Afinitor

Afinitor information, interactions and side effects, AFINITOR (everolimus), an inhibitor of mammalian target of rapamycin (mTOR), is an antineoplastic agent.

The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18- dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20pentaone.

The molecular formula is C53H83NO14 and the molecular weight is 958.2. The structural formula is:

afinitor

AFINITOR Tablets are supplied for oral administration and contain 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus. The tablets also contain anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate as inactive ingredients.

AFINITOR DISPERZ (everolimus tablets for oral suspension) is supplied for oral administration and contains 2 mg, 3 mg, or 5 mg of everolimus. The tablets for oral suspension also contain butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose as inactive ingredients.

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, HER2negative 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.

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. 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.

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 ≤ Grade 1.
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 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. 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.
aSeverity grade description: 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms.
bIf dose reduction is required, the suggested dose is approximately 50% lower than the dose previously administered.
cActivities of daily living (ADL)
dAvoid 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. 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).

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.

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

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%. 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.

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.
  • Assess everolimus trough concentrations approximately 2 weeks after dose reduction.
  • 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.

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. For patients who require treatment with a strong CYP3A4/PgP inducer:

  • Double the dose of AFINITOR Tablets or AFINITOR DISPERZ and assess tolerability.
  • 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.
  • 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.

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.

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. 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). 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.

SIDE EFFECTS

The following serious adverse reactions are discussed in greater detail in another section of the label:

  • Non-infectious pneumonitis.
  • Infections.
  • Angioedema with concomitant use of ACE inhibitors.
  • Oral ulceration.
  • Renal failure.
  • Impaired wound healing.

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

Clinical Study Experience In Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer

The efficacy and safety of AFINITOR (10 mg/day) plus exemestane (25 mg/day) (n=485) versus placebo plus exemestane (25 mg/day) (n=239) was evaluated in a randomized, controlled trial in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (range 28-93 years), and 75% were Caucasian. Safety results are based on a median follow-up of approximately 13 months.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3/4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia. The most common Grade 3/4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, decreased potassium, increased AST, increased ALT, and thrombocytopenia.

Fatal adverse reactions occurred more frequently in patients who received AFINITOR plus exemestane (2%) compared to patients on the placebo plus exemestane arm (0.4%). The rates of treatment-emergent adverse events resulting in permanent discontinuation were 24% and 5% for the AFINITOR plus exemestane and placebo plus exemestane treatment groups, respectively. Dose adjustments (interruptions or reductions) were more frequent among patients in the AFINITOR plus exemestane arm than in the placebo plus exemestane arm (63% versus 14%).

Table 2 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 2: Adverse Reactions Reported ≥ 10% of Patients with Advanced HR+ BC*

 

Any adverse reaction AFINITOR (10 mg/day) + exemestanea
N=482
Placebo + exemestanea
N=238
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
All grades % 100 41 9 90 22 5
Gastrointestinal disorders
  Stomatitisb 67 8 0 11 0.8 0
  Diarrhea 33 2 0.2 18 0.8 0
  Nausea 29 0.2 0.2 28 1 0
  Vomiting 17 0.8 0.2 12 0.8 0
  Constipation 14 0.4 0 13 0.4 0
  Dry mouth 11 0 0 7 0 0
General disorders and administration site conditions
  Fatigue 36 4 0.4 27 1 0
  Edema peripheral 19 1 0 6 0.4 0
  Pyrexia 15 0.2 0 7 0.4 0
  Asthenia 13 2 0.2 4 0 0
Infections and infestations
  Infectionsc 50 4 1 25 2 0
Investigations
  Weight decreased 25 1 0 6 0 0
Metabolism and nutrition disorders
  Decreased appetite 30 1 0 12 0.4 0
  Hyperglycemia 14 5 0.4 2 0.4 0
Musculoskeletal and connective tissue disorders
  Arthralgia 20 0.8 0 17 0 0
  Back pain 14 0.2 0 10 0.8 0
  Pain in extremity 9 0.4 0 11 2 0
Nervous system disorders
  Dysgeusia 22 0.2 0 6 0 0
  Headache 21 0.4 0 14 0 0
Psychiatric disorders
  Insomnia 13 0.2 0 8 0 0
Respiratory, thoracic and mediastinal disorders
  Cough 24 0.6 0 12 0 0
  Dyspnea 21 4 0.2 11 0.8 0.4
  Epistaxis 17 0 0 1 0 0
  Pneumonitisd 19 4 0.2 0.4 0 0
Skin and subcutaneous tissue disorders
  Rash 39 1 0 6 0 0
  Pruritus 13 0.2 0 5 0 0
  Alopecia 10 0 0 5 0 0
Vascular disorders
  Hot flush 6 0 0 14 0 0
Median duration of treatmente 23.9 weeks 13.4 weeks
Grading according to CTCAE Version 3.0
*160 patients (33.2%) were exposed to AFINITOR therapy for a period of ≥ 32 weeks
aExemestane (25 mg/day)
bIncludes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis and lip ulceration
cIncludes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (10%), urinary tract infection (10%), upper respiratory tract infection (5%), pneumonia (4%), bronchitis (4%), cystitis (3%), sinusitis (3%), and also including candidiasis ( < 1%), and sepsis ( < 1%), and hepatitis C ( < 1%).
dIncludes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis
eExposure to AFINITOR or placebo

