Consumer medicine information

NutropinAq

Somatropin

BRAND INFORMATION

Brand name

Nutropin AQ

Active ingredient

Somatropin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using NutropinAq.

What is in this leaflet?

Please read this leaflet carefully before you use NutropinAq.

This leaflet answers some common questions about NutropinAq. 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 using NutropinAq against the benefits he/she expects it will have for you.

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 is NutropinAq?

The active substance of NutropinAq is somatropin. Somatropin is human growth hormone, which is made by genetic engineering using the bacterial micro-organism Escherichia coli. The structure of somatropin is identical to human growth hormone of pituitary origin.

Somatropin has effects that are equivalent to human growth hormone of pituitary origin. Growth hormone exerts significant effects directly on the production of other hormones, e.g. IGF-1, and on metabolic actions. The anabolic and growth-promoting effects of somatropin are in some part indirect effects mediated by IGF-1.

What NutropinAq is used for?

NutropinAq is used for:

  • Long-term treatment of children with growth failure due to inadequate endogenous growth hormone secretion.
  • Long-term treatment of growth failure associated with Turner syndrome.
  • Treatment of prepubertal children with growth failure associated with chronic renal insufficiency up to the time of renal transplantation.
  • Replacement of growth hormone in adults with growth hormone deficiency originating in either childhood or adulthood.

Ask your doctor if you have any questions why NutropinAq has been prescribed for you. Your doctor may have prescribed it for another reason.

Before you use NutropinAq

Do not use NutropinAq:

  • in case of hypersensitivity to somatropin or any of the other ingredients
  • for growth promotion if growing is already finished
  • if an active tumour (cancer) is present. Tell your doctor if you have or have had an active tumour. Tumours must be inactive and you must have finished your anti-tumour treatment before you start your treatment with NutropinAq.
  • during acute critical illness due to complications following open-heart or abdominal surgery, multiple accidental trauma or in case of acute respiratory failure.

Treatment with NutropinAq should be discontinued if evidence of tumour growth develops.

Treatment with NutropinAq should be initiated and monitored by adequately experienced physicians.

Before you start to use it

Tell your doctor if:

  • you have diabetes
  • you have been diagnosed with Prader-Willi Syndrome
  • you have long term kidney disease
  • you have diabetes and worsening or severe eye disease
  • you have problems with your thyroid
  • you have any other hormone problems
  • you are on a controlled sodium diet. NutropinAq contains 8.2mg of sodium per cartridge.

If you have had a tumour (cancer) in the past, especially a tumour affecting the brain, your doctor should pay special attention and examine you regularly for a possible return of the tumour. A small number of growth hormone deficient patients treated with growth hormone have had leukaemia (blood cancer). However, no cause and effect relationship with growth hormone treatment has been proven.

There may be an increased risk of developing an inflammation of the pancreas (pancreatitis) in children compared to adults treated with growth hormone. In case of severe and persistent abdominal pain, consult your doctor.

While you are using NutropinAq

Please ask the doctor for advice if you develop a limp or if you experience hip or knee pain.

If you have diabetes mellitus, please consult the doctor regularly during treatment with NutropinAq. Your insulin dose may require adjustment after treatment with NutropinAq is started.

Tell the doctor if you experience any visual changes, headache, nausea and/or vomiting, especially within the first eight weeks after starting treatment with NutropinAq.

Scoliosis (abnormal curve of the spine) may progress in any child during rapid growth. Your doctor should monitor you for any signs of scoliosis during treatment.

If you undergo a kidney transplant, NutropinAq treatment should be stopped.

If you are taking replacement therapy with glucocorticoids (steroid hormone medicines used to treat allergies, asthma, autoimmune diseases, or your body's response to infection (sepsis)) you should consult your doctor regularly as you may need adjustments of your glucocorticoid dose.

Your doctor may take blood tests during treatment to check your blood count.

Pregnancy:

Treatment with NutropinAq should be discontinued if pregnancy occurs. Please ask your doctor or pharmacist for advice before taking any medicine.

Breast-feeding:

It is not known whether NutropinAq is excreted in human milk. However, absorption of intact protein from the gastrointestinal tract of the infant is unlikely. Please ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines:

No studies on the effects of NutropinAq on the ability to drive and use machines have been performed.

NutropinAq has no known effect on the ability to drive or to use machines.

Taking other medicines

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

NutropinAq and some medicines may interfere with the actions of each other, as listed below:

  • Treatment at the same time with glucocorticoids may reduce the growth-promoting effect of NutropinAq
  • NutropinAq may reduce insulin sensitivity, therefore patients with diabetes mellitus may require adjustment of their anti-diabetic therapy
  • During administration of NutropinAq at the same time as corticosteroids, sex steroids, anticonvulsants or cyclosporin, the effect of treatment with these medicines may be affected. Please ask the doctor for advice
  • In women taking oral estrogen replacement (hormone replacement therapy (HRT)) at the same time, the doctor may need to increase the dose of NutropinAq. Also, if a woman on NutropinAq stops oral estrogen therapy, the dose may need to be reduced. Ask your doctor for advice.
  • Previously undiagnosed adrenal insufficiency may become apparent and require steroid treatment. Patients already treated for adrenal insufficiency may require adjustment of dose during NutropinAq treatment.

