Votrient

Uses

Votrient is used for the treatment of patients with advanced renal cell carcinoma (RCC). Votrient is used for the treatment of patients with advanced soft tissue sarcoma (STS) who have received prior chemotherapy.

Votrient is also used to associated treatment for these conditions: Advanced Renal Cell Carcinoma, Advanced Soft Tissue Sarcoma, Advanced Thyroid cancer

How Votrient works

Votrient is a second-generation multitargeted tyrosine kinase inhibitor against vascular endothelial growth factor receptor-1, -2, and -3, platelet-derived growth factor receptor-alpha, platelet-derived growth factor receptor-beta, and c-kit. These receptor targets are part of the angiogenesis pathway that facilitates the formation of tumour blood vessel for tumour survival and growth.

Dosage

Votrient dosage

Recommended Dosing: The recommended starting dose of Votrient is 800 mg orally once daily without food (at least 1 hour before or 2 hours after a meal). The dose of Votrient should not exceed 800 mg.

Do not crush tablets 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.

Dose Modification Guidelines:

• In advancedrenal cell carcinoma, the initial dose reduction should be 400 mg, and additional dose decrease or increase should be in 200-mg steps based on individual tolerability.
• In advancedsoft tissue sarcoma, a decrease or increase should be in 200-mg steps based on individual tolerability.

Hepatic Impairment

: No dose adjustment is required in patients with mild hepatic impairment. In patients with moderate hepatic impairment, alternatives to Votrient should be considered. If Votrient is used in patients with moderate hepatic impairment, the dose should be reduced to 200 mg per day. Votrient is not recommended in patients with severe hepatic impairment

Side Effects

Common side effects of Votrient include:

• headache
• loss of appetite
• weight loss
• altered sense of taste
• nausea and vomiting (may be severe)
• diarrhea
• numbness/tingling/redness in hands/feet
• changes in hair or skin color
• joint or muscle pain, or
• feeling tired/weak.

Precaution

Hepatic Toxicity and Hepatic Impairment, QT Prolongation, Cardiac Dysfunction, Hemorrhagic Events, Thromboembolic Events, Gastrointestinal Perforation and Fistula, Hypertension, Hypothyroidism, Pregnancy.

Interaction

Co-administration with CYP3A4 (eg, itraconazole, clarithromycin, atazanavir, idinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit juice), P-gp & BCRP inhibitors, high-/low-fat food increases exposure & cone of pazopanib. Co-administration with CYP3A4 (eg, rifampicin) inducers may decrease plasma pazopanib cone. P-gp & BCRP inducers may alter exposure & distribution of pazopanib.

Votrient may alter exposure & distribution of CYP3A4 substrates (eg, midazolam), CYP2C8 substrates (eg, paclitaxel) & UGT1A1 substrates (eg, irinotecan & its active metabolite SN-38). Votrient may increase the ratio of dextrometrophan to dextrophan cone after administration of dextrometrophan. Proton-pump inhibitors (eg, esomeprazole) & other agents that increase gastric pH may decrease bioavailability of pazopanib. Concomitant use with simvastatin & other statins may lead to ALT elevations.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of pazopanib.
• Avoid St. John's Wort. This herb induces CYP3A4 metabolism, which may reduce the serum concentration of pazopanib.
• Take on an empty stomach. Separate pazopanib from meals by at least 1 hour before and 2 hours after eating as food increases pazopanib bioavailability.
• Take separate from antacids. Separate the administration of pazopanib and antacids by several hours.

[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of pazopanib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.

ADJUST DOSING INTERVAL: Food increases the oral bioavailability of pazopanib.

The mechanism of interaction is unknown.

Administration of pazopanib with a high-fat or low-fat meal results in an approximately 2-fold increase in peak plasma concentration (Cmax) and systemic exposure (AUC).

MANAGEMENT: Patients treated with pazopanib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract.

Votrient should be administered at least one hour before or two hours after a meal.

Votrient Drug Interaction

Major: diltiazem, omeprazoleModerate: everolimus, albuterol / ipratropium, prochlorperazine, rosuvastatin, atorvastatin, sorafenib, sunitinibUnknown: contained in alcoholic beverages , ubiquinone, alendronate, levetiracetam, metoprolol, morphine, acetaminophen, metoclopramide, vitamin a topical, montelukast, cholecalciferol

Votrient Disease Interaction

Major: bleeding, liver dysfunction, GI perforationModerate: CV disease, hypothyroidism, lung dysfunction, QT prolongation, hypertension, PRES, proteinuria, thromboembolic disorders

Volume of Distribution

Vd steady state, IV administration 5 mg, cancer patient = 11.1 L (range of 9.15 - 13.4)

Elimination Route

Absorption of pazopanib in cancer patients is slow and incomplete. In patients with solid tumour, over a dose range of 50-2000 mg, absorption is nonlinear. Significant accumulation of pazopanib can also be observed in patients receiving 800 mg once daily for 22 days. Crushing tablets may increase exposure (increase in Cmax and AUC, while Tmax decreases by 2 hours). Bioavailability, oral tablet 800 mg, cancer patient = 21%; Bioavailability may be low due to incomplete absorption from the gastrointestinal tract. The major circulating component of the drug in the systemic is pazopanib, and not its metabolites. Mean maximum plasma concentration= 58.1 µg/mL; Mean AUC= 1037 µg · h/mL;

Half Life

35 hours. Oral absorption is not the rate limiting step of elimination from the plasma.

Clearance

CL, cancer patient, IV administration 5 mg = 4mL/min Half of the absorbed dose is cleared via oxidative metabolism.

Elimination Route

Primarily excreted via feces (82.2%) and to a negligible extent via urine (<4%) in cancer patients. Most of the administered dose is excreted unchanged. Approximately 10% of dose are oxidative metabolites and are mostly eliminated via the feces.

Pregnancy & Breastfeeding use

Votrient can cause fetal harm when administered to a pregnant woman. Based on its mechanism of action, Votrient is expected to result in adverse reproductive effects. In pre-clinical studies in rats and rabbits, pazopanib was teratogenic, embryotoxic, fetotoxic, and abortifacient.

There are no adequate and well-controlled studies of Votrient in pregnant women. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while taking Votrient

Contraindication

Hypersensitivity.

Acute Overdose

Votrient doses up to 2,000 mg have been evaluated in clinical trials. Dose-limiting toxicity (Grade 3 fatigue) and Grade 3 hypertension were each observed in 1 of 3 patients dosed at 2,000 mg daily and 1,000 mg daily, respectively.

Treatment of overdose with Votrient should consist of general supportive measures. There is no specific antidote for overdosage of Votrient.

Hemodialysis is not expected to enhance the elimination of Votrient because pazopanib is not significantly renally excreted and is highly bound to plasma proteins.

Innovators Monograph

You find simplified version here Votrient