Consumer medicine information

Saizen

Somatropin

BRAND INFORMATION

Brand name

Saizen

Active ingredient

Somatropin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Saizen.

SUMMARY CMI

SAIZEN®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using SAIZEN?

SAIZEN contains the active ingredient somatropin (rmc). SAIZEN is used to treat growth failure in children who have a deficiency of natural human growth hormone, growth failure in girls who have a genetic condition called gonadal dysgenesis, often referred to as Turner Syndrome, which may cause short stature, growth hormone deficiency in adults, growth disturbance (growth retardation) in pre-pubertal children with chronic renal insufficiency (CRI), growth disturbance in short children born small for gestational age (SGA) who fail to demonstrate catch-up growth by four years of age or later.

For more information, see Section 1. Why am I using SAIZEN? in the full CMI.

2. What should I know before I use SAIZEN?

Do not use if you have ever had an allergic reaction to SAIZEN or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use SAIZEN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SAIZEN and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use SAIZEN?

  • Your doctor will determine your dose and how frequently you inject (3, 6 or 7 times a week). This depends on why you are being treated with SAIZEN, and your body surface area or body weight.
  • Follow the Instructions for Use provided with the device carefully.

More instructions can be found in Section 4. How do I use SAIZEN? in the full CMI.

5. What should I know while using SAIZEN?

Things you should do
  • Remind any doctor, dentist, nurse or pharmacist you visit that you are using SAIZEN.
  • Tell your doctor as soon as possible if you do not feel well while using SAIZEN.
Things you should not do
  • Do not stop using this medicine suddenly without telling your doctor.
  • Do not use SAIZEN to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not change the dose unless your doctor tells you to.
Driving or using machines
  • Due to its pharmacological profile, somatropin is unlikely to impair patient's ability to drive or to operate machinery.
Looking after your medicine
  • Keep SAIZEN injection solution in the original package, in a refrigerator where the temperature is between 2°C to 8°C (Refrigerate. Do not freeze) and it is not exposed to light.
  • SAIZEN cartridge must be used with an autoinjector device.
  • The autoinjector containing a cartridge of SAIZEN must be stored in the device storage box.

For more information, see Section 5. What should I know while using SAIZEN? in the full CMI.

6. Are there any side effects?

The most serious side effects include symptoms of allergic reactions (e.g. shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin), unexplained limp, hip or knee pain and strong or recurrent headache associated with nausea, vomiting or sight disturbances. For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

SAIZEN®

Active ingredient(s): somatropin (rmc), recombinant human growth hormone

Consumer Medicine Information (CMI)

This leaflet provides important information about using SAIZEN. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using SAIZEN.

Where to find information in this leaflet:

1. Why am I using SAIZEN?
2. What should I know before I use SAIZEN?
3. What if I am taking other medicines?
4. How do I use SAIZEN?
5. What should I know while using SAIZEN?
6. Are there any side effects?
7. Product details

1. Why am I using SAIZEN?

SAIZEN contains the active ingredient somatropin, which is the same as natural human growth hormone, but is made in a laboratory.

SAIZEN is used to treat growth failure in children who have a deficiency of natural human growth hormone, growth failure in girls who have a genetic condition called gonadal dysgenesis, often referred to as Turner Syndrome, which may cause short stature, growth hormone deficiency in adults, growth disturbance (growth retardation) in pre-pubertal children with chronic renal insufficiency (CRI), growth disturbance in short children born small for gestational age (SGA) who fail to demonstrate catch-up growth by four years of age or later.

A doctor who is experienced in the diagnosis and management of growth failure or disturbance will assess if you require treatment with SAIZEN.

Your doctor may have prescribed SAIZEN for another reason.

Ask your doctor if you have any questions about why SAIZEN has been prescribed for you.

2. What should I know before I use SAIZEN?

Warnings

Do not use SAIZEN if:

  • you are allergic to somatropin, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine.
  • you currently have any type of active cancer. All cancer treatments must be finished before starting treatment with SAIZEN.
  • you have an active brain lesion, e.g. brain injury, abscess or tumour.
  • you have diabetic retinopathy, an eye disease caused by complications of diabetes.
  • you have an acute, critical illness, e.g. following major surgery such as open heart surgery or abdominal surgery, or hospitalisation for an accident, or severe breathing disorders.

SAIZEN should not be used for growth promotion in children if their bones have stopped growing.

In children with CRI, treatment with SAIZEN must be discontinued at the time of renal transplantation.

Do not use SAIZEN after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacists for disposal.

If you are not sure whether you should start using this medicine, talk to your doctor.

Check with your doctor if you:

  • have or have had any of the following medical conditions:
    - any type of cancer
    - diabetes mellitus
    Somatropin may cause blood sugar levels to increase. If you are diabetic, your doctor will monitor your treatment and may change your treatment for diabetes.
    - thyroid disorders
    Your doctor may prescribe another hormone to take if you are found to have developed a lack of thyroid hormone.
    - brain disorders
    If you have other hormone deficiencies due to a previous brain condition, your doctor needs to correct these before starting treatment with SAIZEN.
    During treatment with SAIZEN, your doctor will make regular examinations to check that your original brain disorder has not returned.
    Your SAIZEN treatment may need to be stopped if your brain condition returns.
    - scoliosis
    Your doctor needs to monitor for any signs of scoliosis as rapid growth in any child can cause progression of scoliosis.
    - liver or kidney disorders
    Your doctor may need to adjust your SAIZEN treatment if you have any pre-existing condition with your liver or kidney.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Also tell your doctor if you have allergies to any other medicines, foods, preservatives, or dyes.

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your doctor will discuss with you the risks and benefits of using SAIZEN if you are pregnant or breastfeeding.

Children with chronic renal insufficiency (CRI)

Treatment with SAIZEN in children with CRI should only be started after growth disturbance has been confirmed over a period of one year or upon your doctor's discretion (for example not less than 6 months in older children).

Children with CRI should be examined and monitored regularly for evidence of bone disease. It is uncertain whether the bone disease and its complications are affected by growth hormone therapy. Assessment of the hip should be obtained prior to initiating therapy and at regular intervals upon discretion of your doctor.

Children born small for gestational age (SGA)

Children with SGA should be examined and monitored regularly to check the fasting insulin and blood glucose before starting treatment with SAIZEN and every year.

It is recommended to measure your child's IGF-1 level (Insulin-like Growth Factor 1) before start of treatment and twice a year thereafter.

Your doctor will advise you how to measure your blood sugar and will monitor or perform other tests as required.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Medicines that may reduce the effect of SAIZEN include:

  • Corticosteroids
    Tell your doctor if you are taking corticosteroids. Corticosteroids are used to treat several illnesses including asthma, allergies and rheumatoid arthritis. Corticosteroids might stop SAIZEN from working well.
  • Oral estrogen (hormone) replacement medicine
    Tell your doctor if you are using or if you will start to use an oral estrogen (hormone) replacement medicine.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect SAIZEN.

4. How do I use SAIZEN?

SAIZEN therapy should be carried out under the regular guidance of a doctor who is experienced in the diagnosis and management of growth hormone disorders.

How much to take / use

  • Your doctor will determine your dose and how frequently you inject (3, 6 or 7 times a week). This depends on why you are being treated with SAIZEN, and your body surface area or body weight.
  • Follow the instructions provided and use SAIZEN until your doctor tells you to stop.

When to take / use SAIZEN

  • SAIZEN should be used preferably in the evening.

How to inject

  • SAIZEN is intended for you to inject by subcutaneous (under the skin) injection

Your doctor, nurse or pharmacist will instruct and assist you in learning the techniques for preparing the medicine and for self-injection.