Your doctor or pharmacist has more information on medicines to be careful with or avoid while using this medicine.

How to use NutropinAq

How much and how often is it given?

The doctor will advise you about the individualised dose of NutropinAq. Please do not change the dosage without consulting the doctor or pharmacist. In general the dosage will be calculated according to the following rules:

Growth failure in children due to inadequate growth hormone secretion:

0.025 - 0.035 mg/kg bodyweight given as a daily subcutaneous injection.

Growth failure associated with Turner syndrome:

Up to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.

Growth failure associated with chronic renal insufficiency:

Up to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.

Treatment with NutropinAq may be continued up to the time of renal transplantation.

Growth hormone deficiency in adults:

Low initial doses of 0.15 - 0.3 mg given as a daily subcutaneous injection. The dose may be increased stepwise by the doctor according to the patient's individual requirements. The final dose seldom exceeds 1.0 mg/day. In general, the lowest efficacious dose should be received. For older or overweight patients lower doses may be necessary.

NutropinAq is designed for use only with the NutropinAq Pen. The product is for use in one individual only.

Please administer the prescribed dose of NutropinAq solution for injection subcutaneously each day and change the site of injection each time. At the start of treatment it is recommended that a doctor or a nurse give the injection. After training the injection can be given by the patient or his/her carer. The medicine is supplied in a cartridge as a sterile solution with preservative for multiple use. For each single injection please use a new, sterile injection needle. Do not use the solution unless it is clear and not cloudy. Please see also the instructions for use.

Treatment with NutropinAq is a long-term therapy, for further information please ask the doctor.

If you forget to use it

After missing an individual dose a double dose should not be injected. The prescribed dosage regimen should be continued.

If you use more than you should (overdose)

If more NutropinAq than recommended was injected, please consult the doctor.

Acute overdose could lead initially to a glucose decrease (hypoglycaemia) and subsequently to a glucose increase (hyperglycaemia). Long-term overdose may result in an enhanced growth of ears, nose, lips, tongue and cheekbone (gigantism and/or acromegaly). These signs are consistent with the known effects of excess in human growth hormone.

Effects when treatment is stopped:

A disruption or early ending of the treatment with NutropinAq may impair the success of the growth hormone therapy. Please ask the doctor for advice before stopping the treatment.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using NutropinAq.

Like all medicines, NutropinAq can have side effects. Generally these are mild but you may need medical attention if you get some of the side effects.

Very common side effects (affecting more than 1 patient in 10):

Accumulation of fluids in the body (oedema) with swelling of the hands and feet (peripheral oedema), muscle pain (myalgia) and pain in one or more joints (arthralgia) in adults.

Common side effects (affecting between 1 and 10 patients in 100):

  • Feeling of weakness (asthenia)
  • Injection site reactions
  • Headache
  • Underactivity of the thyroid gland (hypothyroidism)
  • Increased muscle tone (hypertonia)
  • Impaired glucose tolerance
  • Development of antibodies to the protein somatropin
  • Pain in one or more joints (arthralgia), muscle pain (myalgia), accumulation of fluids in the body (oedema) and swelling of the hands and feet (peripheral oedema) in children.

Other common side effects which are specific to the disease which NutropinAq is being used to treat are listed below:

Children with growth failure due to growth hormone deficiency:

  • Tumours, including malignant tumours, have occurred, particularly in patients previously diagnosed with cancer.

Children with growth failure associated with Turner Syndrome:

Common:

  • abnormally heavy bleeding at menstruation (menorrhagia)

Children with growth failure due to chronic renal insufficiency:

Common:

  • Renal failure (kidney dysfunction)
  • peritonitis (inflammation of the lining of the abdomen)
  • bone necrosis
  • increase in creatinine blood levels.

Children with chronic renal insufficiency were more likely to develop increased pressure in the brain (intracranial hypertension).

Adults with growth hormone deficiency:

Very common

  • abnormal sensations of tingling, pricking or numbness (paraesthesia).

Common:

  • Increase in blood glucose (hyperglycaemia)
  • increase in blood lipids (hyperlipidaemia)
  • sleeplessness (insomnia)
  • joint disorders, arthrosis (degenerative joint disease)
  • muscle weakness
  • back pain
  • breast pain, breast enlargement (gynaecomastia).

Other side effects not listed above may also occur in some people.

If any side effects are noticed which are not mentioned in the leaflet, please inform the doctor or pharmacist.

If any side effect becomes troublesome or causes concern, tell your doctor immediately or go to the Accident and Emergency department at your nearest hospital. You may need medical attention.

How to store NutropinAq

Storage

Keep out of the reach and sight of children.

Store at 2°C-8°C. Do not freeze.

Keep the container in the outer carton. Protect from light.

After first use, the cartridge may be stored for up to 28 days at 2°C-8°C. Do not remove the cartridge that is being used from the NutropinAq Pen between injections.

Do not use after the expiry date stated on the label of the cartridge and the carton.

Do not use NutropinAq if you notice that the solution is cloudy.

Disposal

If your doctor tells you to stop treatment or the medicine has passed its expiry date, ask your pharmacist what to do with any medicine that is left over.

