Usual Adult Dose for Thyroid Cancer

24 mg orally once a day

Comment:

• Treatment should be continued until disease progression or unacceptable toxicity.

Use: For the treatment of patients with locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)

Usual Adult Dose for Renal Cell Carcinoma

First-Line Treatment of Patients with Advanced Renal Cell Carcinoma:
20 mg orally once a day given in combination with 200 mg IV pembrolizumab over 30 minutes every 3 weeks

Previously Treated Renal Cell Carcinoma:
18 mg orally once a day given in combination with 5 mg everolimus orally once a day

Comments:

• Refer to everolimus prescribing information for recommended dosing information.
• Refer to pembrolizumab prescribing information for recommended dosing information
• Treatment with everolimus should be continued until disease progression or unacceptable toxicity.
• Treatment with pembrolizumab should be continued until disease progression or unacceptable toxicity or up to 2 years.
• After 2 years of combination with pembrolizumab, this drug may be administered as a single agent until disease progression or unacceptable toxicity.

Uses:

• In combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy
• In combination with pembrolizumab for the first-line treatment of adult patients with advanced renal cell carcinoma

Usual Adult Dose for Hepatocellular Carcinoma

• Weight less than 60 kg: 8 mg orally once a day
• Weight 60 kg or greater: 12 mg orally once a day

Comment:

• Treatment should be continued until disease progression or unacceptable toxicity.

Use: For the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC)

Usual Adult Dose for Endometrial Carcinoma

20 mg orally once daily in combination with pembrolizumab 200 mg IV over 30 minutes every 3 weeks

Comments:

• Refer to the pembrolizumab prescribing information for other dosing information.
• Treatment should be continued until disease progression or unacceptable toxicity.

Use: In combination with pembrolizumab for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation

Renal Dose Adjustments

Mild (CrCl 60-89 mL/min) or moderate renal impairment (CrCl 30-59 mL/min): No dose adjustment recommended

Severe renal impairment (CrCl less than 30 mL/min):

• Differentiated thyroid cancer (DTC): Reduce the starting dose to 14 mg orally once a day
• Renal cell carcinoma (RCC): Reduce the starting dose to 10 mg orally once a day
• Endometrial carcinoma: Reduce the starting dose to 10 mg orally once a day
• Hepatocellular Carcinoma (HCC): Data not available
• End stage renal disease: Data not available

Liver Dose Adjustments

Mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment: No dose adjustment recommended

Severe hepatic impairment (Child-Pugh C):

• Differentiated thyroid cancer (DTC): Reduce the starting dose to 14 mg orally once a day
• Renal cell carcinoma (RCC): Reduce the starting dose to 10 mg orally once a day
• Endometrial carcinoma: Reduce the starting dose to 10 mg orally once a day
• Hepatocellular Carcinoma (HCC): Data not available

Dose Adjustments

When administering this drug in combination with everolimus, reduce the dose of this drug first and then the everolimus dose for adverse reactions of both drugs. Refer to the everolimus prescribing information for additional dose modification information.

When administering this drug in combination with pembrolizumab, modify the dosage of one or both drugs as appropriate, interrupt, or reduce of discontinue the dose of this drug as appropriate. Refer to pembrolizumab prescribing information for additional dose modification information.

DOSE REDUCTION BASED ON THE PREVIOUS DOSE LEVEL:
DIFFERENTIATED THYROID CANCER (DTC):
Initial dose level of 24 mg orally once a day:

• First occurrence: Reduce dose to 20 mg orally once a day.
• Second occurrence: Reduce dose to 14 mg orally once a day.
• Third occurrence: Reduce dose to 10 mg orally once a day.

RENAL CELL CARCINOMA (RCC):
Initial dose level of 18 mg orally once a day:

• First occurrence: Reduce dose to 14 mg orally once a day.
• Second occurrence: Reduce dose to 10 mg orally once a day.
• Third occurrence: Reduce dose to 8 mg orally once a day.

ENDOMETRIAL CARCINOMA:
Initial dose level of 20 mg orally once a day:

• First occurrence: Reduce dose to 14 mg orally once a day.
• Second occurrence: Reduce dose to 10 mg orally once a day.
• Third occurrence: Reduce dose to 8 mg orally once a day.

HEPATOCELLULAR CARCINOMA (HCC):
Initial dose level of 12 mg orally once a day:

• First occurrence: Reduce dose to 8 mg orally once a day.
• Second occurrence: Reduce dose to 4 mg orally once a day.
• Third occurrence: Reduce dose to 4 mg orally every other day.

