fostamatinib

General

Pronunciation:
fos-ta-ma-ti-nib


Trade Name(s)

  • Tavalisse

Ther. Class.

antithrombocytopenics

Pharm. Class.

kinase inhibitors

Indications

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

Action

Acts as a tyrosine kinase inhibitor with activity against spleen tyrosine kinase. The major metabolite of fostamatinib, R406, reduces antibody-mediated destruction of platelets.

Therapeutic Effect(s):

Increased platelet counts.

Pharmacokinetics

Absorption: Prodrug that is converted to an active metabolite, R406; absolute bioavailability of R406 is 55%; absorption enhanced by high-calorie, high-fat foods.

Distribution: Extensively distributed to tissues.

Metabolism and Excretion: Metabolized in the gut by alkaline phosphatase to its major active metabolite, R406. R406 primarily metabolized in liver by CYP3A4 isoenzyme and through glucuronidation by UGT1A9. 80% of R406 excreted in feces, 20% in urine.

Half-life: R406– 15 hr.

TIME/ACTION PROFILE (plasma concentrations of R406)

ROUTEONSETPEAKDURATION
POunknown1–4 hrunknown

Contraindication/Precautions

Contraindicated in:

  • OB:   Pregnancy (may cause fetal harm);
  •  Lactation:  Lactation.

Use Cautiously in:

  • Hypertension
  • Rep:   Women of reproductive potential
  • Pedi:   Safety and effectiveness not established in children.

Adverse Reactions/Side Effects

CV: hypertension, chest pain

Derm: rash

GI: HEPATOTOXICITY, diarrhea, nausea, abdominal pain, ↑ liver enzymes

GU: ↓ fertility (females)

Hemat: NEUTROPENIA

Neuro: dizziness, fatigue

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

  •  Strong CYP3A4 inhibitors  may ↑ levels of R406 and risk of toxicity
  •  Strong CYP3A4 inducers  may ↓ levels of R406 and effectiveness; concurrent use not recommended;
  • May ↑ levels of  CYP3A4 substrates ;
  • May ↑ levels of  BCRP substrates, including  rosuvastatin ;
  • May ↑ levels of  P-glycoprotein substrates, including  digoxin.

Route/Dosage

PO (Adults): 100 mg twice daily. After 1 mo, if platelet count has not ↑ to ≥50 × 109 /L, ↑ dose to 150 mg twice daily. Use lowest maintenance dose to maintain platelet count ≥50 × 109 /L. Discontinue after 12 wk if platelet count does not ↑ to level sufficient to prevent clinically relevant bleeding.

Availability

Tablets: 100 mg, 150 mg

Assessment

  • Monitor BP every 2 wk until stable, then monthly during therapy. May cause hypertension.  If Stage 1 hypertension (systolic 130–139 or diastolic 80–89 mmHg) occurs,  begin or increase antihypertensive dose for patients with increased cardiovascular risk; adjust until BP controlled. If BP target not met after 8 wk, reduce fostamatinib to next lower daily dose.  If Stage 2 (systolic ≥140 or diastolic ≥90 mmHg),  begin or increase antihypertensive dose, and adjust until BP controlled. If BP remains ≥140/90 mmHg for >8 wk, reduce to next lower daily dose. If BP ≥160/100 mmHg for >4 wk despite aggressive antihypertensive therapy, interrupt or fostamatinib.  If hypertensive crisis (systolic >180 and/or diastolic >120 mmHg,  interrupt or discontinue fostamatinib. Begin or increase antihypertensive dose, and adjust until BP controlled. If BP returns to >target BP, resume fostamatinib at same dose. If repeat BP is ≥160/100 mmHg or higher for >4 wk despite aggressive antihypertensive treatment, discontinue fostamatinib.
  • Assess for diarrhea. Manage using supportive measures (dietary changes, hydration and/or antidiarrheal medication) early after onset until symptoms resolved.  If symptoms become severe (≥Grade 3),  hold fostamatinib. If diarrhea improves to mild (Grade 1), resume at next lower dose. May require discontinuation of therapy.

Lab Test Considerations:

Obtain a negative pregnancy test before starting therapy.

  • Monitor CBC with platelet count and absolute neutrophil count (ANC) monthly until stable (≥50 × 109 /L). If ANC less than <1.0 × 109 /L and remains low after 72 hr, temporarily interrupt fostamatinib until ANC >1.5 × 109 /L). Resume fostamatinib at next lower dose Then monitor CBC with neutrophils periodically during therapy.
  • Monitor ALT, AST, and bilirubin monthly.  If AST/ALT is ≥3 × ULN and <5 × ULN,  if patient is symptomatic (nausea, vomiting, abdominal pain), hold fostamatinib. Recheck AST/ALT every 72 hr until ALT/AST <1.5 × ULN and total bilirubin remains <2 × ULN. Resume fostamatinib at next lower dose. If patient is asymptomatic: recheck AST/ALT every 72 hr until ALT/AST <1.5 × ULN and total bilirubin remains <2 × ULN. Consider interrupting or reducing dose if AST/ALT is 3–5 × ULN and total bilirubin <2 × ULN. If interrupted, resume fostamatinib at next lower dose when ALT/AST <1.5 × ULN and total bilirubin <2 × ULN. If AST/ALT is ≥5 × ULN and total bilirubin <2 × ULN, hold fostamatinib. Recheck AST/ALT every 72 hr. If AST and ALT decrease, recheck until ALT and AST are below 1.5 × ULN and total bilirubin <2 × ULN; resume fostamatinib at next lower dose.  If AST/ALT persist at ≥5 × ULN for >2 wk,  discontinue fostamatinib.  If AST/ALT ≥3 × ULN and total bilirubin >2 × ULN,  discontinue fostamatinib. If elevated unconjugated (indirect) bilirubin in absence of other liver abnormalities occurs, continue fostamatinib with frequent monitoring as increase may be due to UGT1A1 inhibition.

Potential Diagnoses

Implementation

  • Use lowest dose to achieve and maintain platelet count at least 50 × 109 /L to reduce risk of bleeding.
  • Dose reduction schedule: 300 mg/day: 150 mg AM and PM. 200 mg/day: 100 mg AM and PM. 150 mg/day: 150 mg in AM. 100 mg/day: 100 mg in AM. If further dose reduction needed, discontinue fostamatinib.
  • PO Administer twice daily without regard to food.

Patient/Family Teaching

  • Instruct patient to take fostamatinib as directed. If a dose is missed, omit and take next dose at scheduled time. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
  • Inform patient of need to monitor BP during therapy. Advise patient to notify health care professional if signs and symptoms of hypertension (headaches, confusion, dizziness, chest pain, shortness of breath) occur.
  • Inform patient that diarrhea commonly occurs. Advise patient to treat with supportive measures and notify health care professional if diarrhea becomes severe.
  • Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications.
  • Rep:  May be teratogenic. Advise females of reproductive potential to use effective contraception and to avoid breastfeeding during and for at least 1 mo after last dose. May impair female fertility.
  • Emphasize importance of regular lab tests to monitor of effect and side effects.

Evaluation/Desired Outcomes

Increase and stabilization of platelet counts. Discontinue after 12 wk if platelet count does not ↑ to level sufficient to prevent clinically relevant bleeding.

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