SAIZEN solution for injection is provided in a cartridge with a dedicated autoinjector device (provided separately). The autoinjector device provided with your medicine can either be electronic or hand-operated.

Follow the Instructions for Use provided with the device carefully.

Do not attempt self-injection until you are sure of how to do it.

Do not inject SAIZEN if it contains particles and is not clear.

Where to inject

Use a different injection site each time to lessen the risk of damage to the fat and tissues under the skin.

Prepare the injection site according to the instructions given by your doctor, nurse or pharmacist.

Talk to your doctor, nurse or pharmacist if you experience anything unusual when injecting.

If you forget to use SAIZEN

SAIZEN should be used regularly at the same time each day. If you miss your dose at the usual time, contact your doctor, nurse or pharmacist for advice.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed.

If you have trouble remembering your injection schedule, ask your pharmacist or nurse for some tips.

If you use too much SAIZEN

If you think that you have used too much SAIZEN, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using SAIZEN?

Things you should do

Tell your doctor as soon as possible if you do not feel well while using SAIZEN.

Call your doctor straight away if you:

  • Notice symptoms of an allergic reaction which may include:
    - shortness of breath
    - wheezing or difficulty breathing
    - swelling of the face, lips, tongue or other parts of the body
    - rash, itching or hives on the skin
  • are about to start on taking any new medicines.
  • If you become pregnant while using SAIZEN.

Remind any doctor, dentist or pharmacist you visit that you are using SAIZEN.

Things you should not do

  • Do not stop using this medicine suddenly without telling your doctor.
  • Do not use SAIZEN to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
  • Do not change the dose unless your doctor tells you to.

Driving or using machines

Due to its pharmacological profile, somatropin is unlikely to impair patient's ability to drive or to operate machinery.

Looking after your medicine

  • Keep SAIZEN injection solution in the original package, in a refrigerator where the temperature is between 2°C to 8°C (Refrigerate. Do not freeze) and it is not exposed to light.
  • Do not store it in the freezer.
  • SAIZEN injection is intended for multiple use in one patient only
  • After first injection, store at 2°C to 8°C (Refrigerate. Do not freeze) for a maximum of 28 days.
  • After first injection, if refrigeration is temporarily unavailable, it can be stored for up to 7 days below 25°C. Protect from light. Following this, it must be returned to the refrigerator and stored at 2°C to 8°C (Refrigerate. Do not freeze) for a maximum of 28 days and discard any leftovers.
  • SAIZEN cartridge must be used with an autoinjector device.
  • The autoinjector containing a cartridge of SAIZEN must be stored in the device storage box.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Keep it where young children cannot reach it.

When to discard your medicine

Discard all sharps into a disposal unit.

Ask your doctor or pharmacist what to do if you have any SAIZEN that has expired or is left over from your treatment.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Injection site related:
    - pain, numbness, redness or swelling at the injection site
    - local fat loss
  • Muscle or joint related:
    - pain in muscles or joints
    - stiffness
    - swelling of limbs
  • Infection related:
    - upper respiratory tract infection
    - ear infection
    - chickenpox
  • Gastrointestinal system related:
    - inflammation
    - abdominal pain
  • Respiratory system related:
    - inflammation in some parts of the respiratory tract such as pharynx, bronchial tube, tonsils or nose
Many of these events reflect commonly observed childhood infections or accidental injuries.
These side effects are more common in adult patients. They often appear at the start of treatment and are usually temporary:
  • Metabolism and hormone related:
    - increased thirst, increased need to pass urine, dry mouth or skin (symptoms of high blood sugar levels)
    - shaking and/or light-headedness (symptoms of low blood sugar levels)
    - extreme tiredness, lethargy, muscle weakness or cramps (symptoms of low levels of thyroid hormone)
This can be tested by your doctor and if necessary, he/she will prescribe appropriate treatment.
  • Nervous system related:
    - tingling, numbness, weakness or pain in the fingers or hand, or pain in your arm between hand and elbow (symptoms of pressure on nerve around your wrist).
    - pins and needles sensation
    - headache
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Symptoms of allergic reactions:
  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
Unexplained limp or hip/knee pain
Strong or recurrent headache associated with nausea, vomiting or sight disturbances		Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What SAIZEN contains

Active ingredient (main ingredient)Somatropin (rmc)
Other ingredients (inactive ingredients)Sucrose, poloxamer, phenol, water for injections, sodium hydroxide, citric acid-anhydrous

Do not take this medicine if you are allergic to any of these ingredients.

What SAIZEN looks like

SAIZEN is a solution for injection in a cartridge in three different strengths:

SAIZEN 6 mg contains somatropin (rmc) 6 mg in 1.03 mL (5.83 mg/mL) (AUST R 166475)

SAIZEN 12 mg contains somatropin (rmc) 12 mg in 1.5 mL (8.00 mg/mL) (AUST R 166478)

SAIZEN 20 mg contains somatropin (rmc) 20 mg in 2.5 mL (8.00 mg/mL) (AUST R 166479)

Who distributes SAIZEN

Sponsor in Australia:

Merck Healthcare Pty Ltd
Suite 1, Level 1, Building B
11 Talavera Road
Macquarie Park NSW 2113

For SAIZEN education and support, call connections for growth on 1800 724 936.

For any questions about SAIZEN, call Merck Australia Medical Information on + 61 2 8977 4100.

This leaflet was prepared in May 2024.

Published by MIMS July 2024

BRAND INFORMATION

Brand name

Saizen

Active ingredient

Somatropin

Schedule

S4

 

1 Name of Medicine

Somatropin (rmc), recombinant human growth hormone.

2 Qualitative and Quantitative Composition

Saizen solution for injection.

Somatropin (rmc) 6 mg/1.03 mL (5.83 mg/mL), 12 mg/1.5 mL (8.00 mg/mL) or 20 mg/2.5 mL (8.00 mg/mL). Saizen solution for injection also contains sucrose, poloxamer, phenol and water for injection. Sodium hydroxide and citric acid are used for pH adjustment.

3 Pharmaceutical Form

Saizen solution for injection.

Saizen solution for injection is presented as a sterile liquid (opalescent white to off-white solution, practically free from visible particles) in glass cartridges for multidose use.

4 Clinical Particulars

4.1 Therapeutic Indications

I. Growth failure in children due to human growth hormone deficiency.
II. Growth failure in girls with gonadal dysgenesis (Turner syndrome), confirmed by chromosomal analysis.
III. Growth disturbance (growth retardation) in prepubertal children due to chronic renal insufficiency (CRI).
IV. Growth disturbance (current height standard deviation score (H SDS) < -2.5 and parental adjusted H SDS < -1) in short children born small for gestational age (SGA) with a birth weight and/or length below -2 standard deviations (SD), who failed to show catch-up growth (height velocity standard deviation score (HV SDS) < 0 during the last year) by four years of age or later.
V. Saizen is indicated for replacement therapy in adults with pronounced growth hormone deficiency as diagnosed in 2 different dynamic tests for growth hormone deficiency and defined by peak GH concentrations of less than 2.5 nanogram/mL. Adults must also fulfil the following criteria.

Childhood onset.

Patients who were diagnosed as growth hormone deficient during childhood must be retested and their growth hormone deficiency confirmed before replacement therapy with Saizen is started.

Adult onset.

Patients must have growth hormone deficiency as a result of hypothalamic or pituitary disease and at least one other hormone deficiency diagnosed (except for prolactin) and adequate replacement therapy instituted, before replacement therapy using growth hormone may begin.

4.2 Dose and Method of Administration

Dosage.

Treatment should be discontinued when a satisfactory adult height has been reached or when epiphyses are closed.
The maximum recommended daily dose should not be exceeded.

