Nplate 500 micrograms powder and solvent for solution forinjection

Nplate?s active ingredient is romiplostim, which is a protein used to treat low platelet counts in patients with immune (idiopathic) thrombocytopenic purpura (called ITP). ITP is a disease in which your body?s immune system destroys its own platelets. Platelets are the cells in your blood that help seal cuts and form blood clots. Very low platelet counts can cause bruising and serious bleeding.

Nplate is used to treat adult patients (aged 18 years and over) who have had their spleen removed for chronic ITP and who have been previously treated with corticosteroids or immunoglobulins, where these treatments don?t work.

Nplate may also be used in previously treated adult patients (aged 18 years and over) with chronic ITP in whom surgery is not an option.

Nplate works by stimulating the bone marrow (part of the bone which makes blood cells) to produce more platelets. This should help to prevent bruising and bleeding associated with ITP.

DO NOT use Nplate

• if you are allergic (hypersensitive) to romiplostim or to any of the other ingredients of Nplate.
• if you are allergic to other medicines that are produced by DNA technology using the micro-organism Escherichia coli ( E. coli) .

Take special care with Nplate

• If you stop taking Nplate a low blood platelet count (thrombocytopenia) is likely to reoccur. If you stop taking Nplate your platelet count will have to be monitored, and your doctor will discuss appropriate precautions with you.
• If you are at risk of blood clots or if blood clots are common in your family. The risk of blood clotting may also be increased if you:
• have liver problems;
• are elderly;
• are bedridden;
• have cancer;
• are taking the contraceptive pill or hormone replacement therapy;
• have recently had surgery or suffered an injury;
• are obese (overweight);
• are a smoker. Please tell your doctor if any of these apply to you before taking Nplate.

If you have very high blood platelet counts this may increase the risk of blood clotting. Your doctor will adjust your dose of Nplate to ensure that your platelet count does not become too high.

Bone marrow changes (increased reticulin and possible bone marrow fibrosis)

Long-term use of Nplate may cause changes in your bone marrow. These changes may lead to abnormal blood cells or your body making less blood cells. The mild form of these bone marrow changes is called ?increased reticulin? and has been observed in Nplate clinical trials. It is not known if this may progress to a more severe form called ?fibrosis.? Signs of bone marrow changes may show up as abnormalities in your blood tests. Your doctor will decide if abnormal blood tests mean that you should have bone marrow tests or if you should stop taking Nplate.

Worsening of blood cancers

Your doctor may decide to take a bone marrow biopsy if they decide it is necessary to ensure that you have ITP, and not another condition such as MDS.

Loss of response to romiplostim

If you experience a loss of response or failure to maintain a platelet response with romiplostim treatment, you doctor will investigate the reasons why including whether you are experiencing increased bone marrow fibres (reticulin) or have developed antibodies which neutralise romiplostim?s activity.

Nplate is not recommended for use in children below age 18.

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.

If you are also taking medicines which prevent blood clots (anticoagulants or antiplatelet therapy) there is a greater risk of bleeding. Your doctor will discuss this with you.

If you are taking corticosteroids, danazol, and/or azathioprine, which you may be receiving to treat your ITP, these may be reduced or stopped when given together with Nplate.

Pregnancy and breast-feeding

It is important to tell your doctor if you are pregnant; think you may be pregnant; or plan to get pregnant. Nplate is not recommended for use if you are pregnant unless indicated by your doctor.

It is not known whether romiplostim is present in human milk. Nplate is not recommended for use if you are breast-feeding. A decision on whether to discontinue breast-feeding or discontinue therapy with romiplostim should be made taking into account the benefit of breast-feeding to your child and the benefit of romiplostim therapy to you.

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

Driving and using machines

No studies on the effects on the ability to drive and use machines have been performed. You should speak with your doctor before driving or using machines, as some side effects (e.g., temporary bouts of dizziness) may impair your ability to do so safely.

Nplate will be given under the direct supervision of your doctor, who will closely control the amount of Nplate given to you.

Nplate is administered once a week as an injection under the skin (subcutaneous).

Your initial dose is 1 microgram of Nplate per kilogram of your body weight once a week. Your doctor will tell you how much you must take. Nplate should be injected once per week in order to keep your platelet counts up. Your doctor will take regular blood samples to measure how your platelets are responding and may adjust your dose as necessary.

Once your platelet count is under control, your doctor will continue to regularly check your blood. Your dose may be adjusted further in order to maintain long-term control of your platelet count.