Product Description

What it looks like

NutropinAq 10 mg (5mg/mL) solution for injection in a cartridge.

NutropinAq is a solution for subcutaneous use. The clear, colourless, sterile solution for multidose use is contained in a cartridge of glass, closed with a rubber stopper and a rubber seal.

NutropinAq is available in pack sizes of 1 and 3 cartridges.

Ingredients

Each cartridge of NutropinAq contains 2 mL of solution with a total of 10 milligrams corresponding to 30 International Units (IU) of the active substance somatropin.

The other ingredients are sodium chloride, phenol, polysorbate 20, sodium citrate, citric acid anhydrous and water for injections

Further Information

If you have any further questions on your NutropinAq treatment, or are unsure of the information, please see your doctor, who will be able to assist you.

Sponsor

Ipsen Pty Ltd
Level 5
627 Chapel Street
South Yarra Victoria 3141

Australian Registration Number (AUST R):

116678 (NutropinAq 5mg/mL)

134206 (NutropinAq Pen)

Date of preparation of this leaflet.
January 2023

NutropinAq Pen

Instructions for use with NutropinAq

DO NOT INJECT THE MEDICINE UNTIL YOUR DOCTOR OR NURSE HAS THOROUGHLY TRAINED YOU IN THE PROPER TECHNIQUES.

Caution:

Before using your NutropinAq Pen, please read the following instructions carefully. We also suggest you consult your doctor or nurse for a demonstration.

The NutropinAq Pen is designed for use only with cartridges of NutropinAq (for subcutaneous use only). Only use the pen needles recommended by your doctor or nurse.

The dosage scale located beside the window of the cartridge holder should not be used as a dose measurement. It should only be used to estimate the dosage remaining in the cartridge. Always refer to the LCD (Liquid Crystal Display), not audible clicks, for setting an injection of NutropinAq. The clicks are only audible confirmation that the black dose knob has been moved.

Always store the pen and cartridges in a clean, safe place in the refrigerator at a temperature between 2-8°C and out of children's reach.

Protect from intense light. Use a cooler to store your NutropinAq Pen when travelling. The NutropinAq is designed to withstand a nominal (one hour maximum) period of time outside of the refrigerator on a daily basis. Avoid areas of extreme temperature. Check the expiry date of the cartridge before use.

To guard against the spread of infection, follow these safety measures:

  • Wash your hands thoroughly with soap and water before using your pen.
  • Clean the cartridge rubber seal with an alcohol swab or cotton ball saturated with alcohol.
  • Avoid touching the cartridge rubber seal at all times.
  • If you accidentally touch the cartridge rubber seal, clean it with an alcohol swab.
  • The product is for use in one individual only.
  • Use needles only once.

NutropinAq Pen Components:

Shown above are the items necessary for giving an injection. Gather all the pen components prior to use.

Your NutropinAq will be supplied separately.

Part I: Preparing and Injecting

Follow the instructions in this section if you are using the pen for the first time or are replacing an empty cartridge.

Inspect all new cartridges prior to use. Occasionally, after refrigeration, you may notice that small colourless particles are present in the NutropinAq solution. This is not unusual for solutions containing proteins like NutropinAq and does not affect the strength of the product. Allow the cartridge to come to room temperature and gently swirl. Do not shake. If the solution is cloudy or hazy or contains any solid matter, the cartridge should not be used. Return the cartridge to your pharmacist or prescribing doctor.

  1. Remove the green pen cap and unscrew the cartridge holder from the pen. If necessary, remove the empty cartridge and discard it properly.

  1. Press the white reset button.
  2. Turn the black dose knob counter-clockwise back to its starting position until it no longer turns. (See illustration).

Then turn the dose knob clockwise until the first click position is reached (approximately 1/4 turn). This ensures that the plunger push rod is reset to the starting position. If this is not done when the dosage knob is first pushed in, NutropinAq will be wasted or the cartridge may crack.
  1. Insert cartridge into the cartridge holder, then screw the cartridge holder back onto the pen. (Be careful not to touch the rubber seal.)

  1. Remove the paper seal from a new needle assembly and screw it onto the cartridge holder.
  2. Carefully remove both protective caps from the needle by pulling gently. Do not throw the larger cap away as it will be used later for proper needle removal and disposal.
  3. Holding the pen with the needle pointing upward, gently tap the cartridge holder to move any air bubbles to the top. While still holding the pen in the upright position, push in the black dose knob until it clicks into position. You should see a drop of solution appear.

Be patient. If medicine doesn't appear within a few seconds, you may need to push the reset button again.
  1. If no drop of medicine appears, push the white reset button again. Now turn the black dose knob clockwise (see illustration) by one click (0.1 mg). If you accidentally turn it too far, go back one click (0.1 mg).

  1. While still holding the pen in the upright position, push in the black dose knob again and watch the needle tip for a drop of medicine to appear. Repeat steps 8 and 9 until it appears.
  2. Press the white reset button. (The digital dose display will blink for 5 seconds.)
  3. Set the required dose by turning the black dose knob.

