Fostamatinib disodium hexahydrate is marketed by the brand name of Tavalisse ( Rigel Pharmaceuticals, Inc.). It is a spleen tyrosine kinase inhibitor (SYK) that modulates cellular transduction and antibody formation by inhibiting B cell signaling.

Fostamatinib (Tavalisse) Uses:

Fostamatinib use in ITP (immune thrombocytopenic purpura):

Fostamatinib is an orally bioavailable spleen tyrosine kinase inhibitor that has been approved by the FDA in April 2018 for the treatment of chronic refractory ITP. The FIT 1 and FIT 2 trials evaluated the safety and efficacy of fostamatinib in patients with refractory ITP. Most patients had a long duration of the disease and at least three prior treatments. 48% of the patients had received TPO receptor agonists (Eltrombopag or Romiplostim), 34% had received Rituximab, and 35% had undergone splenectomy. The primary outcome was a persistent platelet count of greater than or equal to 50,000/ul over 14 - 24 weeks. Only 2% of the patients in the placebo vs 18% of the patients in the fostamatinib achieved a platelet count of more than 50,000/ul. The overall response rate was 43% compared to only 14% in the placebo [Ref].

(Tavalisse) Fostamatinib use in IgA nephropathy:

Although Fostamatinib is primarily expressed in the hematopoietic tissues, there is also an expression of the spleen tyrosine kinases in other tissues such as kidneys. The SUN 036 trial evaluated the efficacy of Fostamatinib in patients with Ig A nephropathy and proteinuria. Fostamatinib reduced proteinuria especially in patients with greater than 1000 mg of proteins per day. However, compared to the placebo, the results were not statistically significant [Ref]. Because of its role as an anti-inflammatory drug and in reducing mesangial proliferation with a relatively benign safety profile, it is also being studied in the SIGN (Syk Inhibition for Glomerulonephritis) trial [Ref].

Fostamatinib use in Rheumatoid Arthritis:

Since it acts as an immune-modulator, fostamatinib has been studied in patients with Rheumatoid arthritis. The results of the studies are very variable. The OSKIRA clinical trial program evaluated the efficacy of the drug in patients with active Rheumatoid arthritis who were being treated with methotrexate. The investigators found out that fostamatinib achieved a statistically significant improvement in the ACR 20 improvement response rate at 24 weeks. However, compared to the placebo, it did not result in an improvement in the structural joint damage [Ref]. Another Phase II clinical trial found a statistically significant improvement in the HRQOL outcomes in patients treated with fostamatinib 100 mg two times a day compared to placebo [Ref]. In most of the above studies cited, patients were on Methotrexate treatment and the SYK inhibitor did not affect the pharmacokinetics of the methotrexate. A meta-analysis of the use of Fostamatinib in patients with Rheumatoid arthritis concluded that the drug is moderately effective in patients with active Rheumatoid arthritis [Ref].

Tavalisse (Fostamatinib) in hematological diseases other than ITP:

Tavalisse (Fostamatinib) has been evaluated in both Phase 1 and Phase II clinical trials for the treatment of B-cell NHLs and SLL/CLL. The study found that more than 20% of the patients with multiply relapsed/refractory DLBCL responded to fostamatinib treatment. Significant tumor cell death and clinical response were seen in patients with CLL/SLL and DLBCL (diffuse large B-cell lymphoma) treated with fostamatinib [Ref].

Fostamatinib (Tavalisse) dose in Adults:

Note:

• The lowest possible dose should be used to achieve a platelet count of 50,000/ul or more.
• Treatment should be discontinued if the response to the treatment is not adequate after twelve months of therapy.

Fostamatinib Dose in the treatment of Chronic Refractory ITP (Immune thrombocytopenia:

• 100 mg orally two times a day.
• After one month, if the platelet count does not rise to at least 50,000/mm³, the dose may be increased to 150 mg twice daily.

Missed doses:

• • In case a dose is missed, double dosing should be avoided and the next dose should be taken at the scheduled time.

Fostamatinib Drug interactions [Ref]:

Fostamatinib use in Children:

Efficacy and safety of the drug in children is not established.

Fostamatinib Pregnancy Risk Category: D

• It can cause harm to fetal health and have been linked to severe adverse fetal outcomes in animal studies.
• Effective contraception should be used for at least one month by female patients with reproductive potential.

Use fostamatinib while breastfeeding

• It is unknown if the drug will be excreted into breastmilk.
• Manufacturers recommend that you stop breastfeeding for at most one month after the last dose.

Fostamatinib Dose in Kidney disease:

• The manufacturer has not recommended any adjustment in the dose.
• Adjustment in the dose is, however, not required as renal impairment does not alter the drug metabolism or pharmacokinetics.

Fostamatinib dosage in Liver disease:

• Hepatic impairment at baseline (prior to treatment initiation):

  • The manufacturer has not recommended any adjustment in the dose.
  • Adjustment in the dose is, however, not required as hepatic impairment does not alter the drug metabolism or pharmacokinetics.

• Hepatotoxicity during treatment:

  • Asymptomatic patients with ALT and AST greater than 3 times but less than 5 times the upper limit of normal:

    • Continue treatment and recheck LFTs (ALT and AST) every 72 hours (until AST and ALT levels are no longer greater than 1.5 times the ULN and total bilirubin is less than twice the ULN.
    • Patients with persistently elevated LFTs (AST and ALT greater than 3 - 5 times the ULN with bilirubin levels less than twice the ULN) may need treatment interruption.
    • Treatment should be resumed at a lower dose after the LFTs normalize.

  • Symptomatic patients with ALT and AST ≥3 and <5 times ULN:

    • Withhold treatment in such cases and monitor LFTs every 72 hours.
    • Once the LFTs normalize to less than 1.5 times the ULN, treatment may be resumed at lower doses.