If you use more Nplate than you should

Your doctor will ensure that you receive the right amount of Nplate. If you have been given more Nplate than you should, you may not experience any physical symptoms but your blood platelet counts may rise to very high levels and this may increase the risk of blood clotting. Therefore if your doctor suspects that you have been given more Nplate than you should, it is recommended that you are monitored for any signs or symptoms of side effects and that you are given appropriate treatment immediately.

If you forget to use Nplate

If you have missed a dose of Nplate, your doctor will discuss with you when you should have your next dose.

If you stop using Nplate

If you stop using Nplate, your low blood platelet count (thrombocytopenia) is likely to reoccur. Your doctor will decide if you should stop using Nplate.

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

Very common side effects (seen in more than 1 in 10 people taking Nplate):

• headache.

Common side effects (seen in more than 1 in 100 people taking Nplate):

• bone marrow disorder, including increased bone marrow fibres (reticulin);
• trouble sleeping (insomnia);
• dizziness;
• tingling or numbness of the hands or feet (paraesthesia);
• migraine;
• redness of the skin (flushing);
• blood clot in a lung artery (pulmonary embolism);
• nausea;
• diarrhoea;
• abdominal pain;
• indigestion (dyspepsia);
• constipation;
• itching of the skin (pruritis);
• bleeding under the skin (ecchymosis);
• bruising (contusion);
• rash;
• joint pain (arthralgia);
• muscles pain or weakness (myalgia);
• pain in your hands and feet;
• muscle spasm;
• back pain;
• bone pain;
• tiredness (fatigue);
• injection site reactions;
• swelling in the hands and feet (oedema peripheral);
• flu like symptoms (influenza like illness);
• pain;
• weakness (asthenia);
• fever (pyrexia);
• chills;
• contusion;
• low blood platelet count (thrombocytopenia) and low blood platelet count (thrombocytopenia) after stopping Nplate;
• higher than normal platelet counts (thrombocytosis).

Uncommon side effects (seen in more than 1 in 1000 people taking Nplate):

• bone marrow failure; disorder of the bone marrow that causes scarring (myelofibrosis); enlarged spleen (splenomegaly); bleeding of the vagina (vaginal haemorrhage), bleeding in the rectum (rectal haemorrhage); bleeding mouth (mouth haemorrhage); injection site bleeding (injection site haemorrhage);
• heart attack (myocardial infarction); increased heart rate;
• dizziness or a spinning sensation (vertigo);
• problems with the eyes including: bleeding in the eye (conjunctival haemorrhage); difficulty focussing or blurred vision (accommodation disorder, papilloedema or eye disorder); blindness; itchy eye (eye pruritus); increased tears (lacrimation increased); or visual disturbances;
• problems with the digestive system including: vomiting; bad breath (breath odour); difficulty swallowing (dysphagia); indigestion or heartburn (gastro-oesophageal reflux disease); blood in the stools (haematochezia); stomach discomfort; mouth ulcers or mouth blistering (stomatitis); discoloured teeth (tooth discolouration);
• weight decreased; weight increased; intolerance of alcohol; loss of appetite (anorexia or decreased appetite); dehydration;
• generally feeling unwell (malaise); chest pain; irritability; swelling of the face (face oedema); feeling hot; increased body temperature; feeling jittery;
• influenza; localised infection; inflammation of the passages in the nose and throat (nasopharyngitis);
• problems with the nose and throat including: cough; runny nose (rhinorrhoea); dry throat; shortness of breath or difficulty breathing (dyspneoea); nasal congestion; painful breathing (painful respiration)
• painful swollen joints caused by uric acid (food breakdown product) (gout);
• muscle tightness; muscular weakness; shoulder pain; muscle twitching;
• problems with your nervous system including involuntary muscle contractions (clonus); distorted sense of taste (dysgeusia); decrease in sense of taste (hypogeusia); decreased feeling of sensitivity, especially in the skin (hypoaesthesia); alteration in the nerve functions in the arms and legs (neuropathy peripheral); blood clot in the transverse sinus (transverse sinus thrombosis);
• depression; abnormal dreams;
• hair loss (alopecia); sensitivity to light (photosensitivity reaction); acne; allergic reaction in the skin upon contact with allergen (dermatitis contact); skin manifestation with rash and blisters (eczema); dry skin; redness of the skin (erythema); severe flaking or peeling rash (exfoliative rash); abnormal hair growth; thickening and itching of the skin due to repeated scratching (prurigo); bleeding beneath the surface of the skin or bruising under the skin (purpura); bumpy skin rash (rash papular); itchy skin rash (rash pruritic); generalised itchy rash (urticaria); bump on the skin (skin nodule); abnormal smell to the skin (skin odour abnormal);
• problems with the circulation including blood clot in the vein in the liver (portal vein thrombosis); deep vein thrombosis; low blood pressure (hypotension); increased blood pressure; blocking of a blood vessel or (peripheral embolism); reduced blood flow in the hands, ankles or feet (peripheral ischaemia); swelling and clotting in a vein, which may be extremely tender when touched (phlebitis or thrombophlebitis superficial); blood clot (thrombosis).

