2.1 Recommended Dose for Hepatocellular Carcinoma, Renal Cell Carcinoma, and Differentiated Thyroid Carcinoma
The recommended daily dose of NEXAVAR is 400 mg (2 x 200 mg tablets) taken twice daily without food (at least 1 hour before or 2 hours after a meal). Treatment should continue until the patient is no longer clinically benefiting from therapy or until unacceptable toxicity occurs.
2.2 Dose Modifications for Suspected Adverse Drug Reactions
Temporary interruption of NEXAVAR is recommended in patients undergoing major surgical procedures [see Warnings and Precautions (5.7)].
Temporary interruption or permanent discontinuation of NEXAVAR may be required for the following:
•
Cardiac ischemia or infarction
[see Warnings and Precautions (5.1)]
•
Hemorrhage requiring medical intervention
[see Warnings and Precautions (5.2)]
•
Severe or persistent hypertension despite adequate anti-hypertensive therapy
[see Warnings and Precautions (5.3)]
•
Gastrointestinal perforation
[see Warnings and Precautions (5.5)]
•
QTc prolongation
[see Warnings and Precautions (5.9)]
•
Severe drug-induced liver injury
[see Warnings and Precautions (5.10)]
Dose modifications for Hepatocellular Carcinoma and Renal Cell Carcinoma
When dose reduction is necessary, the NEXAVAR dose may be reduced to 400 mg once daily. If additional dose reduction is required, NEXAVAR may be reduced to a single 400 mg dose every other day [see Warnings and Precautions (5)].
Suggested dose modifications for dermatologic toxicities are outlined in Table 1.
Table 1: Suggested Dose Modifications for Dermatologic Toxicities in Patients with Hepatocellular or Renal Cell Carcinoma
Dermatologic Toxicity Grade
Occurrence
Suggested Dose Modification
Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient’s normal activities
Any occurrence
Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief
Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities
1st occurrence
Continue treatment with NEXAVAR and consider topical therapy for symptomatic relief
If no improvement within 7 days, see below
No improvement within 7 days or 2nd or 3rd occurrence
Interrupt NEXAVAR treatment until toxicity resolves to Grade 0–1
When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day)
4th occurrence
Discontinue NEXAVAR treatment
Grade 3: Moist desquamation, ulceration, blistering or severe pain of the hands or feet, or severe discomfort that causes the patient to be unable to work or perform activities of daily living
1st or 2nd occurrence
Interrupt NEXAVAR treatment until toxicity resolves to Grade 0–1
When resuming treatment, decrease NEXAVAR dose by one dose level (400 mg daily or 400 mg every other day)
3rd occurrence
Discontinue NEXAVAR treatment
Dose modifications for Differentiated Thyroid Carcinoma
Table 2: Recommended Doses for Patients with Differentiated Thyroid Carcinoma Requiring Dose Reduction
Dose Reduction
NEXAVAR Dose
First Dose Reduction
600 mg daily dose
400 mg and 200 mg 12 hours apart (2 tablets and 1 tablet 12 hours apart – either dose can come first)
Second Dose Reduction
400 mg daily dose
200 mg twice daily (1 tablet twice daily)
Third Dose Reduction
200 mg daily dose
200 mg once daily (1 tablet once daily)
When dose reduction is necessary for dermatologic toxicities, reduce the NEXAVAR dose as indicated in Table 3 below.
Table 3: Recommended Dose Modifications for Dermatologic Toxicities for Patients with Differentiated Thyroid Carcinoma
Dermatologic Toxicity Grade
Occurrence
NEXAVAR Dose Modification
Grade 1: Numbness, dysesthesia, paresthesia, tingling, painless swelling, erythema or discomfort of the hands or feet which does not disrupt the patient’s normal activities
Any occurrence
Continue treatment with NEXAVAR
Grade 2: Painful erythema and swelling of the hands or feet and/or discomfort affecting the patient’s normal activities
1st occurrence
Decrease NEXAVAR dose to 600 mg daily
If no improvement within 7 days, see below
No improvement within 7 days at reduced dose
or
2nd occurrence
Interrupt NEXAVAR until resolved or improved to grade 1
If NEXAVAR is resumed, decrease dose (see Table 2)
3rd occurrence
Interrupt NEXAVAR until resolved or improved to grade 1
If NEXAVAR is resumed, decrease dose (see Table 2)
4th occurrence
Discontinue NEXAVAR permanently
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 occurrence
Interrupt NEXAVAR until resolved or improved to grade 1
If NEXAVAR is resumed, decrease dose by one dose level (see Table 2)
2nd occurrence
Interrupt NEXAVAR until resolved or improved to grade 1
When NEXAVAR is resumed, decrease dose by 2 dose levels (see Table 2)
3rd occurrence
Discontinue NEXAVAR permanently
Following improvement of Grade 2 or 3 dermatologic toxicity to Grade 0–1 after at least 28 days of treatment on a reduced dose of NEXAVAR, the dose of NEXAVAR may be increased one 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)