I. Treatment of growth failure due to growth hormone deficiency in children.

The recommended weekly dose is as follows: 0.2 mg/kg bodyweight; or 4 mg/m2 BSA (body surface area).
The weekly dose may be divided as shown in Table 1 and is expressed per injection.

II. Treatment of growth failure in girls with gonadal dysgenesis (Turner syndrome).

The recommended daily dose is 0.045-0.05 mg/kg bodyweight; or 1.4 mg/m2 BSA.

III. Treatment of growth disturbance in children with chronic renal insufficiency.

The recommended daily dose is 0.045-0.05 mg/kg bodyweight; or 1.4 mg/m2 BSA.

IV. Treatment of growth disturbance in short children born small for gestational age.

The recommended starting daily dose is 0.035 mg/kg bodyweight or 1 mg/m2 BSA.
The dose may be increased to a maximum recommended dose of 0.067 mg/kg/day (2 mg/m2/day) based on clinical judgement.
Treatment is usually recommended until final height is reached. Treatment should be discontinued after the first year if HV SDS is below +1. Treatment should be discontinued when final height is reached (defined as height velocity < 2 cm/year) and if bone age is > 14 years (girls) or > 16 years (boys), corresponding to closure of the epiphyseal growth plates.

V. Treatment of growth hormone deficiency in adults.

At the start of Saizen therapy, low doses of 0.15-0.3 mg are recommended, given as a daily subcutaneous injection. The dose should be titrated carefully guided by IGF-1 age adjusted normal values and on the basis of clinical effect and adverse events. The recommended final Saizen dose seldom exceeds 1.0 mg/day. In general, the lowest efficacious dose should be administered. With women showing an increasing IGF-1 sensitivity over time, dose adjustment may be required for women, especially for those on oral estrogen replacement. In older or overweight patients, lower doses may be necessary.

Method of administration.

For medicine preparations intended for self administration by subcutaneous injection, patients should be thoroughly instructed in the correct administration procedures, including methods of preparation, reconstitution and injection techniques. This is especially important if injection devices are used in combination with multidose medicine preparations. Before using the injection devices, patients should be thoroughly trained to ensure that they are competent in the operation of the device. Periodic monitoring/ supervision are also advisable.
Saizen is administered by subcutaneous injection, preferably in the evening. The injection site should be alternated to prevent localised lipoatrophy.

Saizen solution for injection.

Saizen solution for injection must be administered with the dedicated autoinjector device provided separately. For administration, see instructions provided with the device. The solution should not be administered if it contains particles or is not clear.

4.3 Contraindications

Saizen should not be used for growth promotion in children/ patients with closed epiphyses.
Saizen should not be used in patients with hypersensitivity to any constituent of the product (see Section 2 Qualitative and Quantitative Composition).
Saizen is contraindicated where there is evidence of an active intracranial lesion. Intracranial lesions must be inactive for 12 months prior to instituting therapy and Saizen should be discontinued if there is any evidence of recurrent activity.
Saizen is contraindicated in patients with active neoplasia (either newly diagnosed or recurrent). Any pre-existing neoplasia should be inactive and any antitumour treatment must be completed prior to starting treatment with somatropin. Saizen should be discontinued if there is evidence of tumour growth.
Saizen is contraindicated in patients with proliferative or preproliferative diabetic retinopathy.
Saizen should not be initiated to treat patients with acute critical illness due to complications following open heart surgery or abdominal surgery, multiple accident trauma, to patients having acute respiratory failure or patients with similar conditions (see Section 4.4 Special Warnings and Precautions for Use).
In children with chronic renal disease, treatment with somatropin must be discontinued at the time of renal transplantation.

4.4 Special Warnings and Precautions for Use

Saizen therapy should be carried out under the regular guidance of a physician who is experienced in the diagnosis and management of growth hormone deficiency.
When somatropin is administered subcutaneously at the same site over a long period, localised lipoatrophy may result. This can be avoided by frequent rotation of the injection site.

Fluid retention.

Fluid retention is expected during growth hormone replacement therapy in adults. In case of persistent oedema or severe paraesthesia, the dosage should be decreased in order to avoid the development of carpal tunnel syndrome. Adult growth hormone deficiency is a lifelong condition. However, caution should be exercised because experience with prolonged treatment in adults is limited. Other hormonal deficiencies found in hypothalamic disease or pituitary disease should be treated with adequate replacement therapy before Saizen therapy is instituted.

Critically ill patients.

The effects of E. coli derived growth hormone on recovery were studied in two placebo controlled clinical trials involving 522 adult patients who were critically ill due to complications following open heart or abdominal surgery, multiple accident trauma or who were having acute respiratory failure. Mortality was higher (41.9% vs 19.3%) among growth hormone treated patients (doses 5.3-8 mg/day) than among those receiving placebo. Based on this information, these patients must not be treated with somatropin (see Section 4.3 Contraindications). The safety of continuing growth hormone in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation in patients having acute critical illness should be weighed against the potential risk.

Hypothyroidism.

The possible appearance of hypothyroidism in the course of therapy with Saizen should be corrected with thyroid hormone in order to obtain a satisfactory growth response. Thyroid assessment, by thyroid hormone level measurements, should be undertaken before starting Saizen therapy and not less frequently than annually.

Insulin resistance.

Because somatropin can decrease insulin sensitivity, patients treated with growth hormone should be monitored for evidence of glucose intolerance. Saizen should be used with caution in patients with diabetes mellitus or with a family history of diabetes mellitus. For patients with diabetes mellitus, the insulin dose may require adjustment after somatropin therapy is instituted.
Growth hormone administration is followed by a transient phase of hypoglycaemia of approximately 2 hours, then from 2-4 hours onward by an increase in blood glucose levels despite high insulin concentrations. Somatropin may induce a state of insulin resistance which can result in hyperinsulinism and in some patients in hyperglycaemia. To detect an insulin resistance, patients should be monitored for evidence of glucose intolerance. Patients with diabetes mellitus or glucose intolerance should be monitored closely during Saizen therapy.

Children born small for gestational age.

In short children born SGA, other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
For SGA patients, it is recommended to measure fasting insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, increased body mass index, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.
For SGA patients, it is recommended to measure IGF-1 level before start of treatment and twice a year thereafter. If on repeated measurements IGF-1 levels exceed +2 SD compared to references for age and pubertal status, the IGF-1/IGFBP-3 ratio could be taken into account to consider dose adjustment.
Experience in initiating treatment in SGA patients near onset of puberty is limited. It is therefore not recommended to initiate treatment near onset of puberty. Experience with SGA patients with Silver-Russell syndrome is limited.
Some of the height gain obtained with treating short children born SGA with somatropin may be lost if treatment is stopped before final height is reached.

Prader-Willi syndrome.

While Saizen is not indicated for the treatment of paediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome, it should be noted that there have been reports of sleep apnoea and sudden death after initiating therapy with growth hormone in paediatric patients with Prader-Willi syndrome who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection.

Haematological neoplasms.

An increased incidence of leukaemia in growth hormone deficient children has been observed. A causal relationship to growth hormone therapy has not been established.

Tumour occurrence and recurrence.

There are only limited data available in regard to the risk of tumour development under treatment with growth hormone. Therefore, patients treated with growth hormone should be carefully monitored.
In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with growth hormones.
Treatment in growth hormone deficient adults should be attempted only after definitive treatment of pituitary tumour (if present) is completed and all other pituitary hormone deficiencies are corrected as clinically needed.
Patients with growth hormone deficiency secondary to an intracranial tumour or other lesion should be examined frequently for progression or recurrence of the underlying disease process.

Pancreatitis.

Pancreatitis should be considered in somatropin treated patients, especially children, who develop abdominal pain.

