Consumer medicine information

Humatrope

Somatropin

BRAND INFORMATION

Brand name

Humatrope

Active ingredient

Somatropin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Humatrope.

What is in this leaflet

This leaflet is designed to provide you with answers to some common questions about this medicine. It does not contain all the available information and does not take the place of talking with your doctor.

The information in this leaflet was last updated on the date shown on the final page. More recent information on this medicine may be available. Make sure you speak to your pharmacist, nurse or doctor to obtain the most up to date information on this medicine. You can also download the most up to date leaflet from www.lilly.com.au. The updated leaflet may contain important information about HUMATROPE and its use that you should be aware of.

All medicines have risks and benefits. Your doctor has more information about this medicine than is contained in this leaflet. Also, your doctor has had the benefit of taking a full and detailed history from you and is in the best position to make an expert judgement to meet your individual needs.

If you have any concerns about using this medicine, talk to your doctor or health care professional.

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

What HUMATROPE is used for

HUMATROPE is a biosynthetic human growth hormone. It is used in children who do not produce enough natural growth hormone, in girls who have Turner syndrome, in children with chronic renal insufficiency, and children born small for gestational age. HUMATROPE helps these children to grow at a natural rate.

HUMATROPE is also used in adults who do not produce enough natural growth hormone. In adults, HUMATROPE helps to decrease body fat, in growth hormone deficient adults only.

Your doctor may have prescribed HUMATROPE for another reason.

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

Before using HUMATROPE

A doctor who is experienced in the diagnosis and management of patients who do not produce enough natural growth hormone should direct your treatment with HUMATROPE.

Tell your doctor if you have any of the following conditions or if you have ever experienced any of these conditions.

When you must not use HUMATROPE

You must not use HUMATROPE if you have an active tumour (cancer). However, your doctor may prescribe HUMATROPE if you have had a brain tumour and need no further treatment for it. You should be re-examined frequently to make sure that the tumour does not return.

You must not use HUMATROPE cartridges if you are allergic to meta-Cresol or glycerol. Signs of an allergic reaction may include skin rash, itching, shortness of breath or swelling of the face, lips or tongue.

HUMATROPE should not be used for growth promotion in children if their bones have finished growing (closed epiphyses).

You must not use HUMATROPE if you have a dangerous and severe illness due to complications from open heart surgery or stomach surgery, multiple accidental trauma or if you have severe breathing failure.

HUMATROPE should not be used if you have diabetic retinopathy (diabetic eye disease).

You must not use HUMATROPE if the packaging is torn, or the cartridges show signs of tampering.

You must not use HUMATROPE after the expiry date printed on the pack.

If you are not sure whether you should start using HUMATROPE, talk to your doctor or health care professional.

Before you use HUMATROPE

Tell your doctor if you have allergies to:

  • any other medicines
  • any other substances such as foods, preservatives or dyes.

Tell your doctor if you are a diabetic or require insulin treatment. More or less insulin may be needed when using HUMATROPE.

Tell your doctor if you suffer headaches and blurred vision.

Tell your doctor if you have lower than normal levels of adrenocorticotropic hormone (ACTH). Less glucocorticoid therapy may be needed when using HUMATROPE.

Tell your doctor if you have had a brain tumour. You should be examined frequently to make sure that the tumour does not return.

Tell your doctor if you intend to have or have had a kidney transplant. You should stop using HUMATROPE at the time of kidney transplantation.

Treatment with HUMATROPE in children with chronic renal insufficiency should be started only after growth disturbance has been confirmed over a period of at least one year.

Tell your doctor if you have Prader-Willi Syndrome (a condition in children with symptoms of floppiness, obesity, small hands and feet and mental retardation).

Tell your doctor if you have scoliosis (curvature of the spine that can develop during periods of rapid growth).

Tell your doctor if you are pregnant or intend to become pregnant.

Tell your doctor if you are breast-feeding or plan to breast-feed. It is not known whether HUMATROPE passes into breast milk.

Tell your doctor about these things before you use HUMATROPE.

Taking other medicines

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

Some medicines may be affected by HUMATROPE or may affect how it works. These include:

  • cortisone medicines (such as prednisone and anti-asthma inhalers like Becotide®). Combining cortisone medicines with HUMATROPE may reduce the effect of HUMATROPE.
  • orally taken estrogen
  • sex steroids, cyclosporine and some anticonvulsants.

These medicines may be affected by HUMATROPE, or may affect how well it works. You may need to use different amounts of your medicine, or you may need to use different medicines. Your doctor will advise you.

Your doctor or health care professional may have more information on medicines to be careful with or to avoid while using HUMATROPE.

How to use HUMATROPE

Carefully follow all directions given to you by your doctor or health care professional. These may differ from the information contained in this leaflet.

HUMATROPE is given by injection under the skin (subcutaneous) or into a muscle (intramuscular).

It is important to use a different injection site every day. Repeated injections into the same site can cause wasting of fat under the skin or a hardened bump in the skin.

You will be taught to mix and inject HUMATROPE using the HUMATROPE injection device. It is a good idea to refer to the instruction sheet each time you mix and inject HUMATROPE.

How much to use

Your doctor or health care professional will tell you how much HUMATROPE you must use each week.

To gain the best result, it is very important to use HUMATROPE exactly as instructed.

