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Afinitor

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Afinitor

Indications
Dosage
How Supplied

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.

AFINITOR® is not indicated for the treatment of patients with functional carcinoid tumors.

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.

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.

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].

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).

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]. 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.

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].

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 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 ≤ Grade1.
Re-initiate AFINITOR at a lower dose. Discontinue treatment if failure to recover within 4 weeks.
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 Grade 2 Symptomatic but can eat and swallow modified diet No dose adjustment required.Manage with non-alcoholic or salt water (0.9%) mouth wash several times a day.
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. Reinitiate AFINITOR at the same dose. If toxicity recurs at Grade 2, interrupt AFINITOR until recovery to Grade ≤ 1. Reinitiate AFINITOR at a lower dose.
Grade 3 Temporary dose interruption until recovery to Grade ≤ 1. Initiate appropriate medical therapy and monitor. Consider reinitiating 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. Reinitiate 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 alcohol, 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/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 and DRUG INTERACTIONS].

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 and DRUG INTERACTIONS].

St. John's Wort (Hypericum perforatum) may decrease everolimus exposure unpredictably and should be avoided.

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 below]. The recommended starting dose for patients requiring a concomitant strong CYP3A4 inducer is 9 mg/m², once daily [see below]. 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 below]. Adjust dose at 2 week intervals as needed to achieve and maintain trough concentrations of 5 to 15 ng/mL [see below].

Continue treatment until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.

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 coadministration 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.

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 WARNINGS AND PRECAUTIONS]. 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). 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.
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, nelfinavir, voriconazole) in patients receiving AFINITOR Tablets or AFINITOR DISPERZ [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS].

For patients who require treatment with moderate CYP3A4/PgP inhibitors (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem):

  • Reduce the AFINITOR Tablets or AFINITOR DISPERZ dose by approximately 50%. Administer every other day if dose reduction is required for patients receiving the lowest available strength and maintain trough concentrations of 5 to 15 ng/mL [see paragraphs above].
  • Assess everolimus trough concentrations approximately 2 weeks after dose reduction [see paragraphs above].
  • Resume the dose that was used prior to initiating the CYP3A4/PgP inhibitor 2 to 3 days after discontinuation of a moderate inhibitor. Assess the everolimus trough concentration approximately 2 weeks later [see paragraphs above].

Do not ingest foods or nutritional supplements (e.g., grapefruit, grapefruit juice) that are known to inhibit cytochrome P450 or PgP activity.

Strong CYP3A4/PgP Inducers

Avoid the use of concomitant strong CYP3A4/PgP inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available [see WARNINGS AND PRECAUTIONS and DRUG INTERACTIONS]. For patients who require treatment with a strong CYP3A4/PgP inducer:

  • Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability [see paragraphs above].
  • Assess the everolimus trough concentration 2 weeks after doubling the dose and adjust the dose if necessary to maintain a trough concentration of 5 to 15 ng/mL [see paragraphs above].
  • Return the AFINITOR Tablets or AFINITOR DISPERZ dose to that used prior to initiating the strong CYP3A4/PgP inducer if the strong inducer is discontinued, and assess the everolimus trough concentrations approximately 2 weeks later [see paragraphs above].

Do not ingest foods or nutritional supplements (e.g., St. John's Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity.

Administration Of AFINITOR Tablets in SEGA with TSC

Do not combine the 2 dosage forms (AFINITOR Tablets and AFINITOR DISPERZ) to achieve the desired total dose. Use one dosage form or the other.

Administer AFINITOR Tablets orally once daily at the same time every day. Administer either consistently with food or consistently without food [see CLINICAL PHARMACOLOGY].

AFINITOR Tablets should be swallowed whole with a glass of water. Do not break or crush tablets.

Administration And Preparation Of AFINITOR DISPERZ In SEGA With TSC

Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another person.

Do not combine the 2 dosage forms (AFINITOR Tablets and AFINITOR DISPERZ) to achieve the desired total dose. Use one dosage form or the other.

Administer AFINITOR DISPERZ (everolimus tablets for oral suspension) as a suspension only.

Administer AFINITOR DISPERZ orally once daily at the same time every day. Administer either consistently with food or consistently without food [see CLINICAL PHARMACOLOGY].

Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation.

Prepare suspension in water only.

Using an oral syringe:

  • Place the prescribed dose of AFINITOR DISPERZ into a 10-mL syringe. Do not exceed a total of 10 mg per syringe. If higher doses are required, prepare an additional syringe. Do not break or crush tablets.
  • Draw approximately 5 mL of water and 4 mL of air into the syringe.
  • Place the filled syringe into a container (tip up) for 3 minutes, until the AFINITOR DISPERZ tablets are in suspension.
  • Gently invert the syringe 5 times immediately prior to administration.
  • After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe.

Using a small drinking glass:

  • Place the prescribed dose of AFINITOR DISPERZ into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg of AFINITOR DISPERZ per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets.
  • Allow 3 minutes for suspension to occur.
  • Stir the contents gently with a spoon, immediately prior to drinking.
  • After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend remaining particles. Administer the entire contents of the glass.

HOW SUPPLIED

Dosage Forms And Strengths

AFINITOR (everolimus) Tablets

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.

AFINITOR DISPERZ (everolimus tablets for oral suspension)

2 mg tablet for oral suspension

White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D2” on one side and “NVR” on the other.

3 mg tablet for oral suspension

White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D3” on one side and “NVR” on the other.

5 mg tablet for oral suspension

White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D5” on one side and “NVR” on the other.

Storage And Handling

AFINITOR (everolimus) Tablets

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

AFINITOR DISPERZ (everolimus tablets for oral suspension)

2 mg tablets for oral suspension

White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D2” on one side and “NVR” on the other; available in:

Blisters of 28 tablets............................NDC 0078-0626-51

Each carton contains 4 blister cards of 7 tablets each

3 mg tablets for oral suspension

White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D3” on one side and “NVR” on the other; available in:

Blisters of 28 tablets............................NDC 0078-0627-51

Each carton contains 4 blister cards of 7 tablets each

5 mg tablets for oral suspension

White to slightly yellowish, round, flat tablets with a bevelled edge and no score, engraved with “D5” on one side and “NVR” on the other; available in:

Blisters of 28 tablets............................NDC 0078-0628-51

Each carton contains 4 blister cards of 7 tablets each

Store AFINITOR (everolimus) Tablets and AFINITOR DISPERZ (everolimus tablets for oral suspension) 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.

Follow special handling and disposal procedures for anticancer pharmaceuticals.2

AFINITOR Tablets and AFINITOR DISPERZ should not be crushed. Do not take tablets which are crushed or broken.

Manufactured by: Novartis Pharma Stein AG, Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936. Revised Feb 2014

Last reviewed on RxList: 7/14/2014
This monograph has been modified to include the generic and brand name in many instances.

Indications
Dosage
How Supplied
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