fostamatinib (Rx)

Brand and Other Names:Tavalisse
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

tablet

  • 100mg
  • 150mg

Immune Thrombocytopenia (ITP)

Indicated for thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment

Initial dose: 100 mg PO BID

After a month, if platelet count has not increased to at least 50 x 10^9/L, increase dose to 150 mg PO BID

Use the lowest dose to achieve and maintain a platelet count at least 50 x 10^9/L as necessary to reduce the risk of bleeding

Dosage Modifications

Adverse reaction dose reduction schedule

  • Example, if a patient is on the maximum dose at the time of an adverse reaction, the first dose reduction would be from 300 mg/day to 200 mg/day
  • 300 mg/day: (150-mg tablet AM and PM)
  • 200 mg/day: (100-mg tablet AM and PM)
  • 150 mg/day: (150-mg tablet AM)
  • 100 mg/day: (100-mg tablet AM)
  • If further dose reduction <100 mg/day is required, discontinue treatment

Hypertension

  • Stage 1 (systolic [130-139 mmHg] or diastolic [80-89 mmHg])
    • Initiate or increase dose of antihypertensive medication; adjust as needed until BP is controlled
    • If BP target is not met after 8 weeks, reduce to next lower daily dose
  • Stage 2 (systolic [140 to ≤180 mmHg] or diastolic [90 to ≤120 mmHg])
    • Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled
    • If BP remains ≥140/90 mmHg for >8 weeks, reduce to next lower daily
    • If BP remains ≥160/100 mmHg for >4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue fostamatinib
  • Hypertensive crisis (systolic [>180 mmHg] and/or diastolic [>120 mmHg])
    • Interrupt or discontinue fostamatinib
    • Initiate or increase dosage of antihypertensive medication; adjust as needed until BP is controlled
    • If BP returns to less than the target BP, resume at same daily dose
    • If repeat BP is ≥160/100 mmHg for >4 weeks despite aggressive antihypertensive treatment, discontinue fostamatinib

Hepatoxicity

  • AST/ALT (≥3x to <5x upper limit of normal [ULN])
    • Symptomatic: Interrupt fostamatinib; recheck liver function tests (LFTs) q72hr until ALT/AST are below 1.5x ULN and total bilirubin (BL) remains <2x ULN; resume at next lower daily dose
    • Asymptomatic: Recheck LFTs q72hr until ALT/AST are <1.5x ULN and total BL remains <2x ULN; consider interrupting or reducing dose if ALT/AST and total BL remain at AST/ALT 3-5x ULN and total BL remains <2x ULN; if interrupted, resume at next lower daily dose; when ALT/AST are no longer elevated (<1.5x ULN) and total BL remains <2x ULN
  • AST/ALT (≥5x ULN) and total BL (<2x ULN)
    • Interrupt fostamatinib
    • Recheck LFTs q72hr: If AST/ALT decrease, recheck until ALT/AST are no longer elevated (<1.5x ULN) and total BL remains <2x ULN; resume at next lower daily dose
    • If AST/ALT persist at ≥5x ULN for ≥2 weeks, discontinue fostamatinib
  • AST/ALT (≥3x ULN) and total BL (>2x ULN)
    • Discontinue fostamatinib
  • Elevated unconjugated (indirect) BL in absence of other LFT abnormalities
    • Continue fostamatinib; monitor frequently since isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition

Diarrhea

  • Use supportive measures (eg, dietary changes, hydration, and/or antidiarrheal medication) early after the onset until symptoms have resolved
  • If symptoms become severe (≥Grade 3), temporarily interrupt fostamatinib
  • If diarrhea improves to mild (Grade 1), resume at the next lower daily dose

Neutropenia

  • ANC (<1 x 10^9/L) and remains low after 72 hr: Temporarily interrupt fostamatinib until resolved (ANC >1.5 x 10^9/L); resume at the next lower daily dose thereafter

Strong CYP3A4 inhibitor

  • Coadministration with a strong CYP3A4 inhibitor increases exposure to the major active metabolite (R406); monitor for toxicities that may require fostamatinib dose reduction

Dosing Considerations

Monitor

  • Obtain baseline assessments
  • Monitor CBC counts monthly until a stable platelet count (at least 50 x 10^9/L) is achieved; continue monitoring CBC counts regularly thereafter
  • Monitor LFTs monthly
  • Monitor blood pressure q2Weeks until establishment of a stable dose, then monthly thereafter

