Sorafenib Tosylate

First Dose Reduction

400 mg orally once daily

400 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 Reduction

200 mg orally once daily

OR

400 every other day

200 mg orally twice daily

Cardiovascular Events [see Warnings and Precautions (5.1)]

Cardiac Ischemia and/or Infarction

Grade 2 and above

Permanently discontinue.

Congestive Heart Failure

Grade 3

Interrupt † until Grade 1 or less, resume at reduced dose by 1 dose level.‡

Grade 4

Permanently discontinue.

Hemorrhage [see Warnings and Precautions (5.2)]

Grade 2 and above requiring medical intervention

Permanently discontinue.

Hypertension [see Warnings and Precautions (5.3)]

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.‡

Grade 4

Permanently discontinue.

Gastrointestinal Perforation [see Warnings and Precautions (5.5)]

Any grade

Permanently discontinue.

QT Interval Prolongation [see Warnings and Precautions (5.9)]

Greater than 500 milliseconds

OR

Increase from baseline of 60 milliseconds or greater

Interrupt and correct electrolyte abnormalities (magnesium, potassium, calcium).

Use medical judgement before restarting.

Drug-Induced Liver Injury [see Warnings and Precautions (5.10)]

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.

Non-hematological toxicities [see Adverse Reactions (6.1)]

Grade 2

Continue treatment at reduced dose by 1 dose level.

Grade 3

1^st occurrence

Interrupt until Grade 2 or less, then resume at reduced dose by 1 dose level.

No improvement within 7 days

OR

2^nd or 3^rd occurrence

Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels.

4^th occurrence

Interrupt until Grade 2 or less, then resume at reduced dose by 2 dose levels for HCC and RCC or 3 dose levels for DTC.

Hepatocellular and Renal Cell Carcinoma

Differentiated Thyroid Carcinoma

Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities

1^st occurrence

Continue sorafenib tablets and consider topical therapy for symptomatic relief.

If no improvement within 7 days, see below.

Decrease sorafenib tablets to 600 mg daily. If no improvement within 7 days, see below.

No improvement within 7 days at reduced dose

OR

2^nd and 3^rd occurrence

Interrupt sorafenib tablets until resolved or improved to Grade 0 to 1.

Interrupt sorafenib tablets until completely resolved or improved to Grade 1.

When resuming treatment, decrease dose by 1 dose level.

When resuming treatment, decrease dose by 1 dose level for 2^nd occurrence and 2 dose levels for 3^rd occurrence.

4^th occurrence

Discontinue sorafenib tablets 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

1^st occurrence

Interrupt sorafenib tablets until resolved or improved to Grade 0 to 1.

Interrupt sorafenib tablets until completely resolved or improved to Grade 1.

When resuming treatment, decrease dose by 1 dose level.

When resuming treatment, decrease dose by 1 dose level.

2^nd occurrence

Interrupt sorafenib tablets until resolved or improved to Grade 0 to 1.

Interrupt sorafenib tablets until completely resolved or improved to Grade 1.

When resuming treatment, decrease dose by 1 dose level.

When resuming treatment, decrease dose by 2 dose levels.