Key observed laboratory abnormalities are presented in Table 3.

Table 3: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced HR+ BC

 

Laboratory parameter AFINITOR (10 mg/day) + exemestanea
N=482
Placebo + exemestanea
N=238
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Hematologyb
  Hemoglobin decreased 68 6 0.6 40 0.8 0.4
  WBC decreased 58 1 0 28 5 0.8
  Platelets decreased 54 3 0.2 5 0 0.4
  Lymphocytes decreased 54 11 0.6 37 5 0.8
  Neutrophils decreased 31 2 0 11 0.8 0.8
Clinical chemistry
  Glucose increased 69 9 0.4 44 0.8 0.4
  Cholesterol increased 70 0.6 0.2 38 0.8 0.8
  Aspartate  transaminase (AST) increased 69 4 0.2 45 3 0.4
  Alanine transaminase (ALT) increased 51 4 0.2 29 5 0
  Triglycerides increased 50 0.8 0 26 0 0
  Albumin decreased 33 0.8 0 16 0.8 0
  Potassium decreased 29 4 0.2 7 1 0
  Creatinine increased 24 2 0.2 13 0 0
Grading according to CTCAE Version 3.0
aExemestane (25 mg/day)
bReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.

 

Clinical Study Experience In Advanced Pancreatic Neuroendocrine Tumors

In a randomized, controlled trial of AFINITOR (n=204) versus placebo (n=203) in patients with advanced PNET the median age of patients was 58 years (range 20-87), 79% were Caucasian, and 55% were male. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache. The most common Grade 3-4 adverse reactions (incidence ≥ 5%) were stomatitis and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were decreased hemoglobin, hyperglycemia, alkaline phosphatase increased, hypercholesterolemia, bicarbonate decreased, and increased aspartate transaminase (AST). The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, decreased hemoglobin, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased aspartate transaminase (AST), potassium decreased, and thrombocytopenia. Deaths during double-blind treatment where an adverse event was the primary cause occurred in seven patients on AFINITOR and one patient on placebo. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis. There was one death due to pulmonary embolism on the placebo arm. After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rates of treatment-emergent adverse events resulting in permanent discontinuation were 20% and 6% for the AFINITOR and placebo treatment groups, respectively. Dose delay or reduction was necessary in 61% of everolimus patients and 29% of placebo patients. Grade 3-4 renal failure occurred in six patients in the everolimus arm and three patients in the placebo arm. Thrombotic events included five patients with pulmonary embolus in the everolimus arm and one in the placebo arm as well as three patients with thrombosis in the everolimus arm and two in the placebo arm.

Table 4 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo.

