Valtropin 5 mg/1.5 ml powder and solvent for solution forinjection

Your medicine is called Valtropin. It is a human growth hormone, also called somatropin. It has the same structure as the growth hormone that the body produces in the pituitary glands (glands located at the base of the brain). Growth hormone regulates the growth and development of cells. When it stimulates growth of cells in the long bones of the legs and spine, it causes an increase in height.

Valtropin is used

• to treat children(2 to 11 years old) and teenagers (12 to 18 years old) who do not develop to their normal height because of poor bone growth caused by growth hormone deficiency (relative lack of growth hormone), Turner syndrome, or ?chronic renal insufficiency? (a condition in which the kidneys gradually lose their ability to perform their normal functions, such as the removal of wastes and extra fluid from the body).
• to treat adults with severe growth hormone deficiency who already had growth hormone deficiency when they were children or who do not have enough growth hormone during their adult years for some other reason.

In this leaflet the patient is addressed as ?you?. Caregivers administering Valtropin to their children should consider that ?you? refers to the child.

Do not use Valtropin

• if you are allergic (hypersensitive) to somatropin or any of the other ingredients of the powder or solvent of Valtropin, e.g. metacresol (see section 2, ?Take special care with Valtropin ? Occurrence of certain side effects?)
• if you have any kind of tumour (cancer), since growth hormone will make it worse. Tumours must be inactive and anti-tumour therapy complete before growth hormone can be prescribed. If there is evidence of tumour growth, you should stop taking Valtropin.
• for growth promotion in children who have already stopped growing
• if you have had a serious heart or abdominal operation
• if you are being treated for more than one injury following a serious accident
• if you have sudden serious breathing problems

Take special care with Valtropin

Examinations before starting treatment

• A specialist doctor trained in hormone disorders must examine you to decide if it is safe to use Valtropin.
• If you have had a brain tumour a specialist doctor trained in hormone disorders must examine your pituitary function to decide if it is safe to use Valtropin.
• Before children are treated for growth hormone deficiency due to kidney problems, the doctor should observe the child for one year before starting growth hormone treatment.
• If adults have been treated with growth hormone during childhood, they should be re-evaluated for growth hormone deficiency before starting any further treatment with growth hormones.
• Patients with Prader-Willi syndrome should not be treated with Valtropin unless they are also suffering from growth hormone failure.

During or after serious illness

• If you have had a brain tumour, you should be re-examined frequently to make sure that the tumour has not come back.
• If you had cancer as a child. A higher risk for having a second tumour (benign and malignant) has been reported in patients that survived their cancer and were treated with somatropin. Of these second tumours, in particular, brain tumours were the most common.
• If children have had a kidney transplant, growth hormone treatment will be stopped.
• If the child has Turner syndrome, the child?s doctor should carefully check for ear infections such as otitis media, because Turner syndrome patients have an increased risk of ear or other hearing disorders.

Occurrence of certain side effects

• If symptoms like headache (severe and recurrent), visual changes, nausea and/or vomiting occur, please ask your doctor for advice.
• If you have injected Valtropin by mistake into the muscle instead of under the skin, your blood sugar may become too low (hypoglycaemia). Please contact your doctor for further advice.
• If the child begins to limp under treatment with Valtropin, please ask your doctor for advice.
• If you are a child and you are treated with somatropin. You have an increased risk of developing an inflammation of your pancreas (pancreatitis) compared to adults treated with somatropin. Although rare, pancreatitis should be considered in somatropin-treated children who develop abdominal pain.
• Too much growth hormone can cause greater than normal growth of ears, nose, lips, tongue and cheekbone (acromegaly), high blood sugar (hyperglycaemia) and presence of sugar in the urine (glucosuria). Always use Valtropin as recommended by your doctor.
• If an allergic reaction to solvent occurs, the vials should be reconstituted with water for injections without preservative (metacresol) and used as a single use vial (see section 5 ?How to store Valtropin?). Do not use the supplied solvent if you have a known allergy to metacresol preservative.

