Consumer medicine information

Norditropin SimpleXx 5mg, 10mg, and 15mg

Somatropin

BRAND INFORMATION

Brand name

Norditropin

Active ingredient

Somatropin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Norditropin SimpleXx 5mg, 10mg, and 15mg.

What is in this leaflet

This leaflet answers some common questions about Norditropin® SimpleXx®. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you or your child using Norditropin® SimpleXx® against the benefits they expect it will have.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What Norditropin® SimpleXx® is used for

Norditropin® SimpleXx® is human growth hormone [also called somatropin (rbe)], used to treat:

  1. growth failure in children, which may be due to:
  • a condition called Growth Hormone Deficiency, where the gland at the base of the brain (pituitary gland) does not make enough growth hormone
  • a condition called either Small for Gestational Age (SGA) or Intrauterine Growth Retardation (IUGR), where growth failure started during the mother’s pregnancy. Children with SGA/IUGR do not lack growth hormone and are therefore not treated for growth hormone deficiency. Treatment with Norditropin® SimpleXx® promotes catch-up growth and increases final height.
  • Chronic kidney disease
  • Turner syndrome, a genetic condition in girls
  1. growth hormone deficiency in adults

You or your child may have been prescribed Norditropin® SimpleXx® for another reason.

Ask your doctor if you have any questions about why Norditropin® SimpleXx® has been prescribed.

There is no evidence that Norditropin® SimpleXx® is addictive.

Before using Norditropin® SimpleXx®

When you or your child must not use it

You or your child should not use Norditropin® SimpleXx® if you/your child:

  • are allergic to phenol or any other ingredient listed in the ingredient section of this leaflet
    Some of the symptoms of an allergic reaction may include:
    - rash
    - wheezing
    - swelling of the eyelids, face or lips
    - complete collapse
  • have cancer or another form of active tumour
  • have not finished treatment for cancer or another form of tumour
  • have slow growth for reasons other than a lack of growth hormone, except where specific uses are described above
  • have had a kidney transplant in the last 12 months or have had more than one episode of acute rejection (ask your doctor if unsure what this means)
  • have an acute critical illness due to complications following open heart or abdominal surgery or multiple accident trauma
  • have acute respiratory failure

Do not use Norditropin® SimpleXx® if:

  • it is after the expiry date (Expiry) printed on the label and carton
  • the packaging is torn, shows signs of tampering or does not look quite right
  • the solution is not clear and colourless, or does not look quite right

Before you or your child starts to use it

Tell your doctor if you or your child has any medical conditions, especially the following:

  • diabetes
  • cancer or any other kind of tumour
  • impaired kidney function
  • severe or recurring headaches, visual problems, nausea and vomiting. These may be symptoms of raised pressure of the fluid around the brain.
  • tiredness, lethargy, muscle weakness, cramps, feeling the cold, a slow heart rate, dry and flaky skin, hair loss, a deep and husky voice and weight gain. These may be signs and symptoms of hypothyroidism (an under-active thyroid gland causing a decrease in metabolism).
  • development of curvature of the spine (scoliosis) in your child
  • if your child has Turner syndrome and:
    - you notice increased growth of your child’s hands and feet that is not in proportion to their height, or
    - they develop an ear infection.

If any of the above applies, Norditropin® SimpleXx® may not be suitable. Your doctor will give you advice.

Your doctor will measure your child’s height and weight before he or she is prescribed Norditropin® SimpleXx®. If you or your child is growth hormone deficient, your doctor will also need to measure your/their ability to produce growth hormone.

If you or your child is using Norditropin® SimpleXx® due to growth problems associated with a kidney disease, it is important to continue with any treatment for the kidney condition while Norditropin® SimpleXx® is being used.

As growth hormone can affect blood sugar levels, your doctor may perform regular blood checks on you or your child.

Taking other medicines

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

Some medicines may interfere with the growth effect of Norditropin® SimpleXx®. These include:

  • glucocorticoids
  • sex steroids
  • thyroid hormone

If you are unsure whether you or your child is taking these medicines talk to your doctor or pharmacist.

If you or your child is being treated with insulin, the dosage of insulin may have to be adjusted.

If you have not told your doctor about any of the above, tell them before you or your child use Norditropin® SimpleXx®.

Pregnancy and breast-feeding

Tell your doctor if you are pregnant or plan to become pregnant or are breast-feeding. Your doctor can discuss with you the risks and benefits involved.

There is no information on the effects of Norditropin® SimpleXx® during pregnancy or breast-feeding.

Norditropin® SimpleXx® should be used during pregnancy only if clearly needed.

Using Norditropin® SimpleXx®

How much to use

Your doctor will tell you how much Norditropin® SimpleXx® you or your child should use. It depends on factors such as body weight and body surface area.

How and when to use it

Norditropin® SimpleXx® is given as an injection with NordiPen® (an injection pen) under the skin in the evening, 6 or 7 days per week. Injection sites should be varied as shown to you by your doctor or other health professional. This will lessen the risk of damage to the fat and tissues under the skin (lipodystrophy).

Norditropin® SimpleXx® cartridges MUST be used with the matching colour coded NordiPen® to give the correct dose. For example:

  • Norditropin® SimpleXx® 5mg (yellow) MUST be used with NordiPen® 5mg (yellow)
  • Norditropin® SimpleXx® 10mg (blue) MUST be used with NordiPen® 10mg (blue)
  • Norditropin® SimpleXx® 15mg (green) MUST be used with NordiPen® 15mg (green)

Carefully follow the instructions contained in the NordiPen® package insert.

If you have any questions or concerns about how to use Norditropin® SimpleXx®, talk to your doctor or pharmacist.

Norditropin® SimpleXx® is prescribed for you or your child’s personal use only. Do not give it to anyone else.

How long to use it

You or your child may stop using Norditropin® SimpleXx® at any time. Before doing so, you should discuss this first with your doctor.

