Thrombocytopenia of unknown cause is known as immune thrombocytopenia (ITP). Patients may experience skin and mucosal bleeding, and in severe cases, life-threatening intracranial hemorrhage and severe visceral bleeding may occur, endangering their life and health. In April 2018, fostamatinib was approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with chronic immune thrombocytopenia (ITP) who have had an inadequate response to previous treatments. Currently, the drug has not been marketed in China. This article provides a detailed description of fostamatinib's indications, usage and dosage, side effects, contraindications, clinical efficacy, etc.
(1) Indications
Fostamatinib (Tavalisse) is indicated for adult patients with chronic immune thrombocytopenia (ITP) who have had an inadequate response to previous treatments.
(2) Usage and Dosage
Recommended Dose
(1) The recommended starting dose of fostamatinib is 100mg orally, twice daily. After one month, if the platelet count does not increase to ≥50×10⁹/L, the dose of fostamatinib is increased to 150mg twice daily.
(2) Use the lowest dose of fostamatinib to achieve and maintain a platelet count of ≥50×10⁹/L to reduce the risk of bleeding.
(3) Fostamatinib can be taken with or without food. If a dose of fostamatinib is missed, instruct the patient to take the next dose as scheduled in the medication plan.
Monitoring
(1) Monitor the complete blood count (CBC) including platelet count once a month until the platelet count (at least 50×10⁹/L) reaches a stable level, and then continue to monitor the complete blood count including neutrophil count regularly.
(2) Monitor liver function tests (LFTs) once a month, such as alanine transaminase (ALT), aspartate transaminase (AST), and bilirubin.
(3) Monitor blood pressure every 2 weeks until the dose is stable, and then once a month thereafter.
Dose Adjustment for Drug Interactions
Concomitant use of fostamatinib with strong CYP3A4 inhibitors will increase the exposure of R406 (the main active metabolite). When used in combination with strong CYP3A4 inhibitors, monitor for fostamatinib dose-related toxicity and consider whether dosage adjustment is necessary.
Discontinuation
If the platelet count still does not increase to a level sufficient to avoid clinically significant bleeding, discontinue fostamatinib after 12 weeks of treatment.
(3) Target Population
Adults. Pregnant and lactating women, as well as elderly and pediatric patients, should use the drug under the guidance of a doctor.
(4) Contraindications
Not yet clearly defined.
(5) Side Effects
The most common adverse reactions (incidence ≥5% and higher than placebo) are diarrhea, hypertension, nausea, respiratory tract infection, dizziness, increased alanine transaminase/aspartate transaminase, rash, abdominal pain, fatigue, chest pain, and neutropenia.
(6) Precautions
Hypertension
(1) Hypertension can occur during fostamatinib treatment, and patients with pre-existing hypertension may be more susceptible. Blood pressure should be monitored every 2 weeks until the dose is stable, then initiate antihypertensive treatment or adjust the hypertension treatment plan monthly to ensure that blood pressure control is maintained during fostamatinib treatment.
(2) If blood pressure remains elevated despite appropriate treatment, it may be necessary to suspend, reduce, or discontinue the medication.
Hepatic Toxicity
Patients receiving fostamatinib treatment may experience elevated liver function tests (LFTs), mainly increased alanine transaminase and aspartate transaminase. Most patients' transaminase levels can return to baseline within 2-6 weeks after dose adjustment. Monitor liver function tests once a month during treatment. If alanine transaminase or aspartate transaminase increases more than 3 times the upper limit of normal (ULN), suspend, reduce, or discontinue the medication to manage hepatic toxicity.
Diarrhea
(1) Monitor patients for the occurrence of diarrhea. In the early stage of symptom onset, adopt supportive care measures, including dietary changes, rehydration, and/or use of anti-diarrheal drugs to control diarrhea.
(2) If diarrhea worsens (≥Grade 3), it is necessary to suspend, reduce, or discontinue the medication.
