Usual Adult Dose for Renal Cell Carcinoma

800 mg orally once a day until disease progression or unacceptable toxicity

Uses:

• Advanced renal cell carcinoma (RCC)
• Advanced soft tissue sarcoma (STS) with prior chemotherapy

Usual Adult Dose for Soft Tissue Sarcoma

800 mg orally once a day until disease progression or unacceptable toxicity

Uses:

• Advanced renal cell carcinoma (RCC)
• Advanced soft tissue sarcoma (STS) with prior chemotherapy

Renal Dose Adjustments

Mild to moderate renal impairment: No adjustment recommended.
Severe renal impairment: Data not available

Liver Dose Adjustments

Mild (either total bilirubin upper limit of normal [ULN] or less and ALT greater than ULN or bilirubin greater than 1 to 1.5 x ULN and any ALT) hepatic impairment: No adjustment recommended.
Moderate (total bilirubin greater than 1.5 to 3 x ULN and any ALT) or severe (total bilirubin greater than 2 x ULN and any ALT) hepatic impairment: Consider alternatives to this drug or reduce the dose to 200 mg orally once a day.
Severe hepatic impairment (total bilirubin greater than 3 x ULN and any ALT): Not recommended.

RECOMMENDED DOSE ADJUSTMENTS FOR HEPATIC TOXICITY:

• Isolated ALT elevations between 3 and 8 x upper limit of normal (ULN): Continue therapy and monitor liver function weekly until ALT returns to Grade 1 or baseline.
• Isolated ALT elevations of greater than 8 x ULN: Withhold therapy until improvement to Grade 1 or baseline; if benefit outweighs risk for hepatotoxicity, resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks; permanently discontinue therapy if ALT elevations greater than 3 x ULN recur despite dose reduction.
• ALT elevations greater than 3 x ULN occur concurrently with bilirubin elevations greater than 2 x ULN: Permanently discontinue therapy and monitor until resolution. Patients with only a mild, indirect (unconjugated) hyperbilirubinemia (Gilbert's syndrome) and ALT elevations greater than 3 x ULN should be managed per the recommendations outlined for isolated ALT elevations.

Dose Adjustments

RECOMMENDED DOSE REDUCTIONS:
FOR RENAL CELL CARCINOMA:

• First dose reduction: 400 mg orally once a day
• Second dose reduction: 200 mg orally once a day

FOR SOFT TISSUE SARCOMA:

• First dose reduction: 600 mg orally once a day
• Second dose reduction: 400 mg orally once a day

NOTE: Permanently discontinue therapy in patients unable to tolerate the second dose reduction.

RECOMMENDED DOSE REDUCTIONS FOR ADVERSE REACTIONS:
LEFT VENTRICULAR SYSTOLIC DYSFUNCTION:

• Symptomatic or Grade 3: Withhold therapy until improvement to less than Grade 3; resume therapy based on medical judgement.
• Grade 4: Permanently discontinue therapy.

HEMORRHAGIC EVENTS:

• Grade 2: Withhold therapy until improvement to Grade 1 or less; resume at reduced dose; permanently discontinue if Grade 2 recurs after dose interruption and reduction.
• Grade 3 or 4: Permanently discontinue therapy.

ARTERIAL THROMBOTIC EVENTS:

• Any Grade: Permanently discontinue therapy.

VENOUS THROMBOTIC EVENTS:

• Grade 3: Withhold therapy and resume at same dose if managed for at least one week.
• Grade 4: Permanently discontinue therapy.

THROMBOTIC MICROANGIOPATHY:

• Any Grade: Permanently discontinue therapy.

GI PERFORATION:

• Any Grade: Permanently discontinue therapy.

GI FISTULA:

• Grade 2 or 3: Withhold therapy and resume based on medical judgement.
• Grade 4: Permanently discontinue therapy.

INTERSTITIAL LUNG DISEASE (ILD)/PNEUMONITIS:

• Any Grade: Permanently discontinue therapy.

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME (PRES):

• Any Grade: Permanently discontinue therapy.

HYPERTENSION:

• Grade 2 or 3: Reduce dose and initiate or adjust antihypertensive therapy; permanently discontinue therapy if hypertension remains Grade 3 despite dose reduction(s) and adjustment of antihypertensive therapy.