If possible, give the injection in the evening. Normally, the body makes growth hormone at night. Giving the injection at night helps to copy this process.

How long do I use it

Do not stop using HUMATROPE without checking with your doctor.

If you forget to inject it

If you forget to inject HUMATROPE, talk with your doctor or nurse.

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

If you inject too much (Overdose)

If you think that you or anyone else has injected too much HUMATROPE, immediately telephone your doctor or the Poisons Information Centre (13 11 26), or go to Accident and Emergency at your nearest hospital. Do this even if there are no signs of discomfort or poisoning.

If you inject too much HUMATROPE, you may experience sweating, confusion, vomiting, hunger, faintness and dizziness which are all associated with low blood sugar levels.

While you are using HUMATROPE

Things you must do

Tell all doctors and health care professionals who are treating you that you are using HUMATROPE.

If you are about to be started on any new medicine, tell your doctor or health care professional that you are using HUMATROPE.

Tell your doctor if you become pregnant while you are using HUMATROPE.

Change the site of injection every day.

Standard treatment for kidney failure should be continued during treatment with HUMATROPE in children with chronic renal insufficiency.

Things you must not do

Do not give HUMATROPE to anyone else, even if their symptoms seem similar to yours or they have the same condition as you. Your doctor has prescribed HUMATROPE for you and for your condition.

Do not stop using HUMATROPE without checking with your doctor.

Side effects

Tell your doctor or health care professional as soon as possible if you do not feel well while using HUMATROPE.

Like other medicines, HUMATROPE may cause some unwanted side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you experience some of these side effects.

Ask your doctor or health care professional to answer any questions you may have.

Tell your doctor if you notice any of the following side effects and they worry you:

  • mild, temporary swelling
  • skin reactions at the site of injection
  • pain at the site of injection
  • headache
  • weakness
  • localised muscle pain
  • swelling of the hands, ankles or feet
  • back pain, uneven shoulder height or uneven leg length
  • earache
  • 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 (hypothyroidism)
  • tingling or numbness of the hands or feet
  • carpal tunnel syndrome
  • difficulty breathing
  • insomnia (trouble falling asleep or staying asleep)
  • in men, an increase in the size of breast tissue.

Symptoms of high blood sugar levels such as:

  • passing large amounts of urine
  • excessive thirst
  • dry mouth and skin.

Tell your doctor immediately if you notice any of the following:

  • a limp while walking
  • severe or recurrent headache, problems with your eyesight, feeling sick and/or vomiting
  • tiredness, fever, dizziness, looking pale and bone and joint pain.

These side effects are serious and may need urgent medical attention.

Other side effects not listed above may occur in some patients.

Tell your doctor or health care professional if you notice anything that is making you feel unwell.

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

Tell your doctor if you notice anything unusual or if you are concerned about any aspect of your health, even if you think the problems are not connected with this medicine and are not referred to in this leaflet.

After injecting HUMATROPE

Storage

HUMATROPE cartridges and diluent must not be FROZEN or HEATED above room temperature (25°C) at any time.

Store HUMATROPE cartridges and diluent in the refrigerator (2°C to 8°C). They must not be FROZEN.

After the contents of the HUMATROPE cartridge have been mixed with the diluent, it must be stored in a refrigerator at 2°C to 8°C. DO NOT FREEZE.

If any reconstituted product in the HUMATROPE cartridge remains after 28 days, it should be discarded.

Do not keep the mixed HUMATROPE in plastic syringes.

All medicines should be kept where young children cannot reach them.

There will be an expiry date (month, year) on your HUMATROPE container.

The medicine should not be used after this date because it may have lost some of its strength.

Disposal

Empty HUMATROPE cartridges and any needles and syringes should be disposed of in a 'sharps' container or similar puncture proof container composed of hard plastic or glass.

Ask your doctor or nurse where you can dispose of the container once it is full.

When you are approved for HUMATROPE treatment, your supply of cartridges will be sent every three months.

Inform your doctor or nurse of the number of unused cartridges you have remaining when you are due for this new supply.

Do not throw away any unused cartridges.

Product Description

What it looks like

HUMATROPE is a powder and is available in the following strengths:

  • Cartridges of 6 mg (18 IU) with a 3.17 mL diluent syringe. When reconstituted with the diluent provided the cartridge contains Somatropin 2.07 mg/mL.
  • Cartridges of 12 mg (36 IU) with a 3.15 mL diluent syringe. When reconstituted with the diluent provided the cartridge contains Somatropin 4.17 mg/mL.
  • Cartridges of 24 mg (72 IU) with a 3.15 mL diluent syringe. When reconstituted with the diluent provided the cartridge contains Somatropin 8.46 mg/mL.

Ingredients

The active ingredient in HUMATROPE is somatropin (rbe or recombinant growth hormone). It is produced in a laboratory.

Inactive ingredients:

  • mannitol
  • glycine
  • sodium phosphate dibasic
  • phosphoric acid and/or sodium hydroxide.

The diluent contains:

  • meta-cresol
  • glycerol
  • water for injections.

Supplier

HUMATROPE is a product of:

Eli Lilly Australia Pty Ltd
Level 9, 60 Margaret Street
Sydney NSW 2000

Australian Registration Numbers:

HUMATROPE 6 mg (18 I.U.) - AUST R 53423

HUMATROPE 12 mg (36 I.U.) - AUST R 53365.