Scoliosis.

Scoliosis is known to be more frequent in some of the patient groups treated with somatropin, for example Turner syndrome. In addition, rapid growth in any child can cause progression of scoliosis. Signs of scoliosis should be monitored during treatment.

Slipped capital femoral epiphysis.

Patients receiving growth hormone therapy should be observed for the possible onset of a limp, or complaints of hip or knee pain, as this may indicate the development of slipped capital femoral epiphysis.
Patients with growth retardation due to chronic renal insufficiency should be regularly examined and monitored for evidence of progression of renal osteodystrophy. Slipped capital femoral epiphysis or avascular necrosis of the femoral head may occur in children with advanced renal osteodystrophy and it is uncertain whether these complications are affected by growth hormone therapy. Assessment of the hip should be obtained prior to initiating therapy and at regular intervals upon discretion of the physician.

Idiopathic intracranial hypertension.

Fundoscopic examination should be performed routinely before initiating treatment with Saizen to exclude pre-existent papilloedema and repeated if there is any clinical suspicion. In case of severe or recurrent headache, visual problems, nausea and/or vomiting, a fundoscopy for papilloedema is recommended. If papilloedema is confirmed by fundoscopy, a diagnosis of idiopathic intracranial hypertension should be considered and if appropriate, the growth hormone treatment should be discontinued.
At present, there is insufficient evidence to guide clinical decision making in patients with resolved intracranial hypertension. If growth hormone treatment is restarted, careful monitoring for symptoms of intracranial hypertension is necessary.

Antibodies.

As with all somatropin containing products, a small percentage of patients may develop antibodies to Saizen. The binding capacity of these antibodies is low and there is no effect on growth rate. Testing for antibodies to somatropin should be carried out in any patient who fails to respond to therapy (also see Section 4.8 Adverse Effects (Undesirable Effects)).

Chronic renal insufficiency (CRI).

In children with chronic renal insufficiency, renal function should have decreased to below 50% of normal before therapy is instituted. To verify the growth disturbance, growth should have been followed for a year or upon physician discretion (for example not less than 6 months in the older children) before institution of therapy. Conservative treatment for renal insufficiency should have been established and should be maintained during treatment. Treatment should be discontinued at the time of renal transplantation.

Use in renal impairment.

Somatropin clearance is known to be reduced in patients with renal impairment. However, based on clinical data there is no need for dosage adjustment.

Use in hepatic impairment.

Somatropin clearance is known to be reduced in patients with hepatic impairment. However, as Saizen has not been studied in patients with hepatic impairment, the clinical significance of this finding is unknown.

Use in the elderly.

Experience in patients over 60 years is limited.

Paediatric use.

This medicine is indicated for use in paediatric population (see Section 4.1 Therapeutic Indications; Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 5.1 Pharmacodynamic Properties).

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant corticosteroid therapy may inhibit the response to Saizen. If glucocorticoid replacement is required, the dose of somatropin should be carefully adjusted.
In addition, initiation of growth hormone replacement may unmask secondary adrenal insufficiency in some patients by reducing the activity of 11β-hydroxysteroid dehydrogenase, type 1 (11β-HSD1), an enzyme converting inactive cortisone to cortisol. Initiation of somatropin in patients receiving glucocorticoid replacement therapy may lead to manifestation of cortisol deficiency. Adjustment of glucocorticoid dose may be required.
Because oral estrogens may reduce the serum IGF-1 response to somatropin treatment, patients receiving oral estrogen replacement may require dosage adjustment of somatropin.
If a woman taking somatropin begins oral estrogen therapy, the dose of somatropin may need to be adjusted to maintain the serum IGF-1 levels within the normal age-appropriate range. Conversely, if a woman on somatropin discontinues oral estrogen therapy, the dose of somatropin may need to be adjusted to avoid excess of growth hormone and/or side effects.
Published in vitro data indicate that growth hormone may be an inducer of cytochrome P450 3A4. The clinical significance of this observation is unknown. However, when Saizen is administered in combination with medicines known to be metabolised by CYP450 3A4 hepatic enzymes, it is advisable to monitor clinical effectiveness of such medicines.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In E. coli derived growth hormone studies, reproduction was inhibited in male and female rats at doses of 3 IU/kg/day (1 mg/kg/day) or more, with reduced copulation and conception rates, lengthened or absent oestrus cycles, and at 10 IU/kg/day (3.3 mg/kg/day), a lack of responsiveness of females to males, and slight reductions in sperm motility and survival. Rat reproduction was unaffected by (0.3 mg/kg/day) somatropin, which resulted in a systemic exposure (based on body surface area) of approximately twice that anticipated at the maximum clinical dose.
In reproduction studies using recombinant mouse cell derived somatropin, no effects on female fertility were observed in rats treated with somatropin at subcutaneous doses of up to 10 IU/kg/day (equivalent to 20 mg/m2/day, about 14 times the maximum clinical dose on a body surface area basis).
(Category B1)
There are no adequate and well controlled studies in pregnant women. Somatropin was not teratogenic in rats or rabbits at respective doses of up to 14 and 22 times the maximum recommended clinical dose (4.3 IU or 1.4 mg/m2/day), based on body surface area. In rats, somatropin administered from late gestation to weaning, at 14 times the clinical dose based on body surface area, was associated with increased bodyweight of pups at birth and postnatally. Because animal reproductive studies are not always predictive of human response, this medicine should be used during pregnancy only if clearly needed.
 There have been no clinical studies conducted with somatropin in breastfeeding women. It is not known whether somatropin is excreted in human milk. Therefore, caution should be exercised when Saizen is administered to breastfeeding women.
Following subcutaneous administration of radiolabelled somatropin to lactating rats, radioactivity was transferred to milk, reaching four times the concentration found in maternal plasma. However, absorption of the intact protein in the gastrointestinal tract of the infant is extremely unlikely.

4.7 Effects on Ability to Drive and Use Machines

Due to its pharmacological profile somatropin is unlikely to impair the patient's ability to drive or to operate machinery.

4.8 Adverse Effects (Undesirable Effects)

Clinical trial experience.

SGA indication.

Based on published literature and company sponsored studies, the most frequently reported adverse events were headache, arthralgia, bronchitis, pyrexia, nasopharyngitis, upper respiratory tract infection, asthenia, abdominal pain, gastroenteritis, injection site pain, ear infection, pain in extremity, tonsilitis, rhinitis, varicella. Many of these events reflect commonly observed childhood infections or accidental injuries.
In a company sponsored study IMP 20184 (continuation of studies GF 4001 and GF 6283), Table 2 summarises the adverse events that occurred in at least 5% of patients treated with Saizen compared to no treatment. The dose used in IMP 20184, as well as the previous studies (GF 4001 and GF 6283) was 0.067 mg/kg/day.

Adverse events in other indications.

Common adverse events reported in Saizen trials that were not considered to be treatment-related included: upper respiratory tract infection, fever, headache, pharyngitis, otitis media, coughing, vomiting, dyspepsia.
Glucose intolerance was not seen during clinical studies, but a number of subjects had relatively high insulin levels during oral glucose tolerance tests.

Adverse reactions or effects.

The adverse reactions or effects reported below are classified according to frequency of occurrence as follows. Very common: ≥ 1/10; common: ≥ 1/100 to < 1/10; uncommon: ≥ 1/1000 to < 1/100; rare: ≥ 1/10,000 to < 1/1000; very rare: < 1/10,000.

Application site disorders.

Common: injection site reactions (pain, numbness, redness, swelling); localised lipoatrophy, which can be avoided by varying the site of injection.

Body as a whole, general disorders.

Common (in adults), uncommon (in children): fluid retention: peripheral oedema, stiffness, arthralgia, myalgia, paraesthesia.

