VOTRIENT- pazopanib hydrochloride tablet, film coated
Novartis Pharmaceuticals Corporation
Severe and fatal hepatotoxicity has been observed in clinical trials. Monitor hepatic function and interrupt, reduce, or discontinue dosing as recommended [see Warnings and Precautions (5.1)].
VOTRIENT® is indicated for the treatment of adults with advanced renal cell carcinoma (RCC).
VOTRIENT is indicated for the treatment of adults with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.
Limitations of Use: The efficacy of VOTRIENT for the treatment of patients with adipocytic STS or gastrointestinal stromal tumors has not been demonstrated.
The recommended dosage of VOTRIENT is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal) until disease progression or unacceptable toxicity [see Clinical Pharmacology (12.3)]. The dosage should be modified for hepatic impairment and in patients taking certain concomitant drugs [see Dosage and Administration (2.3, 2.4)].
Swallow tablets whole. Do not crush tablets due to the potential for increased rate of absorption which may affect systemic exposure [see Clinical Pharmacology (12.3)].
If a dose is missed, it should not be taken if it is < 12 hours until the next dose.
Table 1 summarizes the recommended dose reductions.
|Dose Reduction||For Renal Cell Carcinoma||For Soft Tissue Sarcoma|
|First||400 mg orally once daily||600 mg orally once daily|
|Second||200 mg orally once daily||400 mg orally once daily|
Permanently discontinue VOTRIENT in patients unable to tolerate the second dose reduction.
Table 2 summarizes the recommended dosage modifications for adverse reactions.
|Abbreviations: ALT, alanine aminotransferase; LVEF, left ventricular ejection fraction; RCC, renal cell carcinoma; STS, soft tissue sarcoma; ULN, upper limit of normal.a National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.|
|Adverse Reaction||Severitya||Dosage Modification|
|Hepatic Toxicity [see Warnings and Precautions (5.1)]||Isolated ALT elevations between 3 × ULN and 8 × ULN||Continue and monitor liver function weekly until ALT returns to Grade 1 or baseline.|
|Isolated ALT elevations of > 8 × ULN||Withhold until improvement to Grade 1 or baseline. If the potential benefit for resuming treatment with VOTRIENT is considered to outweigh the risk for hepatotoxicity, then resume at a reduced dose of no more than 400 mg once daily and measure serum liver tests weekly for 8 weeks.Permanently discontinue if ALT elevations > 3 × ULN recur despite dose reduction(s).|
|ALT elevations > 3 × ULN occur concurrently withbilirubin elevations > 2 × ULN||Permanently discontinue and continue to monitor until resolution.Patients with only a mild, indirect (unconjugated) hyperbilirubinemia, known as Gilbert’s syndrome, and ALT elevations > 3 × ULN should be managed per the recommendations outlined for isolated ALT elevations.|
|Left Ventricular Systolic Dysfunction [see Warnings and Precautions (5.3)]||Symptomatic or Grade 3||Withhold until improvement to Grade < 3. Resume treatment based on medical judgement.|
|Grade 4||Permanently discontinue|
|Hemorrhagic Events [see Warnings and Precautions (5.4)]||Grade 2||Withhold until improvement to Grade ≤ 1. Resume at reduced dose (see Table 1).Permanently discontinue if Grade 2 recurs after dose interruption and reduction.|
|Grade 3 or 4||Permanently discontinue.|
|Arterial Thromboembolic Events [see Warnings and Precautions (5.5)]||Any grade||Permanently discontinue.|
|Venous Thromboembolic Events [see Warnings and Precautions (5.6)]||Grade 3||Withhold VOTRIENT and resume at same dose if managed with appropriate therapy for at least one week.|
|Grade 4||Permanently discontinue.|
|Thrombotic Microangiopathy [see Warnings and Precautions (5.7)]||Any grade||Permanently discontinue.|
|Gastrointestinal Perforation [see Warnings and Precautions (5.8)]||Any grade||Permanently discontinue.|
|Gastrointestinal Fistula [see Warnings and Precautions (5.8)]||Grade 2 or 3||Withhold and resume based on medical judgement.|
|Grade 4||Permanently discontinue.|
|Interstitial Lung Disease (ILD)/Pneumonitis [see Warnings and Precautions (5.9)]||Any grade||Permanently discontinue.|
|Posterior Reversible Encephalopathy Syndrome (PRES) [see Warnings and Precautions (5.10)]||Any grade||Permanently discontinue.|
|Hypertension [see Warnings and Precautions (5.11)]||Grade 2 or 3||Reduce dose (see Table 1) and initiate or adjust anti-hypertensive therapy. Permanently discontinue if hypertension remains Grade 3 despite dose reduction(s) and adjustment of anti-hypertensive therapy.|
|Grade 4 or hypertensive crisis||Permanently discontinue.|
|Proteinuria [see Warnings and Precautions (5.14)]||24-hour urine protein ≥ 3 grams||Withhold until improvement to Grade ≤ 1. Resume at a reduced dose (see Table 1).Permanently discontinue if 24-hour urine protein ≥ 3 grams does not improve or recurs despite dose reductions.|
|Confirmed nephrotic syndrome||Permanently discontinue.|
Moderate and Severe Hepatic Impairment
In patients with moderate hepatic impairment [total bilirubin > 1.5 to 3 × upper limit of normal (ULN) and any alanine aminotransferase (ALT) value], consider alternatives to VOTRIENT. If VOTRIENT is used in patients with moderate hepatic impairment, reduce the VOTRIENT dose to 200 mg orally once daily.
VOTRIENT is not recommended in patients with severe hepatic impairment (total bilirubin > 3 × ULN and any ALT value) [see Use in Specific Populations (8.7)].
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