Tavalisse

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

• Initiate TAVALISSE 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. (
  2.1 Recommended Dosage

  Initiate TAVALISSE at a dose of 100 mg taken orally twice daily. After a month, if platelet count has not increased to at least 50 × 10⁹/L, increase TAVALISSE dose to 150 mg twice daily.

  Use the lowest dose of TAVALISSE to achieve and maintain a platelet count at least 50 × 10⁹/L as necessary to reduce the risk of bleeding.

  TAVALISSE may be taken with or without food. In the case of a missed dose of TAVALISSE, instruct patients to take their next dose at its regularly scheduled time.
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• Manage adverse reactions using dose reduction, interruption of treatment, or discontinuation. (
  2.3 Dose Modification for Adverse Reactions

  TAVALISSE dose modification is recommended based on individual safety and tolerability. Management of some adverse reactions may require dose-interruption, reduction, or discontinuation.

  A dose reduction schedule is provided in Table 1, based on daily dose. For 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.

  Table 1: Dose Reduction Schedule

  Daily Dose	Administered as:
  	AM	PM
  300 mg/day	150 mg	150 mg
  200 mg/day	100 mg	100 mg
  150 mg/day	150 mgOnce daily TAVALISSE should be taken in the morning.	---
  100 mg/dayIf further dose reduction below 100 mg/day is required, discontinue TAVALISSE.	100 mg	---

  The recommended dose modifications for adverse reactions are provided in Table 2.

  Table 2: Recommended Dose Modifications and Management for Specific Adverse Reactions

  Adverse Reaction	Recommended Action
  ALT = alanine aminotransferase; AST = aspartate aminotransferase; BP = blood pressure; BL = bilirubin; ULN = upper limit of normal; LFT = liver function tests (AST, ALT, total BL with fractionation if elevated, alkaline phosphatase); AST/ALT = AST or ALT
  Hypertension
  Stage 1: systolic between 130-139 or diastolic between 80-89 mmHg	Initiate or increase dosage of antihypertensive medication for patients with increased cardiovascular risk, and adjust as needed until BP is controlled. If the BP target is not met after 8 weeks, reduce TAVALISSE to next lower daily dose (refer to Table 1).
  Stage 2: systolic at least 140 or diastolic at least 90 mmHg	Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled. If BP remains 140/90 mmHg or higher for more than 8 weeks, reduce TAVALISSE to next lower daily dose (refer to Table 1). If BP remains 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue TAVALISSE.
  Hypertensive crisis: systolic over 180 and/or diastolic over 120 mmHg	Interrupt or discontinue TAVALISSE. Initiate or increase dosage of antihypertensive medication, and adjust as needed until BP is controlled. If BP returns to less than the target BP, resume TAVALISSE at same daily dose. If repeat BP is 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive treatment, discontinue TAVALISSE.
  Hepatotoxicity
  AST/ALT is 3 × ULN or higher and less than 5 × ULN	If patient is symptomatic (e.g., nausea, vomiting, abdominal pain): Interrupt TAVALISSE. Recheck LFTs every 72 hours until ALT/AST values are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN. Resume TAVALISSE at next lower daily dose (refer to Table 1).
  	If patient is asymptomatic: Recheck LFTs every 72 hours until ALT/AST are below 1.5 × ULN) and total BL remains less than 2 × ULN. Consider interruption or dose reduction of TAVALISSE if ALT/AST and TBL remain in this category (AST/ALT is 3 to 5 × ULN; and total BL remains less than 2 × ULN) If interrupted, resume TAVALISSE at next lower daily dose (refer to Table 1) when ALT/AST are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN.
  AST/ALT is 5 × ULN or higher and total BL is less than 2 × ULN	Interrupt TAVALISSE. Recheck LFTs every 72 hours: If AST and ALT decrease, recheck until ALT and AST are no longer elevated (below 1.5 × ULN) and total BL remains less than 2 × ULN; resume TAVALISSE at next lower daily dose (refer to Table 1). If AST/ALT persist at 5 × ULN or higher for 2 weeks or more, discontinue TAVALISSE.
  AST/ALT is 3 × ULN or higher and total BL is greater than 2 × ULN	Discontinue TAVALISSE.
  Elevated unconjugated (indirect) BL in absence of other LFT abnormalities	Continue TAVALISSE with frequent monitoring since isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition
  Diarrhea
  Diarrhea	Manage diarrhea using supportive measures (e.g., dietary changes, hydration and/or antidiarrheal medication) early after the onset until symptom(s) have resolved. If symptom(s) become severe (Grade 3 or above), temporarily interrupt TAVALISSE. If diarrhea improves to mild (Grade 1), resume TAVALISSE at the next lower daily dose (refer to Table 1).
  Neutropenia
  Neutropenia	If absolute neutrophil count decreases (ANC less than 1.0 × 109/L) and remains low after 72 hours, temporarily interrupt TAVALISSE until resolved (ANC greater than 1.5 × 109/L). Resume TAVALISSE at the next lower daily dose (refer to Table 1).
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• Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to a level sufficient to avoid clinically important bleeding. (
  2.5 Discontinuation

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

  [see Clinical Studies (14)]

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TAVALISSE is available as:

• 100 mg tablet: orange, film-coated, round, biconvex tablets debossed with "100" on one side and "R" on the reverse side.
• 150 mg tablet: orange, film-coated, oval, biconvex tablets debossed with "150" on one side and "R" on the reverse side.

• Pregnancy: Advise women of the risk to a fetus. (
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies and the mechanism of action, TAVALISSE can cause fetal harm when administered to a pregnant woman

  [see Clinical Pharmacology (12.1)].

  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 (see Data). Advise pregnant women of the potential risk to a fetus.

  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 2-4% 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.

  Data

  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.

  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.

  In a peri 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.
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• Lactation: Advise women not to breastfeed. (
  8.2 Lactation

  Risk Summary

  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 TAVALISSE, advise a lactating woman not to breastfeed during treatment with TAVALISSE and for at least 1 month after the last dose.
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• Hypertension: Monitor blood pressure every 2 weeks until stable, then monthly. Manage hypertension using standard antihypertensive treatment and, if needed, interrupt, reduce or discontinue TAVALISSE. (
  5.1 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 and adjust or initiate antihypertensive therapy to ensure maintenance of blood pressure control during TAVALISSE therapy. If increased blood pressure persists despite appropriate therapy, TAVALISSE interruption, reduction or discontinuation may be necessary

  [see Dosage and Administration (2.3)]

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• Hepatotoxicity: Monitor LFTs monthly. If LFT levels are elevated, interrupt, reduce or discontinue TAVALISSE. (
  5.2 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

  [see Adverse Reactions (6.1)]

  . 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

  [see Dosage and Administration (2.3)]

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• Diarrhea: Manage diarrhea with supportive measures. If diarrhea becomes severe, interrupt, reduce or discontinue TAVALISSE. (
  5.3 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)

  [see Dosage and Administration (2.3)]

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• Neutropenia: Monitor ANC monthly, and for infection. If neutrophil count decreases below 1.0 × 10⁹/L, interrupt, reduce or discontinue TAVALISSE. (
  5.4 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

  [see Dosage and Administration (2.3)]

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• Embryo-Fetal Toxicity: TAVALISSE can cause fetal harm. Advise patients of potential risk to a fetus and to use effective contraception. (
  5.5 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. In animal reproduction studies, administration of fostamatinib to pregnant rats and rabbits during organogenesis caused adverse developmental outcomes including embryo-fetal mortality (post-implantation 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.

  [see Use in Specific Populations (8.1)and Clinical Pharmacology (12.1)].
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