Table 4: Adverse Reactions Reported ≥ 10% of Patients with Advanced PNET

 

AFINITOR
N=204
Placebo
N=203
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Any adverse reaction 100 49 13 98 32 8
Gastrointestinal disorders
  Stomatitisa 70 7 0 20 0 0
  Diarrheab 50 5 0.5 25 3 0
  Abdominal pain 36 4 0 32 6 1
  Nausea 32 2 0 33 2 0
  Vomiting 29 1 0 21 2 0
  Constipation 14 0 0 13 0.5 0
  Dry mouth 11 0 0 4 0 0
General disorders and administration site conditions
  Fatigue/malaise 45 3 0.5 27 2 0.5
  Edema (general and peripheral) 39 1 0.5 12 1 0
  Fever 31 0.5 0.5 13 0.5 0
  Asthenia 19 3 0 20 3 0
Infections and infestations
  Nasopharyngitis/ rhinitis/ URI 25 0 0 13 0 0
  Urinary tract infection 16 0 0 6 0.5 0
Investigations
  Weight decreased 28 0.5 0 11 0 0
Metabolism and nutrition disorders
  Decreased appetite 30 1 0 18 1 0
  Diabetes mellitus 10 2 0 0.5 0 0
Musculoskeletal and connective tissue disorders
  Arthralgia 15 1 0.5 7 0.5 0
  Back pain 15 1 0 11 1 0
  Pain in extremity 14 0.5 0 6 1 0
  Muscle spasms 10 0 0 4 0 0
Nervous system disorders
  Headache/ migraine 30 0.5 0 15 1 0
  Dysgeusia 19 0 0 5 0 0
  Dizziness 12 0.5 0 7 0 0
Psychiatric disorders
  Insomnia 14 0 0 8 0 0
Respiratory, thoracic and mediastinal disorders
  Cough/productive cough 25 0.5 0 13 0 0
  Epistaxis 22 0 0 1 0 0
  Dyspnea/dyspnea exertional 20 2 0.5 7 0.5 0
  Pneumonitisc 17 3 0.5 0 0 0
  Oropharyngeal pain 11 0 0 6 0 0
Skin and subcutaneous disorders
  Rash 59 0.5 0 19 0 0
  Nail disorders 22 0.5 0 2 0 0
  Pruritus/pruritus generalized 21 0 0 13 0 0
  Dry skin/xeroderma 13 0 0 6 0 0
Vascular disorders
  Hypertension 13 1 0 6 1 0
  Median duration of treatment (wks) 37 16
Grading according to CTCAE Version 3.0
aIncludes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation.
bIncludes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea.
cIncludes pneumonitis, interstitial lung disease, pulmonary fibrosis and restrictive pulmonary disease.

In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females and none of the 33 females in the placebo group.

Key observed laboratory abnormalities are presented in Table 5.

Table 5: Key Laboratory Abnormalities Reported in ≥ 10% of Patients with Advanced PNET

 

Laboratory parameter AFINITOR
N=204
Placebo
N=203
All grades % Grade 3-4% All grades% Grade 3-4%
Hematology
  Hemoglobin decreased 86 15 63 1
  Lymphocytes decreased 45 16 22 4
  Platelets decreased 45 3 11 0
  WBC decreased 43 2 13 0
  Neutrophils decreased 30 4 17 2
Clinical chemistry
  Alkaline phosphatase increased 74 8 66 8
  Glucose (fasting) increased 75 17 53 6
  Cholesterol increased 66 0.5 22 0
  Bicarbonate decreased 56 0 40 0
  Aspartate transaminase (AST) increased 56 4 41 4
  Alanine transaminase (ALT) increased 48 2 35 2
  Phosphate decreased 40 10 14 3
  Triglycerides increased 39 0 10 0
  Calcium decreased 37 0.5 12 0
  Potassium decreased 23 4 5 0
  Creatinine increased 19 2 14 0
  Sodium decreased 16 1 16 1
  Albumin decreased 13 1 8 0
  Bilirubin increased 10 1 14 2
  Potassium increased 7 0 10 0.5
Grading according to CTCAE Version 3.0

 

Clinical Study Experience In Advanced Renal Cell Carcinoma

The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving AFINITOR and 60 days (range 21-295 days) for those receiving placebo.

