Fostamatinib (Monograph)

Drug class: Blood Formation, Coagulation, and Thrombosis Agents; Miscellaneous

Medically reviewed by Drugs.com on Feb 10, 2024. Written by ASHP.

Introduction

Tyrosine kinase inhibitor; active against spleen tyrosine kinase (SYK).

Uses for Fostamatinib

Chronic Immune Thrombocytopenia

Treatment of thrombocytopenia in adults with chronic immune thrombocytopenia (ITP) who have had an insufficient response to previous treatment.

Has been designated an orphan drug by FDA for treatment of ITP.

International experts recommend fostamatinib (among other agents) as second-line therapy for ITP, generally following lack of platelet response with corticosteroids and/or IV immune globulin (IVIG).

Fostamatinib Dosage and Administration

General

Pretreatment Screening

Verify pregnancy status in females of reproductive potential prior to initiating fostamatinib.

Patient Monitoring

Monitor CBC, including platelets, on a monthly basis until the platelet count is stable (≥50,000/mm³). Thereafter, monitor CBC on a regular basis.
Monitor ANC monthly, and monitor for infection during treatment.
Monitor LFTs monthly (e.g., ALT, AST, and biliburin).
Monitor BP every 2 weeks until a stable dose of fostamatinib is established, then monthly thereafter.
Monitor for diarrhea occurrence.

Administration

Oral Administration

Fostamatinib disodium hexahydrate is administered orally as a tablet.

May be taken with or without food. If a dose is missed, skip the missed dose and take the next dose at the regularly scheduled time.

Dosage

Available as fostamatinib disodium hexahydrate; dosage expressed in terms of fostamatinib.

Adults

Chronic Immune Thrombocytopenia (ITP)

Oral

Initiate at 100 mg twice daily. After 4 weeks, if the platelet count has not increased to ≥50,000/mm³, increase to 150 mg twice daily.

Use lowest effective dosage to achieve and maintain platelet count ≥50,000/mm³.

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

Dosage Modification for Toxicity

Some adverse reactions may require temporary interruption of therapy, dosage reduction, and/or permanent discontinuance of the drug. If dosage reduction is required, the dosage of fostamatinib should be reduced based on daily dose (Table 1).

If further dosage reduction required below 100 mg/day, discontinue fostamatinib.

Table 1. Dosage Reduction Schedule for Fostamatinib1
Total Daily Dose	Morning Dose	Evening Dose
300 mg	150 mg	150 mg
200 mg	100 mg	100 mg
150 mg	150 mg	---
100 mg	100 mg	---

The recommended dosage modification for adverse effects depends on severity (see Table 2).

Abbreviations: ANC, absolute neutrophil count; BP, blood pressure; CV, cardiovascular; DBP, diastolic blood pressure; LFTs, liver function tests; SBP, systolic blood pressure; UGT, UDP-glucuronosyltransferase; ULN, upper limit of normal.

Table 2. Recommended Dosage Modifications for Specific Adverse Effects1
Adverse Reaction	Severity	Recommended Action
Hypertension
	Stage 1: SBP 130—139 mmHg or DBP 80—89 mmHg	Initiate or increase dosage of antihypertensive medication in patients at increased CV risk; adjust until BP controlled If BP not at goal after 8 weeks, reduce daily fostamatinib dose to the next lower daily dose (See Table 1)
	Stage 2: SBP ≥140 mmHg or DBP ≥90 mmHg	Initiate or increase dosage of antihypertensive medication; adjust until BP controlled If BP remains ≥140/90 mmHg for longer than 8 weeks, reduce daily fostamatinib dose to the next lower daily dose (See Table 1) If BP remains ≥160/100 mmHg for longer than 4 weeks despite aggressive antihypertensive therapy, temporarily interrupt or discontinue fostamatinib
	Hypertensive crisis: SBP >180 mmHg or DBP >120 mmHg	Temporarily interrupt or discontinue fostamatinib Initiate or increase dosage of antihypertensive medication; adjust until BP controlled. If BP decreases to below target BP, resume fostamatinib at same daily dosage If BP remains ≥160/100 mmHg for longer than 4 weeks despite aggressive antihypertensive therapy, discontinue treatment with fostamatinib
Hepatotoxicity
	AST/ALT ≥3 x ULN and <5 x ULN	If symptomatic (e.g., nausea, vomiting, and abdominal pain), temporarily interrupt fostamatinib, and recheck LFTs every 72 hours until AST/ALT <1.5 x ULN and total bilirubin <2 x ULN. Resume fostamatinib at the next lower daily dose (See Table 1) If asymptomatic, recheck LFTs every 72 hours until AST/ALT <1.5 x ULN and total bilirubin <2 x ULN. Consider temporary interruption or dosage reduction if AST/ALT remains 3–5 x ULN and total bilirubin remains <2 x ULN. If temporary interruption, resume fostamatinib at next lower daily dose (see Table 1) when AST/ALT no longer elevated (<1.5 x ULN) and total bilirubin <2 x ULN
	AST/ALT ≥5 x ULN and total bilirubin <2 x ULN	Temporarily interrupt fostamatinib Reheck LFTs every 72 hours; if AST/ALT decline, recheck until AST/ALT no longer elevated (<1.5 x ULN) and total bilirubin <2 x ULN; resume fostamatinib at next lower daily dose (see Table 1). If AST/ALT remain ≥5 x ULN for ≥2 weeks, discontinue fostamatinib
	AST/ALT ≥3 x ULN and total bilirubin >2 x ULN	Discontinue fostamatinib
	Elevated unconjugated (indirect) bilirubin in the absence of other LFT abnormalities	May continue fostamatinib with freqent monitoring, as the increase in uconjugated bilirubin may be due to inhibition of UGT1A1
Diarrhea
	Any	Use supportive care measures such as dietary changes, hydration, and/or antidiarrheals early after symptom onset until symptoms resolve
	Grade 3 and above	If symptoms progress to severe (grade 3 or above), temporarily interrupt fostamatinib If diarrhea symptoms improve to mild (grade 1), resume fostamatinib at the next lower daily dose (see Table 1)
Neutropenia
	ANC <1000/mm³	If the ANC decreases to <1000/mm³ and remains low after 72 hours, temporarily interrupt fostamatinib until ANC is recovered above 1500/mm³ Resume fostamatinib at the next lower daily dose (see Table 1)

Special Populations

Hepatic Impairment

No specific dosage recommendations.

Renal Impairment

No specific dosage recommendations.

Geriatric Patients

No specific dosage recommendations.

Cautions for Fostamatinib

Contraindications

None.

Warnings/Precautions

Hypertension

Hypertension reported, including hypertensive crisis. Pre-existing hypertension may increase susceptibility to hypertensive effects of fostamatinib.

While on fostamatinib, monitor BP every 2 weeks until stable, then monthly, adjusting or initiating antihypertensive medications to ensure adequate BP control. If hypertension persists despite appropriate treatment, consider temporary interruption, dosage reduction, or discontinuation of fostamatinib.

Hepatotoxicity

Elevations in LFTs, mainly ALT and AST, may occur.

Within 2—6 weeks of dosage modification, transaminases normalized to baseline levels in most patients.

Monitor LFTs monthly during treatment; if ALT or AST increases to >3 × ULN, manage hepatoxicity with temporary interruption, dosage reduction, or discontinuation of fostamatinib.

Diarrhea

Diarrhea, including severe diarrhea, reported.

Monitor for diarrhea during treatment. Manage using supportive care measures early after symptom onset; supportive care measures include dietary changes and hydration, with or without antidiarrheal medications. If diarrhea becomes severe (grade 3 or greater), manage with temporary interruption, dosage reduction, or discontinuation of fostamatinib.

Neutropenia

Neutropenia and febrile neutropenia reported.

Monitor ANC monthly during treatment, and monitor for presence of infection. If neutropenia or infection develops, manage toxicity with temporary interruption, dosage reduction or discontinuation of fostamatinib.

Fetal/Neonatal Morbidity and Mortality

Based on animal data and its mechanism of action, fostamatinib may result in fetal harm when administered during pregnancy.

Inform pregnant women of the potential fetal risk. Verify pregnancy status in females of reproductive potential prior to initiation of fostamatinib, and advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose.

Specific Populations

Pregnancy.

Based on animal data and its mechanism of action, fostamatinib may result in fetal harm when administered during pregnancy.

No data available in pregnant women.

Verify pregnancy status in females of reproductive potential prior to initiation of fostamatinib, and advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the final dose. Inform pregnant women of the potential fetal risk.

Lactation.

No data available on presence of fostamatinib or its metabolites in human milk. Effects on the breast-fed infant and milk production not known. In rodents, the active metabolite (R406) was detectable in maternal breastmilk at concentrations 5- to 10-fold higher than in maternal plasma. Due to the potential for serious adverse reactions to fostamatinib in the breast-fed infant, advise women to avoid breastfeeding during fostamatinib therapy and for at least 1 month following the final dose.