Monitoring during treatment by your doctor

• Valtropin may affect the way your body handles sugar from food and drink. Your doctor may check the amount of sugar in your urine or blood.
• Valtropin can affect the amount of thyroid hormone in the blood, so you must have thyroid function tests from time to time. If the thyroid is not working properly, Valtropin may not work as well as it should.

Using other medicines

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including medicines obtained without a prescription.

Tell especially your doctor if you are taking

• adrenal steroid hormone such as cortisone or prednisolone
• insulin
• oral oestrogen
• sex hormones, medicines to treat stress response or inflammation (corticosteroids), medicines to treat epilepsy (e.g. carbamazepin)or cyclosporine (a medicine to suppress the immune system). Your doctor may need to adjust the dose of Valtropin or of the other medicine.

Pregnancy

Valtropin should not be used during pregnancy unless clearly necessary. If you become pregnant, tell your doctor immediately.

Breast-feeding
If you are breast-feeding or intend to breast-feed, please ask your doctor for advice before using Valtropin.

Ask your doctor or pharmacist for advice before taking any medicines.

Driving and using machines
Valtropin has no or negligible effect on the ability to drive and use machines.

Important information about some of the ingredients of Valtropin

The accompanying solvent of Valtropin contains metacresol. Do not use this solvent if you are allergic to metacresol (see section 2, ?Do not use Valtropin?). If an allergic reaction to the solvent occurs, the vials should be reconstituted with water for injections and used as a single use vial (see section 5 ?How to store Valtropin?).

Always use Valtropin exactly as your doctor has told you. You should check with your doctor or pharmacist if you are not sure. Do not inject Valtropin yourself if you are not sure about the dose.

Dosage

Your doctor will tell you how much to use. This will vary according to your disease. Please do not change the dosage without consulting your doctor.

The accuracy of the Valtropin dose should be checked every 6 months by your doctor.

In general the dosage will be calculated as described below. However, individual doses may vary, and the doctor may change your dose based on your specific need.

Children

Growth hormone deficiency in children

Inject 0.025 - 0.035 milligrams (mg) for each kilogramme of body weight once daily under the skin (subcutaneously).

Children with Turner syndrome

Inject 0.045 - 0.050 milligrams (mg) for each kilogramme of body weight once daily under the skin (subcutaneously).

Children before puberty, who suffer from long-term kidney problems

Inject 0.045 - 0.050 milligrams (mg) for each kilogramme of body weight once daily under the skin (subcutaneously).

Adults

Growth hormone deficiency in adults

Inject 0.15 - 0.30 milligrams (mg) once daily under the skin (subcutaneously). A lower starting dose may be necessary if you are older or overweight.

If necessary, your doctor will gradually increase this dose according to your individual requirements based on the clinical outcome and measurement of your blood levels of a so called ?growth factor? (known as IGF-1). The total daily dose usually does not exceed 1 mg. IGF-1 concentrations need to be regularly measured and should be maintained below the upper limit of the normal range for your age and sex.

Your doctor will always prescribe the minimum effective dose to be used.

Dosage adjustment

In elderly patients a dose reduction may be necessary.

The dosage of somatropin should be reduced in cases of long lasting swelling (oedema) or severe abnormal sensation (paresthesia), in order to avoid the development of a rare side effect called carpal tunnel syndrome (hand numbness and pain).

Following use of the medicine for some time, it may be necessary to reduce the dose, particularly in men.

When using other medicines the dose of Valtropin or of the other medicine may need to be adjusted (see section 2, ?Using other medicines?).

Administration

Valtropin is intended for subcutaneous use after reconstitution. This means that after reconstitution of the powder with the solvent provided the solution is injected with a short needle into the fatty tissue just under the skin.

If you are injecting this medicine yourself you will be instructed how to prepare and give the injection.

Do not inject Valtropin yourself unless you have received training.

Detailed instructions for subcutaneous administration are provided with this leaflet (see section ?Information on how to self-inject Valtropin? at the end of this leaflet).

If you use more Valtropin than you should
In case more Valtropin was used than recommended, please consult your doctor.

