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Fostamatinib

Medically reviewed by Drugs.com. Last updated on Jul 1, 2019.

Pronunciation

(fos ta ma ti nib)

Index Terms

  • Fostamatinib Disodium Hexahydrate
  • R788
  • R935788
  • Syk Kinase Inhibitor R935788
  • Tavalisse

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as disodium hexahydrate:

Tavalisse: 100 mg, 150 mg

Brand Names: U.S.

  • Tavalisse

Pharmacologic Category

  • Spleen Tyrosine Kinase (Syk) Inhibitor
  • Tyrosine Kinase Inhibitor

Pharmacology

Fostamatinib is a small molecule spleen tyrosine kinase (Syk) inhibitor. Syk affects cellular proliferation, differentiation, survival and immune regulation via IgG Fc-receptor signaling and is also linked to B-cell receptor signaling and autoantibody production (Bussel 2018). The major active metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor and reduces antibody-mediated destruction of platelets.

Distribution

R406: 256 (± 92) L

Metabolism

Fostamatinib: Metabolized in the gut (by alkaline phosphatase) to R406 (active metabolite); R406: Extensively metabolized, primarily via oxidation (by CYP3A4) and glucuronidation (by UGT1A9)

Excretion

Feces (R406: ~80%); Urine (R406: ~20%)

Onset of Action

Median time to response (platelets ≥50,000/mm3): 15 days (Bussel 2018)

Time to Peak

R406: ~1.5 hours (range: 1 to 4 hours)

Half-Life Elimination

R406: 15 (± 4.3) hours

Protein Binding

R406: 98.3%

Use: Labeled Indications

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

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Dosing: Adult

Note: Use the lowest dose necessary to achieve and maintain platelet count of at least 50,000/mm3 as necessary to reduce the risk of bleeding; discontinue after 12 weeks if platelet count does not increase to a level sufficient to avoid clinically important bleeding.

Immune thrombocytopenia (ITP) (chronic, refractory): Oral: Initial: 100 mg twice daily; if platelet count has not increased to at least 50,000/mm3 after 1 month, increase dose to 150 mg twice daily (Bussel 2018).

Missed doses: If a dose is missed, the next scheduled dose should be administered at the regularly scheduled time.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Adjustment for Toxicity

Recommended dose reduction schedule:

Usual maximum dose: 300 mg/day (150 mg twice daily)

First dosage reduction level: 200 mg/day (100 mg twice daily)

Second dosage reduction level: 150 mg/day (150 mg once daily in the morning)

Third dosage reduction level: 100 mg/day (100 mg once daily in the morning)

If further dosage reduction is required (at 100 mg/day), discontinue fostamatinib.

Gastrointestinal toxicity (diarrhea): Manage diarrhea with supportive measures (eg, dietary changes, hydration and/or antidiarrheal medication) early after the onset until symptom(s) have resolved. If symptom(s) become severe (grade 3 or higher), temporarily interrupt fostamatinib. If diarrhea improves to mild (grade 1), resume fostamatinib at the next lower dosage level.

Hypertension:

Stage 1 (systolic between 130 to 139 mm Hg or diastolic between 80 to 89 mm Hg): Initiate antihypertensive therapy (or increase antihypertensive dosage) for patients with increased cardiovascular risk; adjust as needed until blood pressure (BP) is controlled. If BP target is not met after 8 weeks, reduce fostamatinib dose to the next lower dosage level.

Stage 2 (systolic ≥140 to 180 mm Hg or diastolic ≥90 to 120 mm Hg): Initiate antihypertensive therapy (or increase antihypertensive dosage); adjust as needed until BP is controlled. If BP remains ≥140/90 mm Hg for >8 weeks, reduce fostamatinib dose to the next lower dosage level. If BP remains ≥160/100 mm Hg for >4 weeks (despite aggressive antihypertensive therapy), interrupt or discontinue fostamatinib.

Hypertensive crisis (systolic >180 mm Hg and/or diastolic >120 mm Hg): Interrupt or discontinue fostamatinib. Initiate antihypertensive therapy (or increase antihypertensive dosage) and adjust as needed until BP is controlled. If BP returns to less than target BP, resume fostamatinib at the same dose. If BP remains ≥160/100 mm Hg for >4 weeks (despite aggressive antihypertensive therapy), discontinue fostamatinib.

Neutropenia: If ANC <1,000/mm3 and remains low after 72 hours, temporarily interrupt fostamatinib until resolved to ANC >1,500/mm3, then resume fostamatinib at the next lower dosage level.

Administration

Oral: Administer with or without food. Twice-daily doses should be administered in the morning and evening; once-daily doses (due to dose reduction for toxicity) should be administered in the morning.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). Do not remove desiccants from container.

