|
AFINITOR® DISPERZ (everolimus tablets for oral suspension)
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use AFINITOR safely and effectively. See full prescribing information for AFINITOR.
AFINITOR® (everolimus) tablets for oral administration
AFINITOR® DISPERZ (everolimus tablets for oral suspension)
Initial U.S. Approval: 2009
RECENT MAJOR CHANGES
|
Warnings and Precautions, Angioedema (5.3)
|
1/2015
|
INDICATIONS AND USAGE
AFINITOR is a kinase inhibitor indicated for the treatment of:
-
postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane after failure of treatment with letrozole or anastrozole. (1.1)
-
adults with progressive neuroendocrine tumors of pancreatic origin (PNET) that are unresectable, locally advanced or metastatic. AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors. (1.2)
-
adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. (1.3)
-
adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. The effectiveness of AFINITOR in the treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes. (1.4)
AFINITOR and AFINITOR DISPERZ are kinase inhibitors indicated for the treatment of:
-
pediatric and adult patients with tuberous sclerosis complex (TSC) who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. The effectiveness is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC has not been demonstrated. (1.5)
DOSAGE AND ADMINISTRATION
Advanced HR+ BC, advanced PNET, advanced RCC, or renal angiomyolipoma with TSC:
-
10 mg once daily with or without food. (2.1)
-
For patients with hepatic impairment, reduce the AFINITOR dose. (2.2)
-
If moderate inhibitors of CYP3A4 /P-glycoprotein (PgP) are required, reduce the AFINITOR dose to 2.5 mg once daily; if tolerated, consider increasing to 5 mg once daily. (2.2)
-
If strong inducers of CYP3A4 are required, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. (2.2)
SEGA with TSC:
-
4.5 mg/m2 once daily; adjust dose to attain trough concentrations of 5-15 ng/mL. (2.3)
-
Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4 /PgP inducers or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ. (2.3, 2.4)
-
For patients with severe hepatic impairment reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5)
-
If concomitant use of moderate inhibitors of CYP3A4 /PgP is required, reduce the dose of AFINITOR Tablets or AFINITOR DISPERZ by 50%. (2.3, 2.5)
-
If concomitant use of strong inducers of CYP3A4/PgP is required, double the dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.3, 2.5)
DOSAGE FORMS AND STRENGTHS
AFINITOR Tablets: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets with no score (3.1)
AFINITOR DISPERZ (everolimus tablets for oral suspension): 2 mg, 3 mg, and 5 mg tablets for oral suspension with no score (3.2)
CONTRAINDICATIONS
Hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients (4)
WARNINGS AND PRECAUTIONS
-
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. (5.1)
-
Infections: Increased risk of infections, some fatal. Monitor for signs and symptoms, and treat promptly. (5.2)
-
Angioedema: Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema. (5.3)
-
Oral ulceration: Mouth ulcers, stomatitis, and oral mucositis are common. Management includes mouthwashes and topical treatments. (5.4)
-
Renal failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed. (5.5)
-
Impaired wound healing: Increased risk of wound-related complications. Monitor signs and symptoms. Exercise caution in the peri-surgical period. (5.6)
-
Laboratory test alterations: Elevations of serum creatinine, urinary protein, 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. (5.8)
-
Vaccinations: Avoid live vaccines and close contact with those who have received live vaccines. (5.11)
-
Embryo-fetal toxicity: Fetal harm can occur when administered to a pregnant woman. Apprise women of potential harm to the fetus. (5.12, 8.1)
ADVERSE REACTIONS
Advanced HR+ BC, advanced PNET, advanced RCC: Most common adverse reactions (incidence ≥30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache and decreased appetite. (6.1, 6.2, 6.3)
Renal angiomyolipoma with TSC: Most common adverse reaction (incidence ≥ 30%) is stomatitis. (6.4)
SEGA with TSC: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. (6.5)
To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
-
Strong CYP3A4/PgP inhibitors: Avoid concomitant use. (2.2, 2.5, 5.9, 7.1)
-
Moderate CYP3A4/PgP inhibitors: If combination is required, use caution and reduce dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.1)
-
Strong CYP3A4/PgP inducers: Avoid concomitant use. If combination cannot be avoided, increase dose of AFINITOR. (2.2, 2.3, 2.5, 5.9, 7.2)
USE IN SPECIFIC POPULATIONS
-
Nursing mothers: Discontinue drug or nursing, taking into consideration the importance of drug to the mother. (8.3)
-
Hepatic impairment: For advanced HR+ BC, advanced PNET, advanced RCC, or renal angiomyolipoma with TSC patients with hepatic impairment, reduce AFINITOR dose. For SEGA patients with severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ. (2.2, 2.3, 2.5, 5.10, 8.8)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 9/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer (Advanced HR+ BC)
AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole.
1.2 Advanced Neuroendocrine Tumors of Pancreatic Origin (PNET)
AFINITOR® is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.
AFINITOR® is not indicated for the treatment of patients with functional carcinoid tumors.
1.3 Advanced Renal Cell Carcinoma (RCC)
AFINITOR® is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib.
1.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex (TSC)
AFINITOR® is indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery.
The effectiveness of AFINITOR in the treatment of renal angiomyolipoma is based on an analysis of durable objective responses in patients treated for a median of 8.3 months. Further follow-up of patients is required to determine long-term outcomes.
1.5 Subependymal Giant Cell Astrocytoma (SEGA) with Tuberous Sclerosis Complex (TSC)
AFINITOR® Tablets and AFINITOR® DISPERZ are indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.