If you are unsure how long to use Norditropin® SimpleXx®, talk to your doctor.

If you or your child misses a dose

Inject the next dose as normal the next evening. Do not inject extra to make up for the missed dose.

If you or your child uses too much (overdose)

If you inject too much Norditropin® SimpleXx®, contact your doctor.

You or your child should not inject more Norditropin® SimpleXx® than the doctor has prescribed, as it may increase the risk of side effects.

Long term overdosage could result in signs and symptoms of growth hormone excess. Extreme growth hormone excess can result in overgrowth of bones and enlargement of hands and feet.

While you or your child is using Norditropin® SimpleXx®

Things you must do

Check each new Norditropin® SimpleXx® cartridge before you use it. Do not use any cartridge that is damaged or cracked.

Things you must not do

Do not give Norditropin® SimpleXx® to anyone else, even if they have the same condition as you or your child.

Do not use Norditropin® SimpleXx® to treat any other complaints unless your doctor tells you to. `

Do not stop using Norditropin® SimpleXx® or lower the dosage, without first checking with your doctor.

Things to be careful of

Tell your doctor if you or your child is scheduled to have surgery.

If you or your child has a kidney condition, your doctor will closely monitor the kidney function (how well the kidneys are working). If there is any decrease in function, it may be necessary to stop using Norditropin.

Side effects

All medicines can have side effects. Sometimes they are serious, most of the time they are not.

Tell your doctor or pharmacist as soon as possible if you or your child do not feel well while taking Norditropin® SimpleXx®. Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • swollen hands and feet due to fluid retention
  • redness and itching around the area you inject. Some patients may develop local skin reactions at the injection site which appear and disappear during treatment. If you inject too often in the same small area, damage may occur to the fat and tissues under the skin (lipodystrophy).

The above list includes the more common side effects of Norditropin® SimpleXx®. They are usually mild and temporary.

Tell you doctor as soon as possible if you notice any of the following:

  • joint and muscle pain
  • skin rash
  • headache
  • curvature of the spine
  • fluid retention

If you or your child experiences any of these symptoms, the dosage of Norditropin® SimpleXx® may need to be reduced. Discuss this with your doctor.

If any of the following happen, tell your doctor immediately or go to Accident and Emergency at your nearest hospital

  • allergic reaction. Symptoms of this may include rash; wheezing; swelling of the eyelids, face or lips; complete collapse.
  • benign raised pressure of the fluid around the brain. Symptoms of this can include severe or recurring headaches, problems with eye sight, feeling sick or vomiting.

The above list includes serious side effects. You may need urgent medical attention. These side effects are very rare.

In rare cases, the body may form antibodies to Norditropin® SimpleXx®. These antibodies could reduce further growth with Norditropin® SimpleXx® treatment.

In very rare cases, children treated with growth hormone have felt pain in the hip or knee, or have experienced limping. These symptoms may be caused by Legg-Calvé-Perthes disease (disease at the top of the thigh bone) or slipped capital femoral epiphysis (the end of the bone slips from the cartilage) and may not be due to the medicine.

In a small number of patients treated with growth hormone, cancer, including leukaemia or relapse of brain tumours, or raised levels of glucose in the blood (a condition called ‘impaired glucose tolerance’ (IGT)) have been reported. However, there is no evidence that growth hormone is responsible for causing these conditions.

If you think that you or your child are suffering from any of these symptoms or from any other side effects not mentioned here, speak to your doctor or pharmacist.

Do not be alarmed by this list of possible side effects. You or your child may not experience any of them.

Storage

Store unused Norditropin® SimpleXx® cartridges in a refrigerator (2°C to 8°C) in the outer carton, in order to protect from light. Do not use if frozen. Do not freeze or expose to heat. Do not store close to any cooling elements.

While using a Norditropin® SimpleXx® cartridge in an injection pen you can either:

  • Keep it in the pen for up to 4 weeks in a refrigerator (2°C to 8°C),
    or
  • Keep it in the pen for up to 3 weeks at room temperature (below 25°C).

Keep out of the reach of children.

Do not use Norditropin® SimpleXx® which has been frozen or exposed to excess heat.

Never use Norditropin® SimpleXx® after the expiry date printed on the label and carton. The expiry date refers to the last day of that month.

Disposal

If your doctor tells you or your child to stop using Norditropin® SimpleXx®, or the medicine has passed its expiry date, return any unused medicine to your pharmacist for disposal.

Product Description

What it looks like

Norditropin® SimpleXx® is a 1.5mL clear solution for injection into the layer under the skin. It is available in a glass cartridge, ready to go into NordiPen®. Three NordiPen® are available - a different one for each strength of Norditropin® SimpleXx®.

Norditropin® SimpleXx® cartridges MUST be used with the matching colour coded NordiPen® to give the correct dose. For example:

  • Norditropin® SimpleXx® 5mg (yellow) MUST be used with NordiPen 5mg (yellow)
  • Norditropin® SimpleXx® 10mg (blue) MUST be used with NordiPen 10mg (blue)
  • Norditropin® SimpleXx® 15mg (green) MUST be used with NordiPen 15mg (green)

NordiPen® is for use with NovoFine® needles.

Ingredients

Norditropin® SimpleXx® contains the active ingredient, biosynthetic human growth hormone, which is called somatropin (rbe). It is identical to the growth hormone produced in the human body. The abbreviation ‘rbe’ indicates the method of genetic engineering used to manufacture the growth hormone.

Other ingredients in Norditropin® SimpleXx® are: mannitol, histidine, poloxamer, phenol, and water for injections. The quantity of each ingredient is on the label of the box.

Norditropin® SimpleXx® is available in three strengths: 5mg, 10mg, and 15mg. Your doctor will decide which strength is suitable for you or your child.