Nervous system disorders.

Common: headache, carpal tunnel syndrome (in adults). Uncommon: idiopathic intracranial hypertension (benign intracranial hypertension), carpal tunnel syndrome (in children).

Endocrine disorders.

Very rare: hypothyroidism.

Gastrointestinal disorders.

Frequency not known: pancreatitis.

Immune system disorders.

Frequency not known: localised and general hypersensitivity reactions.

Reproductive system and breast disorders.

Uncommon: gynaecomastia.

Musculoskeletal disorders.

Very rare: slipped capital femoral epiphysis (epiphysiolysis capitis femoris).

Metabolism disorders.

Frequency not known: hyperglycaemia, hyperinsulinism, insulin resistance.
Insulin resistance can result in hyperinsulinism and in rare cases in hyperglycaemia.
Hypothyroidism has been reported in a small number of patients during Saizen therapy. It should be noted, however, that hypothyroidism can occur in untreated Turner syndrome patients.
Fluid retention is expected during growth hormone replacement therapy in adults. Oedema, joint swelling, arthralgias, myalgias and paraesthesias may be clinical manifestations of fluid retention. However, these symptoms/ signs are usually transient and dose dependent.
Adult patients with growth hormone deficiency following diagnosis of growth hormone deficiency in childhood reported adverse effects less frequently than those with adult onset growth hormone deficiency.
As with all somatropin containing products, a small percentage of patients may develop antibodies to Saizen. The clinical significance of these antibodies is unknown, though to date the antibodies have been of low binding capacity and have not been associated with growth attenuation except in patients with gene deletions. In very rare instances, where short stature is due to deletion of the growth hormone gene complex, treatment with growth hormone may induce growth attenuating antibodies.

4.9 Overdose

Overdosage could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Moreover, somatropin overdose is likely to cause fluid retention. Long-term overdosage could result in signs and symptoms of acromegaly.
Contact the Poisons Information Centre (telephone 131 126 in Australia or 0800 764 766 in New Zealand) for advice on the management of overdose.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Human growth hormone (hGH) is normally secreted at night during sleep and promotes skeletal, visceral and general body growth through the action of somatomedins or insulin-like growth factors (IGFs). Somatropin raises the serum levels of IGF-1. Growth hormone has a role in building and sustaining lean body mass, facilitating the utilisation of fat mass for energy needs, and maintaining bone mineral density. Apart from its effects on growth, hGH has a variety of effects on lipid, protein and carbohydrate metabolism.

Clinical trials.

Inadequate endogenous growth hormone secretion in children.

Efficacy and safety of Saizen have been studied in five pivotal studies using pretreatment growth measurements compared with treatment growth measured as a method of control.
The effectiveness of growth hormone treatment on growth was assessed primarily by changes in height velocity standard deviation score (HV SDS) and height SDS (H SDS) after at least 24 months of treatment. r-hGH was administered subcutaneously in all of the studies. Patients were randomised in two groups: group 1 (n = 203; 178 naive, 25 non-naive) who received r-hGH 0.6 IU/kg bodyweight/week (0.2 mg/kg/week) via subcutaneous injections three times a week (higher dose, lower frequency); and group 2 (n = 101; 47 naive, 54 non-naive) who received r-hGH 0.45 IU/kg bodyweight/week (0.15 mg/kg/week) seven times a week (lower dose, higher frequency).
Of the 304 prepubertal children included, 225 were previously untreated (treatment naive children) and 79 had been switched to r-hGH (Saizen) from pituitary derived hGH after interruption of therapy for at least 6 months. For both naive and transfer patients in both groups, there was a significant increase in HV, HV SDS and H SDS, at 1 and 2 years, as shown in Table 3.
Children receiving daily injections of r-hGH (both treatment naive and previously treated with pituitary derived hGH) demonstrated a higher growth rate than those receiving three injections per week (group 1 vs group 2; p < 0.001).
An extension study assessed growth response in 69 prepubertal children (19 girls) with idiopathic (n = 48) or organic (n = 21) growth hormone deficiency receiving r-hGH (Saizen) 0.6 IU/kg/week (0.2 mg/kg/week) via three subcutaneous injections. The initial treatment period (2 years), as described above, was followed by an optional extended treatment period during which the total weekly dose of r-hGH was unchanged; however, in most cases, dosing frequency increased to six or seven times per week. The mean duration of treatment was 64.4 months (range 1.2-140.9 months). The median H SDS at the start of the study was -3.8, and this improved significantly to -3.3 (p < 0.001) during the first year after the start of r-hGH therapy; this improvement was maintained throughout the study, resulting in a median value of -1.5 H SDS after 7 years of Saizen therapy. During the first year of r-hGH treatment, the median HV of patients was 8.5 cm/year (-2.8 SDS). During treatment years 2-7, patients' median HVs ranged between 5.5 and 6.7 cm/year (1.0-1.8 SDS). Bone age (BA) did not advance rapidly in response to treatment with r-hGH (1.3 ± 1.0 years/year, compared to 1.4 ± 0.3 years/year in change of height age (HA)).
All studies conducted in prepubertal or pubertal children with inadequate endogenous growth hormone secretion (five studies) demonstrated the safety of somatropin and confirmed the known safety profile. Two patients developed anti-hGH antibodies. In both cases, the antibodies did not have any growth inhibiting effect. None of the patients developed antibodies to host cell protein. Three transfer patients who had anti-hGH antibodies prior to treatment became negative within 6 months of treatment with Saizen.

Turner syndrome.

An open, randomised, multicentre study (phase III) was conducted to assess the efficacy and safety of Saizen (r-hGH) and of the combination with oxandrolone in 91 growth retarded girls with Turner syndrome (TS).
The diagnosis of TS was made on the basis of clinical characteristics and verified by karyotype analysis. The inclusion criteria were absence of the 2nd X chromosome or chromosome aberrations, chronological age (CA) > 5 years, BA < 11 years, height at least 2 SD below the mean for CA and poststimulatory circulating hGH serum levels of > 10 nanogram/mL.
The girls were randomly allocated to one of two original treatment groups: (1) Saizen alone or (2) Saizen in combination with the anabolic steroid oxandrolone. Group 1 received 18 IU/m2/week Saizen increasing to 24 IU/m2/week after the first year. Group 2 received 18 IU/m2/week Saizen and 0.1 mg/kg/day oxandrolone. The oxandrolone dose was reduced to 0.05 mg/kg/day after the first year.
After the second year, the dose of Saizen was 24 IU/m2/week for all groups and two further subgroups were formed: (1a) who received 24 IU/m2/week Saizen and 0.05 mg/kg/day oxandrolone and (2a) who stopped oxandrolone treatment and received 24 IU/m2/week Saizen alone.

Results.

This study demonstrated efficacy in HV, H SDS-CA, height, predicted adult height and final height, with mean heights in each treatment group ranging from 147.5 to 153.6 cm. The mean (± SD) final height was 150.6 ± 5.5 cm. Fifteen patients developed anti-hGH antibodies on at least 1 occasion. However, as the average height of these patients was 149.3 ± 7.1 cm, the development of antibodies does not appear to have a negative impact on growth.
The use of oxandrolone was not associated with additional final height gain, but was associated with virilising side effects.

Adult growth hormone deficiency (GHD).

