Afinitor
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Afinitor
INDICATIONS
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.
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.
The safety and effectiveness of AFINITOR® in the treatment of patients with carcinoid tumors have not been established.
Advanced Renal Cell Carcinoma (RCC)
AFINITOR® is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib.
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 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.
Subependymal Giant Cell Astrocytoma (SEGA)
AFINITOR® is indicated for the treatment of adult and pediatric patients, 3 years of age or older, with SEGA associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not candidates for curative surgical resection.
The effectiveness of AFINITOR is based on an analysis of change in SEGA volume [see Clinical Studies]. Clinical benefit such as improvement in disease-related symptoms or increase in overall survival has not been demonstrated.
DOSAGE AND ADMINISTRATION
AFINITOR should be administered orally once daily at the same time every day, either consistently with food or consistently without food [see CLINICAL PHARMACOLOGY].
AFINITOR tablets should be swallowed whole with a glass of water. AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken. 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.
Continue treatment as long as clinical benefit is observed or until unacceptable toxicity occurs.
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 is 10 mg, to be taken once daily.
Dose Modifications in Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer, Advanced PNET, Advanced RCC, and Renal Angiomyolipoma with TSC
Management of Adverse Reactions
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 approximately 50% lower than the daily dose previously administered [see WARNINGS AND PRECAUTIONS].
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.
Table 1: AFINITOR Dose Adjustment and Management Recommendation for Adverse Reactions
| Adverse Drug Reaction | Severitya | AFINITOR Dose Adjustmentb and Management Recommendations |
| Non-infectious pneumonitis | Grade 1 Asymptomatic, radiographic findings only | No dose adjustment required. Initiate appropriate monitoring. |
| Grade 2 Symptomatic, not interfering with ADLc | Consider interruption of therapy, rule out infection and consider treatment with corticosteroids until symptoms improve to ≤ grade 1. Re-initiate AFINITOR at a lower dose. Discontinue treatment if failure to recover within 4 wks. | |
| Grade 3 Symptomatic, interfering with ADLc; O2 indicated | Interrupt AFINITOR until symptoms resolve to ≤ grade 1. Rule out infection, and consider treatment with corticosteroids. Consider re-initiating AFINITOR at a lower dose. If toxicity recurs at grade 3, consider discontinuation. | |
| Grade 4 Life-threatening, ventilatory support indicated | Discontinue AFINITOR, rule out infection, and consider treatment with corticosteroids. | |
| Stomatitis | Grade 1 Minimal symptoms, normal diet | No dose adjustment required. Manage with non-alcoholic or salt water (0.9%) mouth wash several times a day. |
| Grade 2 Symptomatic but can eat and swallow modified diet | Temporary dose interruption until recovery to grade ≤ 1. Re-initiate AFINITOR at the same dose. If stomatitis recurs at grade 2, interrupt dose until recovery to grade ≤ 1. Re-initiate AFINITOR at a lower dose. Manage with topical analgesic mouth treatments (e.g. benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e. triamcinolone oral paste). d |
|
| Grade 3 Symptomatic and unable to adequately aliment or hydrate orally | Temporary dose interruption until recovery to grade ≤ 1. Re-initiate AFINITOR at a lower dose. Manage with topical analgesic mouth treatments (i.e. benzocaine, butyl aminobenzoate, tetracaine hydrochloride, menthol or phenol) with or without topical corticosteroids (i.e. triamcinolone oral paste).d |
|
| Grade 4 Symptoms associated with life-threatening consequences | Discontinue AFINITOR and treat with appropriate medical therapy. | |
| Other non-hematologic toxicities (excluding metabolic events) | Grade 1 | If toxicity is tolerable, no dose adjustment required. Initiate appropriate medical therapy and monitor. |
