Usual Adult Dose for Hemolytic Anemia

Initial dose: 5 mg orally twice a day
Maintenance dose: 5 to 50 mg orally twice a day

Dose Titration Schedule:

• Week 1 through 4: 5 mg orally twice a day
• Week 5 through 8:
• If hemoglobin is below normal range or a transfusion was required within the last 8 weeks: Dosage should be increased to 20 mg orally twice a day and maintained for 4 weeks.
• If hemoglobin is with normal range and a transfusion has not been required within the last 8 weeks: Dosage should be maintained at 5 mg orally twice a day.
• Week 9 through 12:
• If hemoglobin is below normal range or a transfusion was required within the last 8 weeks: Dosage should be increased to 50 mg orally twice a day and maintained thereafter.
• If hemoglobin is with normal range and a transfusion has not been required within the last 8 weeks: Current dosage should be maintained (5 mg orally twice a day or 20 mg orally twice a day).
• Maintenance: If hemoglobin decreases, up-titration to the maximum of 50 mg orally twice a day (as per the specified schedule) should be considered.

• If current dose is 5 mg orally twice a day:
• Day 1 through 7: 5 mg orally once a day
• Day 8: This drug should be discontinued.
• If current dose is 20 mg orally twice a day:
• Day 1 through 7: 20 mg orally once a day
• Day 8 through 14: 5 mg orally once a day
• Day 15: This drug should be discontinued.
• If current dose is 50 mg orally twice a day:
• Day 1 through 7: 50 mg orally once a day
• Day 8 through 14: 20 mg orally once a day
• Day 15: This drug should be discontinued.

• To gradually increase hemoglobin, this drug should be titrated from 5 mg twice a day to 20 mg twice a day, and then to the maximum recommended dose of 50 mg twice a day; these dose increases should occur every 4 weeks.
• Hemoglobin and transfusion requirement should be assessed before increasing to the next dose level; some patients may reach and maintain normal hemoglobin at 5 mg twice a day or 20 mg twice a day.
• This drug should be discontinued if no benefit has been observed by 24 weeks (based on hemoglobin and hemolysis laboratory results and transfusion requirements).
• To reduce the risk of acute hemolysis, abrupt interruption/discontinuation should be avoided when possible; the dose should be tapered to gradually discontinue the drug. Patients should be monitored for signs of acute hemolysis and worsening of anemia.

Renal Dose Adjustments

Data not available

Liver Dose Adjustments

Moderate or severe liver dysfunction: Not recommended.

Dose Adjustments

For Adverse Reactions and Hemoglobin Levels Above Normal:

• If dose reduction is needed due to an adverse reaction or tolerability, or for hemoglobin above normal, the dose may be reduced to the next lower dose level (20 mg orally twice a day or 5 mg orally twice a day).
• If a patient needs to discontinue this drug, the dose taper schedule should be followed.
• In situations where the risk to the patient due to the adverse reaction or hemoglobin above normal is greater than the risk of acute hemolysis due to sudden withdrawal of the drug, this drug may be stopped without taper and patients should be monitored for signs of acute hemolysis.

• Strong CYP450 3A inhibitors: Coadministration should be avoided.
• Moderate CYP450 3A inhibitors: Monitoring of hemoglobin and for increased risks of adverse reactions from this drug is recommended; when coadministered, this drug should not be titrated beyond 20 mg orally twice a day.
• Strong CYP450 3A inducers: Coadministration should be avoided.
• Moderate CYP450 3A inducers: Alternative therapies should be considered during treatment with this drug; if there are no alternative therapies, hemoglobin should be monitored and the dose should be titrated beyond 50 mg orally twice a day, if necessary, but a maximum recommended dose of 100 mg orally twice a day should not be exceeded.

Precautions

CONTRAINDICATIONS: None

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

Consult WARNINGS section for additional precautions.

Dialysis

Data not available

Other Comments

Administration advice:

• Administer with or without food.
• Swallow whole; do not split, crush, chew, or dissolve the tablets.

• Store at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F).
• Store the blister wallets in original carton until use.

• General: For increased risks of adverse reactions from this drug (during coadministration with moderate CYP450 inhibitors)
• Hematologic: For signs of acute hemolysis and anemia (when discontinuing therapy); hemoglobin (during coadministration with moderate CYP450 inhibitors or inducers)

• Read the US FDA-approved patient labeling (Patient Information).
• If a dose is missed by 4 hours or less, take it as soon as possible; if a dose is missed by more than 4 hours, do not take a replacement dose, and wait until the next scheduled dose. Subsequently, return to the normal dosing schedule.
• Follow health care provider's instructions for discontinuing this drug; upon discontinuation, immediately report any symptoms suggestive of acute hemolysis (including jaundice, scleral icterus, dark urine, dizziness, confusion, fatigue, shortness of breath) to health care provider for further evaluation.