1 Dosing Considerations The following factors should be considered when dosing TAVALISSE: TAVALISSE dosing requirements must be individualised based on the patient’s platelet counts and tolerability. [see Recommended Dose and Dosage Adjustment].
Drug Interactions Concomitant use with strong CYP3A4 inhibitors increases exposure to R406. Monitor for toxicities that may require TAVALISSE dose modifications when given with a strong CYP3A4 inhibitor. TAVALISSE should not be used with strong CYP3A4 inducers [see Recommended Dose and Dosage Adjustment and DRUG INTERACTIONS].
2 Recommended Dose and Dosage Adjustment Initiate TAVALISSE at a dose of 100 mg taken orally twice daily. After 4 weeks, 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 of at least 50 × 109 /L as necessary to reduce the risk of bleeding.
A daily dose of 300 mg must not be exceeded. Efficacy has not been established at lower doses recommended for the management of adverse reactions. Page 5 of 33 Discontinuation Discontinue TAVALISSE after 12 weeks of treatment if the platelet count does not increase to at least 50 ×109/L.
Dose interruption, reduction, or discontinuation may be required to manage adverse reactions including diarrhea, hypertension, hepatotoxicity, and neutropenia (see Table 2). A dose reduction schedule is provided in Table 1, based on daily dose.
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 mg1 --- 100 mg/day2 100 mg1 --- 1 Once daily TAVALISSE should be taken in the morning. 2 If further dose reduction below 100 mg/day is required, discontinue TAVALISSE.
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 Hypertension Stage 1: systolic 130-139 or diastolic 80-89 mmHg Initiate or increase dosage of antihypertensive medication and adjust until blood pressure (BP) is controlled.
If the BP target is not met, reduce TAVALISSE to next lower daily dose (See Table 1).
Stage 2:
BP ≥140-159 mmHg systolic and/or ≥90-99 mmHg diastolic Initiate or increase dosage of antihypertensive medication, and adjust until BP is controlled. If BP remains ≥140 systolic and/or ≥90 mmHg diastolic, reduce TAVALISSE to next lower daily dose (See Table 1).
BP 160-179 mmHg systolic or 100-109 mmHg diastolic Initiate or increase dosage of antihypertensive medication, and adjust until BP is controlled. If BP remains ≥160-179 systolic or ≥100-109 diastolic, interrupt or discontinue TAVALISSE.
Page 6 of 33 Adverse Reaction Recommended Action Hypertensive crisis:
BP ≥180 systolic and/or ≥110 mmHg Or symptomatic at any BP level Interrupt or discontinue TAVALISSE. Initiate or increase dosage of antihypertensive medication, and adjust 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 despite aggressive antihypertensive treatment, discontinue TAVALISSE. Hepatotoxicity AST or ALT ≥3x to <5 x ULN If patient is symptomatic (nausea, vomiting, abdominal pain), interrupt TAVALISSE. 5x ULN and total BL remains <2x ULN.
Resume TAVALISSE at next lower daily dose (See Table 1). 5x ULN and total BL remains <2x ULN. Interrupt or reduce dose of TAVALISSE if ALT or AST remains 3 to 5x ULN and total BL remains <2 x ULN. 5x ULN) and total BL remains <2x ULN.
AST or ALT ≥5 x ULN and total BL <2 x ULN Interrupt TAVALISSE. 5x ULN and total BL remains <2x ULN; resume TAVALISSE at next lower daily dose (See Table 1). If AST or ALT persist at ≥5x ULN for 2 weeks or more, discontinue TAVALISSE.
AST or ALT ≥3 x ULN and total BL >2 x ULN Discontinue TAVALISSE. Elevated unconjugated (indirect) BL in absence of other LFT abnormalities and no signs of liver impairment. 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 (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), interrupt TAVALISSE.
If diarrhea improves to mild (Grade 1), resume TAVALISSE at the next lower daily dose (See Table 1). 5 x 109/L). Resume TAVALISSE at the next lower daily dose (refer to Table 1). 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); ANC = absolute neutrophil count Drug Interactions Concomitant use with strong CYP3A4 inhibitors 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]. TAVALISSE should not be used with strong CYP3A4 inducers [see DRUG INTERACTIONS].
Renal Impairment:
No dose adjustment is necessary in patients with renal impairment.
Hepatic Impairment:
TAVALISSE should not be used in patients with severe hepatic impairment. In patients with mild or moderate hepatic impairment, liver […]