Uncommon side effects that may show up in blood or urine tests (seen in more than 1 in 1000 people taking Nplate):

• anaemia, including a rare type of anaemia in which the red blood cells, white blood cells and platelets are all reduced in number (aplastic anaemia); raised white blood cell count (leukocytosis); excess platelet production (thrombocythaemia); increased platelet counts; abnormal count in the cells in the blood that prevents bleeding (platelet count abnormal); changes in some blood tests (increase in transaminase; blood lactate dehydrogenase increased); or cancer of white blood cells (multiple myeloma);
• protein in the urine.

Other side effects:

A rare disorder characterised by periods of burning pain, redness and warmth in the feet and hands (erythromelalgia).

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 Nplate after the expiry date which is stated on the carton and vial label after EXP. The expiry date refers to the last day of that month.

Store in a refrigerator (2° C ? 8° C).
Do not freeze.
Store in the original carton in order to protect from light.

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

What Nplate contains

• The active substance is romiplostim.

Each vial of Nplate 250 micrograms powder for solution for injection contains 250 micrograms of romiplostim. After reconstitution, a deliverable volume of 0.5 ml solution contains 250 micrograms of romiplostim (500 micrograms/ml).

Each vial of Nplate 500 micrograms powder for solution for injection contains 500 micrograms of romiplostim. After reconstitution, a deliverable volume of 1 ml solution contains 500 micrograms of romiplostim (500 micrograms/ml).

• The other ingredients are: Powder: mannitol (E421), sucrose, L-histidine, hydrochloric acid (for pH adjustment) and polysorbate 20. Solvent: water for injections.

What Nplate looks like and contents of the pack

Nplate is a white powder for solution for injection supplied in a 5 ml glass vial.

Nplate is supplied as a 1 pack or multipack comprising 4 packs. Each pack contains: 1 vial of 250 micrograms or 500 micrograms of romiplostim.
1 pre-filled syringe containing 0.72 or 1.2 ml of water for injections for reconstitution. 1 plunger rod for pre-filled syringe.
1 sterile vial adapter.
1 sterile 1 ml Luer lock syringe.
1 sterile safety needle.
4 alcohol swabs.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Amgen Europe B.V.
Minervum 7061
4817 ZK Breda
The Netherlands

For any information about this medicine, please contact the local representative of the Marketing Authorisation Holder.

BelgiëBelgiqueBelgien s.a. Amgen n.v. TelTél 32 02 7752711 LuxembourgLuxemburg s.a. Amgen BelgiqueBelgien TelTél 32 02 7752711

359 02 805 7020 Magyarország Amgen Kft. Tel. 36 1 35 44 700

eská republika Amgen s.r.o. Tel 420 2 21 773 500 Malta Amgen B.V. The Netherlands Tel 31 076 5732500

Danmark Amgen filial af Amgen AB, Sverige Tlf 45 39617500 Nederland Amgen B.V. Tel 31 076 5732500

Deutschland AMGEN GmbH Tel. 49 89 1490960 Norge Amgen AB Tel 47 23308000

Eesti Amgen Switzerland AG Vilniaus filialas Tel 372 5125 501 Österreich Amgen GmbH Tel 43 01 50 217

Amgen ... . 30 210 3447000 Polska Amgen Sp. z o.o. Tel. 48 22 581 3000

España Amgen S.A. Tel 34 93 600 19 00 Portugal AMGEN Biofarmacêutica, Lda. Tel 351 21 4220550

France Amgen S.A.S Tél 33 01 40 88 27 00 România Amgen România SRL Tel. 4021 527 3000

Slovenija AMGEN zdravila d.o.o. Tel 386 1 585 1767 Ireland Amgen Limited United Kingdom Tel 44 01223 420305

Ísland Vistor hf. Sími 354 535 7000 Slovenská republika Amgen Switzerland AG Slovakia Tel 421 33 321 13 22

Italia Amgen Dompé S.p.A. Tel 39 02 6241121 SuomiFinland Amgen AB, sivuliike SuomessaAmgen AB, filial i Finland PuhTel 358 09 54900500

K Papaellinas Co Ltd 357 22741 741 Sverige Amgen AB Tel 46 08 6951100

Latvija Amgen Switzerland AG Rgas filile Tel 371 29284 807 United Kingdom Amgen Limited Tel 44 01223 420305

Lietuva

Amgen Switzerland AG Vilniaus filialas
Tel.: +370 682 28282

This leaflet was last approved in.

