Usual Adult Dose for Myelofibrosis

For patients with a baseline platelet count of 50 x 10(9)/L or greater:
400 mg orally once a day

Comments:

• Patients who are taking ruxolitinib: Patients should taper off and discontinue ruxolitinib prior to starting this drug.
• Assess thiamine (vitamin B1) levels and nutritional status prior to starting therapy, periodically during therapy, and as indicated.
• Administration with a high fat meal may reduce the incidence of nausea and vomiting.
• Subsequent doses of this drug are subject to dose adjustments based on the concomitant use of CYP450 3A4 inhibitors, renal function, prior adverse reactions, and/or thiamine levels.

Renal Dose Adjustments

Mild to moderate renal dysfunction (CrCl 30 to 89 mL/min): No adjustment recommended.
Severe renal dysfunction (CrCl 15 to 29 mL/min): Reduce the dose to 200 mg/day.

Liver Dose Adjustments

Mild to moderate liver dysfunction: No adjustment recommended.
Severe liver dysfunction (total bilirubin greater than 3 times the upper limit of normal [3 x ULN] and any AST): Not recommended.

Baseline liver function test levels should be obtained before starting treatment; levels should be obtained periodically and when clinically indicated throughout treatment.

Dose Adjustments

DISCONTINUATION OF TREATMENT:

• Treatment should be discontinued in patients unable to tolerate 200 mg/day.

• Reduce the dose of this drug when administering with strong CYP450 3A4 inhibitors to 200 mg orally once a day.
• If the strong CYP450 3A4 inhibitor is discontinued, increase the dose of this drug to 300 mg orally once d day during the first 2 weeks after discontinuation of the CYP450 3A4 inhibitor, and then to 400 mg orally once a day thereafter as tolerated.

• Consider dose reductions in patients who become transfusion-dependent during therapy with this drug.
• Grade 4 Thrombocytopenia or Grade 3 Thrombocytopenia with Active Bleeding: Withhold therapy until resolved to Grade 2 or less or baseline; restart at 100 mg/day below the last given dose.
• Grade 4 Neutropenia: Withhold therapy until resolved to Grade 2 or less or baseline, restart dose at 100 mg/day below the last given dose.

• Grade 3 or Higher Nausea, Vomiting, or Diarrhea Not Responding to Supportive Measures Within 48 Hours: Withhold therapy until resolved to Grade 1 or less or baseline; restart dose at 100 mg/day below the last given dose.
• Grade 3 or Higher ALT, AST, or Bilirubin: Withhold therapy until resolved to Grade 1 or less or baseline; restart dose at 100 mg/day below the last given dose; monitor ALT, AST, and bilirubin (total and direct) more frequently following the dose reduction.
• Discontinue therapy if a Grade 3 or higher elevation recurs
• Grade 3 or Higher Other Nonhematologic Toxicities: Withhold therapy until resolved to Grade 1 or less or baseline; restart dose at 100 mg/day below the last given dose.

• Assess thiamine (vitamin B1) levels and nutritional status prior to starting therapy, periodically during therapy, and as indicated.
• Do not initiate this drug in patients with thiamine deficiency; replete thiamine prior to therapy initiation and during therapy if thiamine levels are low.
• If WE is suspected, immediately discontinue therapy and initiate parenteral thiamine treatment.
• Monitor until symptoms resolve or improve and thiamine levels normalize.

Precautions

US BOXED WARNINGS:
ENCEPHALOPATHY INCLUDING WERNICKE'S:

• Serious and fatal encephalopathy, including Wernicke's, occurred in patients treated with this drug.
• Wernicke's encephalopathy is a neurologic emergency.

• Thiamine levels should be assessed in all patients prior to starting treatment, and then should be assessed periodically during treatment, as clinically indicated.
• This drug should not be started in patients with thiamine deficiency; thiamine should be repleted prior to initiating treatment.
• Treatment should be immediately discontinued and parenteral thiamine initiated if encephalopathy is suspected.
• Patients should be monitored until symptoms resolve and/or thiamine levels resolve.

• None

Dialysis

Data not available

Other Comments

Administration advice:

• This drug may be taken with or without food.
• If a dose is missed, the next scheduled dose should be taken the following day.
• Patients taking ruxolitinib before initiation of this drug should taper and discontinue according to the ruxolitinib prescribing information.

• Store below 86F (30C).

• GASTROINTESTINAL: Amylase and lipase levels
• GENITOURINARY: Creatinine
• HEMATOLOGIC: Complete blood count with platelets
• HEPATIC: Liver function tests
• METABOLIC: Thiamine (Vitamin B1) levels
• RENAL: BUN

• Advise patients to speak to their healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding.