Source: European Medicines Agency (EU) Revision Year: 2020 Publisher: Amgen Europe B.V., Minervum 7061, 4817 ZK Breda, The Netherlands
Nplate is indicated for chronic immune (idiopathic) thrombocytopenic purpura (ITP) patients one year of age and older who are refractory to other treatments (e.g. corticosteroids, immunoglobulins) (see sections 4.2 and 5.1).
Treatment should remain under the supervision of a physician who is experienced in the treatment of haematological diseases.
Nplate should be administered once weekly as a subcutaneous injection.
The initial dose of romiplostim is 1 mcg/kg based on actual body weight.
The volume of romiplostim to administer is calculated based on body weight, dose required, and concentration of product.
Table 1. Guidelines for calculating individual patient dose and volume of romiplostim to administer:
| Individual patient dose (mcg) | Individual patient dose (mcg) = weight (kg) x dose in mcg/kg |
| Actual body weight at initiation of treatment should always be used when calculating initial dose. | |
| In adults, future dose adjustments are based on changes in platelet counts only. | |
| In paediatric patients, future dose adjustments are based on changes in platelet counts and changes in body weight. Reassessment of body weight is recommended every 12 weeks. | |
| If individual patient dose is ≥23 mcg | Reconstitute lyophilised product as described in section 6.6. The resulting concentration is 500 mcg/mL. |
| Volume to administer (mL) = Individual patient dose (mcg) / 500 mcg/mL (Round volume to the nearest hundredth mL) | |
| If individual patient dose is <23 mcg | Dilution is required to ensure accurate dosing. Reconstitute lyophilised product and then dilute the product as described in section 6.6. The resulting concentration is 125 mcg/mL. |
| Volume to administer (mL) = Individual patient dose (mcg) / 125 mcg/mL (Round volume to the nearest hundredth mL) | |
| Example | 10 kg patient is initiated at 1 mcg/kg of romiplostim. |
| Individual patient dose (mcg) = 10 kg x 1 mcg/kg = 10 mcg | |
| Because the dose is <23 mcg, dilution is required to ensure accurate dosing. Reconstitute lyophilised product and then dilute the product as described in section 6.6. The resulting concentration is 125 mcg/mL. | |
| Volume to administer (mL) = 10 mcg / 125 mcg/mL = 0.08 mL |
A subject’s actual body weight at initiation of therapy should be used to calculate dose. The once weekly dose of romiplostim should be increased by increments of 1 mcg/kg until the patient achieves a platelet count ≥50 × 109/L. Platelet counts should be assessed weekly until a stable platelet count (≥50 × 109/L for at least 4 weeks without dose adjustment) has been achieved. Platelet counts should be assessed monthly thereafter and appropriate dose adjustments made as per the dose adjustment table (table 2) in order to maintain platelet counts within the recommended range. See table 2 below for dose adjustment and monitoring. A maximum once weekly dose of 10 mcg/kg should not be exceeded.
Table 2. Dose adjustment guidance based on platelet count:
| Platelet count (x 109/l) | Action |
|---|---|
| <50 | Increase once weekly dose by 1 mcg/kg |
| >150 for two consecutive weeks | Decrease once weekly dose by 1 mcg/kg |
| >250 | Do not administer, continue to assess the platelet count weekly. |
| After the platelet count has fallen to <150 × 109/1, resume dosing with once weekly dose reduced by 1 mcg/kg |
Due to the interindividual variable platelet response, in some patients platelet count may abruptly fall below 50 × 109/L after dose reduction or treatment discontinuation. In these cases, if clinically appropriate, higher cut-off levels of platelet count for dose reduction (200 × 109/L) and treatment interruption (400 × 109/L) may be considered according to medical judgement.
A loss of response or failure to maintain a platelet response with romiplostim within the recommended dosing range should prompt a search for causative factors (see section 4.4, loss of response to romiplostim).
Treatment with romiplostim should be discontinued if the platelet count does not increase to a level sufficient to avoid clinically important bleeding after four weeks of romiplostim therapy at the highest weekly dose of 10 mcg/kg.
Patients should be clinically evaluated periodically and continuation of treatment should be decided on an individual basis by the treating physician, and in non-splenectomised patients this should include evaluation relative to splenectomy. The reoccurrence of thrombocytopenia is likely upon discontinuation of treatment (see section 4.4).
No overall differences in safety or efficacy have been observed in patients <65 and ≥65 years of age (see section 5.1). Although based on these data no adjustment of the dosing regimen is required for older patients, care is advised considering the small number of elderly patients included in the clinical trials so far.
The safety and efficacy of romiplostim in children under the age of one year has not been established.
Romiplostim should not be used in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) unless the expected benefit outweighs the identified risk of portal venous thrombosis in patients with thrombocytopenia associated to hepatic insufficiency treated with thrombopoietin (TPO) agonists (see section 4.4).
If the use of romiplostim is deemed necessary, platelet count should be closely monitored to minimise the risk of thromboembolic complications.
No formal clinical trials have been conducted in these patient populations. Nplate should be used with caution in these populations.
For subcutaneous use.