HUMATROPE 24 mg (72 I.U.) - AUST R 53364

This leaflet was revised in November 2023.

vA2

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Humatrope

Active ingredient

Somatropin

Schedule

S4

 

1 Name of Medicine

Humatrope (somatropin).

2 Qualitative and Quantitative Composition

Humatrope is a highly purified preparation and is available in cartridges containing 6 mg (18 IU*), 12 mg (36 IU*), or 24 mg (72 IU*) somatropin and when reconstituted with the diluent provided the cartridge contains 2.07 mg/mL, 4.17 mg/mL or 8.46 mg/mL somatropin, respectively. Each cartridge also contains the inactive ingredients: mannitol, glycine and dibasic sodium phosphate heptahydrate and is supplied with an accompanying diluent. The diluent contains water for injections, metacresol and glycerol (see Section 6.5 Nature and Contents of Container; Section 6.4 Special Precautions for Storage). The glycerol in the diluent ensures the tonicity of the reconstituted product is within acceptable ranges. Reconstituted solutions have a pH of approximately 7.5.
*The specific activity of the international standard for somatropin is defined as 3 International Units per mg of protein. Humatrope is now labelled based on a specific activity of 3 IU/mg and was formerly labelled based on a specific activity of 2.7 IU/mg.

3 Pharmaceutical Form

Humatrope is a sterile, white, lyophilised powder intended for subcutaneous or intramuscular administration after reconstitution.

4 Clinical Particulars

4.1 Therapeutic Indications

Humatrope is indicated for the long-term treatment of children who have growth failure due to inadequate secretion of normal endogenous growth hormone.
Humatrope is also indicated for the treatment of growth disturbances associated with gonadal dysgenesis (Turner syndrome).
Humatrope is also indicated for the treatment of adults with severe growth hormone deficiency defined as patients with known hypothalamic-pituitary pathology and at least one known deficiency of a pituitary hormone not being prolactin. These patients should undergo a single dynamic test in order to diagnose or exclude a growth deficiency.
In patients with childhood onset isolated GH deficiency, no evidence of hypothalamic-pituitary disease or cranial irradiation, two dynamic tests should be recommended, except for those having low IGF-I concentrations ≤ 2 SDS who may be considered for one test. The cut off point of the dynamic test should be strict.
Humatrope is also indicated for the treatment of growth retardation in prepubertal children with 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 glomerular filtration rate of less than 30 mL/min/1.73 m2.
Humatrope is also indicated for the treatment of growth failure in children born small for gestational age (SGA) who fail to demonstrate catch-up growth by age two to four years (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

The dosage and administration schedule for Humatrope should be individualised for each patient.

Dosage.

Children with endogenous growth hormone deficiency.

The dosage and administration schedule for Humatrope should be individualised for each patient. Generally, the recommended weekly dosage is 0.177 - 0.255 mg/kg (0.53 - 0.765 IU/kg) of bodyweight. The maximal replacement weekly dosage is 0.26 mg/kg (0.78 IU/kg) of bodyweight. It should be divided into equal doses given on 3 alternate days, 6 times per week or daily. The subcutaneous route of administration is preferable; intramuscular injection is also acceptable.

Girls with Turner syndrome.

The recommended weekly or daily dosage is shown in Table 1. The weekly dosage should be divided into 6 to 7 subcutaneous injections to be administered, preferably in the evening.
The optimal concurrent sex steroid therapy has not been determined. In clinical studies (see Section 5.1 Pharmacodynamic Properties, Clinical trials), ethinyloestradiol was commenced at age 13 at 2.5 microgram per day, was increased to 5.0 microgram per day at age > 14 and increased to 20 microgram per day plus medroxyprogesterone acetate 10 mg cyclically at age 15.

Small for gestational age.

The recommended dosage is 0.033 to 0.067 mg/kg bodyweight per day given as a subcutaneous injection. Very short children (i.e. height SDS < -3) and/or older pubertal children: it is recommended to start treatment with larger doses of somatropin (e.g. 0.067 mg/kg/day), and to reduce the dosage gradually towards 0.033 mg/kg/day if substantial catch-up growth is observed during the first few years of therapy. Younger SGA children (e.g. approximately < 4 years) with less severe short stature (baseline height SDS values between -2 and -3): it is recommended to start treatment at a lower dose (e.g. 0.033 mg/kg/day) and titrate the dose as needed over time. In all children, clinicians should carefully monitor the growth response, and adjust the somatropin dose as necessary.

Adult patients.

Either a nonweight based or a weight based dosing regimen may be followed, with doses adjusted based on treatment response, side effects and serum insulin-like growth factor I (IGF-I) concentrations. Dose requirements may decline with increasing age and may differ between male and female patients.
The dosage of somatropin should be decreased in cases of persistent oedema or severe paraesthesia, in order to avoid the development of carpal tunnel syndrome.
Nonweight based dosing: A starting dose of approximately 0.2 mg/day (range, 0.15 - 0.30 mg/day) may be used without consideration of bodyweight, and increased gradually every 1-2 months by increments of approximately 0.1 - 0.2 mg/day.
Weight based dosing: The recommended starting dosage is not more than 0.006 mg/kg (6 microgram/kg) daily. The dosage may be increased according to individual patient requirements to a maximum of 0.0125 mg/kg (12.5 microgram/kg) daily.

Elderly patients.