Manufacturer

Norditropin® SimpleXx® is supplied in Australia by:

Novo Nordisk Pharmaceuticals Pty. Ltd.
Level 3, 21 Solent Circuit,
Baulkham Hills NSW 2153.

This leaflet was prepared on 08 April 2021

Australian Registration Numbers:

Norditropin® SimpleXx® 5mg: AUST R 69360

Norditropin® SimpleXx® 10mg: AUST R 69361

Norditropin® SimpleXx® 15mg: AUST R 69362

Norditropin®, SimpleXx®, NordiPen® and NovoCare® are registered trademarks of Novo Nordisk Health Care AG. NovoFine® is a registered trademark of Novo Nordisk A/S.

© 2021

Novo Nordisk A/S
2880 Bagsvaerd, Denmark

Further information

For further information call the NovoCare® Customer Care Centre on 1800 668 626.

www.novonordisk.com.au

Published by MIMS May 2021

BRAND INFORMATION

Brand name

Norditropin

Active ingredient

Somatropin

Schedule

S4

 

1 Name of Medicine

Somatropin (rbe). Biosynthetic human growth hormone.

2 Qualitative and Quantitative Composition

Somatropin is a polypeptide hormone of recombinant DNA origin. The hormone is synthesised by a special strain of E. coli bacteria that has been modified by the addition of a plasmid which carries the gene for human growth hormone. Somatropin contains the identical sequence of 191 amino acids constituting the naturally occurring pituitary human growth hormone with a molecular weight of about 22,000 Daltons.
Norditropin SimpleXx contains somatropin (rbe) 5 mg, 10 mg or 15 mg in 1.5 mL.
Norditropin FlexPro contains somatropin (rbe) 5 mg, 10 mg or 15 mg in 1.5 mL.
1 mg of somatropin corresponds to 3 IU (International Units) of somatropin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Colourless solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Children.

Treatment of growth failure in children due to pituitary growth hormone deficiency.
Treatment of growth failure in girls due to gonadal dysgenesis (Turner syndrome).
Treatment of growth failure in children due to chronic renal insufficiency whose height is on or less than the twenty-fifth percentile and whose growth velocity is on or less than the twenty-fifth percentile for bone age. Chronic renal insufficiency is defined as a glomerular filtration rate of < 30 mL/min/1.73 m2.
Treatment of severe growth failure due to intrauterine growth retardation (i.e. children born small for gestational age (birthweight and/or length < -2 SD) without spontaneous catch-up growth by 2 years of age).

Adults.

Treatment of adults with severe growth hormone deficiency as diagnosed in the insulin tolerance test for growth hormone deficiency and defined by peak growth hormone concentrations of less than 2.5 nanogram/mL.
In order to establish childhood onset [CO] growth hormone insufficiency, reconfirmation by one provocative test is recommended.
In order to establish isolated growth hormone deficiency two provocative tests are recommended. In adults, the insulin tolerance test is the provocative test of choice. When the insulin tolerance test is contraindicated, alternative provocative tests must be used. The combined arginine or the glucagon test may also be considered; however these tests have less established diagnostic value than the insulin tolerance test.

4.2 Dose and Method of Administration

Dosage.

Treatment of Norditropin should be directed by specialists experienced in the diagnosis and management of growth hormone deficiency. This is also true for the management of Turner syndrome, chronic renal disease and SGA. The dosage must be individualised for each patient in accordance with the individual's response to therapy. Dosages can be calculated according to bodyweight or body surface area.
Generally, daily subcutaneous administration in the evening, 6-7 days per week, is recommended. Rotation of the injection site is recommended to minimise the risk of lipoatrophy. Specific activity for somatropin: 1 mg = 3 International Units (IU).

Paediatric.

Recommended dosages for children with growth hormone deficiency.

25-35 microgram/kg/day.
Equal to: 0.7-1.0 mg/m2/day.

Recommended dosages for Turner syndrome and chronic renal disease.

50 microgam/kg/day.
Equal to: 1.4 mg/m2/day.

Recommended dosages for small for gestational age (SGA).

33-67 microgram/kg/day.
Equal to: 1-2 mg/m2/day.
The dosage must be adjusted to the need of the individual patient. It is recommended to start treatment with 33 microgram/kg/day. If catch-up growth has not commenced after 6 months of observation (and verification of compliance by increase in IGF-1 and/or IGFBP-3) then the physician may increase the dose up to 67 microgram/kg/day according to the patient's needs.
It is recommended that the treating physician advise the parents/ guardians that their children are not being treated for growth hormone deficiency, and that treatment with Norditropin induces catch-up growth during childhood and increases adult height. It is also recommended that parents/ guardians be advised that long-term treatment with somatropin has been associated with impaired glucose tolerance and malignancies. However, causality has not been established and there is no evidence that somatropin treatment is associated with an increased incidence of persistent impaired glucose tolerance or malignancies.

Adults.

Recommended dosages for adults with growth hormone deficiency.

The dosage must be adjusted to the need of the individual patient. It is recommended to start treatment with a low dose of 0.15-0.3 mg/day and to increase the dosage gradually at monthly intervals based on clinical response. Serum insulin-like growth factor 1 (IGF-1) can be used to guide dose titration.
Dose requirements decline with age. Maintenance dosages vary from patient to patient, but seldom exceeds 1.0 mg.

Method of administration.

Instructions for use and handling.

Patients should be reminded to wash their hands thoroughly with soap and water and/or disinfectant prior to any contact with Norditropin SimpleXx/ FlexPro.
Do not use Norditropin SimpleXx/ FlexPro if it does not appear water-clear and colourless. (FlexPro only: check this by turning the pen upside down once or twice.)
Norditropin should not be shaken vigorously at any time.

Norditropin SimpleXx.