| Grade 2 | If toxicity is tolerable, no dose adjustment required. Initiate appropriate medical therapy and monitor. If toxicity becomes intolerable, temporary dose interruption until recovery to grade ≤ 1. Re-initiate AFINITOR at the same dose. If toxicity recurs at grade 2, interrupt AFINITOR until recovery to grade ≤ 1. Re-initiate AFINITOR at a lower dose. | |
| Grade 3 | Temporary dose interruption until recovery to grade ≤ 1. Initiate appropriate medical therapy and monitor. Consider re-initiating AFINITOR at a lower dose. If toxicity recurs at grade 3, consider discontinuation. | |
| Grade 4 | Discontinue AFINITOR and treat with appropriate medical therapy. | |
| Metabolic events (e.g. hyperglycemia, dyslipidemia) | Grade 1 | No dose adjustment required. Initiate appropriate medical therapy and monitor. |
| Grade 2 | No dose adjustment required. Manage with appropriate medical therapy and monitor | |
| Grade 3 | Temporary dose interruption. Re-initiate Afinitor at a lower dose. Manage with appropriate medical therapy and monitor. | |
| Grade 4 | Discontinue AFINITOR and treat with appropriate medical therapy. | |
| a Severity grade description: 1 = mild symptoms; 2
= moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms. b If dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered. c Activities of daily living (ADL) d Avoid using agents containing hydrogen peroxide, iodine, and thyme derivatives in management of stomatitis as they may worsen mouth ulcers. |
||
Hepatic Impairment
Hepatic impairment will increase the exposure to everolimus [see WARNINGS AND PRECAUTIONS and Use In Specific Populations]. 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 and/or P-glycoprotein (PgP) Inhibitors
Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Use caution when co-administered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). 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. 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.
Strong CYP3A4 Inducers
Avoid the use of concomitant strong CYP3A4 inducers (e.g., 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, using 5 mg increments. 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 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 [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
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.
Recommended Dose in Subependymal Giant Cell Astrocytoma
The recommended starting dose of AFINITOR for treatment of patients with SEGA is according to Table 2:
Table
2: Recommended Starting Dose of AFINITOR for Treatment of Patients with SEGA
| Body Surface Area (BSA) | Starting Dose |
| 0.5 m² to 1.2 m² | 2.5 mg once daily |
| 1.3 m² to 2.1 m² | 5 mg once daily |
| Greater than or equal to 2.2 m² | 7.5 mg once daily |
Patients receiving AFINITOR may require dose adjustments based on everolimus whole blood trough concentrations achieved, tolerability, individual response, and change in concomitant medications including CYP3A4-inducing antiepileptic drugs [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. Dose adjustments can be made at two week intervals.
Evaluate SEGA volume approximately 3 months after commencing AFINITOR therapy and periodically thereafter, with subsequent dose adjustments taking into consideration changes in SEGA volume, corresponding trough concentration, and tolerability. Responses have been observed at trough concentrations as low as 3 ng/mL; as such, once acceptable efficacy has been achieved, additional dose increases may not be necessary.
AFINITOR has not been studied in patients with SEGA < 3 years of age or with BSA < 0.58 m².
The optimal duration of therapy for patients with SEGA is unknown.
Dose Modifications in Subependymal Giant Cell Astrocytoma
Management of Adverse Reactions
Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of AFINITOR therapy. If a dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered [see Table 1 and WARNINGS AND PRECAUTIONS]. For dose reductions below the lowest available strength, consider alternate day dosing.
Hepatic Impairment
Adjustment to the recommended 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; however, subsequent dosing should be based on therapeutic drug monitoring (TDM).
AFINITOR is not recommended for use in patients with SEGA who have severe hepatic impairment (Child-Pugh class C).
Everolimus whole blood trough concentration should be assessed approximately 2 weeks after commencing treatment or after any change in hepatic status (Child-Pugh). Dosing should be titrated to attain trough concentrations of 5 to 10 ng/mL [see CLINICAL PHARMACOLOGY].