If you cannot dial the full dose, either start a new cartridge (as described in Part I), or inject the partial dose. Then, start a new cartridge (as described in Part I) to administer the remaining portion of your medication. Your doctor or nurse will advise you on the procedure for administering the last dose in the cartridge.
Prepare the injection site by wiping with an alcohol swab. Injection sites include the upper arms, abdomen, and upper thighs. Change the injection sites to avoid discomfort. Even if you develop a preference for one site, you still should rotate the injection site.

  1. If you are using the passive shield (or no shield) proceed to step 13.

If you are using the active shield, slide the shield onto the pen and push the 2 black lock knobs on the needle shield toward the tip.
  1. Set the tip of the pen on the prepared injection site and press the needle into the skin by pushing the pen downward until the shield is totally depressed. Your doctor or nurse will show you how to do this. Now you are ready to administer the dose. Press down on the black dose knob. Wait 5 seconds after the button is pushed, then withdraw the pen from the skin. A drop of blood may appear. Put a plaster on the injection site if you wish.
  2. Pull the needle shield off the pen (if you have used one) and place the larger needle cap on a flat surface. Slide the needle in to pick it up and push the cap completely down over the needle. Twist off the needle and discard it properly. Your doctor or nurse will tell you how to dispose of the items you have used for the injection. Always store your disposal container out of the reach of children.
  3. Attach the pen cap and return it to its case with the black dose knob pressed in. You should always store the pen in a refrigerator. Do not remove cartridge between injections.
DO NOT FREEZE.

For subsequent injections with the NutropinAq Pen, attach a new needle, push the white reset button and dial your dose.

Part II: Storage and Maintenance

Follow these tips to ensure proper care of your NutropinAq Pen:

  • Always keep your NutropinAq Pen and cartridge refrigerated and protected from light when not in use.
  • You may remove the pen and cartridge from the refrigerator up to 45 minutes prior to use.
  • Do not let your NutropinAq Pen and/or cartridge freeze. Contact your doctor or nurse for a replacement if either the pen or cartridge does not work.
  • Avoid excessive temperatures. The solution in the cartridge is stable for up to 28 days after first use when stored at 2-8°C.
  • If your pen requires cleaning, do not place under water. Use a damp cloth to wipe away dirt. Do not use alcohol.
  • When priming a new cartridge, you may need to repeat Part I, steps 8 and 9 up to a total of 6 times (0.6 mg) to remove air bubbles. Small bubbles may remain and will not affect the dose.
  • The pen should contain the NutropinAq that is being used. Do not remove cartridge between injections.
  • The NutropinAq cartridge may be used for up to 28 days.
  • Do not store the NutropinAq Pen with needle attached.

Published by MIMS March 2023

BRAND INFORMATION

Brand name

Nutropin AQ

Active ingredient

Somatropin

Schedule

S4

 

1 Name of Medicine

Somatropin.

2 Qualitative and Quantitative Composition

Nutropin AQ contains somatropin recombinant DNA 10 mg (30 IU) in 2 mL.
Somatropin is a human growth hormone (hGH) produced by recombinant DNA technology.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection.
Nutropin AQ is a clear colourless solution in a 2 mL cartridge.

4 Clinical Particulars

4.1 Therapeutic Indications

Long-term treatment of children with growth failure due to inadequate endogenous growth hormone secretion.
Long-term treatment of growth failure associated with Turner syndrome.
Treatment of prepubertal children with growth failure associated with chronic renal insufficiency up to the time of renal transplantation.
Treatment of adults with severe growth hormone deficiency as diagnosed in the insulin tolerance test for growth hormone deficiency and defined by peak GH concentrations of less than 2.5 nanogram/mL.

4.2 Dose and Method of Administration

Recommended dosage.

Growth failure in children due to inadequate growth hormone secretion.

0.025-0.035 mg/kg bodyweight given as a daily subcutaneous injection.

Growth failure associated with Turner syndrome.

Up to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.

Growth failure associated with chronic renal insufficiency.

Up to 0.05 mg/kg bodyweight given as a daily subcutaneous injection.
Somatropin therapy may be continued up to the time of renal transplantation.

Growth hormone deficiency in adults.

At the start of somatropin therapy, low initial doses of 0.15-0.3 mg are recommended, given as a daily subcutaneous injection. The dose should be adjusted stepwise, controlled by serum insulin-like growth factor-1 (IGF-1) values. The recommended final dose seldom exceeds 1.0 mg/day. In general, the lowest efficacious dose should be administered. In older or overweight patients, lower doses may be necessary.
Women may require higher doses than men, with men showing an increasing IGF-I sensitivity over time. This means that there is a risk that women, especially those on oral estrogen therapy are under-treated while men are over-treated.
In women on oral estrogen replacement, a higher dose of growth hormone may be required to achieve the treatment goal (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Method of administration.