Norditropin SimpleXx cartridges must be used with the matching colour coded NordiPen to give the correct dose:
Norditropin SimpleXx 5 mg (yellow) must be used with NordiPen 5 mg (yellow).
Norditropin SimpleXx 10 mg (blue) must be used with NordiPen 10 mg (blue).
Norditropin SimpleXx 15 mg (green) must be used with NordiPen 15 mg (green).
Detailed instructions for use are included in the package insert (consumer medicine information) and NordiPen instruction manual. Patients should be advised to read these instructions very carefully.
The product is for multiple use in one patient only.

Norditropin FlexPro.

Norditropin FlexPro is a prefilled pen designed to be used with NovoFine needles (8 mm 30 G or smaller).
Detailed instructions for use are included in the package insert (consumer medicine information). Patients should be advised to read these instructions very carefully.
The product is for multiple use in one patient only.

4.3 Contraindications

Norditropin should not be used in children with closed epiphyses; in patients with retarded growth due to any other cause than pituitary growth hormone deficiency unless specifically indicated (see Section 4.1 Therapeutic Indications); or in patients with a known hypersensitivity to any of the ingredients.
Norditropin should not be used in patients with any evidence of active malignant tumours. Intracranial neoplasm must be inactive and antitumour therapy must be completed prior to instituting Norditropin therapy. Treatment with Norditropin should be discontinued if there is any evidence of recurrent tumour growth.
Growth hormone is contraindicated in patients with proliferative or preproliferative diabetic retinopathy.
Growth hormone is contraindicated in those patients with Prader-Willi syndrome who would otherwise qualify for somatropin therapy (see Section 4.1 Therapeutic Indications) who are severely obese or have respiratory impairment.
In children with chronic renal disease, Norditropin treatment after renal transplantation should not be initiated if the child has a history of more than one acute rejection episode or if the time since transplantation is less than 12 months. In addition to this, Norditropin treatment should be discontinued in case of a new acute rejection episode.
Norditropin should not be initiated to treat patients with acute critical illness due to complications following open heart surgery or abdominal surgery, multiple accident trauma or to patients having acute respiratory failure (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Treatment with Norditropin should be directed by specialists experienced in the diagnosis and management of growth hormone deficiency. This is true also for the management of Turner syndrome, chronic renal disease and SGA.
The maximum recommended daily dose should not be exceeded (see Section 4.2 Dose and Method of Administration).
Norditropin contains the excipient poloxamer 188, which acts as a surfactant. Poloxamer 188 is excreted predominantly in the urine and its exposure is inversely proportional to glomerular filtration rate. High s.c. doses of poloxamer 188, approximately 650 times the maximal expected clinical exposure based on body surface area, have been shown to induce vacuolation of the renal tubules in rats. The findings from some clinical trials of poloxamer 188 have demonstrated that similar extremely high i.v. dosages of poloxamer 188 cause a reversible acute renal dysfunction (i.e. decreased creatinine clearance observed).
Serum thyroxine levels may fall during treatment with Norditropin due to the increased peripheral deiodination of T4 to T3.
Hypothyroidism may develop in patients with pituitary disease. As hypothyroidism interferes with the response to Norditropin therapy patients should have periodic thyroid function tests and thyroid hormone should be substituted when indicated. Patients with Turner syndrome have an increased risk of developing primary hypothyroidism associated with antithyroid antibodies.
Monitoring of growth of hands and feet in Turner syndrome patients treated with growth hormone is recommended and a dose reduction to the lower part of the dose range should be considered if increased growth is observed. Girls with Turner syndrome generally have an increased risk of otitis media, and careful otological evaluation is recommended.
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 indicated.
Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process.
Somatropin has been found to influence carbohydrate metabolism, therefore, patients should be observed for evidence of glucose intolerance. Regular urine testing for evidence of glycosuria should be carried out in all patients. In insulin treated patients, adjustment of insulin dose may be needed after initiation of Norditropin treatment.
Leukaemia has been reported in a small number of growth hormone deficient patients some of whom have been treated with somatropin. Based on current evidence it is unlikely that somatropin is responsible for this. In patients in complete remission from tumours or malignant disease, growth hormone therapy has not been associated with an increased relapse rate. Nevertheless, patients who have achieved complete remission of malignant disease should be followed closely for relapse after commencement of Norditropin therapy.
Very rare cases of benign intracranial hypertension have been reported. If appropriate, somatropin treatment should be discontinued. In cases of severe or recurrent headache, visual symptoms, nausea and/or vomiting, a fundoscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, 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.
Two placebo controlled clinical trials of patients in intensive care units treated with somatropin in high doses (5.3-8 mg/day) have demonstrated an increased mortality among patients suffering from acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure. 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 with growth hormone in patients having acute critical illnesses should be weighed against the potential risk.
If injected subcutaneously, the injection site should be rotated to minimise the risk of lipoatrophy.

Use in renal impairment.

The dosage in children with chronic renal disease is individual and must be adjusted according to the individual response to therapy. The growth disturbance should be clearly established before Norditropin treatment by following growth on optimal treatment for renal disease over one year. Conservative management of uraemia with customary medication and if needed dialysis should be maintained during Norditropin therapy.
Patients with chronic renal disease normally experience a decline in renal function as part of the natural course of their illness. However, as part of the clinical management of the patient during somatropin treatment, renal function should be monitored for excessive decline, including signs of rejection episodes in transplanted patients. Particular caution should be exercised if somatropin is used in children who have had a previous episode of rejection or in whom immunosuppression is not assured (see Section 5.1, Clinical trials).
Patients with chronic renal disease may develop hyperparathyroidism which should be treated appropriately before initiation of Norditropin therapy.

Use in the elderly.

Experience in patients older than 60 years and in patients with more than 10 years' of treatment in adult growth hormone deficiency is still limited.

Paediatric use.

