Consumer medicine information

Nplate

Romiplostim

BRAND INFORMATION

Brand name

Nplate

Active ingredient

Romiplostim

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nplate.

SUMMARY CMI

Nplate®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

▼ This medicine is new or being used differently. Please report side effects. See the full CMI for further details.

1. Why am I using Nplate?

Nplate contains the active ingredient romiplostim. Nplate is used to increase the number of platelets, and to prevent bruising and bleeding associated with a blood disorder called immune thrombocytopenia, commonly abbreviated as ITP.

For more information, see Section 1. Why am I using Nplate? in the full CMI.

2. What should I know before I use Nplate?

Do not use if you have ever had an allergic reaction to romiplostim or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use Nplate? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Nplate and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use Nplate?

Nplate is injected under the skin (subcutaneous).

More instructions can be found in Section 4. How do I use Nplate? in the full CMI.

5. What should I know while using Nplate?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Nplate.
  • Keep all of your test appointments and doctor appointments so that your progress can be checked.
  • Tell your doctor immediately if you become pregnant while taking Nplate.
Things you should not do
  • Do not stop using this medicine unless your doctor tells you. If you stop taking Nplate, you are at risk of bleeding.
Driving or using machines
  • Nplate may cause temporary bouts of dizziness in some people and may impair your ability to safely drive or use machines.
Drinking alcohol
  • There is no information on the effects of using Nplate with alcohol.
Looking after your medicine
  • If you need to store a Nplate pack at home, keep it in the refrigerator, between 2°C and 8°C. Do not freeze it. Keep it out of sight and reach of children.

For more information, see Section 5. What should I know while using Nplate? in the full CMI.

6. Are there any side effects?

Side effects that require urgent medical attention include: signs of an allergic reaction, such as chest tightness, difficulty breathing, swelling of face lips and tongue, rash; and blood clots. Very common side effects include: headache; aches or pains in joints or muscles; dizziness; difficulty sleeping; pain; runny, or blocked nose; inflammation nasal or throat passages; cough; diarrhoea; rash; fever; bruising; infections.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

▼ This medicine is subject to additional monitoring. This will allow quick identification of new safety information. You can help by reporting any side effects you may get. You can report side effects to your doctor, or directly at www.tga.gov.au/reporting-problems.



FULL CMI

Nplate®

Active ingredient(s): romiplostim (ro-mip-lo-stim)

Consumer Medicine Information (CMI)

This leaflet provides important information about using Nplate. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using Nplate.

Where to find information in this leaflet:

1. Why am I using Nplate?
2. What should I know before I use Nplate?
3. What if I am taking other medicines?
4. How do I use Nplate?
5. What should I know while using Nplate?
6. Are there any side effects?
7. Product details

1. Why am I using Nplate?

Nplate contains the active ingredient romiplostim.

Nplate works by stimulating the bone marrow to produce more platelets in patients with a bleeding disorder called ITP. Nplate is used to treat adults and children with ITP.

ITP is the short name for immune thrombocytopenia, a blood disorder where there are lower numbers of platelets than normal in your blood. ITP occurs when your body's immune system attacks and destroys platelets. If you have ITP, you may be at risk of serious, life-threatening bleeding.

Platelets are cells made in the bone marrow which help your blood to clot. Platelets circulate in your blood. If you have low platelets you could bruise more easily than normal or bleed for a long time after being injured.

Nplate should help to prevent bruising and bleeding associated with ITP. Nplate helps to control your condition but does not cure it.

2. What should I know before I use Nplate?

Warnings

Do not use Nplate if you are allergic to:

  • romiplostim, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • other medicines that are produced by DNA technology using Escherichia coli (E. coli).

Check with your doctor if you:

  • have surgery planned
  • have any other medical conditions including:
    - liver problems
    - kidney problems
    - cancer or precancer of the blood
    - blood clots, or if blood clots are common in your family. The risk of blood clots may be increased if you:
    -- are a female taking the contraceptive pill
    -- take hormone replacement therapy
    -- are a smoker
    -- have recently had surgery or an injury
    -- are overweight (obese)
    -- are 65 years of age or older
    -- are bedridden.
  • take any medicines for any other condition. See Section 3. What if I am taking other medicines?

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Use in children

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

Pregnancy

Check with your doctor if you are pregnant or intend to become pregnant. Nplate is not recommended to be used during pregnancy unless advised by your doctor. Your doctor can discuss the risks and benefits with you.

Breastfeeding

Talk to your doctor if you are breastfeeding or intend to breastfeed. Nplate is not recommended for use if you are breast feeding. It is not known whether romiplostim is present in human milk. 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.

3. What if I am taking other medicines?

Some medicines may interfere with Nplate and affect how it works.

Tell your healthcare provider if you take:

  • medicines used to prevent blood clots. There is a greater risk of bleeding when you lower the dose or stop taking Nplate. Your doctor will adjust your dose of Nplate to ensure that your platelet count does not become too high.
  • any of the following medicines to treat your ITP, including, and not limited to:
    - medicines to reduce the activity of your immune system, such as:
    -- azathioprine
    -- corticosteroids
    - danazole (a synthetic hormone)
    - blood products called immunoglobulins, which are used to prevent some infections.
    These may be reduced or stopped when given together with Nplate.
  • any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect Nplate.

4. How do I use Nplate?

How to use Nplate

Nplate is given as an injection, under the skin. This is called a 'subcutaneous' injection. It is given under the guidance of an experienced healthcare professional, by a carer, or can be self-administered by adults.

Self-administration is not recommended in children. It is advised that children receive their Nplate injection from an experienced doctor or nurse.

Follow the instructions provided and use Nplate until your doctor tells you to stop.

If injecting Nplate at home, use a syringe that has graduations in units of 0.01 mL, as the dose may be a very small volume.

When to use Nplate

Nplate should be taken every week to keep your platelet counts in a safe range.

How much to use

Your doctor will determine exactly how much Nplate you need. Dosing is usually between 1 to 10 micrograms per kilogram of body mass.

The dose is tailored to each patient and depends on body weight and platelet count.

The dose will be adjusted by your doctor to maintain long-term control of your platelet count.

Once your platelet count is under control, your doctor will continue to regularly check your blood.

Follow the instructions provided and use Nplate until your doctor tells you to stop.

If you forget to have Nplate

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

If you inject too much Nplate

If you think that you have used/been given too much Nplate, you may need urgent medical attention.

If you receive too much Nplate, you may not experience any physical symptoms. However, your platelet counts may rise to very high levels and this may increase the risk of blood clotting.

You should immediately:

  • Phone the Poisons Information Centre (by calling 13 11 26), or
  • Contact your doctor, or
  • Go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Always take the outer carton of the medicine with you.

5. What should I know while using Nplate?

Things you should do

Continue using your medicine for as long as your doctor tells you. If you stop taking Nplate your platelet count will need to be monitored, and your doctor will discuss appropriate precautions with you.

Keep all of your doctor's appointments so that your progress can be checked.

Remind any doctor, dentist or pharmacist you visit that you are using Nplate.

If you become pregnant while taking Nplate, tell your doctor immediately.

Testing during your treatment

Your doctor will order regular blood tests to check your platelets levels and may adjust your Nplate dose.

If you experience a loss of response or failure to maintain a platelet response with Nplate, your doctor will investigate why. You may have increased bone marrow fibres (reticulin) or have developed antibodies which neutralise Nplate's activity.

Long-term use of Nplate may cause changes in your bone marrow. The changes may lead to abnormal blood cells or your body making less blood cells. The mild form of bone marrow changes is called “increased reticulin”.

Signs of bone marrow changes may show up as unusual blood test results. Your doctor will decide if the results need further tests on your bone marrow or if you should stop taking Nplate.

Call your doctor straight away if you have:

  • swelling of the face, lips, mouth or throat which may cause difficultly in swallowing or breathing;
  • generalised swelling
  • wheezing
  • rash, itching or hives on the skin or flushing.

You may be experiencing a severe allergic reaction and need urgent medical attention.

Things you should not do

  • Do not stop using Nplate. Your doctor will decide if you should stop using Nplate. Your low blood platelet count is likely to recur and put you at risk of bleeding.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how Nplate affects you.

Nplate may cause temporary bouts of dizziness in some people and may impair your ability to safely drive or use machines.

Looking after your medicine

If you need to store Nplate powder at home

  • Keep the vials in the refrigerator, between 2°C and 8°C. Do not freeze.
  • Store it in away from moisture and sunlight.
  • Keep your medicine in the pack until it is time to use it. If you take the powder out of the pack it will not keep well.
  • Keep it where young children cannot reach it.

Follow the instructions in the carton on how to take care of your medicine properly.

If you are injecting Nplate at home, after Nplate powder has been dissolved, use the solution as soon as possible.