Elderly patients may be more sensitive to the action of Humatrope and, therefore, may be more prone to develop adverse effects. A lower starting dose and smaller dose increments should be considered for older patients.

Prepubertal children with growth retardation secondary to chronic renal insufficiency.

The recommended dose is 0.045 mg/kg - 0.050 mg/kg (approximately 0.14 IU/kg) of bodyweight per day, given as a daily subcutaneous injection.

Obese patients.

Obese individuals are more likely to manifest adverse effects when treated with a weight based regimen.

Administration.

Each Humatrope cartridge should be reconstituted using the accompanying diluent syringe. See Reconstitution Instruction Leaflet for comprehensive directions on Humatrope cartridge reconstitution.
The resulting solution should be clear, without particulate matter. If the solution is cloudy or contains particulate matter, the contents must not be injected.
The cartridges have been designed for use only with the Humatrope injection device. The diluent syringe is for single use only. Discard it after use. A sterile needle should be used for each administration of Humatrope.

4.3 Contraindications

Humatrope should not be used when there is any evidence of activity of a tumour. Intracranial lesions must be inactive and antitumour therapy completed prior to the institution of somatropin therapy. Humatrope should be discontinued if there is evidence of tumour growth.
Humatrope cartridges should not be used if the patient is allergic to metacresol or glycerol.
Humatrope should not be used for growth promotion in children with closed epiphyses.
Humatrope 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).
Somatropin is contraindicated in patients with active proliferative or severe nonproliferative diabetic retinopathy.

4.4 Special Warnings and Precautions for Use

The effects of somatropin 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 trauma or who were having acute respiratory failure. Mortality was higher (41.9 % vs. 19.3%) among somatropin treated patients (doses 5.3 - 8 mg/day) compared to those receiving placebo. The safety of continuing somatropin in patients receiving replacement doses for approved indications who concurrently develop these illnesses has not been established. Therefore, the potential benefit of treatment continuation in patients having acute critical illnesses should be weighed against the potential risk.
Cartridges should be reconstituted only with the supplied diluent. Cartridges should not be reconstituted with any other solution.
If injected subcutaneously, the injection sites should be rotated to minimise the risk of lipoatrophy.
Myositis is a very rare adverse event that may be related to the preservative metacresol. In the case of myalgia or disproportionate pain at the injection site, myositis should be considered. Cartridges should not be used if the patient is allergic to metacresol or glycerin.
Therapy with Humatrope should be directed by physicians who are experienced in the diagnosis and management of paediatric patients with growth disorders or adult patients with growth hormone deficiency.
Experience with prolonged treatment in adults is lacking.
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 who were treated with somatropin for growth hormone deficiency during childhood until attainment of final (adult) height should be re-evaluated for growth hormone deficiency after epiphyseal closure and before replacement therapy is commenced at the doses recommended for adults.

Paediatric use.

For paediatric patients, treatment should be continued until the end of the growth has been reached. It is advisable not to exceed the recommended dosage in view of the potential risks of acromegaly, hyperglycaemia and glucosuria.
Girls with Turner syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear or hearing disorders.

Intracranial lesion.

Patients with growth hormone deficiency secondary to an intracranial lesion should be examined frequently for progression or recurrence of the underlying disease process.

Abnormal glucose metabolism and diabetes mellitus.

Because somatropin may induce a state of insulin resistance, patients who receive somatropin should be observed for evidence of abnormal glucose metabolism and/or diabetes mellitus. New onset type 2 diabetes mellitus has been reported in children and adults receiving somatropin. Patients with diabetes mellitus who receive concomitant somatropin may require adjustment of their doses of insulin and/or other antihyperglycaemic agents.

Glucocorticoid replacement therapy.

If glucocorticoid replacement therapy is required, glucocorticoid dosage and compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of growth promoting effects. In patients treated with somatropin, previously undiagnosed secondary hypoadrenalism may be unmasked and such patients may require glucocorticoid replacement therapy.

Hypopituitarism/ hypothyroidism.

In patients with hypopituitarism (multiple pituitary hormone deficiencies), standard hormonal replacement therapy should be monitored closely when somatropin therapy is administered. Hypothyroidism may develop during treatment with human growth hormone and inadequate treatment of hypothyroidism may prevent optimal response to human growth hormone. Therefore, patients should have periodic thyroid function tests and be treated with thyroid hormone when indicated.

Intracranial hypertension.

In cases of severe or recurrent headache, visual problems, nausea and/or vomiting, fundoscopy for papilloedema is recommended. If papilloedema is confirmed, a diagnosis of benign intracranial hypertension should be considered and, if appropriate, somatropin 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.

Fluid retention.

Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention are usually transient and dose dependent.

Slipped capital epiphysis.

Patients with endocrine disorders, including growth hormone deficiency, may develop slipped capital epiphyses. Any child with the onset of a limp during growth hormone therapy should be evaluated.

Children born SGA.

