Afinitor Dosage and Administration

Recommended dose

The recommended dose of Afinitor for treatment of advanced renal cell carcinoma is 10 mg, to be taken once daily at the same time every day, either consistently with or consistently without food. Afinitor tablets should be swallowed whole with a glass of water. The tablets 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 swallowed to ensure the entire dose is administered.

Grapefruit, grapefruit juice, and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment.

Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.

Dose modifications

Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of Afinitor therapy. If dose reduction is required, the suggested dose is 5 mg daily.

Hepatic impairment

  • For patients with moderate hepatic impairment (Child-Pugh class B), reduce the dose to 5 mg daily
  • Afinitor has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this patient population

CYP3A4 and/or PgP inhibitors

  • Use caution when co-administered with moderate CYP3A4 inhibitors (eg, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or moderate P-glycoprotein (PgP) inhibitors
  • If patients require co-administration of a moderate CYP3A4 and/or PgP inhibitor, reduce the Afinitor dose to 2.5 mg daily. The reduced dose of Afinitor is predicted to adjust the area under the curve (AUC) to the range observed without inhibitors
  • An Afinitor dose increase from 2.5 mg to 5 mg may be considered, based on patient tolerance
  • If the moderate inhibitor is discontinued, a washout period of approximately 2 to 3 days should be allowed before the Afinitor dose is increased.
  • Avoid the use of strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole
  • If the moderate inhibitor is discontinued, the Afinitor dose should be returned to the dose used prior to initiation of the moderate CYP3A4 and/or PgP inhibitor
  • Grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity should also be avoided during treatment

Strong CYP3A4 inducers

  • Avoid the use of concomitant strong CYP3A4 inducers (eg, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital)
  • If patients require co-administration of a strong CYP3A4 inducer, consider increasing the Afinitor dose from 10 mg daily up to 20 mg daily (based on pharmacokinetic data), using 5-mg increments
  • This dose of Afinitor is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment in patients receiving strong CYP3A4 inducers
  • If the strong inducer is discontinued, the Afinitor dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer
  • St. John's Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided
Reference
  • Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2011.

AFINITOR is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Important Safety Information

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

Non-infectious Pneumonitis: Non-infectious pneumonitis was reported in 11-14% of patients treated with Afinitor. The incidence of Common Terminology Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 1.6%-4.0% and 0.1%, respectively. Fatal outcomes have been observed. If symptoms are moderate, patients should be managed with dose interruption until symptoms improve. If symptoms are severe, AFINITOR therapy should be discontinued. Under both circumstances, corticosteroids may be indicated and AFINITOR may be reintroduced at 5 mg daily depending on the individual clinical circumstances. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR has immunosuppressive properties and may predispose patients to localized or systemic bacterial, fungal, viral, or protozoal infections (including those with opportunistic pathogens). Viral infections may include reactivation of hepatitis B infection. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with Afinitor. Treatment of pre-existing invasive fungal infections should be completed prior to starting treatment. Be vigilant for signs and symptoms of infection and institute appropriate treatment promptly; interruption or discontinuation of AFINITOR should be considered. Discontinue AFINITOR if invasive systemic fungal infection is diagnosed and institute appropriate treatment.

Oral Ulceration: Oral ulcerations (i.e., mouth ulcers, stomatitis, and oral mucositis) are the most frequently occurring adverse event and occur in approximately 70% of advanced PNET patients, 44% of advanced RCC patients, and 86% of SEGA patients, which were mostly Grade 1 or 2. Grade 3 or 4 stomatitis was reported in 6% of patients with neuroendocrine tumors. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with AFINITOR.

Laboratory Tests and Monitoring: Elevations of serum creatinine, proteinuria, glucose, lipids, and triglycerides, and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Renal function, blood glucose, lipids, and hematologic parameters should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Drug-drug Interactions: Avoid co-administration with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). Use caution and reduce the AFINITOR dose to 2.5 mg daily if co-administration with a moderate CYP3A4 and/or PgP inhibitor is required (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). Avoid co-administration with strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital); however, if co-administration is required, increase the AFINITOR dose from 10 mg daily up to 20 mg daily, using 5 mg increments.

Hepatic Impairment: AFINITOR should not be used in patients with severe hepatic impairment. Exposure of everolimus was increased in patients with moderate hepatic impairment. AFINITOR dose should be reduced to 5 mg daily for patients with moderate hepatic impairment.

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

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.

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 on the AFINITOR arm.

Laboratory Abnormalities: The most common laboratory abnormalities (incidence ≥ 50%, all grades) were: decreased hemoglobin (92%) and lymphocytes (51%); increased cholesterol (77%), triglycerides (73%), glucose (57%) and creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥ 5%) were: decreased hemoglobin (13%), lymphocytes (18%), and phosphate (6%); and increased glucose (16%).

Please see full Prescribing Information for AFINITOR.