Discontinuation

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

<18 years: Safety and efficacy not established

No overall differences in effectiveness were observed in these patients compared with younger patients

Patients aged ≥65 years experienced a higher rate of serious adverse events compared with younger individuals

More patients aged ≥65 years experienced hypertension compared with placebo (39% vs 18%, respectively); individuals younger than 65 years also experience hypertension more often compared with placebo (23 vs 11%, respectively)

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Interactions

Interaction Checker

and fostamatinib

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     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

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            Adverse Effects

            >10%

            Diarrhea (10-21%)

            Hypertension (9-17%)

            Nausea (3-16%)

            1-10%

            Dizziness (2-8%)

            Rash (1-8%)

            Respiratory infection (4-7%)

            Abdominal pain (1-5%)

            ALT/AST >5 and ≤10x ULN (5%)

            Fatigue (4%)

            Chest pain (2-3%)

            Neutropenia (2-3%)

            ALT/AST >3 and ≤5x ULN (3%)

            Hypertension, severe (2%)

            Diarrhea, severe (1%)

            Dizziness, severe (1%)

            Chest pain, severe (1%)

            Neutropenia, severe (1%)

            ALT/AST &g3;10x ULN (1%)

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            Warnings

            Contraindications

            None

            Cautions

            Also see Dosage Modifications for when to interrupt therapy, reduce dose, or discontinue fostamatinib

            Hypertension can occur, including hypertensive crisis; patients with preexisting hypertension may be more susceptible; monitor blood pressure q2Weeks until stable, then monthly, and adjust or initiate antihypertensive therapy for control

            Elevated LFTs (mainly ALT and AST) reported; transaminases typically recover to baseline levels within 2-6 weeks of dose-modification; monitor liver function tests monthly during treatment

            Diarrhea commonly occurs; use supportive care measures (eg, dietary changes, hydration, and/or antidiarrheal medication) early after the onset of symptoms

            Neutropenia reported, including febrile neutropenia; monitor ANC monthly and for infection during treatment

            Based on findings from animal studies and its mechanism of action, can cause fetal harm when administered to pregnant women (see Pregnancy)

            Drug interaction overview

            • Effect of other drugs on fostamatinib
              • Strong CYP3A4 inhibitors: Coadministration increases exposure to R406 (the major active metabolite), which may increase the risk of adverse reactions; fostamatinib dose reduction may be required
              • Strong CYP3A4 inducers: Coadministration not recommended owing to reduced exposure to R406
            • Effect of fostamatinib on other drugs
              • CYP3A4, BCRP, and/or P-gp substrates: Coadministration with fostamatinib may increase concentrations of some substrate drugs; substrate drug may require dose reduction
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            Pregnancy

            Pregnancy

            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 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

            Verify pregnancy status in females with reproductive potential before initiating fostamatinib; advise pregnant females of the potential risk to a fetus

            Fertility

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

            Contraception

            • Females: Use effective contraception during treatment and for at least 1 month after the last dose

            Lactation

            Unknown if distributed in human breast milk

            In rodents, R406 was detected in maternal milk in concentrations 5- to 10-fold higher than in maternal plasma

            Advise a lactating woman not to breastfeed during treatment with fostamatinib and for at least 1 month after the last dose

            Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for the drug, and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK)

            Major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptor; R406 reduces antibody-mediated destruction of platelets

            Absorption

            Values are for active metabolite (R406)

            Absolute bioavailability: 55%

            Peak plasma concentration: 550 ng/mL

            AUC: 7080 ng•hr/mL

            R406 accumulates ~2- to 3-fold upon twice daily dosing at 100-160 mg (0.67-1.06 times the 150-mg dosage)

            Distribution

            Values are for active metabolite (R406)

            Protein bound: 98.3%

            Vd, steady-state: 256 L

            Metabolism

            Prodrug that is converted 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

            Values are for active metabolite (R406)

            Half-life: 15 hr

            Excretion: 80% (feces); 20% (urine)

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            Administration

            Oral Administration

            May take with or without food

            Missed dose: Instruct patients to take their next dose at its regularly scheduled time

            Storage

            Tablets: Store at room temperature (20-25°C [68-77°F]); excursions permitted between 15-30°C (59-86°F); do not remove desiccants

            Do not remove desiccants

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
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            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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