In short children born SGA other medical reasons or treatments that could explain growth disturbance should be ruled out before starting treatment.
In children born SGA it is recommended to measure fasting plasma insulin and blood glucose before start of treatment and annually thereafter. In patients with increased risk for diabetes mellitus (e.g. familial history of diabetes, obesity, severe insulin resistance, acanthosis nigricans) oral glucose tolerance testing (OGTT) should be performed. If overt diabetes occurs growth hormone should not be administered until the patient has been stabilised for diabetes care. Then growth hormone may be introduced with careful monitoring of the diabetic metabolic control. An increase in insulin dosage may be required.
In children born SGA it is recommended to measure the plasma IGF-I concentration level before the start of treatment and twice a year thereafter. If on repeated measurements IGF-I levels exceed +2 SD compared to references for sex, age and pubertal status, the IGF-I/ IGFBP-3 ratio should be taken into account to consider dose adjustment.
Initiating Humatrope treatment in children born SGA near onset of puberty is not recommended because of limited experience.

Chronic renal insufficiency.

Before instituting treatment with Humatrope for growth retardation secondary to chronic renal insufficiency, patients should have been followed for one year to verify growth disturbance. Conservative treatment for renal insufficiency should have been established and should be maintained during treatment. Treatment with Humatrope should be discontinued at the time of renal transplantation.

Prader-Willi syndrome.

There have been reports of sleep apnoea and sudden death in paediatric patients with Prader-Willi syndrome receiving somatropin treatment who had one or more of the following risk factors: severe obesity, history of upper airway obstruction or sleep apnoea, or unidentified respiratory infection. In patients with growth hormone deficiency who also have Prader-Willi syndrome, physicians should consider the benefit/ risk ratio when prescribing somatropin. Humatrope is not indicated in patients who have Prader-Willi syndrome.

Secondary neoplasms in survivors of childhood cancer.

In childhood cancer survivors, an increased risk of a second neoplasm (benign and malignant) has been reported in patients treated with somatropin. Intracranial tumors, in particular meningiomas in patients treated with radiation to the head for their first neoplasm, were the most common of these second neoplasms. However, in childhood cancer survivors, no increased risk of primary cancer recurrence has been reported with somatropin treatment.
Because children with certain rare genetic causes of short stature have an increased risk of developing malignancies, practitioners should thoroughly consider the risks and benefits of starting somatropin in these patients. If treatment with somatropin is initiated these patients should be carefully monitored for development of neoplasms.
Monitor patients receiving somatropin therapy carefully for increased growth, or potential malignant changes, of pre-existing nevi.

Pancreatitis in children.

Children treated with somatropin may 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.

Progression of scoliosis in paediatric patients.

Progression or initial identification of scoliosis is often apparent in children during periods of rapid growth. As somatropin increases growth rate, patients with scoliosis who are treated with somatropin should be monitored for progression.

Use in the elderly.

Elderly patients may be more sensitive to the action of Humatrope and therefore may be more prone to develop adverse effects.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Gender differences have been demonstrated in responsiveness to GH by GH deficient adults, with women requiring higher doses than men to achieve similar IGF-I responses, an effect that is accentuated by oral estrogen replacement in women. Orally administered estrogen suppresses GH dependent IGF-I production in the liver. In a study, women taking oral estrogen required higher doses of GH to achieve acceptable IGF-I concentrations than did age matched men or women using transdermal estrogen. It has also been demonstrated that GH requirements are significantly higher for GH deficient women receiving estrogen replacement (primarily by the oral route) than for eugonadal GH deficient women.
Estrogen replete women, whether premenopausal or postmenopausal, may need higher doses than men. Oral estrogen administration may increase the dose requirements of Humatrope in women.
Somatropin can increase cytochrome P450 (CYP) enzyme activity in humans and may result in reduced plasma concentrations and decreased effectiveness of drugs metabolised by CYP3A such as sex steroids, cyclosporine and some anticonvulsants.
Patients with diabetes mellitus who receive concomitant somatropin may require adjustment of their doses of insulin and/or other antihyperglycaemic agents.
If glucocorticoid replacement therapy is required, glucocorticoid dosage and compliance should be monitored carefully to avoid either adrenal insufficiency or inhibition of growth promoting effects. In patients treated with somatropin, previously undiagnosed secondary hypoadrenalism may be unmasked, and such patients may require glucocorticoid replacement therapy.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Studies in animals have not been conducted to assess the effect of Humatrope on fertility.
(Category B2)
Animal reproduction studies have not been conducted with Humatrope. It is not known whether Humatrope can cause foetal harm when administered to a pregnant woman or can affect reproductive capacity. Somatropin should be given to a pregnant woman only if clearly needed.
 There have been no studies conducted with Humatrope in nursing mothers. It is not known whether Humatrope is excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when somatropin is administered.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse effects identified from clinical trials.

Paediatric patients. In clinical trials in growth hormone deficient patients, approximately 2% of the patients developed antibodies to growth hormone. Nevertheless, even these patients had expected increases in linear growth and other beneficial effects of human growth hormone and did not have any unusual side effects. Although growth limiting antibodies have been observed with other growth hormone preparations (including products of pituitary origin), antibodies in patients treated with Humatrope have not limited growth. The long-term implications of antibody development are uncertain at this time.
In addition to an evaluation of compliance with the treatment program and of thyroid status, testing for antibodies to human growth hormone should be carried out in any patient who fails to respond to therapy.

Common (≥ 1% and < 10%).

A mild and transient oedema, which appeared in 2.5% of patients, was observed early during the course of treatment. Progression of scoliosis, injection site pain and hypersensitivity to the diluent (metacresol/ glycerine) have also been reported.

Uncommon (≥ 0.1% and < 1%).