Grade 4 or hypertensive crisis Permanently discontinue therapy.
PROTEINURIA:

• Urine protein over 24 hours is 3 grams or greater: Withhold therapy until improvement to Grade 1 or less; resume at reduced dose; permanently discontinue therapy if 24-hour urine protein does not improve from 3 grams or greater or recurs despite dose reductions.
• Confirmed nephrotic syndrome: Permanently discontinue therapy.

Strong CYP450 3A4 inhibitors:

• Avoid concomitant use of a strong CYP450 3A4 inhibitor, consider an alternative medication, or reduce dose to 400 mg orally once a day.

Strong CYP450 3A4 inducers:

• Avoid concomitant use of a strong CYP450 3A4 inducer by use of an alternate concomitant medication with no or minimal enzyme induction potential,

This drug is not recommended in patients who cannot avoid chronic use of strong CYP450 3A4 inducers.

Gastric Acid-Reducing Agents:

• Avoid concomitant use of gastric acid-reducing agents; if concomitant use cannot be avoided, consider short-acting antacid in place of proton pump inhibitors (PPIs) and H2-receptor antagonists; separate short-acting antacid and administration of this drug by several hours.

Precautions

US BOXED WARNINGS:

• Severe and fatal hepatotoxicity has been reported.

Recommendation:

• Monitor hepatic function and interrupt, reduce, or discontinue therapy as recommended.

CONTRAINDICATIONS:

• None

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

Consult WARNINGS section for additional precautions.

Dialysis

Peritoneal dialysis or hemodialysis: Data not available

Other Comments

Administration advice:

• This drug should be taken on an empty stomach (at least 1 hour before or 2 hours after a meal).
• Tablets should be swallowed whole; do not crush due to the potential for increased rate of absorption which may affect systemic exposure.
• If a dose is missed, it should not be taken if it is less than 12 hours until the next dose.

Monitoring:

• Monitor serum liver function tests (ALT, AST, bilirubin) before initiation of drug therapy, and at weeks 3, 5, 7, and 9; thereafter, monitor at months 3 and 4, and periodically.
• Blood pressure should be well-controlled before initiating therapy and should be monitored within the first week after starting therapy and frequently thereafter.
• Monitor thyroid function prior to initiating therapy and periodically thereafter.
• Baseline and periodic monitoring of ECGs and maintenance of electrolytes should be performed.
• Baseline and periodic monitoring of left ventricular ejection fraction (LVEF) and congestive heart failure is recommended in patients at risk of cardiac dysfunction including previous anthracycline exposure.
• Baseline and periodic urinalysis is recommended with follow up measurement of 24-hour urine protein.

Patient advice:

• This drug can cause serious liver problems including death. Your doctor will do blood tests to check your liver before and during drug therapy. Tell your doctor right away if you get any of these signs of liver problems such as yellowing of your skin/whites of eyes (jaundice), dark urine, tiredness, nausea or vomiting, loss of appetite, pain on the right side of your stomach, and unusual bruising.
• This drug can harm an unborn baby; avoid pregnancy during therapy. If pregnancy occurs, contact your doctor immediately.
• This drug may cause high blood pressure. Monitor your blood pressure within the first week of therapy and often during therapy. Tell your doctor if you have an increase in blood pressure, blurred vision, confusion, nausea and vomiting, shortness of breath, severe headache, severe anxiety, severe chest pain, or seizures.
• This drug may impair wound healing. Stop this drug at least 7 days prior to surgery and consult your doctor before restarting therapy after surgery.
• Swallow tablets whole with water on an empty stomach, at least 1 hour before or 2 hours after a meal. Do not crush or break the tablets and avoid grapefruit and grapefruit juice.
• This drug can interact with several medications. Tell your doctor about all the medications you take, including prescription and over-the-counter drugs, vitamins, dietary, and herbal supplements.
• This drug may cause side effects including but not limited to diarrhea, hair color changes, nausea, vomiting, and loss of appetite. Tell your doctor if you have any side effect that bothers you or does not go away.

Frequently asked questions

• Does Votrient cure cancer or shrink tumors?
• How long does Votrient stay in your system?
• Is Votrient immunotherapy?
• Is Votrient a chemotherapy treatment?