Females and Males of Reproductive Potential.

No data available on the impact of fostamatinib therapy on fertility. Based on reduced rates of pregnancy in animal studies, fostamatinib may affect fertility in females.

Pediatric Use.

Safety and efficacy not established in pediatric patients; adverse effects on active bone growth observed in nonclinical studies.

Geriatric Use.

In studies of patients with chronic ITP who received fostamatinib, 27% were ≥65 years of age and 11% were ≥75 years of age. No overall differences in efficacy observed relative to younger adults. Serious adverse reactions, adverse reactions leading to treatment withdrawal, and hypertension reported more frequently in geriatric patients.

Hepatic Impairment.

Mild (Child-Pugh A), moderate (Child-Pugh B), or severe (Child-Pugh C) hepatic impairment: Pharmacokinetics not substantially altered.

Renal Impairment.

Moderate renal impairment (Cl_cr 30—49 mL/minute) and end-stage renal disease (ESRD) requiring dialysis: Pharmacokinetics not substantially altered.

Common Adverse Effects

Adverse effects (≥5%) include diarrhea, hypertension, nausea, respiratory infection, dizziness, increases in ALT/AST, rash, abdominal pain, fatigue, chest pain, neutropenia.

Drug Interactions

Fostamatinib disodium metabolized by alkaline phosphatase to its major active metabolite, R406. In vitro, R406 principally metabolized by CYP3A4 and UGT1A9. R406 inhibits CYP3A4 and breast cancer resistance protein (BCRP), and induces CYP2C8.

In vitro, fostamatinib disodium inhibits P-glycoprotein (P-gp). R406 is a substrate of P-gp, but not of organic anion transporter (OAT)1, OAT3, organic cation transporter (OCT) 2, organic anion transporter polypeptide (OATP) 1B1, OATP1B3, multi-drug resistance protein (MRP) 2, or BCRP. R406 inhibits UGT1A1, which can cause increased circulating levels of unconjugated bilirubin, even in the absence of other abnormal LFTs.

Drugs Affecting Hepatic Microsomal Enzymes

Strong CYP3A4 inhibitors: Increased exposure to the active metabolite R406, and increased incidence of adverse effects when used concomitantly. Monitor for signs of toxicities that may necessitate a dosage reduction of fostamatinib.

Strong CYP3A4 inducers: Reduced exposure to the active major metabolite R406. Concomitant use of strong CYP3A4 inducers (e.g., rifampicin) not recommended.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP3A4 substrates: Possible increased exposure to the CYP3A4 substrate (e.g., simvastatin) and increased incidence of adverse effects.

No clinically relevant interactions with concomitant use of fostamatinib with the CYP3A4 substrate midazolam, or the CYP2C8 substrate pioglitazone.

Drugs Affected by Transport Systems

P-gp substrates: Possible increased concentrations of the P-gp substrate (e.g., digoxin) and increased incidence of adverse effects. Monitor for toxicities from the P-gp substrate that may necessitate dosage reduction of the substrate if used concomitantly.

BCRP substrates: Possible increased concentrations of the BCRP substrate (e.g., rosuvastatin) and increased incidence of adverse effects. Monitor for toxicities from the BCRP substrate that may necessitate a dosage reduction of the substrate if used concomitantly.

OAT1/OAT3 transporter substrates: No clinically relevant interactions when fostamatinib used concomitantly with the OAT1 and OAT3 transporter substrate methotrexate.

Specific Drugs

Drug	Interaction	Comments
Digoxin	Increased AUC and peak plasma concentrations of digoxin by 37% and 70%, respectively	Monitor for digoxin toxicities and adjust dosage as necessary
Drugs affecting gastric acidity	No clinically relevant interactions with ranitidine (which increases gastic pH)
Hormonal contraceptives	No clinically relevant interactions with ethinyl estradiol/levonorgestrel
Ketoconazole	Increased AUC and peak plasma concentrations of the active metabolite R406 by 102% and 37%, respectively	Monitor for fostamatinib toxicities that necessitate a dosage reduction
Methotrexate	No clinically relevant interaction observed
Midazolam	No clinically relevant interaction observed
Pioglitazone	No clinically relevant interaction observed
Rifampicin	Decreased AUC and peak plasma concentrations of the active metabolite R406 by 75% and 59%, respectively	Concomitant use not recommended
Rosuvastatin	Increased AUC and peak plasma concentrations of rosuvastatin by 95% and 88%, respectively	Monitor for rosuvastatin toxicities and adjust dosage as necessary
Simvastatin	Increased AUC and peak plasma concentrations of simvastatin by 64% and 113%, respectively, and AUC and peak plasma concentrations of simvastatin acid by 64% and 83%, respectively	Monitor for simvastatin toxicities and adjust dosage as necessary
Verapamil	Increased AUC and peak plasma concentratrations of the active metabolite R406 by 39% and 6%, respectively
Warfarin	No clinically relevant interaction observed