Lipoatrophy has been reported following subcutaneous injection of human growth hormone. Cases of hyperglycaemia have also been reported.

Rare (≥ 0.01% and < 0.1%).

Some rare cases of benign intracranial hypertension and localised muscle pain have been reported.

Very rare (< 0.01%).

Gynaecomastia and insomnia has been reported very rarely in paediatric patients.
Girls with Turner syndrome.

Very common (≥ 10%).

Hypothyroidism occurred in 13.5% of patients with Turner syndrome receiving Humatrope. This was not statistically significantly different from patients who received no treatment.

Common (≥ 1% and < 10%).

Peripheral oedema occurred in 6.8% of patients with Turner syndrome receiving Humatrope. This was not statistically significantly different from patients who received no treatment.
Adult patients.

Very common (≥ 10%).

In the first 6 months of controlled blinded trials, adult onset growth hormone deficient adults experienced a statistically significant increase in oedema (Humatrope 17.3% vs placebo 4.4%, p = 0.043) and peripheral oedema (11.5% vs 0% respectively, p = 0.017).
In patients with adult onset growth hormone deficiency, oedema, muscle pain, joint pain and joint disorder were reported early in therapy and tended to be transient or responsive to dosage titration.

Common (≥ 1% and < 10%).

Localised muscle pain, paraesthesias, gynaecomastia, insomnia, carpal tunnel syndrome and hyperglycaemia have been reported.

Uncommon (≥ 0.1% and < 1%).

In clinical studies in which high doses of Humatrope were administered to healthy adult volunteers, the following events have occurred infrequently: headache, weakness and glucosuria.

Adverse effects identified from spontaneous postmarketing surveillance.

Paediatric patients.

Uncommon (≥ 0.1% and < 1%).

Type 2 diabetes mellitus has been reported.
Leukaemia has been reported in a small number of children who have been treated with growth hormone of pituitary origin, somatrem and Humatrope. The relationship, if any, between leukaemia and growth hormone therapy is uncertain.
Adult patients.

Common (≥ 1% and < 10%).

Respiratory system: dyspnoea, sleep apnoea. Vascular system: hypertension.
Adult cases of type 2 diabetes mellitus have been reported spontaneously.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 131 126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Linear growth. Humatrope stimulates linear growth in children who lack adequate normal endogenous growth hormone, in children with short stature in association with Turner syndrome and in prepubertal children with growth retardation secondary to chronic renal insufficiency.
In vitro, preclinical and clinical testing have demonstrated that Humatrope is therapeutically equivalent to human growth hormone of pituitary origin and achieves equivalent pharmacokinetic profiles in normal adults. The bioavailability of Humatrope is slightly greater when given by the subcutaneous route than by the I.M. route. Treatment of growth hormone deficient children and children with Turner syndrome with Humatrope produces increased growth rate and IGF-1 (insulin-like growth factor/ somatomedin-C) concentrations that are similar to those seen after therapy with human growth hormone of pituitary origin.
In addition, the following actions have been demonstrated for Humatrope and/or human growth hormone of pituitary origin.

A. Tissue growth.

1. Skeletal growth. Humatrope stimulates skeletal growth in patients with growth hormone deficiency, in patients with Turner syndrome and in prepubertal children with growth retardation secondary to chronic renal insufficiency. The measurable increase in body length after administration of either Humatrope or human growth hormone of pituitary origin results from an effect on the growth plates of long bones. Concentrations of IGF-1, which may play a role in skeletal growth, are low in the serum of growth hormone deficient children but increase during treatment with Humatrope. Elevations in mean serum alkaline phosphatase concentrations are also seen.
2. Cell growth. It has been shown that there are fewer skeletal muscle cells in short statured children who lack endogenous growth hormone as compared with normal children. Treatment with human growth hormone of pituitary origin results in an increase in both the number and size of muscle cells.

B. Protein metabolism.

Linear growth is facilitated in part by increased cellular protein synthesis. Nitrogen retention, as demonstrated by decreased urinary nitrogen excretion and serum urea nitrogen, follows the initiation of therapy with human growth hormone of pituitary origin. Treatment with Humatrope results in a similar decrease in serum urea nitrogen.

C. Carbohydrate metabolism.

Children with hypopituitarism sometimes experience fasting hypoglycaemia that is improved by treatment with Humatrope. Large doses of human growth hormone may impair glucose tolerance.

D. Lipid metabolism.

In growth hormone deficient patients, administration of human growth hormone of pituitary origin has resulted in lipid mobilisation, reduction in body fat stores and increased plasma fatty acids.

E. Mineral metabolism.

Retention of sodium, potassium and phosphorus is induced by human growth hormone of pituitary origin. Serum concentrations of inorganic phosphate increased in patients with growth hormone deficiency after therapy with Humatrope or human growth hormone of pituitary origin. Serum calcium is not significantly altered in patients treated with either human growth hormone of pituitary origin or Humatrope.

Clinical trials.

Turner syndrome.