The stimulation of longitudinal growth in children can only be expected until the epiphysial discs are closed. Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders and Legg-Calve-Perthes disease may occur more frequently in patients with short stature. These diseases may present as the development of a limp or complaints of hip or knee pain and physicians should be alerted to this possibility.
The dosage in children with intrauterine growth retardation is individual and must be adjusted according to the individual response to therapy. Norditropin treatment is not indicated for idiopathic short stature or familial short stature.
In SGA children it is recommended that fasting insulin and blood glucose be measured before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, Turner syndrome, severe insulin resistance, acanthosis nigricans), oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs, growth hormone should not be administered.
In SGA children it is recommended that the IGF-1 level be measured 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.
Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Concomitant glucocorticoid therapy may inhibit growth and thereby oppose the growth promoting effect of Norditropin. The effect of growth hormone on final height can also be influenced by additional therapy with other hormones, e.g. gonadotrophin, anabolic steroids, oestrogen and thyroid hormone. Concomitant administration with gonadal steroids may not be optimal clinical practice, since there is evidence that treatment with gonadal steroids plus somatropin may reduce the final height compared to treatment with somatropin alone.
Data from an interaction study performed in growth hormone deficient adults, suggests that somatropin administration may increase the clearance of compounds known to be metabolised by cytochrome P450 isoenzymes. The clearance of compounds metabolised by cytochrome P450 3A4 (e.g. sex steroids, corticosteroids, anticonvulsants and cyclosporine) may be especially increased resulting in lower plasma levels of these compounds. The clinical significance of this is unknown.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

In a fertility study, female rats were treated s.c. with Norditropin for 2 weeks prior to mating and for the first 7 days of pregnancy. Pregnancy rate was reduced at doses ≥ 1 IU/kg/day (equivalent to 2 mg/m2/day, approximately 1.4 times the maximum clinical dose on a body surface area basis) and resorption rate was increased at 3.3 IU/kg/day. However, litter size was increased due to an increased number of released ova. In studies with other recombinant human growth hormone preparations, increased incidences of irregular oestrous cycles and delayed mating time were observed in rats treated with somatropin at s.c. doses of 0.1 IU/kg/day (equivalent to 0.2 mg/m2/day, about 15% of the maximum clinical dose on a body surface area basis) or greater.
(Category B1)
Animal reproduction studies have not been conducted with Norditropin. It is not known whether Norditropin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Another form of recombinant human growth hormone was not teratogenic in rats or rabbits at respective doses of up to 15 and 28 times the maximum recommended clinical dose based on body surface area. In rats, recombinant human growth hormone administered from late gestation to weaning, at 15 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 drug should be used during pregnancy only if clearly needed.
 There have been no studies conducted with Norditropin in nursing mothers and it is not known whether Norditropin is excreted in breast milk. It is unlikely that the intact growth hormone would be excreted in the milk; however, following subcutaneous administration of radiolabelled recombinant human growth hormone to lactating rats, radioactivity was transferred to milk reaching four times the concentration found in maternal plasma. Absorption of any intact protein in the gastrointestinal tract of the infant is extremely unlikely.

4.7 Effects on Ability to Drive and Use Machines

Norditropin is not expected to affect the ability to drive or use machinery.

4.8 Adverse Effects (Undesirable Effects)

When treatment with somatropin is initiated, fluid retention with peripheral oedema may occur, especially in adults.
Carpal tunnel syndrome is common in adults. The symptoms are usually transient, dose dependent and may require transient dose reduction.
Adverse reactions in children are uncommon or rare.

Clinical trial experience.

See Table 1.
In children with Turner syndrome increased growth of hands and feet has been reported during growth hormone therapy.

Post marketing experience.

Rare (less than 1 in 1000) cases of generalised hypersensitivity reactions (e.g. anaphylactic reactions) have been reported. See Section 4.3 Contraindications.
In addition to the above mentioned adverse drug reactions, those presented below have been spontaneously reported and are by an overall judgement considered possibly related to Norditropin treatment.
Slipped capital femoral epiphysis and Legg-Calve-Perthes disease have been reported in children treated with somatropin.
There have been reports of fatalities after initiating therapy with growth hormone in paediatric patients with Prader-Willi syndrome, for which Norditropin is not approved, who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea or unidentified respiratory infection. Male patients with one or more of these factors may be at greater risk than females. Patients with Prader-Willi syndrome should be evaluated for signs of upper airway obstruction and sleep apnoea before initiation of treatment with growth hormone. If pathological findings are observed during the assessment of upper airway obstruction, the patient should be referred to an ear, nose, throat specialist for treatment and resolution of the respiratory disorder before initiating somatropin treatment. The patient should be monitored if sleep apnoea is suspected. If during treatment with growth hormone, patients show signs of upper airway obstruction (including onset of or increased snoring) and/or new onset sleep apnoea, treatment should be discontinued and a new ear, nose, throat assessment should be performed. All patients with Prader-Willi syndrome treated with growth hormone should also have effective weight control and be monitored for signs of respiratory infection.
Table 2 lists further conditions reported in post-marketing experience.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

The maximum generally recommended dosage should not be exceeded due to the potential risk of side effects.
Acute overdosage could lead initially to hypoglycaemia and subsequently to hyperglycaemia. Changes in glucose levels have been detected biochemically, but without clinical signs of hypoglycaemia. Long-term overdosage could result in signs and symptoms consistent with the known effects of human growth hormone excess.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

ATC: H01AC01.

Mechanism of action.

Norditropin increases the growth rate in humans by stimulation of protein synthesis and other metabolic processes.

Growth.

The primary and most intensively studied action of somatropin is the stimulation of linear growth. This effect is demonstrated in patients with somatropin deficiency.

Skeletal growth.