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. Iif used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alpelisib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Alpelisib. Management: Avoid coadministration of BCRP/ABCG2 inhibitors and alpelisib due to the potential for increased alpelisib concentrations and toxicities. If coadministration cannot be avoided, closely monitor for increased alpelisib adverse reactions. Consider therapy modification

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Cladribine: BCRP/ABCG2 Inhibitors may increase the serum concentration of Cladribine. Management: Avoid concomitant use of BCRP inhibitors during the 4 to 5 day oral cladribine treatment cycles whenever possible. If combined, consider dose reduction of the BCRP inhibitor and separation in the timing of administration. Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease serum concentrations of the active metabolite(s) of Fostamatinib. Avoid combination

CYP3A4 Inhibitors (Strong): May increase serum concentrations of the active metabolite(s) of Fostamatinib. Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Digoxin: Fostamatinib may increase the serum concentration of Digoxin. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

PAZOPanib: BCRP/ABCG2 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rosuvastatin: Fostamatinib may increase the serum concentration of Rosuvastatin. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simvastatin: Fostamatinib may increase the serum concentration of Simvastatin. Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy

Talazoparib: BCRP/ABCG2 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Topotecan: BCRP/ABCG2 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Adverse Reactions

>10%:

Cardiovascular: Hypertension (28%)

Central nervous system: Dizziness (11%)

Gastrointestinal: Diarrhea (31%), nausea (19%)

Hepatic: Increased serum ALT (11%)

Respiratory: Respiratory tract infection (11%)

1% to 10%:

Cardiovascular: Chest pain (6%), hypertensive crisis (1%), syncope (1%, serious)

Central nervous system: Fatigue (6%)

Dermatologic: Skin rash (9%)

Gastrointestinal: Abdominal pain (6%), toothache (1%, serious)

Hematologic & oncologic: Neutropenia (6%), febrile neutropenia (1%)

Hepatic: Increased serum AST (9%)

Neuromuscular & skeletal: Arthralgia (1%, serious), limb pain (1%, serious)

Renal: Nephrolithiasis (1%, serious)

Respiratory: Dyspnea (2%, serious), hypoxia (1%, serious)

Warnings/Precautions

Concerns related to adverse effects:

• Gastrointestinal toxicity: Diarrhea occurred in nearly one-third of patients treated with fostamatinib; severe diarrhea occurred rarely. Monitor for the development of diarrhea and manage supportively (eg, dietary changes, hydration, and/or antidiarrheal medication) early after the onset of symptoms. If diarrhea becomes severe (grade 3 or higher), may require treatment interruption, dosage reduction, and/or discontinuation.

• Hepatotoxicity: Elevated liver function tests (predominantly ALT and AST) may occur with fostamatinib treatment; ALT and AST elevations >3 times the upper limit of normal (ULN) have been reported. Transaminases recovered to baseline levels within 2 to 6 weeks of dose modification in most patients. Monitor liver function tests at baseline and monthly during treatment. If ALT or AST increase more than 3 times ULN, manage hepatotoxicity with treatment interruption, dose reduction, or discontinuation.

• Hypertension: Hypertension may occur with fostamatinib; hypertensive crisis has been reported rarely. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of fostamatinib. Monitor blood pressure every 2 weeks until stable and then monthly; adjust or initiate antihypertensive therapy to ensure blood pressure control during fostamatinib treatment. Fostamatinib treatment interruption, dosage reduction, and/or discontinuation may be indicated if hypertension persists despite appropriate antihypertensive therapy.

• Neutropenia: Neutropenia has occurred with fostamatinib treatment; neutropenic fever has been reported rarely. Monitor CBC at baseline and monthly; monitor for infection during treatment. Neutropenia may require fostamatinib treatment interruption, dosage reduction and/or discontinuation.

Disease-related concerns:

• Immune thrombocytopenia: If on a stable dose for 14 days prior to baseline, patients were allowed to continue one other concomitant immune thrombocytopenia medication (eg, corticosteroids at <20 mg/day prednisone equivalent, azathioprine, or danazol) throughout studies; rescue therapies (eg, IV immune globulin, Rho(D) immune globulin, corticosteroids, platelet transfusion) were also allowed (Bussel 2018).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Pediatrics: Due to potential adverse effects on actively growing bones, use in patients under 18 years of age is not recommended.

Monitoring Parameters

CBC including platelets (baseline and monthly until a stable platelet count of ≥50,000/mm3 is achieved, then regularly); liver function tests (ALT, AST, bilirubin [baseline and monthly]); pregnancy test (prior to treatment initiation in females of reproductive potential); blood pressure (baseline and every 2 weeks until stable dose is established, then monthly thereafter). Monitor for signs/symptoms of diarrhea and hepatotoxicity. Monitor adherence.

Pregnancy Considerations

Based on the mechanism of action and information from animal reproduction studies, fostamatinib may cause fetal harm if exposure occurs during pregnancy.

Evaluate pregnancy status in females of reproductive potential prior to therapy; effective contraception should be used during treatment and for at least 1 month after the last fostamatinib dose.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, common cold symptoms, abdominal pain, or loss of strength and energy. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), severe headache, dizziness, passing out, vision changes, severe or persistent diarrhea, confusion, chest pain, shortness of breath, or signs of infection (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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