Prescription Drug Information: TAVALISSE

TAVALISSE- fostamatinib tablet
Rigel Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

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.

2 DOSAGE AND ADMINISTRATION

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.

2.2 Monitoring

After obtaining baseline assessments:

  • Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 × 109 /L) is achieved. Thereafter, continue to monitor CBCs, including neutrophils, regularly.
  • Monitor liver function tests (LFTs) (e.g., ALT, AST, and bilirubin) monthly.
  • Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter.

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
*
Once daily TAVALISSE should be taken in the morning.
If further dose reduction below 100 mg/day is required, discontinue TAVALISSE.
300 mg/day 150 mg 150 mg
200 mg/day 100 mg 100 mg
150 mg/day 150 mg *
100 mg/day 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).

2.4 Dose Modification for Drug Interactions

Concomitant use with a strong CYP3A4 inhibitor increases exposure to R406 (the major active metabolite). Monitor for toxicities of TAVALISSE that may require TAVALISSE dose modifications (see Table 1) when given concurrently with a strong CYP3A4 inhibitor [see Drug Interactions (7.1)].

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)].

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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)].

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)].

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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