  • ALT and AST ≥5 times the ULN and total bilirubin <2 times ULN:

    • Withhold treatment in such cases and monitor LFTs every 72 hours.
    • Once the LFTs normalize to less than 1.5 times the ULN (and bilirubin remains less than twice the ULN), treatment may be resumed at lower doses.
    • However, if the LFTs remain elevated after two weeks of treatment interruption, treatment should be discontinued.

  • ALT and AST ≥3 times ULN and total bilirubin >2 times ULN:

    • Discontinue treatment.
    • However, in patients with isolated raised unconjugated (indirect) bilirubin, treatment may be continued with frequent monitoring.
    • Isolated indirect hyperbilirubinemia may be due to UGT1A1 inhibition.

Tavalisse Fostamatinib Side effects:

• Cardiovascular:

  • Hypertension

• Central nervous system:

  • Dizziness

• Gastrointestinal:

  • Diarrhea
  • Nausea

• Hepatic:

  • Increased serum ALT

• Respiratory:

  • Respiratory tract infection

Less Common Side Effects of Fostamatinib Include:

• Cardiovascular:

  • Chest Pain
  • Hypertensive Crisis
  • Syncope

• Central Nervous System:

  • Fatigue

• Dermatologic:

  • Skin Rash

• Gastrointestinal:

  • Abdominal Pain
  • Toothache

• Hematologic & Oncologic:

  • Neutropenia
  • Febrile Neutropenia

• Hepatic:

  • Increased Serum AST

• Neuromuscular & Skeletal:

  • Arthralgia
  • Limb Pain

• Renal:

  • Nephrolithiasis

• Respiratory:

  • Dyspnea
  • Hypoxia

Fostamatinib (Tavalisse) Contraindications:

There are no contraindications for its use, according to the manufacturer.

Warnings and precautions

• Gastrointestinal toxicity:

  • Up to 1/3 of patients may develop severe diarrhea, sometimes requiring hospitalization
  • If diarrhea occurs, patients should be closely monitored for signs of dehydration.
  • The treatment options include antidiarrheal medication, hydration and diet modification.
  • Treatment may be interrupted, discontinued, or reduced for patients with persistent or severe diarrhea.

• Hepatotoxicity:

  • Patients could develop liver toxicities that can manifest as abnormal liver enzymes (AST or ALT).
  • After a dose adjustment, ALT and AST elevations can return to baseline within 2 - 6 week.
  • Regular monitoring of liver function should be done on patients. 
  • Hepatotoxicity can be treated with dose reduction, discontinuation, or temporary interruption of therapy if the transaminases levels are higher than 3.

• Hypertension:

  • Patients may develop hypertension. It is possible to develop hypertension.
  • Patients who have been hypertensive before the start of therapy are particularly vulnerable to its hypertensive effects.
  • Monitoring blood pressure should be done every two weeks until it stabilizes, then monthly. Antihypertensive medications may require dose adjustment.
  • Patients with uncontrolled hypertension may need to stop, decrease or interrupt treatment temporarily.

• Neutropenia:

  • Patients can develop neutropenia, which can lead to infection.
  • Patients with severe neutropenia might need to be modified, treated interrupted, or discontinued from therapy.

• Immune thrombocytopenia

  • Concomitant treatment may be required with other medications, such as azathioprine and corticosteroids.
  • In severe cases, rescue therapy may include intravenous immuneglobulin, Rh(D) immuneglobulin, corticosteroids and platelet transfusions.

Fostamatinib: Drug Interaction

Monitor:

• CBC (Monitor platelets at baseline and every month until the platelet counts are more than 50,000/mm³)
• Liver function tests including ALT, AST, bilirubin prior to treatment initiation and monthly thereafter. Observe for the clinical features of hepatotoxicity.
• Pregnancy test prior to initiating the treatment in women of reproductive potential.
• Blood pressure every two weeks
• Observe for diarrheal episodes
• Monitor adherence to the treatment.

How to administer Fostamatinib (Tavalisse)?

• It is taken orally with or without food.
• If the dose is taken as once a day (as a result of toxicity), it should be taken early in the morning.
• Twice daily dose should be taken in the morning and evening.

(Tavalisse) Fostamatinib Mechanism of Action:

• It acts as an inhibitor of the spleen Tyrosine Kinase. Spleen Tyrosine Kinase receptors regulate cell differentiation, proliferation, survival, and immune regulation. 
• It also plays a role in autoantibodies and B-cell receptor-mediated signals.
• R406, the active metabolite from fostamatinib reduces antibody-mediated platelet destruction by inhibiting signal transduction at Fc-activating receptors as well as B-cell receptors.
• The platelets take about 15 days to reach a level of greater than 50,000/ul. 
• R406, an active metabolite, of fostamatinib, is mainly bound to plasma proteins (98%).
• After the drug has been absorbed, R406, the active metabolite, of fostamatinib is formed.

MetabolizedAlkaline phosphatase is found in the stomach. R406 then undergoes oxidation or glucuronidation via CYP3A4 (or UGT1A9) respectively. ThebioavailabilityThe active metabolite R406 takes approximately 15 +/-4.3 hours.Attain the maximum serum concentrationIt takes approximately 1.5 hours. The duration of theActive metaboliteIt is the main (80%).excreted20 percent in the feces, and 20% in urine.  

Fostamatinib International Brand Name:

• Tavalisse

Fostamatinib Price (Tavalisse tablets price) in the US [Ref].

• 100 mg (per each): $215.24
• 150 mg (per each): $215.24

Fostamatinib Brand Name in Pakistan:

It is not available in Pakistan.