The solution for injection should be administered subcutaneously each day in the upper arm, abdomen or thigh. The site of injection should be changed. The product is for use in one individual only.
Nutropin AQ is supplied as a sterile solution with preservative for multiple use. The solution should be clear immediately after removal from the refrigerator. If the solution is cloudy, the content must not be injected. Gently swirl. Do not shake vigorously in order not to denature the protein.
Nutropin AQ is intended for use only with the Nutropin AQ Pen. Wipe the rubber seal of the Nutropin AQ with rubbing alcohol or an antiseptic solution to prevent contamination of the contents by microorganisms that may be introduced by repeated needle insertions. It is recommended that Nutropin AQ be administered using sterile, disposable needles.
The Nutropin AQ Pen allows for administration of a minimum dose of 0.1 mg to a maximum dose of 4.0 mg, in 0.1 mg increments.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 List of Excipients).
Somatropin should not be used for growth promotion in patients with closed epiphyses.
Somatropin must not be used when there is any evidence of activity of a tumour. Intracranial lesions must be inactive and antitumour therapy must be completed prior to starting GH therapy. Treatment should be discontinued if there is evidence of tumour growth.
Growth hormone should not be initiated to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental traumas or to treat patients having acute respiratory failure.

4.4 Special Warnings and Precautions for Use

Identified precautions.

The maximum recommended daily dose should not be exceeded (see Section 4.2 Dose and Method of Administration).
In adults with growth hormone deficiency the diagnosis should be established depending on the aetiology.

Adult-onset.

The patient must have growth hormone deficiency as a result of hypothalamic or pituitary disease, and at least one other hormone deficiency diagnosed (except for prolactin). Test for growth hormone deficiency should not be performed until adequate replacement therapy for other hormone deficiencies have been instituted.

Childhood-onset.

Patients who have had growth hormone deficiency as a child should be retested to confirm growth hormone deficiency in adulthood before replacement therapy with Nutropin AQ is started.
In patients with previous malignant disease, special attention should be given to signs and symptoms of relapse.
Patients with pre-existing tumours or growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the lesion. In childhood cancer survivors, an increased risk of a second neoplasm has been reported in patients treated with somatropin after their first neoplasm. Intracranial tumours, in particular meningiomas, in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms.
Nutropin AQ is not indicated for the long-term treatment of paediatric patients who have growth failure due to genetically confirmed Prader-Willi syndrome, unless they also have a diagnosis of growth hormone deficiency. 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.
The effects of 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 accidental traumas 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) compared to those receiving placebo.
The safety of continuing somatropin treatment in patients with acute critical illness in intensive care units due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure receiving replacement doses for approved indications has not been established. Therefore, the benefit/ risk assessment for continuing treatment should be performed carefully.
Patients with growth hormone failure secondary to chronic renal insufficiency should be examined periodically for evidence of progression of renal osteodystrophy.
Paediatric patients with advanced renal osteodystrophy or endocrine disorders, including growth hormone deficiency, have a higher incidence of slipped capital femoral epiphyses and aseptic necrosis of the femoral head. Physicians and parents should be alert to the development of a limp or complaints of hip or knee pain in patients treated with Nutropin AQ. Any patient with the onset of a limp or complaint of hip or knee pain should be evaluated.
Scoliosis may progress in any child during rapid growth. Signs of scoliosis should be monitored during treatment.
Because somatropin may reduce insulin sensitivity, patients should be monitored for evidence of glucose intolerance. For patients with diabetes mellitus, the insulin dose may require adjustment after Nutropin AQ therapy is instituted. Patients with diabetes or glucose intolerance should be monitored closely during somatropin therapy. Nutropin AQ therapy is not indicated in diabetic patients with active proliferative or severe non-proliferative retinopathy.
Intracranial hypertension with papilloedema, visual changes, headache, nausea and/or vomiting has been reported in a small number of patients treated with somatropin. Symptoms usually occur within the first eight weeks of the initiation of Nutropin AQ therapy. In all reported cases, intracranial hypertension associated signs and symptoms resolved after reduction of the somatropin dose or termination of the therapy. Funduscopic examination is recommended at the initiation and periodically during the course of treatment.
Hypothyroidism may develop during treatment with somatropin and untreated hypothyroidism may prevent optimal response to Nutropin AQ. Therefore, patients should have periodic thyroid function tests and should be treated with thyroid hormone when indicated. Patients with severe hypothyroidism should be treated accordingly prior to the start of Nutropin AQ therapy.
Leukaemia has been reported in a small number of GHD patients treated with GH. A causal relationship to somatropin therapy has not been established.
Children treated with somatropin have an increased risk of developing pancreatitis compared to adults treated with somatropin. Although rare, pancreatitis should be considered in somatropin treated children who develop abdominal pain.
Since somatropin therapy following renal transplantation has not been adequately tested, Nutropin AQ treatment should be terminated after that surgery.
Concomitant treatment with glucocorticoids inhibits the growth promoting effects of somatropin. Patients with ACTH deficiency should have their glucocorticoid replacement therapy carefully adjusted to avoid any inhibitory effect on growth. The use of Nutropin AQ in patients with chronic renal insufficiency receiving glucocorticoid therapy has not been evaluated.

Use in hepatic impairment.

In patients with severe liver dysfunction a reduction in somatropin clearance has been noted. The clinical significance of this decrease is unknown.

Use in renal impairment.

Children and adults with chronic renal failure and end-stage renal disease tend to have decreased clearance compared to normal subjects. Endogenous growth hormone production may also increase in some individuals with end-stage renal disease. However, no somatropin accumulation has been reported in children with chronic renal failure or end-stage renal disease dosed with current regimens.
Limited published data for exogenously administered somatropin suggest absorption and elimination half-lives and time of maximum concentration tmax in Turner patients are similar to those observed in both normal and growth hormone deficient populations.