Initial dose level of 8 mg orally once a day:

• First occurrence: Reduce dose to 4 mg orally once a day.
• Second occurrence: Reduce dose to 4 mg orally every other day.
• Third occurrence: Discontinue therapy.

RECOMMENDED DOSE MODIFICATIONS FOR ADVERSE REACTIONS:
HYPERTENSION:
Grade 3:

• Withhold for Grade 3 that persists despite optimal antihypertensive therapy.
• Resume at reduced dose when hypertension is controlled at Grade 2 or less.

Grade 4:

• Permanently discontinue therapy.

CARDIAC DYSFUNCTION:
Grade 3:

• Withhold until improves to Grade 0 to 1 or baseline.
• Resume at reduced dose or discontinue depending on the severity and persistence of adverse reaction.

Grade 4:

• Permanently discontinue therapy.

ARTERIAL THROMBOEMBOLIC EVENT:
Any Grade:

• Permanently discontinue therapy.

HEPATOTOXICITY:
Grade 3 or 4:

• Withhold until improves to Grade 0 to 1 or baseline.
• Either resume at a reduced dose or discontinue depending on severity and persistence of hepatotoxicity.
• Permanently discontinue for hepatic failure.

RENAL IMPAIRMENT OR FAILURE:
Grade 3 or 4:

• Withhold until improves to Grade 0 to 1 or baseline.
• Resume at a reduced dose or discontinue depending on severity and persistence of renal impairment.

PROTEINURIA:
2 grams or greater proteinuria in 24 hours:

• Withhold until less than or equal to 2 grams of proteinuria per 24 hours.
• Resume at a reduced dose.
• Permanently discontinue for nephrotic syndrome.

GI PERFORATION:
Any Grade:

• Permanently discontinue therapy.

FISTULA FORMATION:
Grade 3 or 4:

• Permanently discontinue therapy.

QT PROLONGATION:
Greater than 500 ms or greater than 60 ms increase from baseline:

• Withhold until improves to less than or equal to 480 ms or baseline.
• Resume at a reduced dose.

REVERSIBLE POSTERIOR LEUKOENCEPHALOPATHY SYNDROME (RPLS):
Any Grade:

• Withhold until fully resolved.
• Resume at a reduced dose or discontinue depending on severity and persistence of neurologic symptoms.

OTHER ADVERSE REACTIONS:
Persistent or intolerable Grade 2 or 3 adverse reaction or Grade 4 laboratory abnormality:

• Withhold until improves to Grade 0 to 1 or baseline.
• Resume at reduced dose.

Grade 4 adverse reaction:

• Permanently discontinue therapy.

Precautions

CONTRAINDICATIONS:

• None

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

Consult WARNINGS section for additional precautions.

Dialysis

This drug is not expected to be dialyzable due to its high plasma protein binding.

Other Comments

Administration advice:

• Capsules can be swallowed whole or dissolved in a small glass of liquid.
• This drug can be given with or without food.
• This drug should be taken at the same time each day.
• If a dose is missed and cannot be taken within 12 hours, skip that dose and take the next dose at the usual time.

Storage Requirements:

• Store at 25C (77F); excursions permitted to 15C - 30C (59F - 86F).

Monitoring:

• Cardiovascular: Blood pressure, bleeding, signs and symptoms of cardiac dysfunction, ECG
• Endocrine: TSH levels
• Hepatic: ALT, AST
• Metabolic: Serum electrolytes, blood calcium levels
• Neurologic: New onset or worsening neurological function
• Renal: Proteinuria, regular laboratory renal tests

Patient advice:

• Advise the patient to read the FDA-approved patient labeling.
• Advise patients regarding good oral hygiene practices and to have preventive dentistry performed prior to and throughout treatment.
• Advise patients that this drug can increase the risk for bleeding.
• Advise patients that this drug can increase the risk of fistula formation or gastrointestinal perforation and to seek immediate medical attention for severe abdominal pain.
• Advise patients that this drug to report any clinical symptom of cardiac dysfunction.
• Advise patients to inform their healthcare provider of any planned surgical procedure.
• Advise females of reproductive potential to use effective contraception during treatment and for at least 30 days after the last dose.
• Advise women to discontinue breastfeeding during treatment and for at least 1 week after the last dose.

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