Australian Prescriber review of romiplostim, first bone marrow stimulator, for the treatment of idiopathic thrombocytopenic purpura:
vials containing 375 microgram and 625 microgram for reconstitution
Approved indication: idiopathic thrombocytopenic purpura
Australian Medicines Handbook Appendix A
One of the causes of thrombocytopenia is idiopathic thrombocytopenic purpura. As the platelets are destroyed by antiplatelet autoantibodies the condition is also known as chronic immune thrombocytopenic purpura. Other causes of thrombocytopenia should be excluded before making the diagnosis.
If the platelet count is low enough to require treatment, corticosteroids are usually prescribed first. Patients who do not respond may be given immunoglobulins. Severe thrombocytopenia can be an indication for splenectomy.
A new approach to managing idiopathic thrombocytopenic purpura is to boost platelet production rather than trying to limit platelet destruction. Romiplostim is a genetically engineered protein which binds to the thrombopoietin receptor even though its structure differs from that of human thrombopoietin. Activation of the receptor increases platelet production.
Romiplostim is given by subcutaneous injection. As the volume is small, a syringe with 0.01 mL gradations should be used. The serum concentration peaks after a median of 14 hours and the median half-life is 3.5 days.
A dose-ranging study gave romiplostim to 24 patients with previously treated immune thrombocytopenic purpura. Depending on the platelet count a second injection was given after at least 14 days. In four of the 12 patients given 3, 6 or 10 microgram/kg of romiplostim the platelet count rose to at least twice the baseline count. Lower doses were not effective.1 In another phase of this trial 21 patients were given romiplostim (1, 3 or 6 microgram/kg) or a placebo injection containing the excipients of the formulation every week for six weeks. Seven of the eight patients given 1 microgram/kg and three of the eight given 3 microgram/kg achieved the target concentration for platelets. (The 6 microgram/kg dose was dropped from the trial due to an exaggerated increase in platelets.) Adverse events which were more frequent with romiplostim than its excipients were headache and blistering of the oral mucosa.1
Using the information from the dose-ranging studies, two parallel trials were designed. Starting with 1 microgram/kg weekly the dose of romiplostim was adjusted to achieve a target platelet count of 50–200 x 109/L. One trial enrolled 62 patients and the other enrolled 63 patients following splenectomy. Both trials were placebo-controlled and lasted for six months. Within three weeks half the patients given romiplostim had reached the target. During at least six of the last eight weeks of treatment, 49% of the patients given romiplostim, but only 2% of the placebo group, were in the target range. This durable response was seen in 61% of the non-splenectomised patients and 38% of the splenectomised patients. On average, in patients given romiplostim, the platelet count was above the target for 15.2 weeks in the non-splenectomised group and 12.3 weeks in the splenectomised group. They needed less rescue therapy than patients in the placebo group who only achieved the target for a mean of 0.8 weeks.2
Adverse events which were more frequent with romiplostim than with placebo included headache, epistaxis, arthralgia, myalgia, dizziness, insomnia and abdominal pain.2 As platelet counts rise there could be an increased risk of thrombosis. An increase in the amount of reticulin in the bone marrow can cause morphological changes in blood cells. Peripheral blood films, as well as platelet counts, should be checked during treatment.
Romiplostim is not a cure for immune thrombocytopenic purpura, the platelet count will fall again after treatment is discontinued. As patients are therefore likely to require repeated treatments, establishing the long-term efficacy and safety will be important. The data are limited, but neutralising antibodies have not yet emerged as a major problem. At present the use of romiplostim will be limited to patients who have had an inadequate response to splenectomy, and those who have not had a splenectomy but cannot tolerate or have not responded to corticosteroids and immunoglobulins.
manufacturer provided clinical evaluation
1.Bussel JB, Kuter DJ, George JN, McMillan R, Aledort LM, Conklin GT, et al. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med 2006;355:1672-81.
2.Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, et al. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet 2008;371:395-403.