Use in the elderly.

Clinical studies of Nutropin AQ did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Paediatric use.

See information above (Childhood-onset) regarding paediatric use.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Effect of Nutropin AQ on other medicinal products.

Limited published data indicate that growth hormone treatment increases cytochrome P450 mediated antipyrine clearance. Monitoring is advisable when Nutropin AQ is administered in combination with drugs known to be metabolised by CYP450 liver enzymes, such as corticosteroids, sex steroids, anticonvulsants, and cyclosporin.
Introduction of somatropin treatment may result in inhibition of 11βHSD-1 and reduced serum cortisol concentrations. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. Somatropin may also render low glucocorticoid replacement doses ineffective. Patients treated with glucocorticoid replacement therapy for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses, following initiation of somatropin treatment.

Use with oral estrogen therapy.

If a woman taking somatropin begins oral estrogen therapy, the dose of somatropin may need to be increased 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 reduced to avoid excess of growth hormone and/or side effects.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

The effects of Nutropin AQ on fertility have not been assessed in animal studies. Somatropin is known to be associated with inhibition of reproduction 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 oestrous 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 1 IU/kg/day (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 adult patients.
(Category B2)
Animal reproductive studies have not been conducted with Nutropin AQ. It is not known whether Nutropin AQ can cause foetal 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 studies are not always predictive of human response, Nutropin AQ should be discontinued if pregnancy occurs.
 No study has been conducted with Nutropin AQ in breastfeeding women and it is not known whether somatropin is excreted in human milk. Following subcutaneous administration of radiolabelled recombinant human growth hormone to lactating rats, radioactivity was found in the milk reaching four times the concentration in maternal plasma. However, absorption of intact protein from the gastrointestinal tract of the infant is unlikely.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Nutropin AQ on the ability to drive and use machines have been performed. Somatropin has no known effect on the ability to drive or to use machines.
However, adverse effects of Nutropin AQ include dizziness and blurred vision which could affect the ability to drive or use machines (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

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.
The adverse reactions reported in both adults and children receiving Nutropin or Nutropin AQ are listed in Table 1 and 2, based on experience from clinical trials in all approved indications (642 patients) and a post-marketing surveillance survey (National Cooperative Growth Study [NCGS] in 35,344 patients). Approximately 2.5% of patients from the NCGS have experienced drug related adverse reactions, with most of these adverse reactions being reported in the "general disorders and administration site conditions" system organ class.
In addition, indication specific adverse reactions from the same clinical trials are text below Table 1 and 2.
Within the system organ classes, adverse reactions are listed under headings of frequency using the following categories: very common (≥ 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1000, < 1/100), rare (≥ 1/10,000, < 1/1,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Indication specific adverse drug reactions from clinical trials.

Paediatric patients.

Patients with growth failure due to inadequate growth hormone secretion (n = 236).

Common: CNS neoplasm (2 patients experienced a recurrent medulloblastoma, 1 patient experienced a histiocytoma).

Patients with growth failure associated with Turner syndrome (n = 108).

Common: menorrhagia.

Patients with growth failure associated with chronic renal insufficiency (n = 171).

Common: renal failure, peritonitis, osteonecrosis, blood creatinine increase.
Adult patients.

Adults with growth hormone deficiency (n = 127).

Very common: paraesthesia. Common: hyperglycaemia, hyperlipidaemia, insomnia, synovial disorder, arthrosis, muscular weakness, back pain, breast pain, gynaecomastia.
Patients with endocrinological disorders are more prone to develop an epiphysiolysis.
As with all recombinant proteins, a small percentage of patients may develop antibodies to the protein somatropin. The binding capacity of growth hormone antibodies was lower than 2 mg/L in Nutropin AQ subjects tested, which has not been associated with adversely affected growth rate.

4.9 Overdose

For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).
Acute overdose could lead to hyperglycaemia. Long-term overdose could result in signs and symptoms of gigantism and/or acromegaly consistent with the known effects of excess growth hormone.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: somatropin and analogues.
ATC code: H01AC01.

Mechanism of action.

Somatropin stimulates growth rate and increases adult height in children who lack endogenous growth hormone. Treatment of growth hormone deficient adults with somatropin results in reduced fat mass, increased lean body mass and increased spine bone mineral density was noted in some patient subgroups. Metabolic alterations in these patients include normalisation of insulin-like growth factor-1 (IGF-1) serum levels.
In vitro and in vivo preclinical and clinical tests have demonstrated that somatropin is therapeutically equivalent to human growth hormone of pituitary origin.

Actions that have been demonstrated for human growth hormone.

Tissue growth.

1. Skeletal growth. Growth hormone and its mediator IGF-1 stimulate skeletal growth in growth hormone deficient children by an effect on the epiphyseal plates of long bones. This results in a measurable increase in body length until these growth plates fuse at the end of puberty.
2. Cell growth. Treatment with somatropin results in an increase in both the number and size of skeletal muscle cells.
3. Organ growth. Growth hormone increases the size of internal organs, including kidneys, and increases red blood cell mass.

Protein metabolism.

Linear growth is facilitated in part by growth hormone stimulated protein synthesis. This is reflected by nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during growth hormone therapy.