  • Do not shake or vigorously agitate the vial.
  • Do not use Nplate if the solution is cloudy or discoloured, or if it contains clumps or flakes.
  • Do not save unused Nplate for later administration.
    If the dissolved Nplate solution cannot be used immediately, store it in the refrigerator, between 2°C and 8°C. It can only be stored this way for up to 24 hours.
  • Do not freeze dissolved Nplate solution.

Getting rid of any unwanted medicine

Return any unused or expired Nplate to your pharmacist for safe disposal.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effectsWhat to do
General:
Tiredness; swelling of limbs, hands, or feet; fever; pain; toothache; unusual weakness.
Nervous-system related:
Headache; dizziness; "pins and needles" (numbness or a burning feeling that occurs most often in the hands, arms, legs, or feet, or elsewhere).
Mood-related:
Confusion; trouble sleeping; feeling nervous or anxious.
Gut-related:
Abdominal pain; constipation; nausea; diarrhoea; vomiting; indigestion or uncomfortable feeling in the stomach or belching after eating; decreased appetite.
Muscle-related:
Cramps; muscle pain; aching muscles; muscle tenderness or weakness, not caused by exercise; Joint or muscle pain, including shoulder pain.
Bone-related:
Bone pain; back pain; pain in the extremities.
Breathing-related:
inflammation or pain of the nose, throat or mouth; cough; shortness of breath; difficulty in breathing; chest tightness; stuffy nose; blocked nose.
Bleeding-related:
Tiredness; headaches; being short of breath when exercising; dizziness and looking pale; bleeding or bruising more easily than normal; bleeding gums or in the mouth or nose; bleeding beneath the surface of the skin or bruising under the skin.		Speak to your doctor if you have any of these less serious side effects and they worry you.

Less serious side effects

Less serious side effectsWhat to do
Infection-related:
A common cold; infections of the mouth, nose, throat, voice box and windpipe, or ears; the flu; inflammation of the sinuses; inflammation of the passages that carry air to the lungs; inflammation of the eye (conjunctivitis).
Immune system-related:
Allergic reactions.
Skin-related:
Red or purple, flat, pinhead spots under the skin; rash; itching; skin abrasion; cuts; bruising; hive-like swelling beneath the skin; redness, heat or pain of skin.
Blood vessel-related:
Bruising; blood clots; bleeding; burning pain/redness in the feet, hands, arms, legs, ears and face; high blood pressure.		Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Serious allergy-related:
Swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing.
Immune system-related:
Shortness of breath, flushing, itching, swelling of face and generalized swelling.
Blood and lymphatic system related:
Bone marrow problems (detected in tests); blood clots.		Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side affects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

What Nplate contains

Active ingredient
(main ingredient)		romiplostim
Other ingredients
(inactive ingredients)		histidine
polysorbate 20 (E432)
diluted hydrochloric acid (E507)
Potential allergensmannitol (E421)
sucrose

Do not take this medicine if you are allergic to any of these ingredients.

What Nplate looks like

Nplate is a white powder for solution for subcutaneous injection is supplied in a 5 mL single-dose, clear, glass vial with stopper, aluminium seal, and flip-off cap.

Nplate cartons contain one vial.

Reconstitution and/or dilution yields a clear, colourless, solution. The solution in each vial includes an excess to enable the prescribed dose to be removed.

Nplate 250 micrograms/0.5 mL powder for injection (AUST R 147187).

Nplate 500 micrograms/1 mL powder for injection (AUST R 147188).

Who distributes Nplate?

Amgen Australia Pty Ltd,
Level 11, 10 Carrington Street,
Sydney NSW 2000.
Ph: 1800 803 638

www.amgenmedinfo.com.au

® indicates a registered trademark of Amgen.

This leaflet was prepared in October 2021.

Published by MIMS December 2021

BRAND INFORMATION

Brand name

Nplate

Active ingredient

Romiplostim

Schedule

S4

 

1 Name of Medicine

Romiplostim.

2 Qualitative and Quantitative Composition

Nplate contains the active ingredient, romiplostim.
It is supplied as a sterile, preservative-free, lyophilized white powder in single dose glass vials for reconstitution and subcutaneous (SC) injection.

230 microgram powder for injection.

Each vial contains 230 microgram of romiplostim.
After reconstitution, a deliverable volume of 0.25 mL of solution contains 125 microgram of romiplostim (500 microgram/mL). An overfill is included in each vial to ensure that 125 microgram can be drawn from the vial.

375 microgram powder for injection.

Each vial contains 375 microgram of romiplostim.
After reconstitution, a deliverable volume of 0.5 mL of solution contains 250 microgram of romiplostim (500 microgram/mL). An overfill is included in each vial to ensure that 250 microgram can be drawn from the vial.

625 microgram powder for injection.

Each vial contains 625 microgram of romiplostim.
After reconstitution, a deliverable volume of 1 mL of solution contains 500 microgram of romiplostim (500 microgram/mL). An overfill is included in each vial to ensure that 500 microgram can be drawn from the vial.

Excipient(s) with known effect.

Nplate contains mannitol and sucrose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nplate is a sterile, white, preservative-free, lyophilised powder for reconstitution and administration as a subcutaneous (SC) injection.
The reconstituted solution should be clear and colourless.

4 Clinical Particulars

4.1 Therapeutic Indications

Adults.

Nplate is indicated for treatment of thrombocytopenia in adult patients with primary immune thrombocytopenia (ITP) who are:
non-splenectomised and have had an inadequate response, or are intolerant, to corticosteroids and immunoglobulins;
splenectomised and have had an inadequate response to splenectomy.

Paediatrics.

Nplate is indicated for treatment of thrombocytopenia in paediatric patients aged 1 year and older with primary immune thrombocytopenia (ITP) for at least 6 months who are:
non-splenectomised and have had an insufficient response, or are intolerant, to corticosteroids and immunoglobulins;
splenectomised and have had an inadequate response to splenectomy.

4.2 Dose and Method of Administration

Treatment should be under the guidance of an experienced healthcare provider.
Use the lowest dose of Nplate necessary to achieve and maintain a platelet count ≥ 50 x 109/L. Administer Nplate as a weekly subcutaneous injection, with dose adjustments based upon the platelet count response.
The prescribed Nplate dose may consist of a very small volume (e.g. 0.15 mL). Administer Nplate using a syringe with 0.01 mL graduations only.
Discontinue Nplate if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after 4 weeks at the highest weekly dose of 10 microgram/kg.

Dosage (dose and interval).

Recommended dosage regimen.

Initial dose.

The recommended initial dose for Nplate is 1 microgram/kg, based on actual patient's body weight.

Method of administration.

For subcutaneous use. See Reconstitution instructions.
Patients who have a stable platelet count ≥ 50 x 109/L for at least 4 weeks without dose adjustment may, at the discretion of the supervising experienced healthcare provider, self-administer Nplate. Patients eligible for self-administration of Nplate should be trained in these procedures.
After the first 4 weeks of self-administration, the patient should again be supervised while reconstituting and administering Nplate. Only patients who demonstrate the ability to reconstitute and self-administer Nplate should be allowed to continue doing so.
Self-administration of Nplate is not recommended in children.

Dosage adjustment.

Adjust the weekly dose of Nplate in increments of 1 microgram/kg until the patient achieves a platelet count between 50 x 109/L to ≤ 200 x 109/L.
Assess the platelet count weekly until a stable platelet count (≥ 50 x 109/L for at least 4 weeks without dose adjustment) has been achieved. Obtain platelet counts monthly thereafter. Dose adjustment recommendations are given in Table 1 and Table 2 for Adult and Paediatric patients, respectively.
Do not exceed a maximum weekly dose of 10 microgram/kg.

Dosage calculation.

The volume administered is calculated based on body weight, dose required and concentration of product (see Table 3).

Treatment discontinuation.

Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician.
The recurrence of thrombocytopenia should be expected upon discontinuation of treatment (see Section 4.4 Special Warnings and Precautions for Use, Recurrence of thrombocytopenia after cessation of treatment).

Use of Nplate with concomitant medical ITP therapies.

Medical ITP therapies used in combination with Nplate in clinical studies included corticosteroids, danazol, azathioprine, normal immunoglobulin (IVIG), and anti-D Rho immunoglobulin. If the patient's platelet count is > 50 x 109/L, other medical ITP therapies may be reduced or discontinued (see Section 5.1 Pharmacodynamic Properties, Reduction in permitted concurrent ITP medical therapies; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Reconstitution.

Reconstitute only with sterile Water for Injections as outlined in Table 4. Do not use saline or bacteriostatic water for injection when reconstituting the product.
As the injection volume may be very small, a syringe with graduations to 0.01 mL should be used.
Gently swirl and invert the vial to reconstitute. Do not shake or vigorously agitate the vial. Generally, dissolution of Nplate takes less than 2 minutes (see Section 3 Pharmaceutical Form).

Dilution.