The measurable increase in bone length after administration of somatropin results from its effect on the cartilaginous growth areas of long bones. Studies in vitro have shown that the incorporation of sulphate into proteoglycans is not due to a direct effect of somatropin, but rather is mediated by the somatomedins or insulin-like growth factors (IGF). The somatomedins, among them somatomedin-C (otherwise known as IGF-1), are polypeptide hormones which are synthesised in the liver, kidney and various other tissues. Somatomedin-C (IGF-1) is low in the serum of hypopituitary dwarfs and hypophysectomised humans or animals, but its presence can be demonstrated after treatment with somatropin.

Cell growth.

It has been shown that the total number of skeletal muscle cells is markedly decreased in short stature children lacking endogenous somatropin compared with normal children, and that treatment with somatropin results in an increase in both the number and size of muscle cells.

Organ growth.

Somatropin influences the size of internal organs, and it also increases red cell mass.

Protein metabolism.

Linear growth is facilitated in part by increased cellular protein synthesis. This synthesis and growth are reflected by nitrogen retention which can be quantitated by observing the decline in urinary nitrogen excretion and blood urea nitrogen following the initiation of somatropin therapy.

Carbohydrate metabolism.

Somatropin has a diabetogenic effect. Hypopituitary children sometimes experience hypoglycaemia, and acromegalic adults often suffer from diabetes mellitus. In healthy subjects, very large doses of somatropin may impair glucose tolerance. Although the precise mechanism of the diabetogenic effect of somatropin is not known, it is attributed to blocking the action of insulin rather than blocking insulin secretion. Insulin levels in serum actually increase as somatropin levels increase.

Fat metabolism.

Growth hormone stimulates intracellular lipolysis, and administration of somatropin leads to an increase in plasma free fatty acids, cholesterol and triglycerides. Untreated growth hormone deficiency is associated with increased body fat stores including increased subcutaneous adipose tissue. On somatropin replacement a general reduction of fat stores and of subcutaneous tissue in particular takes place.

Mineral metabolism.

The retention of sodium is less than that of potassium. Serum levels of phosphate increase in patients with growth hormone deficiency after somatropin therapy due to metabolic activity associated with bone growth. Serum calcium levels are not altered. Although calcium excretion in the urine is increased, there is a simultaneous increase in calcium absorption from the intestine. Negative calcium balance, however, may occasionally occur during somatropin treatment.

Connective tissue metabolism.

Somatropin stimulates the synthesis of chondroitin sulphate and collagen as well as the urinary excretion of hydroxyproline.

Clinical trials.

Bioequivalence of Norditropin formulations.

A randomised, single blind, 4 way cross over trial compared three Norditropin SimpleXx formulations with Norditropin PenSet 24 in 28 healthy volunteers. Bioequivalence was demonstrated between each of the Norditropin SimpleXx formulations and Norditropin PenSet 24 after s.c. administration.

Turner syndrome.

There were two prospective, open label studies conducted to establish the efficacy of Norditropin in girls with Turner syndrome.
GHTUR/BPD/6 and 12/NL was a prospective, randomised open label study in girls ≥ 11 years (mean 13.6 years at study entry). All subjects received somatropin 6 IU/m2/day as either a single daily dose or two divided doses until final height. All subjects received oestrogen to induce puberty and later progesterone to induce withdrawal bleeds (although this may not be optimal clinical practice, since there is evidence that treatment with gonadal steroids plus somatropin may reduce the final height compared to treatment with somatropin alone). Nineteen subjects were randomised with the mean duration of treatment of 43.1 months. Seventeen reached final height, and two withdrew at close to final height. Final height was defined by a height velocity < 2 cm/year.
The baseline mean height (n = 19) was 137.71 cm with a mean Karlberg standard deviation score (SDS) of +0.663 and Roede SDS of -3.4. There was no difference in the effect on growth of administering somatropin once or twice per day and the treatment groups were pooled. The mean final height of the 17 subjects who reached final height was 155.08 cm with a mean Karlberg SDS of +1.28 and Roede SDS of -2.13. If all subjects are included, the mean final height is 155.2 cm. Height velocity increased compared to baseline.
Somatropin treated subjects remained shorter than girls without Turner syndrome but gained on average 7.9 cm as a result of somatropin treatment (calculated according to Roede standards).
GHTUR/BPD/5-13/NL is an ongoing prospective, open label multicentre study comparing three doses of somatropin (4, 6 and 8 IU/m2/day) in girls aged 2-11 years, combined with one of two different dosing regimens of 17β-estradiol to induce puberty. 68 subjects are enrolled, with 13 at final height in January 1998, 14 withdrawn and 41 remaining in the study. By April 1999, an additional 12 subjects had attained final height.
In January 1998, of the 14 withdrawn subjects, three had withdrawn due to adverse effects, and the other 11 due to reaching near final height. Analysis of the 13 subjects who had reached a mean final height of 159 ± 7.2 cm by January 1998 showed an average height gain of 9.8 cm as a result of treatment with somatropin after a mean duration of treatment of 7.2 ± 0.69 years. The change from baseline score in the Karlberg and Roede SDS were +2.05 and +1.58, respectively in these 13 subjects.
The two prospective Turner syndrome studies included 85 patients in total. Seven patients experienced peripheral oedema during the trials; however, a dose relationship was not shown. One out of 17 patients in GHTUR/BPD/6 and 12/NL showed impaired glucose tolerance at more than one assessment after three years of growth hormone treatment. In the dose response study, GHTUR/BPD/5-13/NL, no changes in glucose metabolism was detected; however, all but one patient showed an increase in insulin AUC during the trial.

Chronic renal failure.