After reconstitution of the powder, Nplate solution for injection is administered subcutaneously. The injection volume may be very small. Caution should be used during preparation of Nplate in calculating the dose and reconstitution with the correct volume of sterile water for injection. If the calculated individual patient dose is less than 23 mcg, dilution with preservative-free, sterile, sodium chloride 9 mg/mL (0.9%) solution for injection is required to ensure accurate dosing (see section 6.6). Special care should be taken to ensure that the appropriate volume of Nplate is withdrawn from the vial for subcutaneous administration – a syringe with graduations of 0.01 mL should be used.
Self-administration of Nplate is not allowed for paediatric patients.
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
No adverse effects were seen in rats given a single dose of 1,000 mcg/kg or in monkeys after repeated administration of romiplostim at 500 mcg/kg (100 or 50 times the maximum clinical dose of 10 mcg/kg, respectively).
In the event of overdose, platelet counts may increase excessively and result in 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 (see sections 4.2 and 4.4).
Shelf life: 5 years.
After reconstitution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C and for 24 hours at 2°C–8°C, when protected from light and kept in the original vial.
From a microbiological point of view, the medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 25°C or 24 hours in a refrigerator (2°C–8°C), protected from light.
After dilution: Chemical and physical in-use stability has been demonstrated for 4 hours at 25°C when the diluted product was held in a disposable syringe, or 4 hours in a refrigerator (2°C–8°C) when the diluted product was held in the original vial.
From a microbiological point of view, the diluted medicinal product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 4 hours at 25°C in disposable syringes, or 4 hours in a refrigerator (2°C–8°C) in the original vials, protected from light.
Store in a refrigerator (2°C–8°C).
Do not freeze.
Store in the original carton in order to protect from light.
May be removed from the refrigerator for a period of 30 days at room temperature (up to 25°C) when stored in the original carton.
For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.
Single-dose vial (type 1 clear glass) with a stopper (chlorobutyl rubber), seal (aluminium) and a flip-off cap (polypropylene). The 125 mcg vial cap is beige, the 250 mcg vial cap is red and the 500 mcg vial cap is blue.
Carton containing 1 or 4 vials of romiplostim.
Not all pack sizes may be marketed.
Nplate is a sterile but unpreserved medicinal product and is intended for single use only. Nplate should be reconstituted in accordance with good aseptic practice.
Nplate 125 micrograms powder for solution for injection should be reconstituted with 0.44 mL sterile water for injections, yielding a deliverable volume of 0.25 mL. An additional overfill is included in each vial to ensure that 125 mcg of romiplostim can be delivered (see vial content table below).
Nplate 250 micrograms powder for solution for injection should be reconstituted with 0.72 mL sterile water for injections, yielding a deliverable volume of 0.5 mL. An additional overfill is included in each vial to ensure that 250 mcg of romiplostim can be delivered (see vial content table below).
Nplate 500 micrograms powder for solution for injection should be reconstituted with 1.2 mL sterile water for injections, yielding a deliverable volume of 1 mL. An additional overfill is included in each vial to ensure that 500 mcg of romiplostim can be delivered (see vial content table below).
Vial Content:
| Nplate single-use vial | Total vial content of romiplostim | Volume of sterile water for injection | Deliverable product and volume | Final concentration | ||
|---|---|---|---|---|---|---|
| 125 mcg | 230 mcg | + | 0.44 ml | = | 125 mcg σε 0.25 ml | 500 mcg/ml |
| 250 mcg | 375 mcg | + | 0.72 ml | = | 250 mcg σε 0.50 ml | 500 mcg/ml |
| 500 mcg | 625 mcg | + | 1.20 ml | = | 500 mcg σε 1.00 ml | 500 mcg/ml |
Sterile water for injections only should be used when reconstituting the medicinal product. Sodium chloride solutions or bacteriostatic water should not be used when reconstituting the medicinal product.
Water for injections should be injected into the vial. The vial contents may be swirled gently and inverted during dissolution. The vial should not be shaken or vigorously agitated. Generally, dissolution of Nplate takes less than 2 minutes. Visually inspect the solution for particulate matter and discolouration before administration. The reconstituted solution should be clear and colourless and should not be administered if particulate matter and/or discolouration are observed.
For the storage condition after reconstitution of the medicinal product see section 6.3.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Initial reconstitution of romiplostim with designated volumes of sterile water for injections results in a concentration of 500 mcg/mL in all vial sizes. If the calculated individual patient dose is less than 23 mcg (see section 4.2), an additional dilution step to 125 mcg/mL with preservative-free, sterile, sodium chloride 9 mg/mL (0.9%) solution for injection is required to ensure accurate volume (see table below).
Dilution Guidelines:
| Nplate single-use vial | Add this volume of preservative-free, sterile, sodium chloride 9 mg/mL (0.9%) solution for injection to the reconstituted vial | Concentration after dilution |
|---|---|---|
| 125 mcg | 1.38 ml | 125 mcg/ml |
| 250 mcg | 2.25 ml | 125 mcg/ml |
| 500 mcg | 3.75 ml | 125 mcg/ml |
Preservative-free, sterile, sodium chloride 9 mg/mL (0.9%) solution for injection only must be used for dilution. Dextrose (5%) in water or sterile water for injection should not be used for the dilution. No other diluents have been tested.
For the storage condition after dilution of the reconstituted medicinal product see section 6.3.
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