NPLATE 500 micrograms POWDER FOR INJECTABLE SOLUTION

2. What you need to know before you use Nplate

Do not use Nplate

• if you are allergic to romiplostim or any of the other ingredients of this medicine (listed in section 6).
• if you are allergic to other medicines produced by DNA technology using the microorganism Escherichia coli(E. coli).

Warnings and precautions

• If you stop taking Nplate, it is likely that you will have low platelet counts again (thrombocytopenia). If you stop taking Nplate, your platelet count will need to be monitored, and your doctor will discuss the necessary precautions with you.
• If you are at risk of blood clots or if blood clots are common in your family. The risk of blood clots may also be increased if:

• you have liver problems;
• you are an elderly person (≥ 65 years);
• you are bedridden;
• you have cancer;
• you are taking birth control pills or hormone replacement therapy;
• you have recently undergone surgery or have had an injury;
• you are obese (overweight);
• you are a smoker.

Talk to your doctor, pharmacist, or nurse before you start using Nplate.

If you have a very high platelet count, you may be at increased risk of blood clots. Your doctor will adjust your dose of Nplate to make sure that your platelet count is not too high.

Changes in the bone marrow (increase in reticulin and possible fibrosis in the bone marrow)

Long-term use of Nplate may cause changes in your bone marrow. These changes may lead to abnormal blood cells or a lower number of blood cells being produced. A mild form of these changes in the bone marrow is called "increase in reticulin" and has been seen in clinical trials of Nplate. It is not known whether this could progress to a more severe form called "fibrosis". Abnormalities may appear in your blood tests that indicate changes in the bone marrow. Your doctor will decide whether an abnormal blood test means that a bone marrow test should be done or whether Nplate treatment should be stopped.

Worsening of blood cancer

Your doctor may decide to do a bone marrow biopsy if they think it is necessary to make sure that you have ITP and not another disease such as Myelodysplastic Syndrome (MDS). If you have MDS and receive Nplate, you may have an increase in blast cell count and worsening of MDS up to progression to acute myeloid leukemia, which is a type of blood cancer.

Loss of response to romiplostim

If you lose response to romiplostim or are unable to maintain a platelet response during treatment with romiplostim, your doctor will investigate the reasons, including whether you have an increase in bone marrow fibers (reticulin) or whether you have developed antibodies that neutralize the activity of romiplostim.

Children and adolescents

Nplate is not recommended for use in children under 1 year of age.

Other medicines and Nplate

Tell your doctor or pharmacist if you are using, have recently used, or might use any other medicines.

If you are also taking other medicines that prevent blood clots (anticoagulant or antiplatelet treatment), there is a higher 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, you may need to reduce or stop their administration when combined with Nplate.

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine. Nplate should not be used during pregnancy unless your doctor considers it necessary.

It is not known whether romiplostim is excreted in human milk. Nplate should not be used during breastfeeding. The decision to stop breastfeeding or stop romiplostim treatment should be made taking into account the benefits of breastfeeding for the baby and the benefits of romiplostim treatment for the mother.

Driving and using machines

Ask your doctor before driving or using machines, as some of the side effects (e.g., temporary episodes of dizziness) may affect your ability to perform these activities safely.

3. How to use Nplate

Adults and children (from 1 to 17 years):

Nplate must be administered under the direct supervision of a doctor who can accurately control the amount of Nplate administered.

Nplate is given once a week by injection under the skin (subcutaneously).

The initial dose is 1 microgram of Nplate per kilogram of body weight once a week. Your doctor will tell you how much Nplate you should use. Nplate should be injected once a week to maintain platelet counts. Your doctor will regularly take blood samples to evaluate how your platelets are responding and adjust the dose if necessary.

Once your platelet count is under control, your doctor will continue to perform regular blood tests. Your dose may be adjusted later to maintain long-term control of your platelet count.

Children (from 1 to 17 years): in addition to adjusting the dose based on platelet counts, your doctor will also regularly review your weight to adjust your dose.

If you use more Nplate than you should

Your doctor will make sure you receive the right amount of Nplate. If you have received more Nplate than you should, you may not have any physical symptoms, but your blood platelet levels may become very high, and this may increase the risk of blood clots. Therefore, if your doctor suspects that you have received more Nplate than you should, it is recommended that you be monitored for any signs or symptoms of side effects and that you receive appropriate treatment immediately.

If you use less Nplate than you should

Your doctor will make sure you receive the right amount of Nplate. If you have received less Nplate than you should, you may not have any physical symptoms, but your blood platelet levels may become low, and this may cause a risk of bleeding. Therefore, if your doctor suspects that you have received less Nplate than you should, it is recommended that you be monitored for any signs or symptoms of side effects and that you receive appropriate treatment immediately.

If you forget to use Nplate

If you miss a dose of Nplate, your doctor will tell you when you should receive the next dose.

If you stop using Nplate

If you stop using Nplate, you are likely to have low platelet counts again (thrombocytopenia). Your doctor will decide whether you should stop taking Nplate.

4. Possible side effects

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

Possible side effects in adults with ITP

Very common: may affect more than 1 in 10 people

• headache;
• allergic reaction;
• upper respiratory tract infection.

Common: may affect up to 1 in 10 people

• alteration in the bone marrow, including increase in bone marrow fibers (reticulin);
• difficulty sleeping (insomnia);
• dizziness;
• tingling or numbness of the hands or feet (paresthesia);
• migraine;
• flushing;
• blood clot in a pulmonary artery (pulmonary embolism);
• nausea;
• diarrhea;
• abdominal pain;
• indigestion (dyspepsia);
• constipation;
• itching of the skin (pruritus);
• bleeding under the skin (ecchymosis);
• bruising (contusion);
• skin rash;
• joint pain (arthralgia);
• muscle pain or weakness (myalgia);
• pain in hands and feet;
• muscle spasms;
• back pain;
• bone pain;
• fatigue;
• reaction at the injection site;
• swelling in the hands and feet (peripheral edema);
• flu-like symptoms;
• pain;
• weakness (asthenia);
• fever (pyrexia);
• chills;
• bruising;
• swelling of the face, lips, mouth, tongue, or throat that can cause difficulty swallowing or breathing (angioedema);
• gastroenteritis;
• palpitations;
• inflammation of the sinuses (sinusitis);
• inflammation of the airways (bronchitis);
• blood clotting (thrombosis).

Common: may affect up to 1 in 10 people (may be seen in blood or urine tests)

• low platelet count in the blood (thrombocytopenia) and low platelet count in the blood (thrombocytopenia) after stopping treatment with Nplate;
• high platelet count (thrombocytosis);
• anemia.

Uncommon: may affect up to 1 in 100 people

• alteration of the bone marrow; bone marrow disorder that causes scarring (myelofibrosis); enlargement of the spleen (splenomegaly); vaginal bleeding (vaginal hemorrhage), rectal bleeding (rectal hemorrhage); mouth bleeding (oral hemorrhage); bleeding at the injection site (hemorrhage at the injection site);
• heart attack (myocardial infarction); increased heart rate;
• dizziness or spinning sensation (vertigo);
• eye problems including: bleeding in the eyes (conjunctival hemorrhage); difficulty focusing or blurred vision (visual accommodation disorder, papilledema, or eye disorder); blindness; itching of the eyes (ocular pruritus); increased tearing (increased lacrimation); or visual disturbances;
• digestive system problems including: vomiting; bad breath (halitosis); difficulty swallowing (dysphagia); indigestion or stomach acid (gastroesophageal reflux disorder); blood in the stool (hematochezia); stomach upset; mouth ulcers or mouth blisters (stomatitis); tooth discoloration (tooth discoloration);
• weight loss; weight gain; alcohol intolerance; loss of appetite (anorexia or decreased appetite); dehydration;
• general feeling of being unwell (malaise); chest pain; irritability; facial swelling (facial edema); feeling of warmth; increased body temperature; feeling nervous;
• flu; localized infection; inflammation of the nasal passages and throat (nasopharyngitis);
• nose and throat problems including: cough; runny nose (rhinorrhea); dry throat; shortness of breath or difficulty breathing (dyspnea); nasal congestion; painful breathing (painful respiration);
• joint pain and swelling caused by uric acid (gout);
• muscle stiffness; muscle weakness; shoulder pain; muscle contractions;
• nervous system problems including: involuntary muscle contractions (clonus); distorted sense of taste (dysgeusia); decreased sense of taste (hypogeusia); decreased sensitivity, especially in the skin (hypoesthesia); nerve problems in the arms and legs (peripheral neuropathy); blood clot in the transverse sinus (transverse sinus thrombosis);
• depression; abnormal dreams;
• hair loss (alopecia); sensitivity to light (photosensitivity reaction); acne; allergic skin reaction to contact with allergens (contact dermatitis); skin manifestations with rash and blisters (eczema); dry skin; redness of the skin (erythema); severe scaling or blistering skin rash (exfoliative rash); abnormal hair growth; thickening and itching of the skin from repeated scratching (prurigo); bleeding under the skin surface or bruising under the skin (purpura); skin rash with itching (papular rash); skin rash with itching (pruriginous rash); generalized itching rash (urticaria); lump on the skin (skin nodule); abnormal skin odor (abnormal skin odor);
• circulation problems including: blood clots in the liver vein (portal vein thrombosis); low blood pressure (hypotension); high blood pressure; blockage of a blood vessel (peripheral embolism); reduced blood flow in the hands, ankles, or feet (peripheral ischemia); swelling and clotting in a vein, which can be extremely soft to the touch (superficial thrombophlebitis or phlebitis); blood clotting (thrombosis);
• a rare condition characterized by periods of burning pain, redness, and warmth in the hands and feet (erythromelalgia).

