Usual Adult Dose for Thrombocytopenia

100 mg orally 2 times a day; after a month, if platelet count has not increased to at least 50 x 10(9)/L, increase to 150 mg orally 2 times a day

Comments:

• This drug may be taken with or without food.
• In the case of a missed dose, instruct patients to take their next dose at its regularly scheduled time.
• Use the lowest dose to achieve and maintain a platelet count at least 50 x 10(9)/L to reduce the risk of bleeding.

Use: For the treatment of thrombocytopenia in adult patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to a previous treatment

Renal Dose Adjustments

No adjustment recommended.

Liver Dose Adjustments

No adjustment recommended.

Dose Adjustments

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

MANUFACTURER SUGGESTED DOSE REDUCTION SCHEDULE:
300 mg/day: Taken as 150 mg orally in the AM and 150 mg orally in the PM
200 mg/day: Taken as 100 mg orally in the AM and 100 mg orally in the PM
150 mg/day: Taken as 150 mg orally in the AM
100 mg/day: Taken as 100 mg orally in the AM
If further dose reduction is needed, therapy should be discontinued.

RECOMMENDED DOSE MODIFICATIONS FOR SPECIFIC ADVERSE REACTIONS:
HYPERTENSION:

• Stage 1 (systolic between 130 and 139 or diastolic between 80 and 89 mmHg: Initiate or increase dose 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 the dose to the next lower daily dose.
• Stage 2 (systolic at least 140 or diastolic at least 90 mmHg: Initiate or increase dose of antihypertensive medication, and adjust as needed until BP is controlled. If the BP remains 140/90 mmHg or higher for more than 8 weeks, reduce the dose to the next lower daily dose. If BP remains 160/100 mmHg or higher for more than 4 weeks despite aggressive antihypertensive therapy, interrupt or discontinue therapy.

HEPATOTOXICITY:

• AST/ALT is 3 x ULN or higher and less than 5 x ULN: If patient is symptomatic (e.g., nausea, vomiting, abdominal pain), interrupt therapy; recheck LFTs every 72 hours until ALT/AST values are no longer elevated (below 1.5 x ULN) and total bilirubin (BL) remains less than 2 x ULN; resume therapy at next lower daily dose. If patient is asymptomatic, recheck LFTs every 72 hours until ALT/AST are below 1.5 x ULN and total BL remains less than 2 x ULN; consider therapy interruption or dose reduction if ALT/AST and TBL remain in this category (AST/ALT is 3 to 5 x

ULN; and total BL remains less than 2 x ULN); if therapy is interrupted, resume at next lower daily dose when ALT/AST are no longer elevated (below 1.5 x
ULN) and total BL remains less than 2 x ULN.

• AST/ALT is 5 x ULN or higher and total BL is less than 2 x ULN: Interrupt therapy and recheck LFTs every 72 hours; if AST and ALT decrease, recheck until ALT and AST are no longer elevated (below 1.5 x ULN) and total BL remains less than 2 x ULN; resume therapy at next lower daily dose; if AST/ALT persist at 5 x ULN or higher for 2 weeks or more, discontinue therapy.
• AST/ALT is 3 x ULN or higher and total BL is greater than 2 x ULN: Discontinue therapy.
• Elevated unconjugated (indirect) BL in absence of other LFT abnormalities: Continue therapy with frequent monitoring since isolated increase in unconjugated (indirect) BL may be due to UGT1A1 inhibition.

DIARRHEA:

• Manage diarrhea using supportive measures (e.g., dietary changes, hydration and/or antidiarrheal medication) early after the onset until symptoms have resolved.
• If symptom(s) become severe (Grade 3 or above), temporarily interrupt therapy.
• If diarrhea improves to mild (Grade 1), resume therapy at the next lower daily dose.

NEUTROPENIA:

• If absolute neutrophil count decreases (ANC less than 1 x 10(9)/L) and remains low after 72 hours, temporarily interrupt therapy until resolved (ANC greater than 1.5 x 10(9)/L).
• Resume therapy at the next lower daily dose.

DOSE MODIFICATION FOR DRUG INTERACTIONS

• Concomitant use with a strong CYP450 3A4 inhibitor increases exposure to R406 (the major active metabolite). Monitor for toxicities due to this drug that may require dose modifications when given concurrently with a strong CYP450 3A4 inhibitor.

DISCONTINUATION OF THERAPY:

• Discontinue therapy after 12 weeks if the platelet count does not increase to a level sufficient to avoid clinically important bleeding.

Precautions

CONTRAINDICATIONS:

• None

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

No adjustment recommended.

Other Comments

Administration advice:

• This drug may be taken with or without food.
• In case of a missed dose, the next dose should be taken at its regularly scheduled time.

Storage requirements:

• Store at room temperature, 20C to 25C (68F to 77F); excursions permitted between 15C to 30C (59F to 86F).
• Do not remove desiccants.

Monitoring:

• Monitor CBCs, including platelet counts, monthly until a stable platelet count (at least 50 x 10(9)/L) is achieved; thereafter, continue to monitor CBCs, including neutrophils, regularly.
• Monitor liver function tests (LFTs) (e.g., ALT, AST, bilirubin) monthly.
• Monitor blood pressure every 2 weeks until establishment of a stable dose, then monthly thereafter.