In a randomised study to evaluate the efficacy of growth hormone for the treatment of patients with short stature due to Turner syndrome, 75 growth hormone treated patients were compared to a concurrent control group of 65 patients who received no growth hormone. The study was of open, randomised, parallel group design and compared Humatrope to no treatment (a placebo was not used). Ethinyloestradiol was commenced at age 13 and medroxyprogesterone acetate added at age 15. Patients were followed up to final height, achievement of which was defined by bone age > 14 years and growth velocity < 2 cm/year. A total of 27 patients in the Humatrope treated group and 19 patients in the untreated group were analysed as having completed the protocol. The Humatrope treated group, who received a dose of 0.3 mg/kg/week (given 6 times per week) from a mean age of 11.7 years for a mean duration of 4.7 years, attained a mean near final height of 146.0 ± 6.2 cm (n = 27, mean ± SD) as compared to the control group who attained a near final height of 142.1 ± 4.8 cm (n = 19). By analysis of covariance1, the effect of growth hormone therapy was a mean height increase of 5.4 cm (p = 0.001). The study did not define the optimal dose, optimal age to commence therapy or optimise cotherapy with other hormonal therapy.
1Analysis of covariance includes adjustments for baseline height relative to age and for midparental height.

Adult replacement therapy.

Two multicentre trials in adult onset growth hormone deficiency (n = 98) and two studies in childhood onset growth hormone deficiency (n = 67) were designed to assess the effects of replacement therapy with Humatrope. The primary efficacy measures were body composition (lean body mass and fat mass), lipid parameters and the Nottingham Health Profile. The Nottingham Health Profile is a general health related quality of life questionnaire. These four studies each included a 6 month randomised, blinded, placebo controlled phase followed by 12 months of open label therapy for all patients. The Humatrope dosages for all studies were identical: one month of therapy at 0.00625 mg/kg/day followed by the proposed maintenance dose of 0.0125 mg/kg/day.
Adult onset patients and childhood onset patients differed by diagnosis (organic versus idiopathic pituitary disease), body size (normal versus small for mean height and weight) and age (mean = 44 versus 29 years). Lean body mass was determined by bioelectrical impedance analysis (BIA), validated with potassium 40. Body fat was assessed by BIA and sum of skinfold thickness. Lipid subfractions were analysed by standard assay methods in a central laboratory.
Humatrope treated adult onset patients, as compared to placebo, experienced an increase in lean body mass (2.59 versus -0.22 kg, p < 0.001) and a decrease in body fat (-3.27 versus 0.56 kg, p < 0.001). Similar changes were seen in childhood growth hormone deficient patients. These significant changes in lean body mass persisted throughout the 18 month period as compared to baseline for both groups, but for fat mass only in the childhood onset group. A decrease in the waist/ hip ratio was seen in the adult, but not the child onset group. Some increase in body fat mass was seen in both studies during the second six months of treatment. Total cholesterol decreased short-term (first 3 months) although the changes did not persist. However, the low HDL cholesterol levels observed at baseline (mean 0.78 mmol/L and 0.88 mmol/L in adult onset and childhood onset patients) normalised by the end of 18 months of therapy (a change of 0.35 and 0.29 mmol/L for the adult onset and childhood onset groups, p < 0.001). Adult onset patients reported significant improvements as compared to placebo in the following 2 of 6 possible health related domains: physical mobility and social isolation. Patients with childhood onset disease failed to demonstrate improvements in Nottingham Health Profile outcomes. Placebo treated patients also improved against baseline scores. No long-term morbidity or mortality data are available.

Prepubertal children with growth retardation secondary to chronic renal insufficiency.

A total of 28 prepubertal children (5 female, 23 male) with growth retardation secondary to chronic renal insufficiency were enrolled in an open label, uncontrolled study to assess the efficacy and safety of treatment with Humatrope 0.057 mg/kg (0.17 IU/kg) per day. Twenty five children received Humatrope for one year, 16 for two years and six for five years. Mean treatment duration was 2.9 years. The mean chronological age at baseline was 9.1 ± 3.2 years (range: 2.3 to 14.3 years). Efficacy was primarily assessed from changes from baseline in height standard deviation scores (SDS) and height velocity. Height was increased throughout Humatrope therapy with a progressive increase in height SDS at each yearly timepoint assessed. Sixteen children completed two years of therapy and gained a mean of 1.12 ± 0.60 height SD units. Six children completed five years of therapy and gained a mean of 1.83 ± 0.80 height SD units. Overall, for patients included in the efficacy analyses, the mean increase in height SDS at the last measurement of Humatrope therapy was 1.16 ± 0.77 from baseline (95% CI: 0.84 to 1.47, p < 0.001). Height velocity increased at 2 years by a mean of 6.59 ± 2.82 SD units and at 5 years, by a mean of 6.42 ± 2.64 SD units. Overall, for patients included in the efficacy analyses, the mean increase in height velocity SDS at the last measurement of Humatrope therapy was 5.02 ± 3.17 from baseline (95% CI: 3.72 to 6.33, p < 0.001). All of these changes were highly statistically significant. There are no studies of the use of Humatrope following renal transplantation.

Paediatric patients born small for gestational age (SGA) who fail to demonstrate catch-up growth by age 2-4 years.

