Dosage modifications1

Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, NEXAVAR® (sorafenib) has the potential to adversely affect wound healing. Withhold NEXAVAR for at least 10 days prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of NEXAVAR after resolution of wound healing complications has not been established.

Recommended dose reductions for adverse reactions
Dose ReductionHepatocellular Carcinoma and Renal Cell CarcinomaDifferentiated Thyroid Carcinoma
First dose reduction400 mg orally once daily400 mg orally in the morning and 200 mg orally in the evening about 12 hours apart
OR 200 mg orally in the morning and 400 mg orally in the evening about 12 hours apart
Second dose reduction200 mg orally once daily
OR 400 mg every other day
200 mg orally twice daily
Third dose reductionNone200 mg orally once daily

The following may require temporary interruption or permanent discontinuation of NEXAVAR (see table below):

Recommended dosage modifications of NEXAVAR for adverse reactions
Adverse ReactionSeverity*NEXAVAR Dosage Modification
Cardiovascular events  
Cardiac ischemia and/or infarctionGrade 2 and abovePermanently discontinue
Congestive heart failureGrade 3Interrupt until Grade 1 or less, resume at reduced dose by 1 dose level
Grade 4Permanently discontinue
HemorrhageGrade 2 and above requiring medical interventionPermanently discontinue
HypertensionGrade 2
(symptomatic/persistent)
OR Grade 2 symptomatic increase by greater than 20 mm Hg (diastolic) or greater than 140/90 mm Hg if previously within normal limits OR Grade 3
Interrupt until symptoms resolve and diastolic blood pressure less than 90 mm Hg, then resume at reduced dose by 1 dose level If needed, reduce another dose level
Grade 4Permanently discontinue
Gastrointestinal perforationAny gradePermanently discontinue
QT interval prolongationGreater than 500 milliseconds OR Increase from baseline of 60 milliseconds or greaterInterrupt and correct electrolyte abnormalities (magnesium, potassium, calcium)

Use medical judgment before restarting
Drug-induced liver injuryGrade 3 ALT or higher in the absence of another cause§ OR AST/ALT greater than 3 x upper limit normal (ULN) with bilirubin greater than 2 x ULN in the absence of another cause§Permanently discontinue
Non-hematological toxicitiesGrade 2Continue treatment at reduced dose by 1 dose level
Grade 3 
1st occurrenceInterrupt until Grade 2 or less, then resume at reduced dose by 1 dose level
No improvement within 7 days OR 2nd or 3rd occurrenceInterrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels
4th occurrenceInterrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC and RCC or 3 dose levels for DTC
Grade 4Permanently discontinue
Adverse Reaction
Cardiovascular events
Adverse Reaction
Cardiac ischemia and/or infarction
Severity*NEXAVAR Dosage Modification
Grade 2 and abovePermanently discontinue
Adverse Reaction
Congestive heart failure
Severity*NEXAVAR Dosage Modification
Grade 3Interrupt until Grade 1 or less, resume at reduced dose by 1 dose level
Severity*NEXAVAR Dosage Modification
Grade 4Permanently discontinue
Adverse Reaction
Hemorrhage
Severity*NEXAVAR Dosage Modification
Grade 2 and above requiring medical interventionPermanently discontinue
Adverse Reaction
Hypertension
Severity*NEXAVAR Dosage Modification
Grade 2
(symptomatic/persistent)
OR Grade 2 symptomatic increase by greater than 20 mm Hg (diastolic) or greater than 140/90 mm Hg if previously within normal limits OR Grade 3
Interrupt until symptoms resolve and diastolic blood pressure less than 90 mm Hg, then resume at reduced dose by 1 dose level
If needed, reduce another dose level
Severity*NEXAVAR Dosage Modification
Grade 4Permanently discontinue
Adverse Reaction
Gastrointestinal perforation
Severity*NEXAVAR Dosage Modification
Any gradePermanently discontinue
Adverse Reaction
QT interval prolongation
Severity*NEXAVAR Dosage Modification
Greater than 500 milliseconds OR Increase from baseline of 60 milliseconds or greaterInterrupt and correct electrolyte abnormalities (magnesium, potassium, calcium) Use medical judgment before restarting
Adverse Reaction
Drug-induced liver injury
Severity*NEXAVAR Dosage Modification
Grade 3 ALT or higher in the absence of another cause§ OR AST/ALT greater than 3 x upper limit normal (ULN) with bilirubin greater than 2 x ULN in the absence of another cause§Permanently discontinue
Adverse Reaction
Non-hematological toxicities
Severity*NEXAVAR Dosage Modification
Grade 2Continue treatment at reduced dose by 1 dose level
Severity*
Grade 3
Severity*NEXAVAR Dosage Modification
1st occurrenceInterrupt until Grade 2 or less, then resume at reduced dose by 1 dose level
Severity*NEXAVAR Dosage Modification
No improvement within 7 days OR 2nd or 3rd occurrenceInterrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels
Severity*NEXAVAR Dosage Modification
4th occurrenceInterrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC and RCC or 3 dose levels for DTC
Severity*NEXAVAR Dosage Modification
Grade 4Permanently discontinue
Recommended dosage modifications for dermatologic toxicities
Dermatologic
Toxicity Grade
OccurrenceNEXAVAR Dosage Modification
  Hepatocellular and Renal Cell CarcinomaDifferentiated Thyroid Carcinoma
Grade 2:
Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities
1st occurrenceContinue NEXAVAR and consider topical therapy for symptomatic relief
If no improvement within 7 days, see below
Decrease NEXAVAR to
600 mg daily
If no improvement within 7 days, see below
No improvement within 7 days at reduced dose