CYP3A4 and/or P-glycoprotein (PgP) Inhibitors
Avoid the use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Use caution when co-administered with moderate CYP3A4 and/or PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem). If patients require co-administration of a moderate CYP3A4 and/or PgP inhibitor, reduce the AFINITOR dose by approximately 50% to maintain trough concentrations of 5 to 10 ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, consider alternate day dosing. Subsequent dosing should be individualized based on therapeutic drug monitoring. Everolimus trough concentrations should be assessed approximately 2 weeks after the addition of a moderate CYP3A4 and/or PgP inhibitor. 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 and the everolimus trough concentration should be re-assessed approximately 2 weeks later [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
Strong CYP3A4 Inducers
Avoid the use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital). For patients requiring a concomitant strong CYP3A4 inducer, double the AFINITOR dose. Subsequent dosing should be individualized based on therapeutic drug monitoring. If the strong inducer is discontinued, the AFINITOR dose should be returned to the dose used prior to initiation of the strong CYP3A4 inducer and the everolimus trough concentrations should be assessed approximately 2 weeks later [See WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].
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.
Therapeutic Drug Monitoring in Subependymal Giant Cell Astrocytoma
Routine everolimus whole blood therapeutic drug concentration monitoring is recommended for all patients using a validated assay. Trough concentrations should be assessed approximately 2 weeks after commencing treatment. Dosing should be titrated to attain trough concentrations of 5 to 10 ng/mL.
There is limited safety experience with patients having trough concentrations > 10 ng/mL. If concentrations are between 10 and 15 ng/mL, and the patient has demonstrated adequate tolerability and tumor response, no dose reductions are needed. The dose of AFINITOR should be reduced if trough concentrations > 15 ng/mL are observed.
If concentrations are < 5 ng/mL, the daily dose may be increased by 2.5 mg every 2 weeks, subject to tolerability. Daily dose may be reduced by 2.5 mg every 2 weeks to attain a target of 5 to 10 ng/mL. If dose reduction is required for patients receiving 2.5 mg daily, alternate day dosing should be used.
Trough concentrations should be assessed approximately 2 weeks after any change in dose, after an initiation or change in co-administration of CYP3A4 and/or PgP inducers or inhibitors, or after any change in hepatic status (Child-Pugh Classification) [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS].
HOW SUPPLIED
Dosage Forms And Strengths
2.5 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other.
5 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.
7.5 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “7P5” on one side and “NVR” on the other.
10 mg tablet
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other.
Storage And Handling
2.5 mg tablets
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other; available in:
Blisters of 28 tablets..................................................................NDC 0078-0594-51
Each carton contains 4 blister cards of 7 tablets each
5 mg tablets
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other; available in:
Blisters of 28 tablets..................................................................NDC 0078-0566-51
Each carton contains 4 blister cards of 7 tablets each
7.5 mg tablets
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “7P5” on one side and “NVR” on the other; available in:
Blisters of 28 tablets..................................................................NDC 0078-0620-51
Each carton contains 4 blister cards of 7 tablets each
10 mg tablets
White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other; available in:
Blisters of 28 tablets..................................................................NDC 0078-0567-51
Each carton contains 4 blister cards of 7 tablets each
Store AFINITOR (everolimus) tablets at 25° C (77° F); excursions permitted between 15° –30° C (59° –86° F). See USP Controlled Room Temperature. Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children.
Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published [see REFERENCES].
AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.
REFERENCES
1. Motzer RJ, Bacik J, Schwartz LH, et al. Prognostic factors for survival in previously treated patients with metastatic renal cell cancer. J Clin Oncol (2004) 22:454-63.
2. NIOSH Alert: Preventing occupational exposures to antineoplastic and other hazardous drugs in healthcare settings. 2004. U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, DHHS (NIOSH) Publication No. 2004-165.
3. OSHA Technical Manual, TED 1-0.15A, Section VI: Chapter 2. Controlling Occupational Exposure to Hazardous Drugs. OSHA, 1999. http://www.osha.gov/dts/osta/otm/otm_vi/otm_vi_2.html
4. American Society of Health-System Pharmacists. ASHP guidelines on handling hazardous drugs. Am J Health-Syst Pharm. (2006) 63:1172-93.
5. Polovich, M., White, J. M., & Kelleher, L.O. (eds.) 2005. Chemotherapy and biotherapy guidelines and recommendations for practice (2nd. ed.) Pittsburgh, PA: Oncology Nursing Society.
Manufactured by: Novartis Pharma Stein AG Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936. Revised: July 2012
Last reviewed on RxList: 8/2/2012
This monograph has been modified to include the generic and brand name in many instances.
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