If you have used too much Valtropin, initially your blood sugar may decrease and become too low (hypoglycaemia) and subsequently increase and become too high (hyperglycaemia). If you have used too much Valtropin over a longer period, this may result in a greater than normal growth of ears, nose, lips, tongue and cheekbone (acromegaly).

If you forget to use Valtropin
Do not take a double dose to make up for forgotten doses. Continue with the prescribed dosage regimen. If you have any doubts, please contact your doctor.

If you stop using Valtropin

Please ask your doctor for advice before stopping treatment. Interruption or early stopping of treatment with Valtropin may impair the success of the growth hormone therapy.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Like all medicines, Valtropin can cause side effects, although not everybody gets them.

The side effects of medicines are classified as follows:

very common affects more than 1 user in 10 common affects 1 to 10 users in 100 uncommon affects 1 to 10 users in 1,000 rare affects 1 to 10 users in 10,000 very rare affects less than 1 user in 10,000 not known Frequency cannot be estimated from the available data

You may experience any of the following side effects after administration of Valtropin:

Very common Headache in adults Abnormal sensation, such as pricking, tingling, or itchiness paresthesia in adults Joint pain arthralgia in adults Tissue swelling caused by accumulation of fluid in tissue oedema in adults Common Development of proteins that bind other substances antibody building Underactive thyroid gland hypothyroidism Impaired ability to reduce sugar levels glucose tolerance Mild increase of blood sugar levels mild hyperglycaemia 1 in children 1 - 10 in adults Abnormal increase of muscle tone hypertonia Sleeplessness insomnia in adults Increased blood pressure hypertension in adults Shortness of breath dyspnoea in adults Temporary interruption of breathing during sleep sleep apnoea in adults Numbness and tingling in fingers and palm of the hand due to squeezed nerve at hand wrist carpal tunnel syndrome in adults Joint pain arthralgia in children Muscle pain myalgia Tissue swelling caused by accumulation of fluid in tissue oedema in children Injection site reactions, weakness asthenia Uncommon Increased growth of new tissue cancer, neoplasm Lack of red blood cells anaemia Too little sugar in the blood hypoglycaemia, Blood phosphate level above normal hyperphosphatemia

Personality disorder Rapid uncontrollable movement of the eyes nystagmus Swelling of the optic nerve head papilloedema Double vision diplopia Dizziness vertigo Accelerated heart beat tachycardia Vomiting Stomach pain abdominal pain, wind flatulence Nausea Fat tissue decrease lipodystrophy, thinning of the skin skin atrophy, inflammation and peeling of skin exfoliative dermatitis, swelling similar to after insect stings urticaria, increased growth of male type hair on a womans body hirsutism, thickening of skin tissue skin hypertrophy Decrease in the muscle mass muscle atrophy, bone pain Numbness and tingling in fingers and palm of the hand due to squeezed nerve at hand wrist carpal tunnel syndrome in children Involuntary loss of urine urinary incontinence, blood in the urine haematuria, passing more urine than normal polyuria, pollakiuria, abnormal urine Genital discharge Enlargement of the male breast gland gynaecomastia in adults Injection site reactions like thinning of skin tissue, a copious discharge of blood from the blood vessels, thickening Weakness in children Rare Sugar disease diabetes mellitus Nerve disorder outside the brain and spinal cord neuropathy, increased pressure in the skull intracranial pressure increased High blood pressure in the skull benign intracranial hypertension Abnormal sensation of the skin, such as pricking, tingling and itchiness paresthesia in children Increased blood pressure hypertension in children Diarrhoea Abnormal results in kidney function tests Very rare Sleeplessness insomnia in children Enlargement of the male breast gland gynaecomastia in children Frequency not known Single case of acute allergic reaction involving itching and swelling similar to insect stings and itching Severe reduction of insulin effects insulin resistance

In patients with adult-onset growth hormone deficiency swelling, muscle pain, joint pain and disorders have been reported early in therapy with somatropin but these effects tended to be transient (short-lived).

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

• Keep out of the reach and sight of children.
• Do not use Valtropin after the expiry date which is stated on the labels and the carton after EXP. The expiry date refers to the last day of that month.