Lipid metabolism.

In GH deficient patients, administration of GH resulted in lipid mobilisation, reduction in body fat stores, increased plasma fatty acids. A decrease in plasma cholesterol levels was noted in adult growth hormone deficient patients with childhood onset.

Carbohydrate metabolism.

Patients with inadequate growth hormone secretion sometimes experience fasting hypoglycaemia that is improved by treatment with somatropin. Growth hormone therapy may decrease insulin sensitivity and impair glucose tolerance.

Mineral metabolism.

Somatropin induces retention of sodium, potassium and phosphorus. Serum concentration of inorganic phosphorus are increased in patients with growth hormone deficiency after Nutropin AQ therapy due to metabolic activity associated with bone growth and increased tubular reabsorption in the kidney. Serum calcium is not significantly altered by somatropin. Adults with growth hormone deficiency show low bone mineral density and, in the childhood onset patient, Nutropin AQ has been shown to increase spine bone mineral density in a dose dependent manner.

Connective tissue metabolism.

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

Body composition.

Adult growth hormone deficient patients treated with somatropin at a mean dosage of 0.014 mg/kg/bodyweight daily demonstrate a decrease in fat mass and increase in lean body mass. When these alterations are coupled with the increase in total body water and bone mass, the overall effect of somatropin therapy is to modify body composition, an effect that is maintained with continued treatment.

Clinical trials.

Paediatric growth hormone deficiency (PGHD).

Two open label, uncontrolled multi-centre studies were performed in support of this indication. In one study, all patients (n = 67) were previously untreated and in the other study, 63 patients were previously untreated and 9 children were previously treated with Nutropin. A dose of 0.043 mg/kg/day sc was administered in both studies.
128/139 patients completed 12 months of therapy. Average treatment times were 3.2 and 4.6 years in the respective studies.
The primary efficacy variable was growth rate and in both studies there was a significant improvement in the naïve patients, increasing from 4.2 to 10.9 cm/year in one study and from 4.8 to 11.2 cm/year in the other at 12 months. The growth rate decreases after the first year in both studies, but continues to be greater than pre-treatment levels for up to 48 months treatment (7.1 cm/year). The data on height SDS improve each year over the whole period of the studies, increasing from -3.0 to -2.7 at baseline to -1.0 to -0.8 at month 36.
The predicted adult height (PAH) was also used as a descriptive measure in these studies, and it increased from 157.7 to 161.0 cm at baseline to 161.4 to 167.4 cm at month 12 and 166.2 to 171.1 cm at month 36.

Adult growth hormone deficiency (AGHD).

Two multi-centre, placebo-controlled, double-blind studies in patients diagnosed with Adult Growth Hormone Deficiency were conducted.
One study was conducted in 166 subjects with adult-onset GHD, mean age 48.3 years, at doses of 0.0125 or 0.00625 mg/kg/day.
A second study was conducted in 64 previously treated subjects with childhood onset GHD, mean age 23.8 years, at randomly assigned doses of 0.025 or 0.0125 mg/kg/day. The studies were designed to assess the effects of replacement therapy with GH on body composition and muscle strength or physical performance (co-primary endpoints).
In terms of body composition, in both studies Nutropin treatment resulted in significant changes (p < 0.0001) compared to placebo in total body % fat (-6.3 to -3.6 vs + 0.2 to -0.1), trunk % fat (-7.6 to -4.3 vs +0.6 to 0.0) and total body % lean (+3.6 to +6.4 vs -0.2 to +0.2). These changes were highly significant at the 12 month time point in both studies.
Muscle strength and physical endurance were not markedly abnormal at baseline and no statistically significant effects of Nutropin therapy were observed in the two studies.
Changes in LDL cholesterol and LDL:HDL ratio, and evaluation of bone mineral density were secondary endpoints of the studies. In the adult-onset study, significant decreases from baseline to month 12 in LDL cholesterol and LDL:HDL ratio were seen in the Nutropin group compared to the placebo group, p < 0.02. In the childhood onset study, significant decreases from baseline to month 12 in total cholesterol, LDL cholesterol and LDL:HDL ratio were seen in the high dose Nutropin group only, compared to the placebo group, p < 0.05.
No significant changes in BMD were observed in this cohort of adult-onset AGHD patients. In the childhood onset study, a special statistical analysis of the data concluded that at 24 months all groups had an increase in BMD from baseline, although there was no statistically significant dose response for total body BMD. Lumbar spine BMD had statistically significant increases in both treated groups and the increase was dose dependent.
In both studies, quality of life assessments were generally normal at baseline and did not improve through treatment.

Effects of Nutropin on growth failure associated with chronic renal insufficiency (CRI).