Neutropenia
(1) Monitor the absolute neutrophil count (ANC) once a month and monitor patients for infection during fostamatinib treatment.
(2) Manage toxicity by suspending, reducing, or discontinuing the medication.
Embryo-Fetal Toxicity
(1) Based on animal studies and its mechanism of action, administration of fostamatinib to pregnant women may cause harm to the fetus. Pregnant women should be warned of the potential risk to the fetus.
(2) It is recommended that women of childbearing potential use effective contraception for at least 1 month after the last dose during treatment.
(7) Therapeutic Effect
Fostamatinib is an oral Syk inhibitor. In two clinical trials, FIT1 and FIT2, its efficacy and safety in patients with persistent/chronic immune thrombocytopenia were evaluated. The results showed that 18% of patients in the fostamatinib treatment group achieved stable remission, compared with only 2% in the control group. 43% of patients in the fostamatinib treatment group achieved an overall response, compared with 14% in the control group. The median time to response in the fostamatinib treatment group (100mg/day) was 15 days, and 83% of patients responded within 8 weeks.
The most common adverse reactions are diarrhea, hypertension, nausea, dizziness, and increased alanine transaminase, most of which are mild or moderate and can be relieved spontaneously or through drug treatment (antihypertensive, antikinetic drugs). Studies have confirmed that fostamatinib produces clinically significant remission in patients with immune thrombocytopenia with good safety.
(8) Drug Interactions
Effects of Other Drugs on Fostamatinib
(1) Strong CYP3A4 Inhibitors
Concomitant use of fostamatinib with strong CYP3A4 inhibitors will increase the exposure of R406 (the main active metabolite), which may increase the risk of adverse reactions. Therefore, when used in combination with strong CYP3A4 inhibitors, monitor for fostamatinib dose-related toxicity and consider whether dosage adjustment is necessary. Strong CYP3A4 inhibitors include itraconazole (broad-spectrum antifungal), ketoconazole (broad-spectrum antifungal), voriconazole (broad-spectrum antifungal), etc.
(2) Strong CYP3A4 Inducers
Concomitant use of fostamatinib with strong CYP3A4 inducers can reduce the exposure of R406. Therefore, it is not recommended to use fostamatinib in combination with strong CYP3A4 inducers. Strong CYP3A4 inducers include rifampicin (anti-tuberculosis), rifapentine (anti-tuberculosis, anti-leprosy), phenytoin (anti-epileptic, anti-arrhythmic, trigeminal neuralgia), etc.
Effects of Fostamatinib on Other Drugs
(1) CYP3A4 Substrates
Concomitant use of fostamatinib with CYP3A4 substrates may increase the drug concentration of some CYP3A4 substrates. Therefore, when used in combination with CYP3A4 substrates, monitor for fostamatinib dose-related toxicity and consider whether dosage adjustment is necessary. CYP3A4 substrates include cimetidine, ketoconazole, acetaminophen, etc.
(2) BCRP Substrates
Concomitant use of fostamatinib with BCRP substrates may increase the drug concentration of some BCRP substrates. Therefore, when used in combination with BCRP substrates, monitor for fostamatinib dose-related toxicity and consider whether dosage adjustment is necessary. BCRP substrates include methotrexate, daunorubicin, mitoxantrone, etc.
(3) P-gp Substrates
Concomitant use of fostamatinib with P-gp substrates may increase the drug concentration of P-gp substrates (such as digoxin). Monitor for toxicity of P-gp substrate drugs. When used in combination with fostamatinib, dosage reduction may be necessary. P-gp substrates include pazopanib (advanced renal cell carcinoma, soft tissue sarcoma, epithelial ovarian cancer, non-small cell lung cancer), everolimus (advanced renal cell carcinoma, pancreatic neuroendocrine tumors), etc.
(9) Storage Conditions
Fostamatinib is a round, biconvex, orange film-coated tablet. It should be stored at room temperature of 20-25°C. Do not remove the desiccant from the bottle.