The effectiveness of AFINITOR Tablets and AFINITOR DISPERZ is based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in patients with SEGA and TSC has not been demonstrated [see Clinical Studies (14.5)].
2 DOSAGE AND ADMINISTRATION
AFINITOR is available in two dosage forms: tablets (AFINITOR Tablets) and tablets for oral suspension (AFINITOR DISPERZ).
-
AFINITOR Tablets may be used for all approved indications.
-
AFINITOR DISPERZ is approved for the treatment of patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC).
2.1 Recommended Dose in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced PNET, Advanced RCC, and Renal Angiomyolipoma with TSC
The recommended dose of AFINITOR Tablets is 10 mg, to be taken once daily at the same time every day. Administer either consistently with food or consistently without food [see Clinical Pharmacology (12.3)]. AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.
Continue treatment until disease progression or unacceptable toxicity occurs.
2.2 Dose Modifications in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced PNET, Advanced RCC, and Renal Angiomyolipoma with TSC
Adverse Reactions
Management of severe or intolerable adverse reactions may require temporary dose interruption (with or without a dose reduction of AFINITOR therapy) or discontinuation. If dose reduction is required, the suggested dose is approximately 50% lower than the daily dose previously administered [see Warnings and Precautions (5)].
Table 1 summarizes recommendations for dose reduction, interruption or discontinuation of AFINITOR in the management of adverse reactions. General management recommendations are also provided as applicable. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.
Hepatic Impairment
Hepatic impairment will increase the exposure to everolimus [see Warnings and Precautions (5.10) and Use in Specific Populations (8.8)]. Dose adjustments are recommended:
-
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.
-
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.
-
Severe hepatic impairment (Child-Pugh class C) – If the desired benefit outweighs the risk, a dose of 2.5 mg daily may be used but must not be exceeded.
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.
CYP3A4/P-glycoprotein (PgP) Inhibitors
Avoid the use of strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see Warnings and Precautions (5.9) and Drug Interactions (7.1)].
Use caution when co-administered with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4/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. If the moderate inhibitor is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the moderate CYP3A4/PgP inhibitor.
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.
Strong CYP3A4/PgP Inducers
Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). If patients require co-administration of a strong CYP3A4/PgP inducer, consider doubling the daily dose of AFINITOR using increments of 5 mg or less. This dose of AFINITOR is predicted, based on pharmacokinetic data, 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/PgP inducers. If the strong inducer is discontinued, consider a washout period of 3 to 5 days, before the AFINITOR dose is returned to the dose used prior to initiation of the strong CYP3A4/PgP inducer [see Warnings and Precautions (5.9) and Drug Interactions (7.2)].
St. John’s Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided.
2.3 Recommended Dose in SEGA with TSC
The recommended starting dose is 4.5 mg/m2, once daily. The recommended starting dose for patients with severe hepatic impairment (Child-Pugh class C) or requiring moderate CYP3A4/PgP inhibitors is 2.5 mg/m2, once daily [see Dosage and Administration (2.5)]. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m2, once daily [see Dosage and Administration (2.5)]. Round dose to the nearest strength of either AFINITOR Tablets or AFINITOR DISPERZ.
Do not combine AFINITOR Tablets and AFINITOR DISPERZ to achieve the desired total dose.
Use therapeutic drug monitoring to guide subsequent dosing [see Dosage and Administration (2.4)]. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL [see Dosage and Administration (2.4, 2.5)].
Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.
2.4 Therapeutic Drug Monitoring in SEGA with TSC
Monitor everolimus whole blood trough levels routinely in all patients. When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment.
Assess trough concentrations approximately 2 weeks after initiation of treatment, a change in dose, a change in co-administration of CYP3A4/PgP inducers and/or inhibitors, a change in hepatic function, or a change in dosage form between AFINITOR Tablets and AFINITOR DISPERZ. Once a stable dose is attained, monitor trough concentrations every 3 to 6 months in patients with changing body surface area or every 6 to 12 months in patients with stable body surface area for the duration of treatment.
Titrate the dose to attain trough concentrations of 5 to 15 ng/mL.
-
For trough concentrations less than 5 ng/mL, increase the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ).
-
For trough concentrations greater than 15 ng/mL, reduce the daily dose by 2.5 mg (in patients taking AFINITOR Tablets) or 2 mg (in patients taking AFINITOR DISPERZ).
-
If dose reduction is required for patients receiving the lowest available strength, administer every other day.
2.5 Dose Modifications in SEGA with TSC
Adverse Reactions
Temporarily interrupt or permanently discontinue AFINITOR Tablets or AFINITOR DISPERZ for severe or intolerable adverse reactions. If dose reduction is required when reinitiating therapy, reduce the dose by approximately 50% [see Dosage and Administration (2.2) and Warnings and Precautions (5)]. If dose reduction is required for patients receiving the lowest available strength, administer every other day.
Hepatic Impairment
-
Reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% in patients with SEGA who have severe hepatic impairment (Child-Pugh class C) [see Dosage and Administration (2.3)]. Adjustment to the starting dose for patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment may not be needed. Subsequent dosing should be based on therapeutic drug monitoring.
-
Assess everolimus trough concentrations approximately 2 weeks after commencing treatment, a change in dose, or any change in hepatic function [see Dosage and Administration (2.3, 2.4)].
CYP3A4/P-glycoprotein (PgP) Inhibitors
Avoid the use of concomitant strong CYP3A4/PgP inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfi |
|