Data is presented from two multi-centre, controlled studies conducted for 2 years and followed by an open label uncontrolled extension. In both studies, Nutropin (formulation without polysorbate 20) at a dose of 0.05 mg/kg/day sc, was used.
128 patients received Nutropin over the 24-month controlled phase of the studies and 139 patients were treated with Nutropin in the open extension phases. The primary endpoints were growth rate and change in height SDS.
In both studies, a significant increase in growth rate compared to placebo was seen over the first 12 months treatment period (9.1 to 10.9 cm/year vs 6.2 to 6.6 cm/year), which decreased slightly in the second year (7.4 to 7.9 cm/year vs 5.5 to 6.6 cm/year). In both studies, there was also a significant increase in height SDS in the Nutropin groups in comparison to placebo or untreated group, from -2.9 SDS to -1.4 SDS at month 24 in the Nutropin group vs no change in height SDS in placebo group (-2.8 to -2.9 SDS), and from -2.9 to -1.9 SDS at month 12 in the Nutropin group vs no change in untreated group. A total of 58% and 65% of Nutropin treated patients who were below normal range at baseline had reached heights within the normal range by month 24 in the two studies.
A statistically significant increase in predicted adult height SDS was observed in the Nutropin groups of both studies, from -1.6 or -1.7 at baseline to -0.7 or -0.9 at month 24. This continued to increase in those patients treated for 36 and 48 months.
IGF-I levels, which were low in the patients recruited into the studies, were restored to within the normal range with Nutropin therapy.

Turner syndrome.

117 patients were treated in a multi-centre, open label, controlled study. 36/117 received Nutropin 0.0125 mg/kg three times a week (TIW) with an average treatment time of 4.7 years. 81/117 received 0.054 mg/kg Nutropin daily with an average treatment time of 4.6 years. Patients under 11 years of age were also randomised to receive estrogen therapy, either in late (15 years) or early (12 years) adolescence.
The primary efficacy variable was adult height. Growth rate in treated patients increased significantly from 3.6-4.1 cm/year at baseline to 6.7-8.1 cm/year at month 12, 6.7-6.8 cm/year at month 24 and 4.5-5.1 cm/year at month 48. This was accompanied by a significant increase in Turner height SDS from -0.1 to 0.5 at baseline to 0.0 to 0.7 at month 12 and 1.6 to 1.7 at month 48.
Nutropin conferred substantial increases in growth compared to historical controls in all groups. A consistently more rapid advance of bone age was seen in the early than in the late estrogen group.

5.2 Pharmacokinetic Properties

The pharmacokinetic properties of Nutropin AQ have only been investigated in healthy adult males.

Absorption.

The absolute bioavailability of recombinant human growth hormone after subcutaneous administration is about 80%.

Distribution.

Animal studies with somatropin showed that growth hormone localises to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for somatropin in healthy adult males is about 50 mL/kg bodyweight, approximating the serum volume.

Metabolism.

Both the liver and the kidney have been shown to be important protein catabolising organs for growth hormone. Animal studies suggest that the kidney is the dominant organ of clearance. Growth hormone is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation.

Excretion.

After subcutaneous bolus administration, the mean terminal half-life t1/2 of somatropin is about 2.3 hours. After intravenous bolus administration of somatropin, the mean terminal half-life t1/2β or t1/2γ is about 20 minutes and the mean clearance is reported to be in the range of 116-174 mL/hour/kg.

Pharmacokinetics in special patient populations.

Available literature data suggest that somatropin clearance is similar in adults and children.
Clearance and mean terminal half-life t1/2 of somatropin in adult and paediatric growth hormone deficient patients are similar to those observed in healthy subjects.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenicity studies have not been conducted with Nutropin AQ. In studies with other recombinant human growth hormone preparations, there was no evidence of gene mutation in bacterial reverse mutations assays, chromosomal damage in human lymphocytes and rat or mouse bone marrow cells, gene conversion in yeast or unscheduled DNA synthesis in human carcinoma cells.

Carcinogenicity.

The carcinogenicity potential of Nutropin AQ has not been investigated in long-term animal studies. 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

Sodium chloride, phenol, polysorbate 20, sodium citrate dihydrate and citric acid, water for injections.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. In the absence of compatibility studies, this 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

Store at 2°C - 8°C. Do not freeze.
Keep the container in the outer carton. Protect from light.
A cartridge that is in the pen should not be removed during injections.
Chemical and physical in use stability has been demonstrated for 28 days at 2°C - 8°C.
From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days at 2°C - 8°C. The Nutropin AQ is designed to withstand a nominal (one hour maximum) period of time outside of the refrigerator on a daily basis. Do not remove the cartridge that is being used from the Nutropin AQ Pen between injections.
After first opening, the product may be stored for up to 28 days at 2°C - 8°C.

6.5 Nature and Contents of Container

2 mL of solution in a cartridge (Type I glass) closed with a stopper (butyl rubber) and a seal (rubber). Pack sizes of 1 and 3 cartridges.

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

Chemical structure.

Somatropin is a single-chain protein of 191 amino acids with a molecular weight of 22,125 daltons. Somatropin is synthesized in a specific laboratory strain of E. coli bacteria as a precursor consisting of the rhGH molecule preceded by the secretion signal from an E. coli protein. This precursor is then cleaved in the plasma membrane of the cell. The native protein is secreted into the periplasm where it is folded appropriately. The primary and secondary structures of somatropin are identical with pituitary-derived human growth hormone.
Nutropin AQ is supplied as a sterile solution with preservative for multiple use. The solution is nearly isotonic and has a pH of approximately 6.0.

CAS number.

12629-01-5.

7 Medicine Schedule (Poisons Standard)

S4.

Summary Table of Changes