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The following information is intended for medical or healthcare professionals only:

Nplate is a sterile but unpreserved product and is intended for single use only. Nplate should be reconstituted in accordance with good aseptic practice.

• Nplate 250 micrograms powder for solution for injection should be reconstituted with 0.72 ml sterile water for injections, yielding a deliverable volume of 0.5 ml. An additional overfill is included in each vial to ensure that 250 µg of romiplostim can be delivered. or
• Nplate 500 micrograms powder for solution for injection should be reconstituted with 1.2 ml sterile water for injections, yielding a deliverable volume of 1 ml. An additional overfill is included in each vial to ensure that 500 µg of romiplostim can be delivered.

Sodium chloride solutions or bacteriostatic water should not be used when reconstituting the medicinal product. Water for injections should be injected into the vial. The vial contents may be swirled gently and inverted during dissolution. The vial should not be shaken or vigorously agitated. Generally, dissolution of Nplate takes less than 2 minutes. Visually inspect the solution for particulate matter and discolouration before administration. The reconstituted solution should be clear and colourless and should not be administered if particulate matter and/or discolouration are observed.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 25°C or 24 hours in a refrigerator (2°C ? 8°C), protected from light.

Any unused product or waste material should be disposed of in accordance with local requirements.

1. Remove the plastic cap from Nplate powder vial and clean rubber stopper using the provided alcohol swab. 2. Attach vial adapter to Nplate vial by peeling off paper backing from vial adapter, keeping the vial adapter in its packaging. Keeping the vial on the bench, push the vial adapter down onto the centre of the vial until it is firmly in place. Note To prevent contamination of the product, do not touch the vial adapter spike or Luer lock. 3. Remove and discard vial adapter packaging. 4. Attach plunger rod to the pre-filled syringe of water for injections by twisting the plunger rod clockwise onto the syringe plunger, until you feel a slight resistance.

5. Holding the pre-filled syringe of water for injections with one hand, bend the tip of the white plastic cover downward with your other hand. This will break the seal of the white plastic cover. Once the seal is broken, pull cover off to separate the grey rubber cap from the clear plastic syringe tip. 6. Keeping the vial on the bench, attach the pre-filled syringe of water for injections to vial adapter hold the outer edge of the vial adapter with one hand and twist the syringe tip clockwise onto the adapter with the other hand until you feel a slight resistance. 7. Very slowly and gently expel all water into powder vial. Water should flow slowly onto powder. GENTLY swirl the vial until all of the powder has dissolved and the fluid in the vial is clear and colourless. Do not shake or agitate vial NOTE This may take up to 2 minutes for the powder to completely dissolve. Note From a microbiological point of view, the product must be used immediately after reconstitution. If reconstituted product is not used immediately, the syringe should not be removed from the vial adapter to maintain microbiological integrity. Before continuing Do visually inspect the reconstituted solution for particulate matter andor discoloration. The reconstituted solution should be clear and colourless and should not be administered if particulate matter andor discolouration are observed. Do make sure solution is fully dissolved before removing syringe. 8. Remove the empty pre-filled syringe from the vial adapter. 9. Remove 1 ml administration syringe from package. Attach the 1 ml syringe to vial adapter of reconstituted solution by twisting the syringe tip onto the vial adapter until you feel a slight resistance. 10. Turn assembled syringe-vial unit upside down, so the vial of reconstituted product is above the syringe. Withdraw all of the medicinal product solution into the administration syringe.

11. Ensure the correct amount of solution for the patient dose is in the administration syringe by expelling any excess solution back into the vial. Note Remove all air bubbles from syringe to ensure precise solution amount is in syringe. 12. Twist off administration syringe from vial adapter. Attach safety needle to the filled administration syringe by twisting needle clockwise into syringe Luer lock tip. 13. Prepare injection site with a new alcohol swab. Pull back on the pink safety cover toward the syringe and away from the needle. Remove clear needle shield from prepared needle by holding syringe in one hand and carefully pulling shield straight off with the other hand. 14. Administer subcutaneous injection following local protocols and good aseptic technique. 15. After injecting, activate the pink safety cover by pushing the cover forward using the same hand until you hear andor feel it clicklock. 16. Immediately discard syringe and needle into an approved Sharps Container.