Data from 2 clinical trials demonstrate the effectiveness of Humatrope in promoting linear growth in short children born SGA who fail to demonstrate catch-up growth.
The primary objective of study 1 was to demonstrate that the increase from baseline in height SDS after 1 year of treatment would be similar when Humatrope is administered according to an individually adjusted dose (IAD) regimen or a fixed high dose (FHD) regimen. The height increases would be considered similar if the lower bound of the 95% confidence interval (CI) for the mean difference between the groups (IAD-FHD) was greater than -0.5 height SDS. This 2 year, open label, multicenter, European study enrolled 193 prepubertal, non-GH deficient children with mean chronological age 6.8 ± 2.4 years (range: 3.0 to 12.3). Additional study entry criteria included birthweight < 10th percentile and/or birth length SDS < -2 for gestational age, and height SDS for chronological age ≤ -3. Exclusion criteria included syndromal conditions (e.g. Turner syndrome), chronic disease (e.g. diabetes mellitus), and tumor activity. Children were randomised to either a FHD (0.067 mg/kg/day (0.47 mg/kg/week); n = 99) or an IAD treatment group (n = 94). The initial Humatrope dosage in the IAD treatment group was 0.035 mg/kg/day (0.25 mg/kg/week). The dosage was increased to 0.067 mg/kg/day in those patients in the IAD group whose 1 year height gain predicted at month 3 was < 0.75 height SDS (n = 40) or whose actual height gain measured at year 1 was < 0.75 height SDS (n = 11). Approximately 85% of the randomised patients completed 2 years of therapy.
At baseline, the FHD and IAD treatment groups had comparable height SDS (mean -3.9; Table 2). Although the mean 1 year height increase in the IAD group was statistically significantly lower than that observed in the FHD group, the study achieved its primary objective by demonstrating that the increase from baseline in height SDS in the IAD group was clinically similar (noninferior) to that in the FHD group (mean between group difference = -0.3 SDS (95% CI: -0.4, -0.2 SDS)). The mean changes from baseline in height SDS at the end of the 2 year study were 1.4 and 1.6 SDS in the IAD and FHD groups, respectively. The results were similar when children who entered puberty during the study were removed from the analysis. See Table 2.
Study 2 was an open label, multicenter, single arm study conducted in France, during which 35 prepubertal, non-GH deficient children were treated for 2 years with Humatrope 0.067 mg/kg/day (0.47 mg/kg/week). Mean chronological age at baseline was 9.3 ± 0.9 years (range: 6.7 to 10.8). Additional study entry criteria included birth length SDS < -2 or < 3rd percentile for gestational age, and height SDS for chronological age < -2. Exclusion criteria included syndromal conditions (e.g. Turner syndrome), chronic disease (e.g. diabetes mellitus), and any active disease. All 35 patients completed the study. Mean height SDS increased from a baseline value of -2.7 (SD 0.5) to -1.5 (SD 0.6) after 2 years of Humatrope treatment.
These studies were not designed as dose finding studies, nor were they designed to capture quality of life measures.
Some of the height gain obtained with treating short children born SGA with growth hormone may be lost if treatment is stopped before reaching final height.

5.2 Pharmacokinetic Properties

A dose of 100 micrograms (0.27 IU**)/kg to adult male volunteers will give a peak serum level (Cmax) of about 55 nanogram/mL, a half-life (t1/2) of nearly four hours and maximal absorption (AUC(0 to ∞)) of about 475 nanogram.hour/mL.

5.3 Preclinical Safety Data

Genotoxicity.

Somatropin showed no evidence of mutagenic activity in bacterial or mammalian cells and showed no activity in an assay for DNA damage in rodent hepatic cells.

Carcinogenicity.

Associations between elevated serum IGF-1 concentrations and risks 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

For full list of excipients, see Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Before reconstitution.

Each Humatrope cartridge is stable for 3 years when refrigerated between 2°-8°C. The diluent syringes are stable for 3 years when stored below 30°C. Avoid freezing diluent for Humatrope.

After reconstitution.

Each Humatrope cartridge is stable for up to 28 days when reconstituted with diluent for Humatrope and refrigerated between 2° to 8°C. Avoid freezing reconstituted Humatrope. Daily room temperature exposure should not exceed 30 minutes after reconstitution.

6.5 Nature and Contents of Container

Each Humatrope cartridge contains 6 mg (18 IU), 12 mg (36 IU) or 24 mg (72 IU) of human growth hormone and when reconstituted with the diluent provided the cartridge contains 2.07 mg/mL, 4.17 mg/mL or 8.46 mg/mL somatropin respectively The cartridge also contains the inactive ingredients mannitol, glycine and dibasic sodium phosphate. Phosphoric acid and/or sodium hydroxide may have been added at the time of manufacture to adjust the pH. The 6 mg cartridge is supplied in a combination package with an accompanying 3.17 mL syringe of diluting solution, and the 12 mg and 24 mg with an accompanying 3.15 mL syringe of diluting solution. The diluent contains water for injections with metacresol (0.3% for 6 mg, 12 mg and 24 mg diluent) as a preservative and glycerol (1.7% for 6 mg and 0.29% for 12 mg and 24 mg diluent).

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.

Humatrope (somatropin, rbe, for injection) is a polypeptide hormone of recombinant DNA origin. Humatrope has 191 amino acid residues and a molecular weight of about 22,125 daltons. The amino acid sequence of the peptide is identical to that of human growth hormone of pituitary origin. Humatrope is synthesised in a strain of Escherichia coli that has been modified by the addition of the gene for human growth hormone.
The biological effects of Humatrope are equivalent to human growth hormone of pituitary origin.

CAS number.

CAS No.: 12629-01-5.

7 Medicine Schedule (Poisons Standard)

Prescription Medicine.

Summary Table of Changes