Tolerability and Safety Data in aRCC

Adverse events are frequently class-related and different from those seen with vascular endothelial growth factor receptor-tyrosine kinase inhibitors
(VEGFR-TKIs)^1,2,3

A randomized, placebo-controlled trial of Afinitor, a once-daily oral mammalian target of rapamycin (mTOR) inhibitor, in patients with aRCC who received prior treatment with sunitinib and/or sorafenib (274 in Afinitor arm/137 in placebo arm) yielded the following adverse events data¹:

For patients in the Afinitor arm, the most frequent adverse event was stomatitis (mostly Grades 1-2), occurring in 44% of patients.¹

Rates of treatment-emergent (irrespective of causality) adverse events resulting in permanent discontinuation were 14% and 3% for the Afinitor and placebo groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. The most common causes of treatment delay or dose reduction in the Afinitor group were infections, stomatitis, and pneumonitis.¹

There were also reports of non-infectious pneumonitis, infections, and kidney failure (including acute renal failure)—some fatal—in patients taking Afinitor. Elevations in serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions in hemoglobin, lymphocytes, neutrophils, and platelets were also reported.¹

Important Safety Information

There have been reports of non-infectious pneumonitis, infections and kidney failure (including acute renal failure) in patients taking AFINITOR, some with fatal outcomes. Oral ulceration is the most frequently occurring adverse event and occurred in 44% of AFINITOR-treated patients. Most were Grade 1 or 2. Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have also been reported.

Please see additional Important Safety Information at the bottom of this page.
Please see full Prescribing Information.

Important Safety Information

Hepatic Impairment: Exposure to everolimus was increased in patients with hepatic impairment. For advanced RCC patients with severe hepatic impairment (Child-Pugh class C), AFINITOR may be used at a reduced dose if the desired benefit outweighs the risk. For patients with mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, a dose reduction is recommended.

Vaccinations: The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR.

Please see additional Important Safety Information at the bottom of this page.
Please see full Prescribing Information.

Warnings and precautions¹

• Non-infectious pneumonitis: Monitor for clinical symptoms or radiological changes; fatal cases have occurred. Manage by dose reduction or discontinuation until symptoms resolve, and consider use of corticosteroids
• Infections: Increased risk of infections, some fatal. Monitor for signs and symptoms, and treat promptly
• Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common. Management includes mouthwashes (without alcohol or peroxide) and topical treatments
• Renal failure events: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Afinitor
• Laboratory test alterations: Elevations of serum creatinine, blood glucose, and lipids may occur. Decreases in hemoglobin, neutrophils, and platelets may also occur. Monitor renal function, blood glucose, lipids, and hematologic parameters prior to treatment and periodically thereafter
• Drug-drug Interactions: Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4 inhibitors should be avoided
• Hepatic Impairment: Exposure of everolimus was increased in patients with moderate hepatic impairment
• Vaccinations: Avoid live vaccines and close contact with those who have received live vaccines
• Use in pregnancy: Fetal harm can occur when administered to a pregnant woman. Apprise women of potential harm to the fetus

Important Safety Information

Use in Pregnancy: Fetal harm can occur if AFINITOR is administered to a pregnant woman. Women of childbearing potential should be advised to use an effective method of contraception while using AFINITOR and for up to 8 weeks after ending treatment.

Please see additional Important Safety Information at the bottom of this page.
Please see full Prescribing Information.

Dosing and Administration for Afinitor in aRCC

Dosing recommendations and adjustments¹

• The recommended dose is one 10 mg tablet once daily
• Afinitor should be taken consistently with or consistently without food
• Afinitor should be taken at the same time every day
• Afinitor should be swallowed whole with a glass of water and should not be chewed or crushed
• For patients unable to swallow tablets, Afinitor tablet(s) should be dispersed completely in a glass of water (containing approximately 30 mL) by gently stirring, immediately prior to drinking. The glass should be rinsed with the same volume of water and the rinse should be completely swallowed to ensure that the entire dose is administered
• Hepatic impairment will increase the exposure to everolimus and dose adjustments are recommended. Dose adjustments should also be made if a patient's hepatic (Child-Pugh) status changes during treatment
  
• 5 mg tablets and 2.5 mg tablets are available if dose adjustment is required
• Decrease to 5 mg daily for severe and/or intolerable adverse events if necessary (may require dose interruption)
• Increase up to 20 mg daily in 5 mg increments if co-administering strong CYP3A4 inducers
  • If the strong inducer is discontinued, return the Afinitor dose to the dose used prior to initiation of the strong CYP3A4 inducer
• For patients with mild hepatic impairment (Child-Pugh class A), the recommended dose is 7.5 mg daily. The dose may be decreased to 5 mg if not well tolerated
• For patients with moderate hepatic impairment (Child-Pugh class B), the recommended dose is 5 mg daily. The dose may be decreased to 2.5 mg if not well tolerated

• Decrease to 2.5 mg daily if co-administering moderate CYP3A4 and/or PgP inhibitor
  • A dose increase from 2.5 mg daily to 5 mg daily may be considered based on patient tolerance
  • If the moderate inhibitor is discontinued, increase the Afinitor dose after a washout period of approximately 2 to 3 days to the dose used prior to initiation of the moderate inhibitor

Contraindication¹

AFINITOR is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Instruct your patients about the proper administration procedure¹

If your patient misses a dose of Afinitor, it can still be taken up to 6 hours after the time they would normally take it. If more than 6 hours have elapsed, your patient should skip the dose for that day, and take their dose the next day at the usual time. Patients should not take 2 doses to make up for the one that they missed.

Drug interactions¹

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Grapefruit, grapefruit juice and other foods that are known to inhibit cytochrome P450 and PgP activity may increase everolimus exposures and should be avoided during treatment. St. John's Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided.

Agents that increase Afinitor concentration: In healthy subjects, compared to Afinitor treatment alone, there were significant increases in everolimus exposure when Afinitor was co-administered with ketaconazole, erythromycin, and verapamil.

Concomitant strong inhibitors of CYP3A4 should not be used.

Use caution when Afinitor is used in combination with moderate CYP3A4 and/or PgP inhibitors. If alternative treatment cannot be administered reduce the Afinitor dose.

Agents that decrease Afinitor concentration: In healthy subjects, co-administration of Afinitor with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 63% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of Afinitor when co-administered with strong CYP3A4 inducers if alternative treatment cannot be administered. St. John's Wort may decrease everolimus exposure unpredictably and should be avoided

Important Safety Information

Adverse Reactions: The most common adverse reactions (incidence ≥ 30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common
Grade 3/4 adverse reactions (incidence ≥ 5%) were infections (10%), dyspnea (7%), stomatitis (5%) and fatigue (5%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed in the AFINITOR arm.

Please see additional Important Safety Information at the bottom of this page.
Please see full Prescribing Information.