Storage conditions of the unopened medicine

• Store in a refrigerator (2°C - 8°C). Do not freeze.
• The non-reconstituted medicine can be kept at room temperature (not above 25°C) for one single period of up to 4 weeks before use.

Shelf-life after reconstitution with solvent

• After reconstitution with the solvent provided the medicine may be stored in the refrigerator (2°C - 8°C) for a maximum of 21 days.

Shelf-life after reconstitution with water for injections (NOT tap water)

• After reconstitution with water for injections the medicine must be used immediately and as a single use vial.

Do not use Valtropin if you notice that the solvent or the reconstituted solution is cloudy or discoloured or if contains particulate matters.

Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to dispose of medicines that are no longer required. These measures will help to protect the environment.

What Valtropin contains

Powder:

• The active substance is somatropin. One vial of powder contains 5 mg somatropin (corresponding to 15 IU). After reconstitution with 1.5 ml solvent, 1 ml contains 3.33 mg somatropin (corresponding to 10 IU).
• The other ingredients are glycine, mannitol, sodium phosphate monobasic, sodium phosphate dibasic and for pH (acidity) adjustment sodium hydroxide and hydrochloric acid.

Solvent:

• The pre-filled syringe contains water for injections and metacresol (see section 2, ?Important information about some of the ingredients of Valtropin?).

What Valtropin looks like and contents of the pack

Valtropin is presented as a powder and solvent for solution for injection.

One pack contains:

• 5 mg of white to almost white powder in a glass vial closed with a rubber stopper and a cap
• 1.5 ml of solvent in a pre-filled syringe closed with a tip cap, for reconstitution as a clear solution.

Marketing Authorisation Holder and Manufacturer

BioPartners GmbH
Kaiserpassage 11
D-72764 Reutlingen
Germany
Tel: +49 (0) 7121 948 7756
Fax: +49 (0) 7121 346 255

This leaflet was last approved in {MM/YYYY}

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INFORMATION ON HOW TO SELF-INJECT Valtropin

Please read the following instructions carefully before using Valtropin.

Introduction
The following instructions explain how to inject Valtropinyourself. Please read the instructions carefully and follow them step by step. Your doctor or his/her assistant will instruct you how to self-inject Valtropin. Do not attempt to inject yourself unless you are sure you understand the procedure and requirements of self-injection.

General notes

For patients with a known allergy to metacresol, Valtropin should not be reconstituted with the supplied solvent (see section 2, ?Do not use Valtropin?). If allergy to the accompanying solvent occurs, the vials should be reconstituted with water for injections: please fill a syringe with 1.5 ml of water for injections and follow the same instructions as for the pre-filled syringe (see section 5 ?How to store Valtropin?). Do not use tap water.

Collect the necessary items before you begin. These are:
Supplied in the pack

• the Valtropinvial with powder for solution for injection
• the pre-filled syringe with 1.5 ml solvent for solution for injection NOT supplied in the pack
• sterile injection syringe and needles
• alcohol swabs
• dry gauze or cotton pad
• an adhesive plaster
• disposal box for used syringes and needles.

Preparing the solution

1. Wash your hands thoroughly with soap and water before preparing the medicine.

2. Take the Valtropin carton out of the refrigerator and take the powder vial and pre-filled syringe with solvent out of the box. Check that the medicine is within the expiry date.

3. Remove the protective plastic cap from the powder vial.

4. Clean the rubber stopper on the top of the powder vial with an alcohol swab. After cleaning do not touch the top of the vial.

Vial containing the powder of your medicine

5. Take the pre-filled syringe with solventsupplied in the pack to prepare your medicine. Remove the rubber tip cap and firmly attach a needle to the syringe. Your doctor or his/her assistant will tell you what size of needle to use.

6. Remove the needle guard without touching the needle.

7. Slowly insert the needle straight through the centre of the rubber stopper of the vial.

8. Slowly inject all of the solvent (1.5 ml) into the powder vial aiming the stream of liquid against the side of the vial. DO NOT aim it at the white powder at the bottom of the vial.

Before taking the syringe out of the vial, draw in the same amount of air (1.5 ml) as the solvent you injected to reduce the pressure in the vial. Withdraw the syringe and replace the needle guard.

9. Swirl the vial GENTLY to completely dissolve the contents. DO NOT SHAKE.

Dissolving up your medicine

10. The resulting solution should be clear, without particles.

11. Label the vial with the date on which you prepared the solution.

Preparing the injection

12. Clean the rubber stopper on the top of the vial with an alcohol swab again. After cleaning do not touch the top of the vial.

Vial containing the solution of your medicine

13. Take the injection syringe and the needle supplied by your pharmacy or hospital, to withdraw the solution of medicine. Remove the injection syringe from its sterile packaging and attach the needle to the syringe.

14. Fill the syringe with air by pulling the plunger back to the level that represents your dose as prescribed by your doctor.

15. Remove the needle guard without touching the needle.

16. Slowly insert the needle straight through the centre of the rubber stopper of the vial.

17. Gently push the plunger to discharge the air in the syringe into the vial.

18. Turn the vial upside down with the needle still in it and hold the vial in one hand. Hold the syringe with the needle in the vial pointing up. Ensure that the tip of the needle is in the solution. Using your other hand slowly pull back the plunger in a continuous motion to draw the correct dose into the syringe ensuring that the needle tip remains in the solution.

Withdrawing the right volume of your medicine with the help of the syringe markings

19. Remove the syringe from the needle leaving the needle in the vial without touching the tip of the syringe. Withdraw the needle, replace the needle guard and dispose in a closed container. For handling the vial see ?Injecting the solution?, step 32.

20. Take a new needle (one that is suitable for subcutaneous injection) and place it firmly onto the tip of the syringe.

Syringe containing your medicine being attached to a new needle

21. Remove the needle guard from the syringe needle and check for air bubbles in the syringe.

22. If you see any bubbles, pull the plunger slightly back; tap the syringe gently, with the needle pointing up, until the bubbles disappear. Push the plunger slowly back up to the correct dose.

23. Replace the needle guard and place the syringe with the needle on a flat surface.

Injecting the solution

24. Ensure the solution is at room temperature. If the solution is cold, warm the syringe between your palms.

25. Inspect the solution prior to administration: if the solution is discoloured or if you can see any solid particles in the liquid the solution MUST NOT be injected.

26. Select the injection site according to the recommendation of your doctor. It is very important that you vary the injection site each time you give the medicine.

27. Cleanse the injection site with an alcohol swab and wait for the area to dry.

28. Check that the correct dose of Valtropin solution is in the syringe. Hold the syringe in your hand as you would hold a pencil.

29. Squeeze a big skin fold between your thumb and index finger. Insert the needle into the pinched skin at a 45° to 90° angle with a quick, firm motion. This hurts less than pushing the needle in slowly.

30. Slowly (over a few seconds) inject the solution by gently depressing the plunger until the syringe is empty.

31. Withdraw the needle quickly and apply pressure over the injection site with a dry gauze or cotton pad for several seconds. If there is bleeding, cover the injection site with an adhesive plaster.

32. Dispose the used syringe in a closed container. Be sure to return the vial to the refrigerator. When empty, discard the vial as well. For shelf-life after reconstitution see section 5 ?How to store Valtropin?. If the powder is reconstituted with water for injections, then the vial is for single use only. Any unused solution should be discarded.

ANNEX IV

GROUNDS FOR ONE ADDITIONAL RENEWAL

GROUNDS FOR ONE ADDITIONAL RENEWAL

Based upon the data that have become available since the granting of the initial Marketing Authorisation, the CHMP considers that the benefit-risk balance of Valtropin remains positive, but considers that its safety profile is to be closely monitored for the following reasons:

Valtropin was approved in the EU on 24 April 2006, and was placed on the market in Germany on 6 January 2009. The placing on the market was temporarily ceased as of 1 June 2009 for economical reasons. 5 packs of Valtropin were sold in total during the 6 months of marketing in the EU. No post-authorisation adverse events have been reported thus far.

Therefore, in view of the very limited post-marketing safety data available for Valtropin, the CHMP is of the opinion that one additional five-year renewal on the basis of pharmacovigilance grounds is required.