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.

What is in this leaflet

This leaflet answers some common questions about Nplate.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Nplate against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

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

What Nplate is used for

Nplate is used to treat low blood platelet counts in people with immune (idiopathic) thrombocytopenic purpura (called ITP). ITP is a disease in which your immune system destroys your platelets.

Platelets are the cells in your blood that help seal cuts and form blood clots. If you have too few platelets you could bruise more easily than normal. You could also bleed for a long time after being injured. If your platelet count is very low, you may be at risk of serious, life-threatening bleeding.

This medicine works by increasing the number of platelets made by your body. Nplate makes your bone marrow produce more platelets. This helps to prevent bruising and bleeding.

Your doctor, however, may prescribe Nplate for another purpose.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. This medicine is available only with a doctor's prescription.

Before you are given Nplate

When you must not be given it

Do not use Nplate if you have an allergy to:

  • any medicine containing romiplostim
  • any of the ingredients listed at the end of this leaflet.
  • any medicines that are produced using the bacteria E.coli.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • add any other specific reactions listed in the PI.

Do not use it after the expiry date (EXP) date printed on the pack. If you use it after the expiry date has passed, it may have no effect, or an unexpected effect.

It may affect your developing baby if you take it during pregnancy.

Do not use it if the packaging is torn or shows signs of tampering.

Do not use it if the Nplate solution is cloudy or discoloured, or if it contains clumps or flakes.

If you are not sure whether you should be given this medicine, talk to your doctor.

Before you given it

Tell your doctor if:

  • you have allergies to:
    - any other medicines
    - any other substances such as foods, preservatives or dyes.
  • you are pregnant or intend to become pregnant
    - Nplate is not recommended to be used during pregnancy. Your doctor can discuss with you the risks and benefits involved.
    - you are breast-feeding or planning to breast-feed.
  • you have or have had any of the following medical conditions:
    - liver problems
    - kidney problems
    - blood clot
    - cancer or precancer of the blood

If you have not told your doctor about any of the above, tell him/her before you start taking Nplate.

Tell your doctor if you stop taking Nplate. Your blood platelet count may return to low levels and put you at risk of bleeding if you stop taking Nplate. Your doctor will discuss the risks with you.

Taking other medicines

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

How Nplate is given

Nplate is given as an injection under the skin. This is called a subcutaneous injection.

Nplate should be given to you under the guidance of an experienced doctor or nurse.

Self-administration is not recommended in children.

It is recommended that children receive their Nplate injection from an experienced doctor or nurse.

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

How much is given

Adult
When you first start using Nplate your dose is 1 microgram per kilogram of your body weight, given once a week.

Your doctor will adjust your dose of Nplate depending on your blood platelet count.

Children (1 to 17 years)
When you first start using Nplate your dose is 1 microgram per kilogram of your body weight, given once a week.

Your doctor will adjust your dose of Nplate depending on your blood platelet count and any changes in your body weight.

When to use it

Nplate is injected once per week to keep your platelet counts in a safe range.

How long to use it

Continue using your medicine for as long as your doctor tells you. This medicine helps control your condition, but does not cure it.

If you are given too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Nplate.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are using it

Things you must do

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

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

Telephone Amgen Medical Information Line on 1800 803 638 (free call within Australia) to enrol in Amgen's Pregnancy Surveillance Program if you become pregnant whilst using Nplate.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may do some blood tests to check your platelet levels from time to time to make sure the medicine is working.

Children (1 to 17 years)
Your doctor will regularly check your body weight to ensure your dose of Nplate is right for you.

Things you must not do

Do not use Nplate to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine without checking with your doctor. If you stop taking it you may return to a low blood platelet count. You will be at risk of bruising and bleeding.

If you are taking medicines which prevent blood clots (anticoagulants or -anti-platelet therapy) when you lower the dose or stop taking Nplate, you will have a greater risk of bleeding.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Nplate.

This medicine helps most people with low platelet counts, but may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. Your doctor has weighed the risks of using this medicine against the benefits they expect it will have for you.

Do not be alarmed by the lists of possible side effects. You may not experience any of them.

Ask your doctor, nurse or pharmacist to answer any questions you may have.