A dilution is required when the calculated individual patient dose is less than 23 microgram.
Initial reconstitution of Nplate with designated volumes of sterile Water for Injections results in a concentration of 500 microgram/mL (see Table 4). If the calculated individual patient dose is less than 23 microgram (see Section 4.2 Dose and Method of Administration), then dilute reconstituted Nplate to 125 microgram/mL with preservative-free, sterile, 0.9% sodium chloride. This dilution step is required to ensure accuracy in preparation (see Table 5).
See Section 6.2 Incompatibilities; Section 6.4 Special Precautions for Storage.

Administration precautions.

Caution should be used during preparation of Nplate, both in calculating the dose and in reconstitution with the correct volume of sterile water for injections.
Special care should be taken to ensure that the appropriate volume of Nplate is withdrawn from the vial for subcutaneous administration (see Section 4.4 Special Warnings and Precautions for Use, Medication errors; Section 4.9 Overdose).
Parenteral drug products, including Nplate solution, should be inspected visually for particulate matter and/or discolouration prior to administration. Do not use the contents of the container if any particulates or discolouration are observed.
Nplate must be used within: 24 hours of reconstitution; and/or 4 hours of dilution (see Section 6.4 Special Precautions for Storage).
Each Nplate vial is for single use in one patient only. Discard any residue.
Do not add other medications to solutions containing Nplate.

4.3 Contraindications

Nplate is contraindicated in patients with known hypersensitivity to E. coli-derived products, romiplostim, or any other product ingredient (see Section 6.1 List of Excipients).

4.4 Special Warnings and Precautions for Use

General.

See Administration precautions in Section 4.2.
Nplate should only be used in patients with ITP whose degree of thrombocytopenia and clinical condition increase the risk of bleeding. Nplate should not be used in other clinical conditions associated with thrombocytopenia.
The following special warnings and precautions are observed or theoretical class effects of TPO receptor stimulators.

Recurrence of thrombocytopenia after cessation of treatment.

Thrombocytopenia is likely to recur upon discontinuation of Nplate; some patients may develop thrombocytopenia of greater severity than was present prior to Nplate. There is increased risk for bleeding if Nplate is discontinued in the presence of anticoagulants or anti-platelet agents. Patients should be closely monitored for a decrease in platelet count and medically managed to avoid bleeding upon discontinuation of Nplate. It is recommended that, if treatment with Nplate is discontinued, weekly complete blood counts (CBCs) be obtained for at least 2 weeks and alternative ITP treatment for worsening thrombocytopenia be considered according to current treatment guidelines. Additional medical management may include cessation of anticoagulant and/or anti-platelet therapy, reversal of anticoagulation, or platelet support.
Serious life-threatening or fatal bleeding events after discontinuation of Nplate have been reported.

Increased bone marrow reticulin.

Reticulin has been observed in the bone marrow of some ITP patients prior to treatment with Nplate and appeared to increase in some patients treated with Nplate. Increased bone marrow reticulin is believed to be due to the increased number of megakaryocytes in the bone marrow which may subsequently release cytokines. In clinical studies with Nplate, reticulin has not been associated with adverse clinical sequelae, cases of chronic idiopathic myelofibrosis (CIMF), or secondary myelofibrosis, and may improve upon discontinuation of Nplate.
Increased reticulin can be detected through bone marrow biopsy and may be suggested by morphological changes in the peripheral blood cells.
Prior to and during treatment with Nplate, examine peripheral blood smears and complete blood counts for new or worsening morphological abnormalities (e.g. teardrop and nucleated red blood cells, immature white blood cells) or cytopenia(s). If a patient develops new or worsening morphological abnormalities or cytopenia(s), discontinue treatment with Nplate and consider performing a bone marrow biopsy, with appropriate staining for fibrosis. Cytogenetic analysis of the bone marrow sample for clonal abnormality should also be considered.
The long-term risk for progression to myelofibrosis is unknown.

Thrombotic/ thromboembolic complications.

Platelet counts above the normal range present a theoretical risk for thrombotic/ thromboembolic complications. The incidence of thrombotic/ thromboembolic events observed in the control groups were comparable to Nplate in clinical studies. No association between these events and elevated platelet counts was observed. Dose adjustment guidelines should be followed (see Section 4.2 Dose and Method of Administration).
In the post-marketing setting, thrombotic/ thromboembolic events have been observed (see Section 4.8 Adverse Effects (Undesirable Effects), Post-marketing experience).
To minimise the risk for thrombocytosis, do not use Nplate in an attempt to "normalise" platelet counts. Follow the dose adjustment guidelines to achieve and maintain a platelet count of ≥ 50 x 109/L (see Section 4.2 Dose and Method of Administration).
Cases of thromboembolic events including portal vein thrombosis have been reported in patients with chronic liver disease receiving Nplate. Nplate should be used with caution in this population.
Caution should be used when administering Nplate to patients with known risk factors for thromboembolism including but not limited to inherited (e.g. Factor V Leiden) or acquired risk factors (e.g. ATIII deficiency, antiphospholipid syndrome), advanced age, patients with prolonged periods of immobilisation, malignancies, contraceptives and hormone replacement therapy, surgery/ trauma, obesity and smoking.

Risk of progression of myeloid malignancies or existing myelodysplastic syndromes (MDS).

TPO receptor stimulators are haematopoietic growth factors that lead to thrombopoietic progenitor cell expansion, differentiation, and platelet production. The TPO receptor is predominantly expressed on the surface of cells of the myeloid lineage; there is no confirmed expression of the TPO receptor on solid tumours. TPO has been shown to stimulate the proliferation of a subset of acute myeloblastic leukaemia cells in vitro. There is, therefore, a theoretical concern that romiplostim may stimulate the progression of existing myeloid malignancies or MDS.
In clinical studies of treatment with Nplate in adult patients with MDS, cases of progression to acute myeloid leukaemia (AML), a potential clinical outcome of MDS, were reported. In addition, there were cases of transient blast cell increases, which did not progress to AML. The risk-benefit profile for Nplate has not been established in MDS or other non-ITP patient populations.
A randomised, double-blind, placebo-controlled trial enrolling patients with severe thrombocytopenia and International Prognostic Scoring System (IPSS) low or intermediate-1 risk MDS was terminated due to more cases of AML observed in the Nplate treatment arm. This trial consisted of a 58-week study period with a 5-year long-term follow-up phase. The subjects were randomised 2:1 to treatment with Nplate or placebo (167 Nplate, 83 placebo). During the 58-week study period, progression to AML occurred in 10 (6.0%) subjects in the Nplate arm and 4 (4.8%) subjects in the placebo arm (hazard ratio [95% CI] = 1.20 [0.38, 3.84]). Of the 250 subjects, 210 (84.0%) entered the long-term follow-up phase of this study. With 5-years of follow-up, 29 (11.6%) subjects showed progression to AML, including 20/168 (11.9%) subjects in the Nplate arm versus 9/82 (11.0%) subjects in the placebo arm (HR [95% CI] = 1.06 [0.48, 2.33]). The incidence of death (overall survival) was 55.7% (93/167) in the Nplate arm versus 54.2% (45/83) in the placebo arm (HR [95% CI] = 1.03 [0.72, 1.47]). In the baseline low IPSS group, there was a higher incidence of death in the Nplate arm [41.3% (19/46)] compared to the placebo arm [30.4% (7/23)] [HR (95% CI) = 1.59 (0.67, 3.80)].
In a single arm trial of Nplate given to 72 subjects with thrombocytopenia-related MDS, 8 (11.1%) subjects were reported as having possible disease progression, of which 3 (4.2%) had confirmation of AML during follow up. In addition, in 3 (4.2%) subjects, increased peripheral blood blast cell counts decreased to baseline after discontinuation of Nplate.

Loss of response to Nplate.

A loss of response or failure to maintain a platelet response with Nplate should prompt a search for causative factors including neutralising antibodies to Nplate (see Section 4.8 Adverse Effects (Undesirable Effects), Immunogenicity) and increased bone marrow reticulin (see Section 4.4 Special Warnings and Precautions for Use, Increased bone marrow reticulin).

Medication errors.

Medication errors including overdose and underdose have been reported in patients receiving Nplate. In some paediatric patients, accurate dosing relies on an additional dilution step after reconstitution (see Section 4.2 Dose and Method of Administration, Dilution). Overdose may result in an excessive increase in platelet counts associated with thrombotic/ thromboembolic complications. If the platelet counts are excessively increased, discontinue Nplate and monitor platelet counts. Reinitiate treatment with Nplate in accordance with dosing and administration recommendations. Underdose may result in lower than expected platelet counts and potential for bleeding. Platelet counts should be monitored in patients receiving Nplate (see Section 4.4 Special Warnings and Precautions for Use, Thrombotic/ thromboembolic complications; Section 4.2 Dose and Method of Administration; Section 4.9 Overdose).

Use in hepatic or renal impairment.

Experience is limited in patients with severe hepatic or renal impairment. Nplate should be used with caution in these populations. Thromboembolic events have been reported in patients with chronic liver disease receiving Nplate (see Section 4.4 Special Warnings and Precautions for Use, Thrombotic/ thromboembolic complications).

Use in the elderly.

