Fostamatinib – Uses, Dosage, Side Effects, Interaction

The active metabolite of fostamatinib, R406, is an inhibitor of spleen tyrosine kinase (Syk). It binds reversibly to the ATP binding pocket with high affinity (Ki = 30nM), inhibiting the kinase activity with an IC50 of 41nM. Syk is a cytosolic protein kinase and part of the signaling cascade which occurs with Fc receptors, TCRs, and BCRs. It contains two src homology 2 (SH2) domains separated by a linker domain. These SH2 domains bind to tyrosine residues on the immunoreceptor tyrosine-based activating motif phosphorylated by Lyn, another kinase in the cascade. This motif is located on the cytoplasmic regions of several immune receptors including Fc receptors, TCRs, BCRs, and natural killer cell receptors. The flexibility provided by the linker enables the protein to bind to many receptor types. Inhibition of Syk suppresses downstream signal transduction. While Syk plays a role in some pathways involved in the generation of the oxidative burst by neutrophils or phagocytosis by macrophages, R406 does not have a significant effect on these processes. This is likely due to redundant pathways which do not involve Syk. Similarly, Syk does not produce significant effects on platelet? activation despite its involvement in glycoprotein IV and integrin-based signaling. Activation of antibody-dependent cell-mediated toxicity by natural killer cells is also unaffected despite the involvement of Syk in Fc receptor signaling. R406 binds to the adenosine A3 receptor as an antagonist as well as the adenosine and monoamine uptake transporters as an inhibitor. It has also been found to be an inhibitor of UDP glucuronosyltransferase UGT1A1, phosphodiesterase PDE5, fatty acid amide hydrolase, 5-lipoxygenase, cathepsin L, and cathepsin S. R406 appears to inhibit a wide range of kinases at higher concentrations. It is thought that inhibition of some of these targets may be responsible for the increase in blood pressure seen with fostamatinib.

• Fostamatinib is indicated for use in the treatment of chronic immune thrombocytopenia (ITP) in patients who have had an insufficient response to previous therapy.
• Tables are indicated for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who are refractory? to other treatments.
• Fostamatinib is a spleen tyrosine kinase inhibitor used to treat chronic immune thrombocytopenia after attempting one other treatment.
• Treatment of idiopathic? thrombocytopenic purpura as a model for immunomodulation
• Treatment of chronic idiopathic arthritis? (including rheumatoid arthritis, ankylosing spondylarthritis, psoriatic arthritis?,. and juvenile idiopathic arthritis )
• Fostamatinib is an orally available small-molecule inhibitor of spleen tyrosine kinase that is used to treat chronic immune thrombocytopenia.
• For the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.
• Fostamatinib has been investigated for the treatment and basic science of Rheumatoid Arthritis and Immune Thrombocytopenic Purpura (ITP).
• Recently, fostamatinib has been identified as a potential therapeutic for controlling acute respiratory distress syndrome? (ARDS) in patients with severe COVID-19 through its ability to modulate the SYK kinase.
• Chronic immune thrombocytopenia

Contraindications

• low levels of a type of white blood cell called neutrophils
• high blood pressure
• liver problems
• diarrhea?
• pregnancy
• a patient who is producing milk and breastfeeding
• a significant drop in a certain type of white blood cell called a neutrophil?

Dosage?

Strengths: 100 mg; 150 mg

Thrombocytopenia

• 100 mg orally 2 times a day; after a month, if platelet count has not increased to at least 50 x 10(9)/L, increase to 150 mg orally 2 times a day
• This drug may be taken with or without food.
• In the case of a missed dose, instruct patients to take their next dose at its regularly scheduled time.
• Use the lowest dose to achieve and maintain a platelet count at least 50 x 10(9)/L to reduce the risk of bleeding.

Dose Adjustments

• Dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose interruption, reduction, or discontinuation.

MANUFACTURER SUGGESTED DOSE REDUCTION SCHEDULE:

• 300 mg/day: Taken as 150 mg orally in the AM and 150 mg orally in the PM
• 200 mg/day: Taken as 100 mg orally in the AM and 100 mg orally in the PM
• 150 mg/day: Taken as 150 mg orally in the AM
• 100 mg/day: Taken as 100 mg orally in the AM
• If further dose reduction is needed, therapy should be discontinued.