A multicentre, randomised, double blind, placebo controlled clinical trial was conducted in 115 GHD adults comparing the effects of Saizen and placebo on body composition. Patients in the active treatment arm were treated with Saizen at an initial dose of 0.005 mg/kg/day for one month which was increased to 0.01 mg/kg/day if tolerated for the remaining five months of the study.
Primary endpoints. The primary endpoint was the treatment difference on the change from baseline in lean body mass (LBM) measured by dual energy X-ray absorptiometry (DXA) after 6 months. Treatment with Saizen produced highly significant (p < 0.001) increases from baseline in LBM compared to placebo (Table 4).
Sixty-seven (58%) of the 115 randomised patients were male. The adjusted mean treatment difference on the increase in LBM from baseline was significantly greater in males (2.9 kg) than females (0.8 kg).
Ninety-seven (84%) of the 115 randomised patients had adult onset (AO) GHD. The adjusted mean treatment differences on the increase in LBM from baseline was significantly different in AO GHD (2.1 kg, p < 0.001). The difference in childhood onset (CO) GHD (1.0 kg) was not significantly different; however, there were relatively few patients with CO GHD (n = 18) on which to base the comparison.
Secondary endpoints.

Treadmill exercise test (Weber protocol).

There was a slightly greater increase, albeit not statistically significant, in VO2max in the Saizen group compared to placebo (Saizen: baseline 21.21 ± 7.71 mL/kg/min N = 36, 6 months 25.50 ± 7.78 mL/kg/min N = 26; placebo: baseline 23.36 ± 6.98 mL/kg/min N = 35, 6 months 26.47 ± 8.58 mL/kg/min, N = 31). No statistically significant differences were noted for anaerobic threshold.

Analysis of the treatment difference on the change from baseline in total fat mass (by DXA).

Revealed a statistically significant reduction of total fat mass (p < 0.0001) in the Saizen group compared to placebo (Saizen: baseline 27.73 ± 10.72 kg N = 59, 6 months 23.82 ± 9.65 kg N = 52; placebo: baseline 28.90 ± 14.83 kg N = 54, 6 months 29.12 ± 15.33 kg N = 52). Anthropometry demonstrated no statistically significant differences between the treatment groups for skin folds, waist/ hip ratio or bodyweight. The sum of circumferences decreased significantly in the Saizen group relative to placebo (p < 0.017).

Saizen also produced beneficial effects on several bone turnover markers.

Including bone specific alkaline phosphatase, C-terminal propeptide, osteocalcin and urine deoxypyridinoline and intact parathyroid. The changes in total bone mineral content and body cell mass were not statistically different between the treatment groups.

Perceived wellbeing.

No significant differences were found in Nottingham health profile or the general wellbeing index.

Handgrip strength.

No statistically significant differences were found between the treatment groups in the assessments of dominant or nondominant handgrip strength.

Midthigh cross sectional MRI.

No statistically significant differences were found between the treatment groups in the assessments of percentages of fat, muscle or bone.

Cardiac function.

Two dimensional echocardiography showed statistically significant differences between the treatment groups for ejection fraction percentage (increase in the Saizen group, p < 0.048; Saizen: baseline 54.90 ± 11.21% N = 52, 6 months 60.89 ± 9.47% N = 48; placebo: baseline 54.41 ± 12.91% N = 50, 6 months 57.30 ± 8.61% N = 49) and left ventricular end systolic volume (decrease in the Saizen group, p < 0.035; Saizen: baseline 35.83 ± 17.61 mL N = 52, 6 months 30.40 ± 15.35 mL N = 49; placebo: baseline 39.04 ± 16.00 mL N = 48, 6 months 37.69 ± 16.64 mL N = 49).
One hundred and eleven patients were treated with Saizen for an additional 12 to 36 months in an open label follow-up study. During this period, the positive effects on LBM and fat mass achieved during initial treatment were maintained.

Chronic renal insufficiency (CRI).

Evidence of the safety and effectiveness of Saizen for the treatment of growth disturbance due to CRI is provided by the results of analysis of data from a study (4941) conducted with Saizen and published studies of clinical experience with r-hGH identified via a systematic literature review.
Study 4941. An open label, multicentre study was conducted to evaluate the safety and efficacy of Saizen for the treatment of growth failure in children with CRI. Patients with growth failure and CRI were included in the study. CRI was defined as patients with end stage renal disease on dialysis, or 12 months postkidney transplant, or compensated renal insufficiency with glomerular filtration rate (GFR) ≤ 30 mL/min per 1.73 m2. Growth failure was defined as height of at least 2 SD and growth velocity of at least 0.5 SD below the mean for CA. Each patient's pretreatment growth period served as a control for subsequent treatment periods. Patients were treated with Saizen 28 IU/m2/week (0.35 mg/kg/week), administered by daily subcutaneous injections for the first 3 years of treatment, which could be increased to 36 IU/m2/week (0.45 mg/kg/week) from the fourth year of treatment onwards in patients demonstrating insufficient growth.
A preliminary analysis was performed at one and two year timepoints. The primary efficacy endpoints for this analysis included increase in HV as well as H SDS and HV SDS for CA, calculated from baseline to the study timepoints. The secondary endpoint included the change in linear growth relative to the change in skeletal maturation (ΔHA/ΔBA ratio), as a measure of the preservation or loss of potential final height. Subgroup analysis was undertaken in all parameters after stratifying the patients according to their renal status.
Long-term analysis was performed following 8 years of treatment. The primary endpoint for the long-term analysis was the change in H SDS for CA, calculated from baseline, at onset of puberty and at study endpoint, and stratified according to final height status and overall. The secondary endpoint included the change in HV SDS during Saizen treatment. Other efficacy endpoints included parental adjusted H SDS and mean actual height.

Results. Preliminary analysis (1 and 2 years of treatment).

A total of 81 children were included in the study. The mean (± SD) CA was 8.6 ± 3.9 years with a BA of 5.7 ± 3.0 years.

Changes in height velocity (HV).

After 12 months: of the 63 children available for analysis, 59 (94%) experienced an increase over baseline in HV. Mean HV (± SD) increased by 4.4 ± 4.0 cm/year (p < 0.001).
After 24 months: of the 44 children available for analysis, 39 (89%) experienced a sustained increase over baseline in HV. The mean HV for this cohort was 7.5 ± 2.9 cm/year, an increase of 3.0 ± 3.6 cm/year over baseline (p < 0.001).

Changes in height standard deviation score (H SDS).

After 12 months: of the 63 children available for analysis, 55 (87%) experienced an increase over baseline in H SDS. Mean H SDS increased by 0.7 ± 0.7 (p < 0.001).
After 24 months: in the 44 children available for analysis, 39 (89%) experienced a sustained increase over baseline in H SDS. The percentage of children achieving a normal H SDS increased by 43% (19 of 44). For the group as a whole, the mean H SDS increased by 1.2 ± 1.2 (p > 0.001).

Changes in height velocity standard deviation score (HV SDS).

After 12 months: of the 54 children available for analysis, 52 (96%) experienced an increase over baseline in HV SDS. Mean HV SDS increased by 6.2 ± 5.0 (p < 0.001).
After 24 months: of the 36 children available for analysis, 34 (94%) experienced a sustained increase over baseline. Mean HV SDS increased by 3.4 ± 3.5 (p < 0.001).
The ΔHA/ΔBA was 1.6 ± 2.2 after the first year and 1.1 ± 0.6 after the second year of treatment, suggesting an improvement in predicted final height.

Analysis of efficacy based on renal status.