Of 204 patients who received Nplate in ITP clinical studies, 38 (19%) were ≥ 65 years, and 18 (9%) were ≥ 75. No overall differences in safety or efficacy were observed between older and younger patients in the placebo-controlled studies, but greater sensitivity of older individuals cannot be ruled out.

Paediatric use.

The safety and efficacy of Nplate in paediatric patients aged 1 year and older were evaluated in two randomised, placebo controlled studies: a Phase I/II (Study 5) and a Phase III study (Study 4).
Similar to data from the adult ITP trials, Nplate induced high rates of durable and overall platelet response with a similar safety profile in children with symptomatic immune thrombocytopenia of more than 6 months duration.

Effects on laboratory tests.

No interactions with laboratory and diagnostic tests have been identified.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No formal drug-drug interaction studies of Nplate have been performed.
ITP medical therapies used in combination with Nplate in clinical studies included corticosteroids, danazol, and/or azathioprine, normal immunoglobulin (IVIG) and anti-D Rho immunoglobulin.
Platelet counts should be monitored when combining Nplate with other ITP medical therapies in order to avoid platelet counts outside of the recommended range (see Section 4.2 Dose and Method of Administration).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Romiplostim had no observed effect on the fertility of male and female rats at subcutaneous doses up to 100 microgram/kg administered 3 times weekly (up to 9 times the serum AUC in humans at the maximum recommended clinical dose). The predictive value of this animal study is limited, however, due to the frequent development of drug-neutralising antibodies.
(Category B3)
The safety and efficacy of romiplostim in pregnant women has not been established.
Embryo-foetal development studies showed no increase in foetal abnormalities in rats given subcutaneous doses of romiplostim of up to 100 microgram/kg every second day during gestation (up to 3 times the serum AUC in humans at the maximum recommended clinical dose). The predictive value of these studies is limited, though, by the low animal:human exposure level and the development of drug-neutralising antibodies in the species. In a pre- and post-natal development study in rats, stillbirths were increased and perinatal pup survival was decreased at this dose level. An increase in post-implantation loss was observed in mice receiving a subcutaneous dose of 100 microgram/kg every third day.
Romiplostim crosses the placenta in rats and maternal transmission to the developing foetus may occur in humans.
There are no studies with romiplostim in pregnant women. Nplate should not be used during pregnancy unless the potential benefit justifies the potential risk to the foetus.
Patients who use romiplostim during pregnancy or become pregnant while receiving this drug are encouraged to enrol in Amgen's Pregnancy Surveillance Program. Enrolment may be arranged by telephoning Amgen's Medical Information line on 1800 803 638 (free call within Australia).
 It is not known whether romiplostim is present in human milk. Many drugs are present in human milk and because of the potential for adverse effects in breastfed infants from romiplostim, a decision should be made to discontinue breastfeeding or discontinue the drug, taking into account the potential benefit of the drug to the mother or the potential benefit of breastfeeding to the infant.
Women who are breastfeeding while receiving this drug are encouraged to enrol in Amgen's Lactation Surveillance Program. Enrolment may be arranged by telephoning Amgen's Medical Information line on 1800 803 638 (free call within Australia).

4.7 Effects on Ability to Drive and Use Machines

No studies on the ability to drive and use machines have been performed with Nplate. Patients should be informed that in clinical trials mild to moderate, transient bouts of dizziness were experienced by some patients.

4.8 Adverse Effects (Undesirable Effects)

Summary of safety profile.

Adverse events reported in fifteen ITP clinical trials are shown in Table 6. Based on an analysis of patients enrolled in four placebo-controlled studies, in one SOC-controlled study, and ten uncontrolled studies adverse events were reported in 1016 (94.2%) patients receiving Nplate (n = 1078, including 104 paediatric patients) and in 129 (93.5%) patients receiving placebo/SOC (n = 138, including 5 paediatric patients). The majority of these events were mild to moderate in nature, with severe, life-threatening or fatal adverse events reported in 38.4% of patients receiving placebo/SOC and in 39.6% of patients receiving Nplate.
The most commonly reported adverse events were headache, nasopharyngitis and arthralgia.

Serious adverse events/ deaths/ withdrawals/ interventions from the two phase III placebo-controlled studies (study 1 and 2).

Fourteen adult patients (17%) treated with Nplate (n = 84) experienced serious adverse events, two (2%) of whom had 3 serious adverse events assessed by the investigator as possibly related to treatment: bone marrow disorder determined to be increased reticulin, peripheral embolism, and peripheral ischemia. Eight (20%) patients treated with placebo (n = 41) experienced serious adverse events.
There were four fatal adverse events during the two placebo-controlled studies: 1 (1%) patient receiving Nplate and 3 (7%) placebo-treated patients; none of the deaths were considered treatment-related. The Nplate-treated patient died following an intracranial haemorrhage that occurred after Nplate was discontinued in the presence of anti-platelet therapy. The fatal adverse events in the placebo-treated patients were (n (%)): cerebral haemorrhage (1 (2%)), pulmonary embolism (1 (2%)) and primary atypical pneumonia following hospitalisation for an intracranial bleed (1 (2%)).
Twenty-five patients discontinued treatment: 5 (6.0%) patients receiving Nplate and 20 (48.8%) placebo-treated patients. Three patients treated with Nplate discontinued treatment due to serious adverse events: B-cell lymphoma in a patient with pre-existing lymphadenopathy and several lymphoid aggregates in the bone marrow, bone marrow disorder determined to be increased reticulin, and intracranial haemorrhage after discontinuation of Nplate in the presence of anti-platelet therapy. One placebo-treated patient discontinued the study because of metastases to the liver.
Eighty three percent of patients in both Nplate and placebo groups had adverse events leading to intervention (e.g. alteration or discontinuation of study medication, other medications or therapies administered, hospitalisation). The most common adverse events leading to intervention in both the Nplate and placebo groups, respectively, were headache (29% vs 27%), upper respiratory tract infection (13% vs 10%), and arthralgia (12% vs 7%).

Adverse drug reactions.

Adults.

Adverse drug reactions for Nplate are presented in Table 7 with frequencies derived from all thirteen clinical studies (Adult ITP Safety Set, n = 1046). Among the adverse drug reactions in Table 7 are those where the subject incidence was ≥ 5% higher in the Nplate arm versus the placebo arm in the two Phase III placebo-controlled studies, (the majority of which were mild to moderate in severity), as well as those from across the entire adult ITP clinical program.
Adverse drug reactions from the two Phase III placebo-controlled studies (Study 1 and Study 2, (Nplate n = 84, placebo n = 41)) that did not show a > 5% difference between the Nplate arm and the placebo arm included headache, which was the most commonly reported adverse drug reaction, occurring in 35% of patients receiving Nplate and 32% of patients receiving placebo. Headache occurred at a higher incidence in splenectomised patients receiving Nplate (43%) compared with patients receiving placebo (33%) (Study 2, Nplate n = 42, placebo n = 21). In non-splenectomised patients, headaches occurred in 26% of patients receiving Nplate and 30% of patients receiving placebo (Study 1, Nplate n = 42, placebo n = 20). Headaches were usually mild or moderate and managed with non-narcotic analgesics.
Adverse drug reactions from the two Phase III placebo controlled studies with a 5% higher subject incidence in the Nplate arm (n = 84) versus placebo arm (n = 41) included arthralgia (26% versus 20%), dizziness (17% versus 0%), insomnia (16% versus 7%), myalgia (14% versus 2%), pain in extremity (13% versus 5%), abdominal pain (11% versus 0%), shoulder pain (8% versus 0%), dyspepsia (7% versus 0%), and paraesthesia (6% versus 0%).
Less common adverse drug reactions observed from all thirteen clinical studies (Adult ITP Safety Set, n = 1046) were recurrent thrombocytopenia after cessation of treatment with some patients developing thrombocytopenia of greater severity than was present prior to Nplate, increased bone marrow reticulin, and thrombocythemia (see Section 4.4 Special Warnings and Precautions for Use, Recurrence of thrombocytopenia after cessation of treatment, Increased bone marrow reticulin).

Long-term safety in adults.

Information on the long-term safety of Nplate is derived from the 291 adult patients in the long-term extension study. The median duration of treatment in these patients was 78 weeks (range: 1 to 277 weeks), with a median weekly dose of 4 microgram/kg.
Study duration-adjusted rates were calculated in order to account for the variable amounts of time that individual patients were enrolled on study. Study duration-adjusted adverse event incidence rates were expressed as the number of events per 100 patient years on study. Two hundred and ninety-one adult patients reported 6933 adverse events while they were receiving Nplate for a study duration adjustment event rate of 1106.5 events per 100 patient years on study.
The most common adverse events (study duration-adjusted event rates) were headache (65.8 events per 100 patient years), contusion (53.8 events per 100 patient years), epistaxis (37.0 events per 100 patient years), nasopharyngitis (29.7 events per 100 patient years), arthralgia (24.9 events per 100 patient years), and fatigue (39.6 events per 100 patient years).
The serious adverse events expressed as study duration adjusted event rates with > 1% incidence rate were thrombocytopenia (4.9 events per 100 patient years), ITP (2.6 events per 100 patient years), congestive cardiac failure (2.1 events per 100 patient years), and pneumonia (1.9 events per 100 patient years).