Five studies (including some with substudies) were conducted to establish the efficacy of Norditropin on growth in children with chronic renal failure (CRF) pretransplant. One multipart study was conducted in children with CRF post-transplant. Two of the substudies were prospective, double blind, placebo controlled studies of the effect on growth of six months of treatment with Norditropin 28 IU/m2/week in children with CRF pretransplant (GHCRF/BPD/1/NL study 1) and post-transplant (the first year of GHCRF/BPD/2-5/NL in prepubertal patients). The other studies were either dose comparison studies (14 vs 28 or 32 and 28 vs 56 IU/m2/week for up to 30 months), or follow-up studies in patients continuing to receive somatropin after previous participation in one of the placebo controlled or dose comparison studies. There are no final height data on children who began treatment prior to puberty and quality of life data are not available. Norditropin SimpleXx was not used in the five studies, as all studies were initiated prior to its development.
GHCRF/BPD/1/NL (study 1) and GHCRF/BPD/2-5/NL (first 12 months) were randomised, double blind, placebo controlled studies on prepubertal children, involving 22 and 11 patients, respectively. In both studies, children were randomised to receive placebo or Norditropin 28 IU/m2/week for 6 months, followed by the alternate treatment for 6 months. Although final height data were not attained, both studies showed that there was a significantly greater height velocity (equivalent of 9.8 vs 3 and 9.2 vs 3.75 cm/year, respectively) and height velocity standard deviation score (5.9 vs 1.75 and 6.7 vs -0.6, respectively) with Norditropin than placebo, indicating that six months treatment increased height velocity. No longer-term placebo controlled studies have been conducted.
The results of Norditropin treatment in children with CRF indicate that it resulted in short-term increases in growth velocity, which diminished after the first 6-12 months. The safety profile of Norditropin in post-transplant children is similar to that in the pretransplant setting; however, there is uncertainty about whether there is an increase in the frequency of renal allograft rejection episodes in children with renal transplants who are treated with somatropin. An increase in the incidence of rejection was seen in some trials but not in others. The risk appeared greatest in children who had had a previous episode of rejection, in whom immunosuppression was not maintained, or who received higher than the recommended dose of somatropin.
Peripheral oedema was not reported during the five CRF studies. In three subjects (out of 124 patients randomised to the trials) OGTT were categorised as diabetic during the trial, of which one diabetic response was assumed to be prednisone induced.

Small for gestational age (SGA).

There were three studies conducted to establish the efficacy of Norditropin in short children born SGA mainly due to intrauterine growth retardation. The efficacy parameters did not include quality of life measures as endpoints and were based on auxological criteria alone.
GHRETARD/BPD/14-20-21/NL (study 1) is an ongoing multicentre, double blind, randomised, two arm study comparing two doses of somatropin (3 or 6 IU/m2/day (0.033 or 0.067 mg/kg/day)) for up to nine years. In the original study (14/NL), 79 short children born with IUGR without catch-up growth were included; 78 children completed two years and continued in the extension trial (20/NL) for a further two years. A total of 75 children completed four years and entered the second extension of the trial (21/NL), and somatropin treatment was continued at the same dose until final height. By August 2001, 18 children completed the study, 37 were still ongoing, and 24 were withdrawn (18 withdrawn due to attaining satisfactory height) during the nine year trial period.
During the first year of therapy, height velocity (HV) increased from a mean of 5.6 cm/year to 10.0 cm/year in the low dose group and from 5.4 cm/year to 11.7 cm/year in the high dose group. HV subsequently decreased with time, but remained higher than pretreatment HV up to seven years. The difference in HV between the two dose groups was statistically significant at years 1 and 2. Results of other efficacy variables indicated a substantial effect on linear growth resulting in a mean change in Roede SDS from -3.1 to -0.6 and from -3.1 to -0.1 in the two dose groups, respectively, after eight years of somatropin treatment. Long-term treatment (up to 9 years) was safe and well tolerated, and there were no withdrawals due to serious adverse events.
GHRETARD/BPD/16-20/NL (study 2) was a single centre, open label study, in which 11 (8 females and 3 males) children (who failed to meet the inclusion criteria for inclusion in 14/NL due to age and/or puberty) were included. Trial conduct in 16/NL was the same as that for 14/NL with the exception that all children received somatropin at a dose of 6 IU/m2/day. After two years of treatment, these children were allowed to continue in 20/NL for a further two years. After a total of four years, children, who had not reached final height, continued treatment in 21/NL at the same dose of somatropin until final height was reached. Of the 11 children, nine completed the study (four reaching final height, and five reaching near final height).
Data on the first four years of treatment were analysed; final height data on children in this study were pooled with 21/NL and reported separately (see Table 3). Overall, there was an increase in HV from pretreatment to year 1. HV then declined yearly primarily due to the fact that subjects were nearing final height. Height standard deviation score (HSDS) increased from a mean of -2.62 at baseline to -1.85 at year 4.
Data on final height (defined by a height velocity < 1 cm/year) are available on 40 subjects in studies 1 and 2. Of the subjects (26 males and 14 females) analysed, 10 subjects were GHD and 30 (20 males and 10 females) were non-GHD, including 11 subjects (7 males and 4 females) with a baseline height < -3 SD. Mean final height data are shown in Table 3.
GHRETARD/F/1/F (study 3) was a prospective, randomised, open label, parallel group, multicentre study comparing three regimens of somatropin for two years. Patients were randomised to one of three treatment groups: 0.2 IU/kg/day (six days/week) continuous treatment; 0.2 IU/kg/day (six days/week) noncontinuous treatment (alternating periods of six months treatment and nontreatment); and 0.4 IU/kg/day (six days/week) noncontinuous treatment (alternating periods of six months treatment and nontreatment). Of the 139 children randomised and allocated to the three treatment groups (46, 47 and 46, respectively), 133 completed the study.
A dramatic change in HV from approximately 4.8 cm/year to 10 cm/year was found in all treatment groups during the first six months of the study. Continuous treatment with 1.2 IU/kg/week resulted in the most beneficial growth in comparison to the alternating treatment regimens. Except for during off treatment periods, all regimens resulted in increased HV and height gain during childhood. The alternating 2.4 IU/kg/week regimen did not appear to be more efficient than the alternating 1.2 IU/kg/week regimen. There was a statistically significant difference (p < 0.001) in HSDS between the treatment groups, showing an increase of 1.42 from -3.19, of 0.86 from -3.06, and of 1.02 from -3.11 in the three groups, respectively.