RECOMMENDED DOSE MODIFICATIONS FOR SPECIFIC ADVERSE REACTIONS:
HYPERTENSION:

• Stage 1 (systolic between 130 and 139 or diastolic between 80 and 89 mmHg: Initiate or increase dose of antihypertensive medication for patients with increased cardiovascular risk, and adjust as needed until BP is controlled. If the BP target is not met after 8 weeks, reduce the dose to the next lower daily dose.
• Stage 2 (systolic at least 140 or diastolic at least 90 mmHg: Initiate or increase dose of antihypertensive medication, and adjust as needed until BP is controlled. If the BP remains 140/90 mmHg or higher for more than 8 weeks, reduce the dose to the next lower daily dose. If BP remains 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue therapy.

HEPATOTOXICITY:

• AST/ALT is 3 x ULN or higher and less than 5 x ULN: If the patient is symptomatic (e.g., nausea?, vomiting?, abdominal pain?), interrupt therapy; recheck LFTs every 72 hours until ALT/AST values are no longer elevated (below 1.5 x ULN) and total bilirubin? (BL) remains less than 2 x ULN; resume therapy at next lower daily dose. If the patient is asymptomatic, recheck LFTs every 72 hours until ALT/AST are below 1.5 x ULN and total BL remains less than 2 x ULN; consider therapy interruption or dose reduction if ALT/AST and TBL remain in this category (AST/ALT is 3 to 5 x
• ULN; and total BL remains less than 2 x ULN); if therapy is interrupted, resume at the next lower daily dose when ALT/AST are no longer elevated (below 1.5 x
• ULN) and total BL remains less than 2 x ULN.
• AST/ALT is 5 x ULN or higher and total BL is less than 2 x ULN: Interrupt therapy and recheck LFTs every 72 hours; if AST and ALT decrease, recheck until ALT and AST are no longer elevated (below 1.5 x ULN) and total BL remains less than 2 x ULN; resume therapy at next lower daily dose; if AST/ALT persist at 5 x ULN or higher for 2 weeks or more, discontinue therapy.
• AST/ALT is 3 x ULN or higher and total BL is greater than 2 x ULN: Discontinue therapy.
• Elevated unconjugated (indirect) BL in absence of other LFT abnormalities: Continue therapy with frequent monitoring since the isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition.

DIARRHEA:

• Manage diarrhea using supportive measures (e.g., dietary changes, hydration, and/or antidiarrheal medication) early after the onset until symptoms have resolved.
• If symptom(s) become severe (Grade 3 or above), temporarily interrupt therapy.
• If diarrhea improves to mild (Grade 1), resume therapy at the next lower daily dose.

NEUTROPENIA:

• If absolute neutrophil count decreases (ANC less than 1 x 10(9)/L) and remains low after 72 hours, temporarily interrupt therapy until resolved (ANC greater than 1.5 x 10(9)/L).
• Resume therapy at the next lower daily dose.

DOSE MODIFICATION FOR DRUG INTERACTIONS

• Concomitant use with a strong CYP450 3A4 inhibitor increases exposure to R406 (the major active metabolite). Monitor for toxicities due to this drug that may require dose modifications when given concurrently with a strong CYP450 3A4 inhibitor.

DISCONTINUATION OF THERAPY:

• Discontinue therapy after 12 weeks if the platelet count does not increase to a level sufficient to avoid clinically important bleeding.

Administration advice:

• This drug may be taken with or without food.
• In case of a missed dose, the next dose should be taken at its regularly scheduled time.

Side Effects

The Most Common

• diarrhea
• nausea
• dizziness
• rash
• abdominal pain
• fatigue
• severe diarrhea
• headache, confusion, dizziness, chest pain, or shortness of breath
• pain in the upper right part of the stomach
• yellowing of the skin or eyes
• dark colored urine
• nausea
• vomiting

More common

• Black, tarry, stools
• blurred vision
• chest pain
• chills
• cough
• diarrhea
• dizziness
• fever
• headache
• lower back or side pain
• nervousness
• painful or difficult urination
• pale skin
• pounding in the ears
• slow or fast heartbeat
• sore throat
• stomach pain
• ulcers, sores, or white spots in the mouth
• unusual bleeding or bruising
• unusual tiredness or weakness

Rare

• severe diarrhea;
• stomach pain (upper right side);
• dark urine, jaundice (yellowing of the skin or eyes);
• headaches, chest pain, shortness of breath; or
• fever, sore throat, or other signs of infection.
• increased blood pressure;
• diarrhea, nausea, stomach pain;
• abnormal liver function tests;
• chest pain;
• dizziness, tiredness;
• rash; or
• cold symptoms such as stuffy nose, sneezing, and sore throat.

Drug Interactions

References