Adult population with ITP duration up to 12 months.

The safety profile of Nplate was similar across adult patients, regardless of ITP duration. Specifically in the integrated analysis of ITP ≤ 12 months duration (n = 311), 277 adult patients with ITP ≤ 12 months duration and who received at least one dose of Nplate from among those patients in 9 ITP studies were included. In the integrated analysis, the following adverse reactions (at least 5% incidence and at least 5% more frequent with Nplate compared with placebo or standard of care) occurred in Nplate patients with ITP duration up to 12 months but were not observed in those adult patients with ITP duration > 12 months: bronchitis (8.3%), sinusitis (5.4%), vomiting (7.2%).

Adverse events in paediatric studies.

The Paediatric ITP Safety Set is comprised of patients from four paediatric clinical studies [20060195 (Phase I/II), 20030213 (Phase II open label, long term dose), 20080279 (Phase III), 20090340 (Phase II open label extension)].
The safety profile up to 24 weeks in the Nplate-treated patients in the Paediatric ITP Randomised Safety Set and the long-term safety in paediatrics were similar to that previously seen for Nplate.
Most adverse events were mild (grade 1) or moderate (grade 2) in severity. More paediatric patients receiving Nplate (24.5%) had serious adverse events compared with placebo (4.2%). The adverse event data for the placebo subjects reflected a shorter duration of exposure from participation in the randomised placebo-controlled studies 20060195 and 20080279. All subjects who enrolled in the longer duration extension studies received only Nplate. There were no fatal adverse events for subjects in either treatment group (see Table 8). There were no discontinuations (of study treatment or from study) due to AEs in the paediatric clinical studies.

Adverse reactions in paediatrics.

The adverse drug reactions were determined by selecting treatment emergent adverse events (TEAEs) for subjects in either the Paediatric ITP Safety Set or Paediatric Randomised ITP Safety Set, who received at least one dose of Nplate and for which there was a ≥ 5% higher subject incidence in the Nplate group compared with the placebo group, as well as at least a 5% higher subject incidence in the Nplate-treated subjects (in either safety set). The majority of these adverse reactions were mild to moderate in severity (see Table 9).
The adverse drug reaction of thrombocytosis occurred uncommonly, with a subject incidence in the Paediatric ITP Safety Set of 1 (0.4%). Subject incidence was 1 (0.4%) for either grade ≥ 3 or serious thrombocytosis.
In paediatric patients of age ≥ 1 year receiving Nplate for ITP, adverse drug reactions with a subject incidence of ≥ 10% in the overall Paediatric ITP Randomised Safety Set (Study 5 and Study 4) were contusion (41%), upper respiratory tract infection (31%), and oropharyngeal pain (25%), pyrexia (24%), diarrhoea (20%), rash (15%) and abdominal pain upper (14%).
Nasopharyngitis, upper respiratory tract infection, rhinitis, pharyngitis, conjunctivitis, ear infection, gastroenteritis, sinusitis, cough, oropharyngeal pain, abdominal pain upper, diarrhoea, rash, purpura, urticaria, pyrexia, peripheral swelling, contusion were additional adverse reactions from paediatric studies compared to those seen in adult studies. The adverse reaction thrombocytosis in adult studies occurred commonly (Common, ≥ 1/100 to < 1/10), compared to at a lower subject incidence in paediatric studies (Uncommon, ≥ 1/1000 to < 1/100).

Analysis of reported bleeding events.

Adults.

In the two Phase III placebo-controlled studies (Study 1 and 2) an inverse relationship between bleeding events and platelet counts was observed. All clinically significant (≥ grade 3) bleeding events occurred at platelet counts < 30 x 109/L. All bleeding events > grade 2 occurred at platelet counts < 50 x 109/L.
The incidence of bleeding events in the two Phase III adult placebo-controlled studies (Study 1 and 2) is shown in Table 10. Nine patients reported a bleeding event that was considered serious (5 (6%) Nplate, 4 (10%) placebo). Bleeding events that were grade 2 or higher were reported by 15% of patients treated with Nplate and 34% of patients treated with placebo (see Table 10).
For the phase III ITP long-term safety set, the study duration-adjusted event rate of grade 2 or higher bleeding events was 98 per 100 patient-years for patients treated with Nplate and 132 per 100 patient-years for placebo-treated patients.
These trends in bleeding event rates were observed in the context of a greater reduction of concomitant ITP medications among patients receiving Nplate relative to placebo. In addition, there was a higher incidence of rescue medication use among patients receiving placebo (see Section 5.1 Pharmacodynamic Properties, Use of rescue therapies).
In study 4 (open-label study), the duration-adjusted incidence of grade 2 or higher bleeding events was 24 per 100 patient-years in patients treated with Nplate and 36 per 100 patient-years in patients receiving the standard of care.

Paediatrics.

In the Phase III paediatric study, the mean (SD) number of composite bleeding episodes was 1.9 (4.2) for the Nplate arm and 4.0 (6.9) for the placebo arm. The subject incidence of rescue medication use, a secondary objective, was not statistically significant (see Section 5.1, Clinical trials).
In Study 5, the composite bleeding episode was defined as clinically significant bleeding events or the use of a rescue medication to prevent a clinically significant bleeding event during weeks 2 through 25 of the treatment period. A clinically significant bleeding event was defined as a Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 grade ≥ 2 bleeding event. The mean (SD) number of composite bleeding episodes (clinical grade ≥ 2) was 1.9 (4.2) for the Nplate arm and 4.0 (6.9) for the placebo arm with a median (Q1, Q3) number of bleeding events of 0.0 (0, 2) for the Nplate arm and 0.5 (0, 4.5) in the placebo arm. The overall duration-adjusted rate per 100 subject-years was 8.1 in the Nplate arm and 18.4 in the placebo arm. In an ad hoc analysis, the duration-adjusted rate (per 100 patient-weeks) of these episodes was lower with Nplate than placebo (8.1 vs 18.4; treatment difference -10.3, 95% CI: -14.7, -5.9).

Immunogenicity.

Romiplostim has no amino acid sequence homology to endogenous thrombopoietin (eTPO). Therefore, any anti-product antibodies formed are unlikely to cross react with eTPO.
Clinical trial patients were screened for immunogenicity to Nplate using an immunoassay capable of detecting both high and low affinity binding antibodies that bind to romiplostim and cross-react with eTPO. The samples that tested positive for binding antibodies were further evaluated for neutralising capacity.
In a pooled analysis of adult ITP subjects treated with Nplate, the incidence of pre-existing antibodies to romiplostim was 3.7% (35/958), and the incidence of binding antibody development during Nplate treatment was 6.2% (60/961). The incidence of pre-existing antibodies to eTPO was 3.2% (31/956) and the incidence of binding antibody development to eTPO during Nplate treatment was 3.4% (33/960). Of the adult patients with positive binding antibodies that developed to either romiplostim or TPO, 4 patients had neutralising activity to romiplostim, but these antibodies did not cross react with endogenous TPO.
As with all therapeutic proteins, there is a potential for immunogenicity. If formation of neutralising antibodies is suspected, contact Amgen to perform assays for antibodies.
If severe thrombocytopenia develops during Nplate treatment, assess patients for the formation of neutralising antibodies.
In a pooled analysis of paediatric ITP patients treated with Nplate, the incidence of binding antibodies to romiplostim at any time was 9.6% (27/282). Of the 27 paediatric patients, 2 had pre-existing binding non-neutralising romiplostim antibodies at baseline. Additionally, 2.8% (8/282) developed neutralising antibodies to romiplostim during treatment. A total of 3.9% (11/282) paediatric patients had binding antibodies to TPO at any time during Nplate treatment. Of these 11 paediatric patients, 2 had pre-existing binding non-neutralising antibodies to TPO and none had neutralising activity to TPO. One patient (0.35%) had a weakly positive postbaseline result for neutralising antibodies against TPO while on study (consistently negative for anti-romiplostim antibodies) with a negative result at baseline. The patient showed a transient antibody response for neutralising antibodies against TPO, with a negative result at the patient's last timepoint tested within the study period.
In the postmarketing registry study, a total of 2.2% (4/184) adult patients developed binding, non-neutralising antibody against TPO. The incidence of binding antibody post-treatment was 3.8% (7/184) to romiplostim, of which 0.5% (1/184) was positive for neutralising antibodies to romiplostim. In paediatric patients, the incidence of binding antibody post-treatment was 16% (3/19) to romiplostim, of which 5.3% (1/19) were positive for neutralising antibodies to romiplostim. There were no antibodies detected to TPO.
Immunogenicity assay results are highly dependent on the sensitivity and specificity of the assay used in detection and may be influenced by several factors, including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to romiplostim with the incidence of antibodies to other products may be misleading.

Post-marketing experience.

Cases of erythromelalgia have been reported.
Cases of hypersensitivity reactions including angioedema have been reported. Patients also experienced symptoms consistent with anaphylaxis.

Reporting of suspected adverse reactions.

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

4.9 Overdose

In the event of overdose, platelet counts may increase excessively and result in thrombotic/ thromboembolic complications. If the platelet counts are excessively increased, treatment with Nplate should be discontinued and platelet counts should be monitored (see Section 4.4 Special Warnings and Precautions for Use, Recurrence of thrombocytopenia after cessation of treatment, Thrombotic/ thromboembolic complications, Medication errors).
Reinitiate treatment with Nplate in accordance with Dose and Method of Administration.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmaceutical group: antihaemorrhagics, other systemic haemostatics; ATC code: B02BX04.

Mechanism of action.

Romiplostim increases platelet production through binding and activation of the thrombopoietin receptor, a mechanism analogous to endogenous thrombopoietin (eTPO). The TPO receptor is predominately expressed on cells of the myeloid lineage such as megakaryocyte progenitor cells, megakaryocytes and platelets.
In clinical studies, treatment with Nplate resulted in dose-dependent increases in platelet count. The peak platelet counts in immune (idiopathic) thrombocytopenic purpura (ITP) patients who received a single subcutaneous dose of 1-10 microgram/kg Nplate were 1.3 to 14.9 times greater than the baseline platelet count over a 2 to 3 week period; the response was variable among patients. The platelet counts of ITP patients who received doses of 1 or 3 microgram/kg Nplate at weekly intervals for 6 weeks were within the range of 50 to 450 x 109/L for most patients, but the response was variable. Individual dose adjustment of Nplate is recommended, and the dose adjustment should be based on the observed platelet count (see Section 4.2 Dose and Method of Administration).

Clinical trials.

Adults. The safety and efficacy of Nplate in adults was evaluated in two Phase III, randomised, placebo-controlled, double-blind studies in adults with chronic ITP (Study 1 and Study 2) and an open-label single-arm study (Study 3).
Study 1 and Study 2 were conducted in adults with ITP who had completed at least one treatment and had a platelet count of ≤ 30 x 109/L prior to study entry; they are representative of the entire spectrum of such ITP patients.

Study 1 (20030212).

Study 1 (20030212) evaluated patients who had not undergone a splenectomy and had an inadequate response or were intolerant to prior ITP therapies. Patients had been diagnosed with ITP for a median of 2.1 years (range 0.1 to 31.6) at the time of study entry. Patients had a median of 3 (range 1 to 7) treatments for ITP prior to study entry and a median platelet count of 19 x 109/L. Study 2 (20030105) evaluated patients who had undergone a splenectomy and continued to have thrombocytopenia. Patients had been diagnosed with ITP for median of 8 years (range 0.6 to 44.8) at the time of study entry. In addition to a splenectomy, patients had received a median of 6 (range 3 to 10) treatments for ITP prior to study entry. Their median platelet count was 14 x 109/L at study entry.
With exception of splenectomy status, study design was the same for both studies. Patients (≥ 18 years) were randomised in a 2:1 ratio to receive a starting dose of Nplate 1 microgram/kg or placebo. Patients received single weekly SC injections for 24 weeks. Doses were adjusted to maintain platelet counts (50 to 200 x 109/L). In both studies, efficacy was determined by an increase in the proportion of patients who achieved a durable platelet response. A durable platelet response was defined as a weekly platelet count ≥ 50 x 109/L for at least 6 weeks during weeks 18 through 25 in the absence of rescue therapy at any time during the treatment period. In the placebo-controlled studies, the most frequently used weekly dose for splenectomised patients was between 2 and 7 microgram/kg (25th-75th percentile respectively; median 3 microgram/kg). For non-splenectomised patients, it was between 1 and 3 microgram/kg (25th-75th percentile respectively; median 2 microgram/kg).
A significantly higher proportion of patients receiving Nplate achieved a durable platelet response compared to patients receiving placebo in both studies: study 1, 61% versus 5% and study 2, 38% versus 0%, respectively (see Table 11). Treatment with Nplate provided significant improvements compared to placebo in both clinical studies for all efficacy endpoints for all patients randomised to the studies based on an intention to treat analysis (see Table 11).
In both Study 1 and Study 2, 30% of patients treated with Nplate achieved a platelet count above 50 x 109/L by week 2, 54% by week 4 and 50% to 70% of patients maintained platelet counts ≥ 50 x 109/L for the remainder of the treatment period. In the placebo group, 0% to 7% of patients were able to achieve a platelet count response during the 6 months of treatment.
Figure 1 shows the median weekly platelet counts over the 6 months of treatment in the treatment period in the phase III studies.
Following discontinuation of Nplate during both studies, seven patients maintained platelet counts of ≥ 50 x 109/L until week 36 without requiring further treatment with Nplate and were therefore not enrolled in the long-term open-label extension study.
Results of studies in adult patients with newly diagnosed and persistent ITP.

Study 3 (20080435).

This was a single-arm, open label study in adult patients who had an insufficient response (platelet count ≤ 30 x 109/L) to first line therapy. The study enrolled 75 patients of whom the median age was 39 years (range 19 to 85) and 59% were female. The median time from ITP diagnosis to study enrolment was 2.2 months (range 0.1 to 6.6). Sixty percent of patients had ITP duration < 3 months and 40% had ITP duration ≥ 3 months. The median platelet count at screening was 20 x 109/L. Prior ITP treatments included corticosteroids, immunoglobulins and anti-D immunoglobulins. Patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the studies. Rescue therapies (i.e. corticosteroids, IVIG, platelet transfusions, anti-D immunoglobulin, dapsone, danazol, and azathioprine) were permitted.
Patients received single weekly SC injections on Nplate over a 12-month treatment period, with individual dose adjustments to maintain platelet counts (50 x 109/L to 200 x 109/L). During the study, the median weekly Nplate dose was 3 microgram/kg (25th-75th percentile: 2-4 microgram/kg).
Of the 75 patients enrolled is Study 3, 70 (93%) had a platelet response ≥ 50 x 109/L during the 12-month treatment period. The mean number of months with platelet response during the 12-month treatment period was 9.2 (95% CI: 8.3, 10.1) months; the median was 11 (95% CI: 10, 11) months. The Kaplan Meier estimate of the median time to first platelet response was 2.1 weeks (95% CI: 1.1, 3.0). Twenty-four (32%) patients had sustained treatment-free remission as defined by maintaining every platelet count ≥ 50 x 109/L for at least 6 months in the absence of Nplate and any medication for ITP (concomitant or rescue); the median time to onset of maintaining every platelet count ≥ 50 x 109/L for at least 6 months was 27 weeks (range 6 to 57).
Use of Nplate in non-splenectomised ITP patients compared with medical standard of care.

Study 4 (20060131).

Study 4 was an open-label study evaluating the safety and efficacy of Nplate compared with medical standard of care (SOC) treatment in non-splenectomised adult patients (aged ≥ 18 years) with ITP and platelet counts < 50 x 109/L, who received at least one prior standard therapy for ITP. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44.2) at the time of study entry. Patients had a median platelet count at enrolment of 29 x 109/L. Medical SOC treatments were selected and prescribed by the investigator according to standard institution practices or therapeutic guidelines.
Patients were randomised in a 2:1 ratio to receive a starting dose of Nplate 3 microgram/kg or SOC. Nplate was administered by single weekly SC injections for 52 weeks. Doses were adjusted throughout the study within a range of 1 to 10 microgram/kg in order to maintain platelet counts (50 to 200 x 109/L). Of the 157 patients randomised to receive Nplate, the median (range) duration of exposure was 52.0 weeks (2 to 53). The most frequently used weekly dose was between 3 and 5 microgram/kg (25th-75th percentile respectively; median 3 microgram/kg).
For both co-primary endpoints, the Nplate group showed significantly greater improvement (i.e. lower rate of splenectomy and lower rates of treatment failure) compared to patients assigned to receive SOC. As shown in Table 12, the odds of undergoing a splenectomy is significantly lower in the Nplate group than the SOC group, with an odds ratio (Nplate vs. SOC) of 0.17 (95% Cl: 0.15, 0.61).
Paediatrics. The safety and efficacy of Nplate in paediatric patients aged 1 year and older with ITP were evaluated in two randomised, placebo-controlled, double-blind studies (Study 5 and Study 6).
Study 5 (20080279) was a Phase III study with 24 weeks of Nplate treatment and Study 6 (20060195) was a Phase I/II study with 12 weeks of Nplate treatment (up to 16 weeks for eligible responders who entered a 4-week pharmacokinetic assessment period).
Both studies enrolled paediatric patients (≥ 1 year to < 18 years of age) with thrombocytopenia (defined by a mean of two platelet counts ≤ 30 x 109/L with neither count > 35 x 109/L in both studies) with ITP, regardless of splenectomy status.

Study 5 (20080279).

Sixty-two patients were randomised in a 2:1 ratio to receive Nplate (n = 42) or placebo (n = 20) and stratified into 1 of 3 age cohorts. In the pivotal phase III placebo-controlled study, the starting dose of Nplate was 1 microgram/kg and weekly dose increments continued in increments of 1 microgram/kg to a maximum dose of 10 microgram/kg in an attempt to reach the target platelet count > 50 x 109 microgram/kg/L. The most frequently used weekly dose was between 3 - 10 microgram/kg and the maximum allowed dose on study was 10 microgram/kg (25th - 75th percentile respectively; median 5.5 microgram/kg). Patients received single subcutaneous weekly injections for 24 weeks.
The primary endpoint was the incidence of durable response, defined as achieving at least 6 weekly platelet counts of ≥ 50 x 109/L during weeks 18 through 25 of treatment. Overall, a significant greater proportion of patients in the Nplate arm achieved the primary endpoint compared with patients in the placebo arm (p = 0.0018). A total of 22 patients (52%) had durable platelet response in the Nplate arm compared with 2 (10%) in the placebo arm: ≥ 1 to < 6 years 38% vs 25%; ≥ 6 to < 12 years 56% vs 11%; ≥ 12 to < 18 years 56% vs 0 (see Table 13). See Figure 2.

Study 6 (20060195).

Twenty-two paediatric patients were randomised in a 3:1 ratio to receive romiplostim (n = 17) or placebo (n = 5). Doses were increased in increments of 2 microgram/kg every 2 weeks and the target platelet count was ≥ 50 x 109/L.
Treatment with Nplate resulted in statistically significantly greater incidence of platelet response compared with placebo (p = 0.0008). None of the patients in the placebo arm achieved either endpoint (see Table 13). No statistical test was performed for the number of composite bleeding episodes endpoint as the statistical testing for the incidence of rescue medication use was not significant.
Reduction in permitted concurrent ITP medical therapies.

Adults.

In both placebo-controlled, double-blind studies, patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the study (i.e. corticosteroids, danazol and/or azathioprine). Twenty-one non-splenectomised and 18 splenectomised patients received on-study ITP medical treatments (primarily corticosteroids) at the start of study. All splenectomised patients who were receiving Nplate were able to reduce the dose by more than 25% or discontinue the concurrent ITP medical therapies by the end of the treatment period compared to 17% of the placebo-treated patients. Seventy three percent of non-splenectomised patients receiving Nplate were able to reduce the dose by more than 25% or discontinue concurrent ITP medical therapies by the end of the study compared to 50% of placebo-treated patients.

Paediatrics.

In the integrated analysis, the prevalence of concurrent ITP therapy use was 42.6% (120 of 282 patients) and the incidence of rescue medication use was 33.7% (95 of 282) at any time during treatment. There was a reduction in concomitant medication use over time. The prevalence of concurrent ITP therapy use was 34.0% from months 1 to 6, 23.2% from months 7 to 12, 18.1% in year 2, 17.6% in year 3, 12.1% in year 4, 5.6% in year 5, and 0% from year 6 through year 10 (with the exception of the use of concomitant medications reported in 1 subject [12.5%] in year 7).
The incidence of rescue medication use was 33.7% (95 of 282 paediatric patients) at any time during treatment. There was a reduction in rescue medication over time. The incidence of rescue medication use was 25.5% from months 1 to 6, 15.4% from months 7 to 12, 11.4% in year 2, 11.8% in year 3, and 6.1% in year 4. There was no reported rescue medication use in years 5 through year 10.
Use of rescue therapies.

Adults.

Rescue therapies (i.e. corticosteroids, normal immunoglobulin (IVIG), platelet transfusions, anti-D Rho immunoglobulin) were permitted in both placebo-controlled, double-blind studies for bleeding, wet purpura, or if the patient was at immediate risk of bleeding. The total incidence of rescue therapy use was considerably higher for placebo-treated patients than for Nplate treated patients (see Table 11).
In both placebo-controlled, double-blind studies, patients already receiving ITP medical therapies at a constant dosing schedule were allowed to continue receiving these medical treatments throughout the study (i.e. corticosteroids, danazol and/or azathioprine). Twenty-one non-splenectomised and 18 splenectomised patients received on-study ITP medical treatments (primarily corticosteroids) at the start of study. All splenectomised patients who were receiving Nplate were able to reduce the dose by more than 25% or discontinue the concurrent ITP medical therapies by the end of the treatment period compared to 17% of the placebo-treated patients. Seventy three percent of non-splenectomised patients receiving Nplate were able to reduce the dose by more than 25% or discontinue concurrent ITP medical therapies by the end of the study compared to 50% of placebo-treated patients.

Paediatrics.

The incidence of rescue medication use was 32.6% (73 of 224 paediatric patients) at any time during treatment. There was a trend towards a reduction in rescue medication over time.
Long-term extension study.

Adults.

Adult patients who had completed a prior Nplate study (including the Phase III studies) were allowed to enrol in a long-term open-label extension study. Subjects were enrolled after completing a previous romiplostim ITP study. Following subsequent amendments there was no requirement for subjects to wait until platelet counts had fallen to < 50 x 109/L, and to wash out certain ITP treatments prior to entering the study.
Patients in the long-term extension continued with weekly dosing and individual dose adjustments of Nplate based on platelet counts. Patients who had received placebo in the placebo-controlled studies received an initial dose of 1 microgram/kg Nplate in the extension study. Patients who were treated with Nplate in the placebo-controlled studies were re-initiated at their previous dose of Nplate, if the Nplate-free period was < 24 weeks; if > 24 weeks, patients received an initial dose of 1 microgram/kg Nplate. The majority of patients treated with Nplate responded quickly, reaching a median count of 50 x 109/L after receiving 1 to 3 doses of Nplate. These platelet counts were maintained within the therapeutic range of 50 to 200 x 109/L throughout the remainder of the study.
Results from an integrated analysis of patients from the placebo-controlled studies who continued into the extension study support the long-term use of Nplate (median duration 78 weeks, with 292 adult patients treated for up to 277 weeks).
After the initial dose adjustment period, the majority (> 75%) of adult patients were able to maintain their dose within 2 microgram/kg, suggesting maintenance of clinical effect over time in the absence of significant Nplate dosage increases. The overall incidence of rescue medication use in adult patients was 33.3%. Approximately 13% (37/292) of adult patients entered this study on concurrent ITP therapy. Twenty (54.1%) of these patients discontinued concurrent ITP therapy by the end of the study. Patients who had bone marrow biopsies (n = 38) showed no evidence of type I collagen. However, trichrome staining for type I collagen was inconsistently performed.
Data from patients previously treated with Nplate in one of the placebo-controlled studies confirm the ability of Nplate to sustain a response over an extended period of time in the majority of patients. In addition, these data demonstrate the ability of Nplate to increase platelet counts in patients from the studies who previously received placebo. Former placebo patients who received Nplate in the extension study showed a pattern of platelet count increases similar to patients who received Nplate in the pivotal studies.
Due to the heterogeneity of the population with regard to inclusion criteria, disease baseline characteristics, treatment history, concurrent medication, Nplate dose received and length of treatment included in this study, data on the long-term efficacy and safety of Nplate should be interpreted with caution.

Paediatrics. Study 7 (20030213).

Study 7, conducted in 20 paediatric patients was an extension of the Phase I/II study (Study 6). Paediatric patients in Study 7 were administered Nplate once weekly.
Patients who had received placebo in the placebo-controlled studies received an initial dose of 1 microgram/kg Nplate in the extension study. Patients who were treated with Nplate in the placebo-controlled studies were re-initiated at their previous dose of Nplate. Platelet response (≥ 50 x 109/L at any time during the study) was achieved in 100.0% of the paediatric patients (95% CI: 83.2%, 100.0%). A platelet count of ≥ 100 x 109/L was reached in 90.0% of paediatric patients and a peak platelet count of ≥ 150 x 109/L was reached in 85.0% of paediatric patients. The overall incidence of rescue medication use in study 6 was 20.0% (4 paediatric patients).

Study 8 (20090340).

Study 8 (20090340), conducted in 65 paediatric patients, was an extension of clinical studies 20030213 (Phase II open label) and 20080279 (Phase III). Sixty-five paediatric patients received at least one dose of Nplate and one subject withdrew from the study before the first dose of Nplate. Nplate was administered subcutaneously on a weekly basis with a maximum permitted dose of 10 microgram/kg. Across the study, the overall subject incidence of platelet response (1 or more platelet count ≥ 50 x 109/L in the absence of rescue medication) was 93.8% (61 of 65 patients). The subject incidence of platelet response was similar across age groups and similar between subjects coming from either of the previous studies.

Study 9 (20101221).