Deficiency in adults.

Clinical data are available on seven placebo controlled studies and uncontrolled extensions from four of these studies. The placebo controlled studies range in duration from 4 to 12 months involving a total of 420 subjects (222 and 198 subjects in the somatropin and placebo arms, respectively, equivalent to 94 patient years (somatropin treatment) and 84 patient years (placebo treatment)). Two-thirds of the subjects had adult onset [AO] growth hormone insufficiency. Results, available on 203 subjects from 3 of the 4 studies which used the insulin tolerance test to diagnose GH deficiency, showed 71% of subjects had a peak growth hormone concentration of less than 2.5 nanogram/mL. Primary outcomes commonly measured across the studies included the efficacy and safety of Norditropin on body composition, muscle strength, exercise capacity, and bone metabolism. Secondary outcomes included the effects of Norditropin on lipid metabolism, thyroid metabolism, pituitary, adrenal and gonadal function, cellular and humoral immune function and quality of life. Overall, the studies demonstrated progressive improvement and partial normalisation of some surrogate outcome parameters measured in those patients administered somatropin. Outcomes statistically significantly improved by the end of twelve months as compared to placebo included: body composition [total body fat, skinfold thickness, total body fat, total body lean mass, waist/ hip ratio]; bone metabolism [increased osteocalcin]; mineral metabolism [increased alkaline phosphatase]; and thyroid metabolism [increased serum free T3]. Trial analyses were undertaken in accordance with approved study protocols and subsequent amendments. Due to unknown correlations between the assessments and dependencies between hypotheses on primary efficacy and safety outcomes, adjustment for multiple comparisons was not carried out.
Uncontrolled extension data are available from four of the seven studies. Involving over 182 subjects and ranging in duration from 16 months to five years [83 subjects ≥ 2 years, 40 subjects ≥ 4 years], these demonstrated overall that some of the modifications seen in the shorter term, placebo controlled studies continued to show progressive change (relative to baseline) and approach values close to normal individuals at three years. The long-term clinical significance of these changes is not clear. By three years, adults on somatropin replacement show normalisation/ progressive improvement in the following outcomes: body composition [lean body mass to fat ratio]; bone metabolism [lumbar spine BMC, osteocalcin, whole body BMC]; thyroid metabolism [increased serum free T3]; lipid metabolism [LDL, HDL, cholesterol] and cardiac status [resting systolic/ diastolic BP levels]. Following four years of somatropin replacement, sustained change was shown with the following outcomes: body composition [muscle volume and mass, bodyweight, total body fat, waist/ hip ratio]; bone metabolism [lumbar spine BMD, osteocalcin, hydroxyproline]; thyroid metabolism [increased serum free T3]; and cardiac status [systolic/ diastolic BP levels]. There was no statistically significant improvement in quality of life measurements; however, the changes were consistent and in a direction denoting improvement.
The somatropin related adverse effects observed in the studies were mild to moderate and reversible with the most frequent side effects arising from the salt and water retaining effects of the hormone manifesting mainly as fluid retention. These symptoms occurred in the early weeks of treatment and improved or disappeared with dosage reduction.
Overall, the studies demonstrated that somatropin replacement leads to a correction of the abnormalities in body composition caused by untreated growth hormone deficiency. The long-term studies not only showed that the early changes are maintained, but also that some endpoints continue to improve beyond twelve months of somatropin replacement. This observation demonstrates that several of the actions of somatropin on body structure and function occur slowly and may take several years to normalise.

5.2 Pharmacokinetic Properties

IV infusion of Norditropin SimpleXx (33 nanogram/kg/min for 3 hours) to nine growth hormone deficient patients gave the following results: serum half-time of 21.1 ± 1.7 min, metabolic clearance rate of 2.33 ± 0.58 mL/kg/min and a distribution space of 67.6 ± 14.6 mL/kg.

5.3 Preclinical Safety Data

Genotoxicity.

There was no evidence of Norditropin-induced genotoxicity in assays for gene mutation in bacteria or chromosomal damage in mouse bone marrow cells in vivo.

Carcinogenicity.

Somatropin raises the serum levels of IGF-1. 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

Mannitol, histidine, poloxamer, phenol and water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, the medicinal product must not be mixed with other medicinal products.

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.

6.4 Special Precautions for Storage

Before use: store in a refrigerator (2°C-8°C) in the outer carton, in order to protect from light. Do not store close to any cooling elements. Do not freeze.
When in use, the product may be stored for a maximum of 28 days in a refrigerator (2°C-8°C), alternatively stored for a maximum of 21 days below 25°C. Do not store close to any cooling elements. Do not freeze.
Norditropin retains its biological potency until the date of expiry indicated on the label.

6.5 Nature and Contents of Container

Norditropin SimpleXx cartons containing 1 x 1.5 mL cartridge and 3 x 1.5 mL cartridges.

Somatropin 5 mg, 10 mg or 15 mg solution for s.c. injection in a colourless glass cartridge.
The cartridge contains a rubber plunger and is closed with a rubber closure.

Norditropin FlexPro: cartons containing 1 x 1.5 mL prefilled pen.

Multi-dose, disposable, pre-filled pens, consisting of somatropin 5 mg, 10 mg or 15 mg solution for s.c. injection in a colourless glass cartridge, permanently sealed in a peninjector.
The push button, pen cap and cartridge holder on the pen-injector is colour coded according to strength: 5 mg/1.5 mL (yellow), 10 mg/1.5 mL (blue) and 15 mg/1.5 mL (green).
The cartridge contains a rubber plunger and is closed with a rubber closure.
*Not all presentations and pack sizes may be available.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.

Not applicable.

CAS number.

Not applicable.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes