Tavalisse

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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Tavalisse Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Fostamatinib disodium hexahydrate 100mg, 150mg; tabs.

    Pharmacological Class

    Tyrosine kinase inhibitor.

    How Supplied

    Tabs—60

    How Supplied

    Tavalisse 100 mg are round, biconvex, orange, film-coated tablets debossed with "100" on one side and "R" on the reverse side.

    Tavalisse 150 mg are oval, biconvex, orange, film-coated tablets debossed with "150" on one side and "R" on the reverse side.

    Storage

    Store at room temperature, 20° C to 25° C (68° F to 77° F); excursions permitted between 15° C to 30° C (59° F to 86° F).

    Manufacturer

    Rigel Pharmaceuticals Inc.

    Generic Availability

    NO

    Tavalisse Indications

    Indications

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

    Tavalisse Dosage and Administration

    Adult

    ≥18yrs: Initially 100mg twice daily. Increase to 150mg twice daily if platelet count not at ≥50x109/L after 4 weeks. Discontinue if insufficient increase in platelet count after 12 weeks. Dose modifications: see full labeling.

    Children

    <18yrs: not recommended.

    Tavalisse Contraindications

    Not Applicable

    Tavalisse Boxed Warnings

    Not Applicable

    Tavalisse Warnings/Precautions

    Warnings/Precautions

    Monitor CBCs, including platelets, monthly until stable count (≥50x109/L) achieved, then periodically thereafter. Monitor LFTs monthly. Discontinue if AST/ALT >5xULN for ≥2wks or ≥3xULN and total bilirubin >2xULN. Monitor blood pressure every 2 weeks until stable dose established, then monthly thereafter. Interrupt or discontinue dose if hypertensive crisis (>180/120mmHg) occurs; discontinue if repeat BP >160/100mmHg for >4 weeks. Temporarily interrupt if severe diarrhea (Grade ≥3) occurs; resume at next lower daily dose if improved to Grade 1. Monitor ANC monthly and for infection. Temporarily interrupt if ANC <1x109/L occurs and remains low after 72hrs until resolved; resume at next lower daily dose. Use lowest effective dose. Embryo-fetal toxicity. Use effective contraception during and for ≥1 month after last dose. Pregnancy; confirm negative status prior to initiation. Nursing mothers: not recommended (during and for ≥1 month after last dose).

    Warnings/Precautions

    Hypertension

    • Hypertension can occur with Tavalisse treatment; hypertensive crisis occurred in 1% of patients.
    • Patients with pre-existing hypertension may be more susceptible to the hypertensive effects of Tavalisse.
    • Monitor blood pressure every 2 weeks until stable, then monthly; adjust or initiate antihypertensive therapy to ensure blood pressure control during Tavalisse therapy. 
    • Dose interruption, reduction, or discontinuation may be necessary if increased blood pressure persists despite appropriate therapy. 

    Hepatotoxicity

    • Elevated liver function tests (LFTs), mainly ALT and AST, can occur with Tavalisse.
    • 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 Tavalisse. For most patients, transaminases recovered to baseline levels within 2 to 6 weeks of dose-modification.
    • Monitor liver function tests monthly during treatment. If ALT or AST increase more than 3×ULN, manage hepatotoxicity using Tavalisse interruption, reduction, or discontinuation.

    Diarrhea

    • Diarrhea occurred in 31% of patients treated with Tavalisse. Severe diarrhea occurred in 1% of patients treated with Tavalisse.
    • 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 Tavalisse if diarrhea becomes severe (Grade 3 or above).

    Neutropenia

    • Neutropenia occurred in 6% of patients treated with Tavalisse; febrile neutropenia occurred in 1% of patients.
    • Monitor the ANC monthly, and for infection during treatment.
    • Manage toxicity with Tavalisse interruption, reduction or discontinuation.

    Embryo-Fetal Toxicity

    • Based on findings from animal studies and its mechanism of action, Tavalisse can cause fetal harm when administered to a pregnant woman. 
    • 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. 

    Pregnancy Considerations

    There is no available data in pregnant women to inform the drug-associated risk.

    Based on findings from animal studies and the mechanism of action, Tavalisse can cause fetal harm when administered to a pregnant woman. For females of reproductive potential, verify pregnancy status prior to initiating Tavalisse.

    Nursing Mother Considerations

    There is no data on the presence of fostamatinib and/or its metabolites in human milk, the effects on the breastfed child, or on milk production. 

    Because of the potential for serious adverse reactions in a breastfed child from Tavalisse, advise a lactating woman not to breastfeed during treatment with Tavalisse and for at least 1 month after the last dose.

    Pediatric Considerations

    Safety and effectiveness in pediatric patients have not been established. Tavalisse is not recommended for use in patients <18 years of age because adverse effects on actively growing bones were observed in nonclinical studies.

    Geriatric Considerations

    No overall differences in effectiveness were observed in these patients compared to younger patients.

    Tavalisse Pharmacokinetics

    Absorption

    After oral administration of Tavalisse, the absolute bioavailability of R406, the major active metabolite, was 55%. The median tmax of R406 is ~1.5 hours (range: 1 to 4 hours).

    Distribution

    In in vitro studies, the R406 is 98.3% protein bound in human plasma. 

    Metabolism

    Tavalisse is metabolized in the gut by alkaline phosphatase to the major active metabolite, R406.

    R406 is extensively metabolized, primarily through pathways of CYP450-mediated oxidation (by CYP3A4) and glucuronidation (by UDP glucuronosyltransferase [UGT]1A9). 

    Elimination

    The mean terminal half-life of R406 is ~15 (± 4.3) hours. Following an oral dose of Tavalisse, ~80% of the R406 metabolite is excreted in feces; ~20% excreted in the urine. The major component excreted in urine was R406 N-glucuronide. 

    Tavalisse Interactions

    Interactions

    Concomitant strong CYP3A4 inducers: not recommended. Concomitant strong CYP3A4 inhibitors or substrates; monitor for toxicity. May potentiate concomitant BCRP (eg, rosuvastatin) or P-gp (eg, digoxin) substrates: monitor for toxicity.

    Tavalisse Adverse Reactions

    Adverse Reactions

    Diarrhea, hypertension, nausea, respiratory infection, dizziness, ALT/AST increase, rash, abdominal pain, fatigue, chest pain, neutropenia.

    Tavalisse Clinical Trials

    Clinical Trials

    Tavalisse was studied in two placebo-controlled efficacy and safety studies (referred to as FIT-1 [ClinicalTrials.gov Identifiers: NCT02076399] and FIT-2 [NCT02076412]), and in an open-label extension study referred to as FIT-3 (ClinicalTrials.gov Identifier: NCT 02077192).

    Randomized, Placebo-Controlled Studies

    • A total of 150 patients with persistent or chronic ITP, who had an insufficient response to previous treatment were enrolled in two identical, double-blind, placebo-controlled studies that were conducted in different countries. 
    • Patients were randomized 2:1 to Tavalisse or placebo for 24 weeks; randomization was stratified with respect to prior splenectomy and severity of thrombocytopenia. 
    • Stable concurrent ITP therapy was allowed, and rescue therapy was permitted, if needed. 
    • All patients initially received the study drug at 100 mg twice daily (or matching placebo). 
    • Based on platelet count and tolerability, dose escalation to 150 mg twice daily (or matching placebo) was undertaken in 88% of patients at Week 4 or later. 
    • Patients who did not respond to treatment after 12 weeks, as well as patients who completed the 24-week double blind study, were eligible to enroll in open-label extension study (FIT-3).
    • At baseline, the median platelet count was 16×109/L (with almost half [45]% <15×109/L) and 47% were on stable ITP therapy.
    • In Study FIT-1 (n=76), 51 patients were randomized to the Tavalisse group and 25 to the placebo group.
    • In Study FIT-2 (n=74), 50 patients were randomized to the Tavalisse group and 24 to the placebo group.
    • The efficacy of Tavalisse was based on stable platelet response (at least 50×109/L on at least 4 of the 6 visits between Weeks 14 to 24). 
    • Results in FIT-1 showed 18% of the Tavalisse group achieved stable platelet response vs 0% in the placebo group (P =.03). While in FIT-2, 16% of the Tavalisse group achieved stable platelet response vs 4% in the placebo group (P-value not significant).

    Extension Study

    • The FIT-3 trial is an open label extension study. 
    • Patients from FIT-1 and FIT-2 who completed 24 weeks of treatment, or who did not respond to treatment any time after 12 weeks, were eligible to enroll in this study.
    • Patients designated as responders (defined as achievement of platelet count of at least 50×109/L) at the time of roll over continued in the extension study at their current trial dose and regimen.
    • Patients who entered the extension study as non-responders (defined as platelet count <50×109/L) received Tavalisse 100 mg twice daily regardless of their dose and regimen in the prior study.
    • For the FIT-3 trial (n=123), 44 patients were previously randomized to placebo; 79 patients were previously randomized to Tavalisse.
    • Stable response was prospectively defined as no 2 visits (at least 4 weeks apart) with a platelet count <50×109/L, without an intervening visit with a platelet count of at least 50×109/L, within a period of 12 weeks following initial achievement of the target platelet count.
    • Sixty-one of the 123 subjects (50%) have discontinued from the study early.
    • In the prospective analysis, the 44 patients treated with placebo in the prior study were evaluated for stable response for Tavalisse. Ten of these subjects (23%) met the criteria for stable response.

    Among the patients who achieved stable response in FIT-1, FIT-2 and FIT-3 trials, 18 patients maintained the platelet count of at least 50×109/L for 12 months or longer.

    Tavalisse Note

    Not Applicable

    Tavalisse Patient Counseling

    Patient Counseling

    Hypertension

    Inform patients that periodic monitoring of their blood pressure is required, as high blood pressure has occurred in patients taking Tavalisse.

    Advise patients to undergo routine blood pressure monitoring; contact their health care provider if blood pressure is elevated or if they experience signs or symptoms of hypertension. 

    Hepatotoxicity

    Inform patients that periodic monitoring of their liver enzymes is required, and any elevations will be managed appropriately, including interruption, reduction, or discontinuation of Tavalisse.

    Diarrhea

    Advise patients to use supportive care measures, and if diarrhea becomes severe, it may necessitate interruption, reduction, or discontinuation of Tavalisse.

    Neutropenia

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

    Embryo-Fetal Toxicity

    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 Tavalisse.

    Lactation

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

    Others

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

    Cost Savings Program

    The Tavalisse Services and Support Program is available here.

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