Uncommon: may affect up to 1 in 100 people (may be seen in blood or urine tests)

• a rare type of anemia in which the red blood cells, white blood cells, and platelets are reduced in number (aplastic anemia);
• increase in the number of white blood cells (leukocytosis);
• excess production of platelets (thrombocythemia); increase in platelet count; abnormal platelet count;
• abnormalities in some blood tests (increased transaminases; increased lactate dehydrogenase in the blood);
• blood cancer (multiple myeloma);
• proteins in the urine.

Possible side effects in children with ITP

Very common: may affect more than 1 in 10 people

• upper respiratory tract infection;
• pain in the mouth and throat (oropharyngeal pain);
• itching, runny nose, or stuffy nose (rhinitis);
• cough;
• pain in the upper abdomen;
• diarrhea;
• rash;
• fever (pyrexia);
• bruising (contusion).

Common: may affect up to 1 in 10 people

• gastroenteritis;
• sore throat and discomfort when swallowing (pharyngitis);
• eye inflammation (conjunctivitis);
• ear infection;
• inflammation of the sinuses (sinusitis);
• swelling in the limbs, hands/feet;
• bleeding under the skin surface or bruising under the skin (purpura);
• itchy rash (urticaria).

Uncommon: may affect up to 1 in 100 people

• high platelet count (thrombocytosis).

Reporting of side effects

If you experience any side effects, talk to your doctor, pharmacist, or nurse. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Nplate

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date which is stated on the carton and on the label of the vial after EXP. The expiry date refers to the last day of the month shown.

Store in a refrigerator (between 2°C and 8°C).

Do not freeze.

Store in the original package to protect from light.

When stored in the original package, this medicine can be out of the refrigerator for a maximum of 30 days at room temperature (up to 25°C).

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

6. Container Contents and Additional Information

Nplate Composition

• The active ingredient is romiplostim.

Each vial of Nplate 125 micrograms powder for injectable solution contains a total of 230 micrograms of romiplostim. An additional volume has been added to each vial to ensure that 125 micrograms of romiplostim can be administered. After dissolution, a final product volume of 0.25 ml of solution contains 125 micrograms of romiplostim (500 micrograms/ml).

Each vial of Nplate 250 micrograms powder for injectable solution contains a total of 375 micrograms of romiplostim. An additional volume has been added to each vial to ensure that 250 micrograms of romiplostim can be administered. After dissolution, a final product volume of 0.5 ml of solution contains 250 micrograms of romiplostim (500 micrograms/ml).