In the subgroup analysis, data were available from 44 children after the second year of treatment. Of these 44 children, 24 were in the compensated group and 8 were in the dialysis group. Data from the first year of treatment showed a significant increase in HV by +5.7 ± 5.1 cm/year over baseline (n = 24, p < 0.001) in the compensated group, and +4.6 ± 7.5 cm/year over baseline (n = 8, p < 0.001) in the dialysis group. After two years of treatment, HV increased from 5.0 ± 4.3 at baseline to 8.0 ± 3.8 (n = 24, p < 0.001) in the compensated group, and from 4.6 ± 6.4 at baseline to 5.9 ± 5.6 (n = 8, p = 0.211) in the dialysis group.
H SDS increased significantly in the compensated group, from -3.9 ± 2.0 at baseline to -2.8 ± 1.9 after 12 months of treatment (n = 24, p < 0.001), to -2.1 ± 2.0 after 24 months of treatment (n = 24, p < 0.001). In the dialysis group, less pronounced increase was seen in H SDS, although it was still greater than the baseline (from -3.9 ± 3.0 to -3.2 ± 2.8 after 12 months treatment (n = 8, p < 0.004), to -3.0 ± 3.0 after 24 months treatment (n = 8; p = 0.014)).
In HV SDS, both compensated and dialysis groups experienced a significant increase after 12 months of treatment, from -2.1 ± 2.5 at baseline to 5.3 ± 4.8 (compensated, n = 20, p < 0.001), and from -2.0 ± 4.1 to 3.4 ± 7.9 (dialysis, n = 7, p < 0.001). After two years of treatment, a significant increase in HV SDS was still seen in the compensated group (from -2.1 ± 2.5 to 2.7 ± 4.3 (n = 20, p < 0.001)). However, the increase was less pronounced in the dialysis group (from -2.0 ± 4.1 to -0.5 ± 7.0 (n = 7, p = 0.176)).
In terms of secondary endpoint, the ΔHA/ΔBA ratio in all groups was close to unity at baseline and was greater than 1.0 in all groups after 1 year of treatment reaching statistical significance in the compensated group.

Follow-up analysis (2-8 years of treatment).

Longer-term data were available from 31 patients who continued after 2 years of treatment and received between 2.2 and 7.8 years of treatment with Saizen (mean duration of study was 63.31 ± 18.26 months). Baseline was defined as the last recorded value before or on the day of inclusion.
Of the 31 patients, four patients reached final height (defined as HV < 2 cm/year and Tanner puberty score ≥ 4), 6 patients reached near final height (defined as HV > 2 cm/year, age > 16 years (boys) or > 14 years (girls) and 21 patients were in nonfinal height group. In the overall group, mean H SDS during Saizen treatment increased from -3.12 ± 1.22 at baseline to -1.83 ± 1.88 at onset of puberty and there was a further increase to -1.21 ± 1.73 at study endpoint.
According to final height status, the gain in H SDS from baseline to study end was the greatest in the nonfinal height group (2.16 ± 1.25, p < 0.0001) compared to the final height (1.26 ± 0.40, p = 0.1250) and the near final height (1.44 ± 1.66, p = 0.0625) groups.

Children born small for gestational age (SGA).

Evidence of the effectiveness and safety of Saizen for the treatment of growth disturbance in short children born SGA is supported by data from published studies of clinical experience with r-hGH identified via a systematic literature review and company-sponsored studies.

Publications identified from systematic literature review.

The summaries of relevant trials identified by the systematic literature review in children born SGA (meeting the criteria of birth length and/or weight < -2 SDS, starting treatment aged > 4 years and treated until attainment of adult height) using r-hGH treatment are provided below:
Campos-Martorell, et al (Endocrinol Diabetes Nutr 2021; 68: 612-620) carried out a retrospective, observational study to evaluate prepubertal and pubertal height gain in 78 short children born SGA (51 boys, 27 girls) treated with r-hGH from prepubertal age. They were followed to adult height attainment, considered when there was no change in height or change < 0.5 cm in two consecutive measures at 6 to 12-month intervals, and bone age was 15 to 16 years for boys and 13.5 to 14 years for girls. Median r-hGH dose was 0.033 mg/kg/day, mean (± SD) age at treatment start was 7.3 ± 2.0 years (boys), 6.0 ± 1.8 (girls) and mean H SDS was -3.3 ± 0.7 (boys) and -3.4 ± 0.7 (girls). The cohort was followed up for 11.6 ± 2.1 years (boys) and 11.3 ± 2.1 years (girls).
A progressive increase in H SDS was seen during r-hGH treatment, as shown in Table 5, with the greatest gain occurring during the prepubertal period. The children attained an adult height of -1.7 ± 0.7 SDS, corresponding to 165.8 ± 4.4 (boys) and -1.6 ± 1.0 SDS, corresponding to 153.5 ± 5.3 cm (girls).
No statistically significant differences, except for age when r-hGH was initiated, were seen between boys and girls for any H SDS values, or for those born pre-term and term. The authors concluded that the response to r-hGH treatment in short children born SGA is heterogenous, so dose should be individualised and treatment should be started at young age.
Beisti Ortego, et al (Med Clin (Barc) 2020; 154: 289 - 294) carried out a retrospective study in 80 short children born SGA treated with r-hGH to assess adult height attained and factors that determine treatment response. Adult height was defined as the height reached by the patients at Tanner 5 stage (adult) with a growth rate below 2 cm/year in the last year and < 1 cm/year in the last 6 months. Children were tested for r-hGH secretory status at baseline. The dose of r-hGH used in the non-deficiency group (0.033 mg/kg/day) was higher than that used in the GH deficiency (GHD) group (0.027 mg/kg/day). The age at treatment onset was 10.06 ± 2.49 years, with H SDS of -2.59 ± 0.6 SDS. The average duration of treatment was 4.68 ± 2.24 years.
Average age at the end of treatment at adult height was 15.92 ± 1.34 years and mean adult H SDS was -1.63 ± 0.65, with H SDS gain from baseline to adult height of 0.96 ± 0.70. The H SDS gain was significantly (p < 0.05) higher for patients who started treatment when prepubertal versus those who were pubertal, as shown in Table 6.
Factors associated with greater adult height gain were lower height, weight and BMI at start of treatment, lower chronological and bone age with lower IGF-1 before treatment, greater distance to target height, higher growth velocity the first and second year of treatment, and higher height gain before and during puberty.
The authors concluded that r-hGH treatment was effective in improving adult height, with better results in children who started treatment when prepubertal, and response did not depend on pituitary GH status.
Arroyo Ruiz, et al (Ther Adv Endocrinol Metab 2022; 13: 1-14) carried out a prospective, longitudinal, observational study of 61 short children born SGA, treated with r-hGH and who reached adult height. The primary objective was to analyse the efficacy of r-hGH treatment by studying the factors affecting the final response to treatment assessed by adult height and height gain. Adult height was defined as growth rate < 2 cm/year. Treatment started before onset of puberty and the mean dose was 0.035 mg/kg/day. Mean (±SD) age at start of r-hGH treatment was 6.37 ± 1.79 years and 6.05 ± 1.83 years for boys (n=28) and girls (n=33), respectively. Baseline H SDS was -2.91 ± 0.62 (boys) and -3.22 ± 0.75 (girls).
A progressive increase in height was seen from the start to completion of r-hGH treatment, as shown in Table 7.
H SDS did not differ significantly between boys and girls at any point. Of the initial 96 patients, 61 patients (28 boys and 33 girls) reached adult height. Adult H SDS gain from treatment start was 0.99 ± 0.8 and 1.49 ± 0.94 for boys and girls, respectively (p < 0.008). Adult height (SDS) was within the normal range (> -2) for 53% of boys and 75% of girls, although there was no significant difference in adult H SDS between genders (p > 0.05). The pubertal height gain was 22.6 ± 5.8 cm in boys and 18.8 ± 4.5 cm in girls.
The authors concluded that the H SDS gain in the first year is the most important factor in determining r-hGH treatment response, followed by the difference from mid-parental H SDS at start of treatment.
Dahlgren, et al (Pediatr Res 2005; 57: 216 - 222) carried out an observational study of 77 short children born SGA, treated with r-hGH until adult height, with the aim to assess long-term growth response. Treatment started before onset of puberty, at a dose of 0.033 mg/kg/day. During puberty, 24 children (17 males/7 females) were randomised to a dose of 0.066 mg/kg/day. A comparator group comprised 34 short children born SGA who did not receive r-hGH treatment. r-hGH treatment was stopped at adult height when growth velocity was < 1 cm/year and height was monitored for at least 2 more years.
Mean age at start of treatment was 10.7 ± 2.5 years and H SDS was -2.8 ± 0.7.
The final height of 86% of the r-hGH treated children was within their target height (i.e. ≥ -1 SDS from their mid-parental height), compared with only 52% of the untreated group (p < 0.001). The mean gain in H SDS from the start of treatment to final height was 1.3 SD ± 0.8 (corresponding to 9 cm). Among those treated for > 2 prepubertal years, mean gain was 1.7 SDS ± 0.7 (12 cm), and for those treated < 2 prepubertal years the gain was 0.9 SDS ± 0.7 (6 cm) (p < 0.001).
It was concluded that r-hGH could normalise adult height and height gain before puberty and was maintained to adult height.
Renes, et al (Clin Endocrinol 2015; 82: 854 - 864) conducted an open-label, longitudinal study of 170 short children born SGA treated with r-hGH, to investigate the efficacy of r-hGH treatment on adult height and assess the relationship of catch-up growth and pubertal growth with adult H SDS attained. At the start of treatment, the children were either prepubertal or early pubertal, with median age of 7.1 years (interquartile range (IQR): 5.4 to 9.4) and median H SDS of -3.0 (IQR: -3.4 to -2.5). The r-hGH treatment dose was 1 mg/m2/day (0.033 mg/kg/day), adjusted every 3 months according to body surface area. In girls < 11 years and boys < 12 years, with a relatively short height at the onset of puberty, puberty was postponed for 2 years using a gonadotropin releasing hormone analogue (GnRHa) in addition to r-hGH treatment (n=29). Adult height was defined as growth rate < 0.5 cm in the previous 6 months.
In the adult height ITT analyses, mean (SDS) adult height for 83 boys was 170.8 (6.8) cm, corresponding to -1.9 (1.0) SDS. The target height-corrected adult height was -1.2 (0.9) SDS. Mean adult height for 87 girls was 158 (5.8) cm, corresponding to -1.9 (0.9) SDS. The target height-corrected adult height was -1.4 (0.9 SDS).
In the adult height uncensored cases analyses, adult height was reached in 136 children (66 boys)/70 (girls). Median age at adult height was 17.4 (IQR: 16.6 to 18.1) years for boys, after 9.6 (7.5 to 11.1) years of treatment. For girls, median age was 15.7 (IQR: 14.9 to 16.3) years, after 9.0 (7.0 to 10.2) years of treatment. Adult H SDS was -1.8 (-2.5 to -1.2) and -1.9 (-2.4 to -1.1) for boys and girls, respectively. The adult H SDS difference from mid-parental H SDS was within the normal range of > -2 for 73% of the children overall, 76% of the 107 children who received r-hGH only and 60% of the 29 who received r-hGH plus GnRHa. At puberty, H SDS declined with -0.4 (-0.9 to 0.3) SDS in boys and -0.5 (-0.8 to 0.2) SDS in girls. This resulted in a significantly lower total height gain SDS compared to the prepubertal height gain SDS (p < 0.001).
It was concluded that in short children born SGA, adult height was improved by treatment with r-hGH with better gain when starting at a younger age. However, H SDS declined from mid-puberty due to an early reduction in growth velocity.
A meta-analysis conducted by Maiorana and Cianfarani (Pediatrics 2009; 124: e519-e531) examined the evidence of long-term r-hGH treatment in short children born SGA. Four randomised controlled trials comprising 270 treated children and 155 untreated children treated to attainment of adult height were included in the meta-analysis. Mean ± SD age at start of study was 8.6 ± 0.8 years (range 7.9 to 10.7). The dose of r-hGH was either 0.033 or 0.067 mg/kg/day and the mean duration of r-hGH treatment was 7.3 ± 0.35 years.
The meta-analysis found that mean adult height gain of the r-hGH treated group significantly exceeded controls by 0.9 SDS (5.7 cm) (p < 0.0001). Mean gain in adult H SDS was 1.5 (9.4 cm) for treated children compared with 0.25 (1.6 cm) for untreated children (p < 0.0001). When corrected for mid-parental height, mean adult H SDS was -0.46 in the treated group versus -1.26 for the untreated group (p < 0.0001). The overall mean H SDS corrected for mid-parental height was 1.46 (9.2 cm) in the treated group versus 0.4 (2.5 cm) in the untreated group (p < 0.0001). No significant difference in adult height was observed between the two r-hGH dose regimens.