Fostamatinib Pharmacokinetics

Absorption

Bioavailability

Fostamatinib disodium is a prodrug; undergoes metabolism in the gut to its major active metabolite, R406.

Exposure to R406 approximately dose-proportional at dosages up to 200 mg twice daily (1.3 times the maximum recommended human dose [MHRD] of 150 mg twice daily).

With twice daily administration of 100—160 mg doses of fostamatinib disodium (0.67 to 1.06 the MRHD of 150 mg twice daily), accumulation of R406 2- to 3-fold.

Following oral administration, peak plasma concentrations of R406 attained in a median of 1.5 hours (range: 1—4 hours); plasma levels of fostamatinib are negligible.

Bioavailability of R406 after fostamatinib disodium administration, 55%.

Food

Administration of fostamatinib disodium with a high-calorie, high-fat meal increases the R406 AUC and peak plasma concentrations by 23% and 15%, respectively; however, may be taken with or without food.

Special Populations

Systemic exposure to fostamatinib disodium not affected by age, sex, race/ethnicity, renal impairment (Cl_cr 30—49 mL/minute or end-stage renal disease [ESRD] requiring dialysis) or hepatic impairment (Child Pugh Class A, B, or C).

Distribution

Extent

Not known whether excreted into human milk. In rodents, R406 detectable in breastmilk.

Plasma Protein Binding

R406: 98.3% bound to human plasma proteins.

Elimination

Metabolism

Pro-drug fostamatinib disodium undergoes metabolism by alkaline phosphatase in the gut to the major active metabolite, R406.

R406 principally metabolized by CYP3A4 and UGT1A9.

Elimination Route

80% of R406 in feces (majority as R406, O-desmethyl R406, and a metabolite produced by gut bacteria from O-desmethyl R406 metabolite), 20% of R406 recovered in urine (majority as R406 N-glucuronide).

Half-life

Mean half-life of R406 approximately 15 hours.

Stability

Storage

Oral

Tablets

20—25ºC; excursions permitted between 15—30ºC. Do not remove desiccants.

Actions

Tyrosine kinase inhibitor, active against spleen tyrosine kinase (SYK).
The major active metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor, and reduces antibody-mediated platelet destruction.

Advice to Patients

Inform patients that fostamatinib may be taken without regard to food; if a dose of fostamatinib is missed, patients may skip the missed dose and take their next dose at the regularly scheduled time.
Inform patients that periodic blood pressure monitoring is necessary during treatment with fostamatinib, because high blood pressure has occurred in some patients receiving the drug. Inform patients of the signs and symptoms of high blood pressure, and advise patients to routinely monitor blood pressure and to contact their health care provider if blood pressure elevations occur, or if they experience signs or symptoms of high blood pressure.
Inform patients that periodic liver function testing is required during treatment with fostamatinib. Inform patients that any liver function abnormalities (possibly indicative of liver injury) may be managed by treatment interruption, dosage reduction, or discontinuation of fostamatinib.
Advise patients that diarrhea can be managed using supportive care measures; however, if diarrhea becomes severe, it may be managed by treatment interruption, dosage reduction, or discontinuation of fostamatinib.
Inform patients that CBC monitoring during fostamatinib treatment is required and that a neutrophil decrease may be managed by treatment interruption, dosage reduction, or discontinuation of fostamatinib.
Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.
Advise females to inform their clinician if they are or plan to become pregnant or plan to breast-feed. Female patients should be made aware of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with fostamatinib, and for at least 1 month following discontinuation. Advise women who are lactating to not breast-feed during treatment with fostamatinib, and to avoid breastfeeding for at least one month following the last dose of fostamatinib.
Inform patients of other important precautionary information.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Fostamatinib is obtained through designated specialty pharmacies. Contact manufacturer or consult the manufacturer website ([Web]) for specific availability information.