OR

2nd and 3rd occurrence
Interrupt NEXAVAR until resolved or improved to Grade 0 to 1Interrupt NEXAVAR until completely resolved or improved to Grade 1
When resuming treatment, decrease dose by 1 dose levelWhen resuming treatment, decrease dose by 1 dose level for 2nd occurrence and 2 dose levels for 3rd occurrence
4th occurrenceDiscontinue NEXAVAR treatment
Grade 3:
Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living
1st occurrenceInterrupt NEXAVAR until resolved or improved to Grade 0 to 1Interrupt NEXAVAR until completely resolved or improved to Grade 1
When resuming treatment, decrease dose by 1 dose levelWhen resuming treatment, decrease dose by 1 dose level
2nd occurrenceInterrupt NEXAVAR until resolved or improved to Grade 0 to 1Interrupt NEXAVAR until completely resolved or improved to Grade 1
When resuming treatment, decrease dose by 1 dose levelWhen resuming treatment, decrease dose by 2 dose levels
3rd occurrenceDiscontinue NEXAVAR treatment
Dermatologic
Toxicity Grade
OccurrenceNEXAVAR Dosage Modification
  Hepatocellular and Renal Cell Carcinoma
Grade 2:
Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities
1st occurrenceContinue NEXAVAR and consider topical therapy for symptomatic relief
If no improvement within 7 days, see below
No improvement within 7 days at reduced dose

OR

2nd and 3rd occurrence
Interrupt NEXAVAR until resolved or improved to Grade 0 to 1
When resuming treatment, decrease dose by 1 dose level
4th occurrenceDiscontinue NEXAVAR treatment
Grade 3:
Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living
1st occurrenceInterrupt NEXAVAR until resolved or improved to Grade 0 to 1
When resuming treatment, decrease dose by 1 dose level
2nd occurrenceInterrupt NEXAVAR until resolved or improved to Grade 0 to 1
When resuming treatment, decrease dose by 1 dose level
3rd occurrenceDiscontinue NEXAVAR treatment
Dermatologic
Toxicity Grade
OccurrenceNEXAVAR Dosage Modification
  Differentiated Thyroid Carcinoma
Grade 2:
Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities
1st occurrenceDecrease NEXAVAR to 600 mg daily
If no improvement within 7 days, see below
No improvement within 7 days at reduced dose

OR

2nd and 3rd occurrence
Interrupt NEXAVAR until completely resolved or improved to Grade 1
When resuming treatment, decrease dose by 1 dose level for 2nd occurrence and 2 dose levels for 3rd occurrence
4th occurrenceDiscontinue NEXAVAR treatment
Grade 3:
Moist desquamation, ulceration, blistering, or severe pain of the hands or feet, resulting in inability to work or perform activities of daily living
1st occurrenceInterrupt NEXAVAR until completely resolved or improved to Grade 1
When resuming treatment, decrease dose by 1 dose level
2nd occurrenceInterrupt NEXAVAR until completely resolved or improved to Grade 1
When resuming treatment, decrease dose by 2 dose levels
3rd occurrenceDiscontinue NEXAVAR treatment

Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0 or 1 for at least 28 days on a reduced dose of NEXAVAR, the dose of NEXAVAR may be increased 1 dose level from the reduced dose. Approximately 50% of patients requiring a dose reduction for dermatologic toxicity are expected to meet these criteria for resumption of the higher dose and roughly 50% of patients resuming the previous dose are expected to tolerate the higher dose (that is, maintain the higher dose level without recurrent Grade 2 or higher dermatologic toxicity).

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