Study 9 (20101221), conducted in 203 paediatric patients, was a phase III single arm open label multicentre study in patients with ITP diagnosed for at least 6 months and who received at least one prior ITP therapy (excluding Nplate) or were ineligible for other ITP therapies. Two hundred and four patients were enrolled in the study across three age groups. Of these, 203 patients received at least one dose of Nplate and 1 patient did not receive Nplate. Nplate was administered subcutaneously, on a weekly basis, with a starting dose of 1 microgram/kg in increments to a maximum dose of 10 microgram/kg, to attain a target platelet count between 50 x 109/L and ≤ 200 x 109/L.
The incidence of patients who had at least one platelet response from week 2 to end of study was 88.2% (179 of 203 patients) overall and was similar across all age groups. Analysis of platelet response rate over time showed that overall percentage of patients with a platelet response at week 2 was 23%. The total response rate increased over time on overall study and across all age groups.
Open label study evaluating changes in bone marrow reticulin and collagen.

Adults.

An open-label trial prospectively evaluated bone marrows for reticulin formation and collagen fibrosis in adult patients with ITP receiving Nplate treatment. The modified Bauermeister grading scale was used for both assessments. Patients were administered Nplate by subcutaneous injection once weekly for up to 3 years. Based on cohort assignment at time of study enrolment, patients were evaluated for bone marrow reticulin and collagen at year 1 (cohort 1), year 2 (cohort 2) or year 3 (cohort 3) in comparison to the baseline bone marrow at start of study. From the total of 169 patients enrolled in the 3 cohorts, 132 (78.1%) patients were evaluable for bone marrow collagen fibrosis and 131 (77.5%) patients were evaluable for bone marrow reticulin formation. In total, 1.5% (2 of 132) of patients with an evaluable bone marrow trichrome stain result developed collagen. There was no detectable collagen in the one patient who underwent repeat testing 12 weeks after discontinuation of Nplate.
Progression of reticulin fibre formation of modified Bauermeister grade greater than or equal to 2 grades or more change or an increase to Grade 4 collagen was reported in 6.9% (9/131) of patients: 0/34 subjects in Cohort 1 (at 1 year), 2/39 (5.1%) subjects in Cohort 2 (at 2 years) and 7/58 (12.1%) subjects in Cohort 3 (at 3 years).
Among those subjects who had an increased modified Bauermeister grade to grade 3 or grade 4 and underwent follow-up bone marrow biopsy in the study, increases in reticulin grade were reversible after discontinuation of romiplostim. Reticulin was not associated with adverse clinical sequelae.

Paediatrics.

An open label clinical trial evaluated the incidence of changes in bone marrow findings and increased reticulin at year 1 or year 2 following exposure to Nplate. The modified Bauermeister grading scale was used for both assessments. Patients were administered Nplate by subcutaneous injection once weekly for up to 3 years.
Sixty-six patients were enrolled in the study and of these patients, 30 patients were in cohort 1 (bone marrow samples were taken at baseline and year 1) and 36 patients were in cohort 2 (bone marrow samples taken at baseline and year 2).
No patients demonstrated any bone marrow abnormalities that were not consistent with an underlying diagnosis of ITP at baseline or during treatment. The Bauermeister scores of patients were below 1 at either baseline or during treatment, no patient met the primary endpoints for the development of collagen or increased bone marrow. At the end of the clinical study, there were no patients that had repeat follow-up bone marrow biopsy, as this was only performed on patients that are withdrawn from the study due to the presence of collagen or change to grade 3 reticulin.

5.2 Pharmacokinetic Properties

Distribution.

The pharmacokinetics of romiplostim involves target-mediated disposition through binding to the TPO receptors on the platelets and megakaryocytes. This results in non-linear volume of distribution and clearance.
The serum concentration of romiplostim administered at pharmacologically active doses (< 3 microgram/kg) was not measurable in most samples collected from healthy volunteers and patients with ITP, despite the use of a very specific and sensitive ELISA with a lower limit of quantification of 18 picogram/mL.
In patients with ITP who received chronic weekly treatment of Nplate subcutaneously (median duration of treatment 39 weeks, with up to 84 weeks for 100 patients), the pharmacokinetics of romiplostim over the dose range of 3 to 15 microgram/kg indicated that peak serum concentrations were observed about 7 to 50 hours post-dose (median: 14 hours). The half-life values ranged from 1 to 34 days (median: 3.5 days). The serum concentrations varied among patients and did not correlate with the dose administered.

Excretion.

The elimination of serum romiplostim is in part dependent on the TPO receptor on platelets. As a result, for a given dose, patients with high platelet counts are associated with low serum concentrations of romiplostim and vice versa. In another ITP clinical study no accumulation in serum concentrations was observed after weekly administration of 3 microgram/kg Nplate for 6 weeks.

Special populations.

Elderly.

The pharmacokinetic profile has not been assessed in the elderly.

Paediatric.

Pharmacokinetic data of romiplostim were collected from two studies in 21 paediatric subjects with ITP. In Study 6 (20060195), romiplostim concentrations were available from 17 subjects at doses ranging from 1 to 10 microgram/kg. In Study 8 (20090340), an open-label extension study, an intensive romiplostim concentrations were available from 4 subjects (2 at 7 microgram/kg and 2 at 9 microgram/kg). Serum concentrations of romiplostim in paediatrics with ITP were within the range observed in adult ITP subjects receiving the same dose range of romiplostim. Similar to adults with ITP, romiplostim pharmacokinetics are highly variable in paediatric subjects with ITP and are not reliable, nor predictive. The data are insufficient to draw any meaningful conclusion relating to the impact of dose and age on the pharmacokinetics of romiplostim.

Impaired hepatic function.

The pharmacokinetic profile has not been assessed in patients with impaired hepatic function.

Impaired renal function.

The pharmacokinetic profile has not been assessed in patients with impaired renal function.

Race/ethnicity.

Differences in safety and efficacy based on race or ethnicity have not been established.

5.3 Preclinical Safety Data

Genotoxicity.

The genotoxic potential of romiplostim has not been investigated.

Carcinogenicity.

The carcinogenic potential of romiplostim has not been investigated. There is a theoretical concern that romiplostim may stimulate the proliferation of existing cancerous cells that express the TPO receptor (see Section 4.4 Special Warnings and Precautions for Use, Risk of progression of myeloid malignancies or existing myelodysplastic syndromes (MDS)).

6 Pharmaceutical Particulars

6.1 List of Excipients

Nplate also contains the following ingredients: mannitol, sucrose, histidine, polysorbate 20, and hydrochloric acid-dilute (for pH adjustment).

6.2 Incompatibilities

Nplate should only be reconstituted with sterile Water for Injection. Do not mix with other medicinal product solutions.
Nplate should not be mixed with other medicinal products or given as an infusion. No other medications should be added to solutions containing romiplostim.
When dilution is required (see Section 4.2 Dose and Method of Administration, Table 5), preservative-free sterile 0.9% sodium chloride only must be used. Do not use glucose (5%) in water or sterile Water for Injections. Other diluents have not been tested.

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

Nplate should be stored at 2°C to 8°C (Refrigerate. Do not freeze). Vials should be kept in their carton to protect from light until time of use.
Reconstituted solutions of Nplate should be stored at 2°C to 8°C (Refrigerate. Do not freeze), protected from light, for up to 24 hours. However, for microbiological reasons, the reconstituted solution should be used as soon as practicable after reconstitution/preparation.
To reduce microbiological hazard, diluted Nplate should be used immediately. If not used immediately, store for no more than: 4 hours at 25°C in disposable syringes, or 4 hours in a refrigerator (2° to 8°C) in the original vials.

6.5 Nature and Contents of Container

Nplate is available in a pack containing 1 vial of either:

Presentations available in Australia.

250 microgram/0.5 mL presentation.

375 microgram romiplostim; extractable dose per vial is 250 microgram in 0.5 mL. An overfill is included in each vial to ensure that 250 microgram of romiplostim can be delivered.

500 microgram/1 mL presentation.

625 microgram romiplostim; extractable dose per vial is 500 microgram in 1.0 mL. An overfill is included in each vial to ensure that 500 microgram of romiplostim can be delivered.

Presentation not available in Australia.

125 microgram/0.25 mL presentation.

230 microgram romiplostim; extractable dose per vial is 125 microgram in 0.25 mL. An overfill is included in each vial to ensure that 125 microgram of romiplostim can be delivered.

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.


Romiplostim, a member of the thrombopoietin (TPO) mimetic class, is an Fc-peptide fusion protein (peptibody) that signals and activates intracellular transcriptional pathways via the TPO receptor (also known as c-Mpl) to increase platelet production. The peptibody molecule is comprised of a human immunoglobulin IgG1 Fc domain, with each single-chain subunit covalently linked at the C-terminus to a peptide chain containing two thrombopoietin receptor-binding domains. Romiplostim is produced by recombinant DNA technology in Escherichia coli (E. coli).

CAS number.

267639-76-9.

7 Medicine Schedule (Poisons Standard)

S4 Prescription Medicine.

Summary Table of Changes