Each vial of Nplate 500 micrograms powder for injectable solution contains a total of 625 micrograms of romiplostim. An additional volume has been added to each vial to ensure that 500 micrograms of romiplostim can be administered. After dissolution, a final product volume of 1 ml of solution contains 500 micrograms of romiplostim (500 micrograms/ml).

• The other components are mannitol (E421), sucrose, L-histidine, hydrochloric acid (for pH adjustment), and polysorbate 20.

Product Appearance and Container Contents

Nplate is a white powder for injectable solution supplied in a single-dose glass vial.

Each container contains 1 or 4 vials of 125 micrograms (beige cap), 250 micrograms (red cap), or 500 micrograms (blue cap) of romiplostim.

Only certain pack sizes may be marketed.

Marketing Authorization Holder and Manufacturer

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

Netherlands

Marketing Authorization Holder

Amgen Europe B.V.

Minervum 7061

4817 ZK Breda

Netherlands

Manufacturer

Amgen Technology (Ireland) Unlimited Company

Pottery Road

Dun Laoghaire

Co Dublin

Ireland

Manufacturer

Amgen NV

Telecomlaan 5-7

1831 Diegem

Belgium

For further information on this medicinal product, please contact the local representative of the marketing authorization holder.

Date of Last Revision of this Leaflet

Other Sources of Information

Detailed information on this medicinal product is available on the European Medicines Agency website http://www.ema.europa.eu

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This information is intended for healthcare professionals only:

Reconstitution:

Nplate is a sterile product without preservatives and is intended for single use. Nplate should be reconstituted following aseptic practice guidelines.

• Nplate 125 micrograms powder for injectable solutionshould be reconstituted with 0.44 ml of sterile water for injectable preparations to produce a final volume of 0.25 ml. Each vial contains an additional amount to ensure that 125 µg of romiplostim can be administered (see table below for vial contents).

• Nplate 250 micrograms powder for injectable solutionshould be reconstituted with 0.72 ml of sterile water for injectable preparations to produce a final volume of 0.5 ml. Each vial contains an additional amount to ensure that 250 µg of romiplostim can be administered (see table below for vial contents).

• Nplate 500 micrograms powder for injectable solutionshould be reconstituted with 1.2 ml of sterile water for injectable preparations to produce a final volume of 1 ml. Each vial contains an additional amount to ensure that 500 µg of romiplostim can be administered (see table below for vial contents).

Vial Contents:

Only sterile water for injectable preparations should be used to reconstitute the medicinal product. Sodium chloride solutions or bacteriostatic water should not be used to reconstitute the medicinal product.

The sterile water for injectable preparations should be injected into the vial. During dissolution, a gentle circular motion should be performed and the vial contents inverted. The vial should not be shaken or vigorously agitated.Reconstitution of Nplate usually takes less than 2 minutes. The solution should be visually inspected for particles or discoloration before administration. The reconstituted solution should be clear and colorless and should not be administered if particles and/or discoloration are observed.

From a microbiological point of view, the reconstituted medicinal product should be used immediately. If not used immediately, the storage times and conditions are the responsibility of the user and should not exceed 24 hours at 25°C or 24 hours in the refrigerator (between 2°C and 8°C), protected from light.

Disposal of the unused medicinal product and all materials that have come into contact with it should be done in accordance with local regulations.

Dilution (required when the patient's individual dose calculation is less than 23 µg).

The initial reconstitution of romiplostim with designated volumes of sterile water for injectable preparations results in a concentration of 500 µg/ml in all vial sizes. If the patient's individual dose calculation is less than 23 µg, additional dilution is required to achieve a concentration of 125 µg/ml with sterile sodium chloride 9 mg/ml (0.9%) solution without preservativesto ensure an accurate dose (see table below).

Dilution Guidelines:

Sterile sodium chloride 9 mg/ml (0.9%) solution without preservatives should only be used for dilution. Dextrose (5%) in water or sterile water for injectable preparations should not be used for dilution. No other diluents have been tested.

From a microbiological point of view, the diluted medicinal product should be used immediately. If not used immediately, the storage times and conditions are the responsibility of the user and should not exceed 4 hours at 25°C in disposable syringes or 4 hours in the original vials in the refrigerator (between 2°C and 8°C), protected from light.