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Tavalisse

Generic Name: Fostamatinib Disodium
Class: Blood Formation, Coagulation, and Thrombosis Agents; Miscellaneous
Chemical Name: [6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-3-oxopyrido[3,2-b][1,4]oxazin-4-yl]methyl dihydrogen phosphate
Molecular Formula: C23H24FN6Na2O9P
CAS Number: 1025687-58-4

Medically reviewed by Drugs.com. Last updated on May 4, 2020.

Introduction

Fostamatinib disodium is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK).

Uses for Tavalisse

Fostamatinib disodium has the following uses:

Fostamatinib disodium is a kinase inhibitor indicated for the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment.1

Tavalisse Dosage and Administration

General

Fostamatinib disodium is available in the following dosage form(s) and strength(s):

Tablets: 100 mg, 150 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

  • Initiate fostamatinib disodium at 100 mg orally twice daily with or without food. After 4 weeks, increase to 150 mg twice daily, if needed, to achieve platelet counts of at least 50 × 109/L as necessary to reduce the risk of bleeding.1

  • Consult manufacturer's labeling for the recommended management of adverse reactions using dose reduction, interruption of treatment, or discontinuation.1

  • Discontinue fostamatinib disodium after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding.1

Cautions for Tavalisse

Contraindications

None.1

Warnings/Precautions

Hypertension

Hypertension can occur with fostamatinib disodium treatment; hypertensive crisis occurred in 1% of patients. Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of fostamatinib disodium. 1

Monitor blood pressure every 2 weeks until stable, then monthly and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during fostamatinib disodium therapy. If increased blood pressure persists despite appropriate therapy, fostamatinib disodium interruption, reduction or discontinuation may be necessary.1

Hepatotoxicity

Elevated liver function tests (LFTs), mainly ALT and AST, can occur with fostamatinib disodium.1

In the placebo-controlled studies, laboratory testing showed maximum ALT/AST levels more than 3 × the upper limit of normal (ULN) in 9% of patients receiving fostamatinib disodium. For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose modification.1

Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3 × ULN, manage hepatotoxicity using fostamatinib disodium interruption, reduction, or discontinuation.1

Diarrhea

Diarrhea occurred in 31% of patients treated with fostamatinib disodium. Severe diarrhea occurred in 1% of patients treated with fostamatinib disodium. Monitor patients for the development of diarrhea. Manage diarrhea using supportive care measures, including dietary changes, hydration and/or antidiarrheal medication, early after the onset of symptoms. Interrupt, dose reduce, or discontinue fostamatinib disodium if diarrhea becomes severe (Grade 3 or above).1

Neutropenia

Neutropenia occurred in 6% of patients treated with fostamatinib disodium; febrile neutropenia occurred in 1% of patients.1

Monitor the ANC monthly, and for infection during treatment. Manage toxicity with fostamatinib disodium interruption, reduction or discontinuation.1

Embryofetal Toxicity

Based on findings from animal studies and its mechanism of action, fostamatinib disodium can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryofetal mortality (postimplantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations) at maternal exposures (AUCs) approximately 0.3 and 10 times the human exposure at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose.1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies and the mechanism of action, fostamatinib disodium can cause fetal harm when administered to a pregnant woman.1

There are no available data in pregnant women to inform the drug-associated risk. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes that were directly attributed to exposure in utero to the major fostamatinib metabolite (R406) at maternal exposures (AUC) as low as 0.3 and 10 times the exposure in patients at the maximum recommended human dose (MRHD), respectively. Advise pregnant women of the potential risk to a fetus.1

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 24% and 15-20%, respectively. An estimated background risk of major birth defects and miscarriage for the chronic ITP population is 8% and 4-11%, respectively.1

Animal Data: In a fertility and early embryonic development study in female rats, fostamatinib was administered orally for 15 days before mating to Day 7 of pregnancy, which caused a slight decrease in pregnancy rates and an increase in post-implantation loss were seen at maternal doses approximately 4.2 times the dose in patients at the MRHD.1

In embryo-fetal development studies, pregnant animals were orally administered fostamatinib during the period of organogenesis at doses up to 25 and 50 mg/kg/day in rats and rabbits, respectively. The adverse developmental outcomes included an increase in embryo-fetal mortality (post-implantation loss), alterations to growth (lower fetal weights), and structural abnormalities (variations and malformations). These effects occurred at maternal exposures (AUCs) of 3,763 ng•h/mL in rats and 111,105 ng•h/mL in rabbits that were approximately 0.3 and 10 times the human exposure at the MRHD in rats and rabbits, respectively.1

In a perinatal and postnatal development study in rats, fostamatinib was orally administered at doses of 2.5, 12.5, and 25 mg/kg/day from gestation day 7 until lactation day 20. The dose of 25 mg/kg/day was associated with maternal toxicity, including decreased body weights, body weight gains, and food consumption. At doses as low as 12.5 mg/kg/day fostamatinib caused increases in newborn mortality (neonatal mortality), alterations in growth and/or development (lower neonatal weights into post-weaning and structural abnormalities [malformations]). Functional impairment (delayed sexual maturation) was observed at 25 mg/kg/day. There was no evidence of neurobehavioral defects (maze learning and shuttle box avoidance) or immunological compromise (influenza host resistance challenge) in the F1 generation or latent untoward effects in the F2 generation. The maternal doses were approximately 2.1 and 4.2 times the MHRD in patients.1

Lactation

There are no data on the presence of fostamatinib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. In rodents, R406 (the major active metabolite) was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma. Because of the potential for serious adverse reactions in a breastfed child from fostamatinib disodium, advise a lactating woman not to breastfeed during treatment with fostamatinib disodium and for at least 1 month after the last dose.1

Females And Males Of Reproductive Potential

Based on animal studies, fostamatinib disodium can cause fetal harm when administered to a pregnant woman. For females of reproductive potential, verify pregnancy status prior to initiating fostamatinib disodium.1

Advise females of reproductive potential to use effective contraception during treatment with fostamatinib disodium and for at least 1 month after the last dose.1

There are no data on the effect of fostamatinib disodium on human fertility. Based on the finding of reduced pregnancy rates in animal studies, fostamatinib disodium may affect female fertility.1

Pediatric Use

Safety and effectiveness in pediatric patients have not been established. Fostamatinib disodium is not recommended for use in patients less than 18 years of age because adverse effects on actively growing bones were observed in nonclinical studies. In subchronic, chronic, and carcinogenicity studies of fostamatinib disodium, chondrodystrophy of the femoral head was seen in rodents. In a study in juvenile rabbits, growth plate dysplasia was observed in the proximal femur and femoro-tibial joint, and bone marrow cellularity was reduced in the femur and sternum.1

Geriatric Use

Of the 102 patients with ITP who received fostamatinib disodium, 28 (27%) were 65 years of age and older, while 11 (11%) were 75 years of age and older. In patients 65 years of age and older, 6 (21%) patients experienced serious adverse events and 5 (18%) experienced adverse events leading to treatment withdrawal while in patients under 65 years of age, 7 (9%) and 5 (7%) experienced serious adverse events and adverse events leading to treatment withdrawal, respectively. In patients 65 years of age and older who received fostamatinib disodium, 11 (39%) patients experienced hypertension versus 2 (18%) placebo compared to 17 (23%) in patients under 65 of age versus 4 (11%) placebo. No overall differences in effectiveness were observed in these patients compared to younger patients.1

Common Adverse Effects

The most common adverse reactions (≥5% and more than placebo) are diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increased, rash, abdominal pain, fatigue, chest pain and neutropenia.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP3A4 Inhibitors: Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite).1

  • Strong CYP3A4 Inducers: Concomitant use is not recommended.1

Actions

Mechanism Of Action

Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor. The fostamatinib metabolite R406 reduces antibody-mediated destruction of platelets.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

  • Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking fostamatinib disodium. Inform patients of the signs and symptoms of hypertension. Advise patients to undergo routine blood pressure monitoring and to contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension.1

  • Inform patients that periodic monitoring of their liver enzymes is required, and any elevations (which may indicate liver injury) will be managed appropriately, including interruption, reduction, or discontinuation of fostamatinib disodium.1

  • Advise patients to use supportive care measures for treatment of diarrhea; if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of fostamatinib disodium.1

  • Inform patients that monitoring of their complete blood counts is required, and a decrease in neutrophils may necessitate interruption, reduction, or discontinuation of fostamatinib disodium.1

  • Advise patients to inform their healthcare providers of all their medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products.1

  • Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after receiving the last dose of fostamatinib disodium.1

  • Advise lactating women not to breastfeed during treatment with fostamatinib disodium and for at least 1 month after the last dose.1

  • Inform patients that fostamatinib disodium may be taken with or without food. In the case of a missed dose of fostamatinib disodium, instruct patients to take their next dose at its regularly scheduled time.1

Additional Information

AHFSfirstRelease. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

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 Disodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

100 mg

Tavalisse

Rigel Pharmaceuticals Inc.

150 mg

Tavalisse

Rigel Pharmaceuticals Inc.

AHFS Drug Information. © Copyright 2020, Selected Revisions May 14, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Rigel Pharmaceuticals, Inc.. TAVALISSE (FOSTAMATINIB) ORAL prescribing information. 2018 Apr. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=21149cc3-049b-43e2-b141-c9499160556c

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