Tell your doctor, nurse or pharmacist if you notice any of the following and they worry you:

Adults

  • dizziness
  • headache
  • abdominal pain
  • joint or muscle pain, including shoulder pain
  • pain in your hands and feet
  • trouble or difficulty in sleeping
  • indigestion
  • burning pain, redness and warmth in your hands and feet
  • redness, heat or pain of skin
  • allergic reaction.
  • hive-like swelling beneath the skin

Children (1 to 17 years)

  • upper respiratory tract infection including a cough, runny, or blocked nose
  • inflammation or pain of the nose, throat or mouth
  • upper abdominal pain
  • gastroenteritis or diarrhoea
  • fever
  • itchy or non-itchy rash
  • bruising
  • inflammation of the eye (conjunctivitis)
  • ear infection
  • bleeding beneath the surface of the skin or bruising under the skin
  • swelling in the limbs/hands/feet.

The above list includes the more common side effects of your medicine. They are usually mild and short-lived.

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

  • tingling or numbness in your hands and feet.

If any of the following happens, stop using Nplate and tell your doctor immediately or seek medical attention:

  • swelling of the face, lips, mouth or throat which may cause difficultly in swallowing or breathing.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

Some of these side effects, for example,

Adults

  • low blood platelet count after stopping Nplate,
  • very high platelet count,
  • increased bone marrow fibres

Children (1 to 17 years)

  • very high platelet count

This can only be found when your doctor does tests from time to time to check your progress.

After using Nplate

Storage

If you need to store Nplate:

Keep your medicine in the refrigerator, between 2°C and 8°C. Do not freeze.

Keep your medicine in the pack until it is time to use it. Protect it from light. If you take the powder out of the pack it will not keep well.

Do not shake or vigorously agitate the vial.

After Nplate powder has been dissolved, use the solution as soon as possible.

If the dissolved Nplate solution will not 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.

Use only one dose per vial of dissolved Nplate; do not re-enter the vial. Discard unused portions. Do not save unused Nplate for later administration.

Do not freeze dissolved Nplate solution.

Do not place Nplate or dissolved Nplate solution in a freezer or in the freezer compartment of a refrigerator.

Keep it where children cannot reach it.

Disposal

Return any unused or expired medicine to your pharmacist.

Product description

What it looks like

Your Nplate is supplied as white powder in a glass vial.

Nplate comes in two pack sizes:

  • Nplate 250 µg/0.5 mL and
  • Nplate 500 µg/1 mL

Each pack contains one vial.

It is prepared for use by dissolving the powder in sterile Water for Injections:

250µg/0.5mL vial containing 375µg romiplostim: powder dissolved in 0.72mL sterile Water for Injections

500µg/1mL vial containing 625µg romiplostim: powder dissolved in 1.2mL sterile Water for Injections.

The powder should dissolve in less than 2 minutes.

Ingredients

Active ingredient: romiplostim (rbe).

Inactive ingredients: mannitol, sucrose, histidine, diluted hydrochloric acid and polysorbate 20.

This medicine does not contain lactose, gluten, tartrazine or any other azo dyes.

Manufacturer/ Supplier

Nplate is supplied in Australia by:

Amgen Australia Pty Ltd
(ABN 31 051 057 428)
Level 7, 123 Epping Road
NORTH RYDE NSW 2113
Medical Information 1800 803 638

This leaflet was prepared in June 2019.

Australian Registration Numbers:

375 µg vial: 147187

625 µg vial: 147188

Nplate is a registered trademark of Amgen.

Published by MIMS October 2019

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 Section 4.2, Administration precautions.
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.

Thrombotic/ thromboembolic events including deep vein thrombosis, pulmonary embolism, and myocardial infarction have been observed with the use of romiplostim in the ITP population. These events have occurred regardless of platelet count (see Section 4.8 Adverse Effects (Undesirable Effects)).
Monitor patients for signs and symptoms of thrombotic/ thromboembolic events and treat promptly as per institutional guidance and standard medical practice.
To minimise the risk for thrombocytosis, do not use Nplate in an attempt to "normalise" platelet counts. Follow the dose adjustment guidance 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.
 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.

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).
Thrombotic/ thromboembolic adverse drug reactions in the ITP patient population included deep vein thrombosis, pulmonary embolism and myocardial infarction. The subject incidence in the romiplostim arms (n = 1046) versus the control arms (n=133, placebo and standard of care) for deep vein thrombosis was 1.4% versus 0.8%, pulmonary embolism 1.2% versus 0.8%, and myocardial infarction 0.8% versus 0%, respectively (see Section 4.4 Special Warnings and Precautions for Use, Thrombotic/ thromboembolic complications).

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.

As with all therapeutic proteins, there is a potential for 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.
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.
Cases of acute myocardial infarction have been reported.

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 in 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