Company-sponsored studies.

The evidence from company-sponsored studies in children born SGA (meeting the criteria of birth length and/or weight < -2 SD, starting treatment aged > 4 years and treated with higher doses and different dose regimens) (Studies GF 4001, GF 6283, IMP 20184) showed consistent results of r-hGH treatment to improve the mean and median H SDS and HV SDS.

5.2 Pharmacokinetic Properties

After intramuscular injection of 4 IU somatropin/m2 body surface area, Cmax (36.9 ± 12.1 nanogram/mL) was measured at 3 hours (Tmax). hGH levels returned to preinjection levels after 12 hours. The AUC24 was 183 nanogram.h/mL. These pharmacokinetic parameters are similar to those reported in the literature for pituitary derived hGH. After subcutaneous injection, Cmax was delayed until 4-6 hours postinjection. The AUC24 for the two routes of administration were similar.
Saizen solution for injection (5.83 mg/mL and 8.00 mg/mL) administered subcutaneously were shown to be bioequivalent to the 8 mg freeze dried formulation.

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence of genotoxicity in assays for gene mutation in bacteria, chromosomal damage in human lymphocytes and rat bone marrow cells, gene conversions in yeast or unscheduled DNA synthesis in human carcinoma cells.

Carcinogenicity.

Associations between elevated serum IGF-1 concentrations and risk of certain cancers have been reported in epidemiological studies. Causality has not been demonstrated. The clinical significance of these associations, especially for subjects treated with somatropin who do not have growth hormone deficiency and who are treated for prolonged periods, is not known.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging. Do not use after the expiry date.

Saizen solution for injection.

Saizen solution for injection should be used with the dedicated autoinjector devices provided separately. After the first injection, the contents of the cartridge should be used within 28 days. After first injection, should refrigeration be temporarily unavailable, the Saizen cartridge in the dedicated autoinjector devices can be stored for up to 7 days at or below 25°C (outside a refrigerator). Following this, the Saizen cartridge must be returned to the refrigerator and stored at 2°C to 8°C (refrigerate, do not freeze) and still used within 28 days after the first injection.

6.4 Special Precautions for Storage

Saizen solution for injection.

Saizen solution for injection should be stored at 2°C to 8°C (refrigerate, do not freeze) in the original package in order to protect from light.

6.5 Nature and Contents of Container

Saizen solution for injection.

Supplied in packs of 1 or 5* glass cartridges for multidose use in one patient only.
* Not currently marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Saizen is a recombinant human growth hormone (r-hGH) which is prepared from genetically engineered mammalian cells (recombinant mouse cells-C127) transformed with a bovine papilloma virus vector containing the human growth hormone coding sequence. According to the European Pharmacopoeia, somatropin (rmc) 3 international units (IU) equals 1 mg somatropin (rmc) by weight. The dose in mg set out below is based on this equivalence.

7 Medicine Schedule (Poisons Standard)

Schedule 4 (Prescription Only Medicine).

Summary Table of Changes