroid Scans Following

THYROGEN Treatment with Scans Following Thyroid

Hormone Withdrawal

Number of

Scan Pairs

by Disease

Category

Concordance of

scan pairs between

THYROGEN scan

and thyroid hormone

withdrawal scan

Study 1 (0.9 mg IM qd x2)

Positive for remnant or cancer

in thyroid bed

Positive for metastatic disease

Total positive withdrawal

scans

Study 2 (0.9 mg IM qd x 2)

Positive for remnant or cancer

in thyroid bed

Positive for metastatic Disease

Total positive withdrawal

scans

Across both studies uptake was detected on the THYROGEN scan but not

observed on the scan after thyroid hormone withdrawal in 5 patients with

remnant or cancer in the thyroid bed.

In the two clinical studies radioiodine scan results using thyroid hormone

withdrawal were taken as the true clinical status of each patient and as the

comparator for THYROGEN scans. Thyroid hormone withdrawal trace-

positive scans were scored conservatively as positive with no allowance

for false positives.

Across the two clinical studies, and scoring all false positives in

favor of thyroid hormone withdrawal, the majority of positive

scans using THYROGEN and thyroid hormone withdrawal were

concordant. The THYROGEN scan failed to detect remnant

and/or cancer localized to the thyroid bed in 17% (14/83) of

patients in whom it was detected by a scan after thyroid hormone

withdrawal. In addition, the THYROGEN scan failed to detect

metastatic disease in 29% (7/24) of patients in whom it was

detected by a scan after thyroid hormone withdrawal.

Thyroglobulin (Tg) Results

THYROGEN Tg Testing Alone and in Combination with

Diagnostic Whole Body Scanning: Comparison with Results

after Thyroid Hormone Withdrawal

In anti-Tg antibody negative patients with a thyroid remnant or

cancer (as defined by a withdrawal Tg ≥ 2.5 ng/mL or a positive

scan [after thyroid hormone withdrawal or after radioiodine

therapy]), the THYROGEN Tg was positive (≥ 2.5 ng/mL) in

69% (40/58) of patients after 2 doses of THYROGEN.

In these same patients, adding the whole body scan increased

the detection rate of thyroid remnant or cancer to 84% (49/58) of

patients after 2 doses of THYROGEN.

Among patients with metastatic disease confirmed by a

post-treatment scan or by lymph node biopsy (35 patients),

THYROGEN Tg was positive (≥ 2.5 ng/mL) in all 35 patients,

while Tg on thyroid hormone suppressive therapy was positive

( ≥ 2.5 ng/mL) in 79% of these patients.

As with thyroid hormone withdrawal, the intra-patient

reproducibility of THYROGEN testing with regard to both Tg

stimulation and radioiodine imaging has not been studied.

Hypothyroid Signs and Symptoms

THYROGEN administration was not associated with the signs

and symptoms of hypothyroidism that accompanied thyroid

hormone withdrawal as measured by the Billewicz scale.

Statistically significant worsening in all signs and symptoms

were observed during the hypothyroid phase (p<0.01) (Figure 1).

Figure 1: Hypothyroid Symptom Assessment Billewicz Scale

Diagnostic Indication 0.9 mg THYROGEN

®

q 24 hours x 2

doses vs. Thyroid Hormone Withdrawal Phase

12.3

Quality of Life

Quality of Life (QOL) was measured during both the diagnostic

study [

see Clinical Studies

14.1

)] and the ablation of thyroid

remnant study [

see Clinical Studies

14.2

)] using the SF-36

Health Survey, a standardized, patient-administered instrument

assessing QOL across eight domains measuring both physical

and mental functioning. In the diagnostic study and in the

remnant ablation study, following THYROGEN administration,

little change from baseline was observed in any of the eight

QOL domains of the SF-36. Following thyroid hormone

withdrawal in the diagnostic study, statistically significant

negative changes were noted in all eight QOL domains of

the SF-36. The difference between treatment groups was

statistically significant (p<0.0001) for all eight QOL domains,

favoring THYROGEN over thyroid hormone withdrawal

(Figure 2). In the remnant ablation study, following thyroid

hormone withdrawal, statistically significant negative changes

were noted in five of the eight QOL domains (physical

functioning, role physical, vitality, social functioning and mental

health).

Figure 2: SF-36 Health Survey Results

Quality of Life Domains

Diagnostic Indication

13.

HOW SUPPLIED/STORAGE AND HANDLING

THYROGEN (thyrotropin alfa for injection) is supplied as a

sterile, non-pyrogenic, lyophilized product. It is available either

in a two-vial kit or a four-vial kit. The two-vial kit contains two

1.1 mg vials of THYROGEN.

THYROGEN is for intramuscular injection to the buttock. The

lyophilized powder should be reconstituted immediately prior to

use with 1.2 mL of Sterile Water for Injection, USP

[see Dosage

and Administration (2.2)].

Each vial of THYROGEN and each

vial of diluent, if provided, is intended for single use.

THYROGEN should be stored at 2-8ºC (36-46ºF).

If necessary, the reconstituted solution can be stored for up to

24 hours at a temperature between 2ºC and 8ºC, while avoiding

microbial contamination.

Protect from light.

1

PATIENT COUNSELING INFORMATION

Adverse Reactions

Inform patients that the most common adverse events from

clinical experience were nausea and headache.

Advise patients to seek immediate medical attention should

they experience severe symptoms.

Important Information

Prior to THYROGEN administration, counsel patients to seek

care immediately for any neurologic symptoms occurring

after administration of the drug.

Inform patients for whom THYROGEN induced

hyperthyroidism could have serious consequences,

hospitalization for administration of THYROGEN and post

administrative observation should be considered.

Dosing and Administration

Patients should be instructed that THYROGEN is

for intramuscular administration into the buttock only.

THYROGEN should not be administered intravenously.

Inform patients the treatment regimen is two doses of

THYROGEN administered at a 24 hour interval.

Encourage patients to remain hydrated prior to treatment with

THYROGEN.

Schedule of Procedures

Inform patients that if diagnostic scanning will be performed,

radioiodine will be given 24 hours after the second injection

of THYROGEN, and patients should return for the scan 48

hours after radioiodine administration.

Inform patients that if serum Tg testing is performed, blood

will be drawn 72 hours or later after the second injection of

THYROGEN.

Inform patients that if remnant ablation is performed

radioiodine will be administered 24 hours after the second

injection of THYROGEN.

THYROGEN is manufactured a by:

Genzyme Europe B.V., Amsterdam, The Netherlands

THYROGEN is a registered trademark of Genzyme Corporation.

Registered owner:

Sanofi-aventis Israel Ltd.

P.O.B 8090, Netanya 4250499

License number: 117 91 29910 00

The format of this leaflet has been determined by the ministry of health

and the content thereof has been checked and approved on 08/2014

THYR-V10.1

GMID:

748725

Previous GMID:

729131

Description:

LEAFLET THYR 0.9MG/1ML IL

Vista Folder #:

4051742

Revision:

Market:

Israel

Language(s):

English

Date:

11 Sep 2019

Operator:

Niamh Garrigan

Min Point Size:

7.5pt body text

Printing Cols:

Black,

Non-Printing Cols:

Dieline

Lot/Batch

Expiry

ID/DOM

Serial No. (S/N)

Product Barcode:

Plant Barcode:

748725

Spec:

WAT_SPEC-000068

Template Ref.:

IE03 PK 0009 (Rev 1)

Dimensions:

261 x 420mm

IDA Industrial Park,

Old Kilmeaden Road,

Waterford, Ireland