The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.

Table 6 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency.

Table 6: Adverse Reactions Reported in at Least 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm

 

AFINITOR 10 mg/day
N=274
Placebo
N=137
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Any adverse reaction 97 52 13 93 23 5
Gastrointestinal disorders
  Stomatitisa 44 4 < 1 8 0 0
  Diarrhea 30 1 0 7 0 0
  Nausea 26 1 0 19 0 0
  Vomiting 20 2 0 12 0 0
  Infections and infestationsb 37 7 3 18 1 0
General disorders and administration site conditions
  Asthenia 33 3 < 1 23 4 0
  Fatigue 31 5 0 27 3 < 1
  Edema peripheral 25 < 1 0 8 < 1 0
  Pyrexia 20 < 1 0 9 0 0
  Mucosal inflammation 19 1 0 1 0 0
Respiratory, thoracic and mediastinal disorders
  Cough 30 < 1 0 16 0 0
  Dyspnea 24 6 1 15 3 0
  Epistaxis 18 0 0 0 0 0
  Pneumonitisc 14 4 0 0 0 0
Skin and subcutaneous tissue disorders
  Rash 29 1 0 7 0 0
  Pruritus 14 < 1 0 7 0 0
  Dry skin 13 < 1 0 5 0 0
Metabolism and nutrition disorders
  Anorexia 25 1 0 14 < 1 0
Nervous system disorders
  Headache 19 < 1 < 1 9 < 1 0
  Dysgeusia 10 0 0 2 0 0
Musculoskeletal and connective tissue disorders
  Pain in extremity 10 1 0 7 0 0
  Median duration of treatment (d) 141 60
Grading according to CTCAE Version 3.0
aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.
bIncludes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis ( < 1%), candidiasis ( < 1%), and sepsis ( < 1%).
cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include:

Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)

General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing ( < 1%)

Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)

Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%), angioedema ( < 1%)

Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus ( < 1%)

Psychiatric disorders: Insomnia (9%)

Nervous system disorders: Dizziness (7%), paresthesia (5%)

Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%), deep vein thrombosis ( < 1%)

Renal and urinary disorders: Renal failure (3%)

Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)

Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%)

Key laboratory abnormalities are presented in Table 7.

Table 7: Key Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm

 

Laboratory parameter AFINITOR 10 mg/day
N=274
Placebo
N=137
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Hematologya
  Hemoglobin decreased 92 12 1 79 5 < 1
  Lymphocytes decreased 51 16 2 28 5 0
  Platelets decreased 23 1 0 2 0 < 1
  Neutrophils decreased 14 0 < 1 4 0 0
Clinical chemistry
  Cholesterol increased 77 4 0 35 0 0
  Triglycerides increased 73 < 1 0 34 0 0
  Glucose increased 57 15 < 1 25 1 0
  Creatinine increased 50 1 0 34 0 0
  Phosphate decreased 37 6 0 8 0 0
  Aspartate transaminase (AST) increased 25 < 1 < 1 7 0 0
  Alanine transaminase (ALT) increased 21 1 0 4 0 0
  Bilirubin increased 3 < 1 < 1 2 0 0
Grading according to CTCAE Version 3.0
aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency.

 

Clinical Study Experience In Renal Angiomyolipoma With Tuberous Sclerosis Complex

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial of AFINITOR in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5). The median age of patients was 31 years (range 18 to 61 years), 89% were Caucasian, and 34% were male. The median duration of blinded study treatment was 48 weeks (range 2 to 115 weeks) for patients receiving AFINITOR and 45 weeks (range 9 to 115 weeks) for those receiving placebo.

The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis and amenorrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hypertriglyceridemia, and anemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia.

The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 9.

Table 8: Adverse Reactions Reported in ≥ 10% of AFINITOR-treated Patients with Renal Angiomyolipoma

 

AFINITOR
N=79
Placebo
N=39
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Any adverse reaction 100 25 5 97 8 5
Gastrointestinal disorders
  Stomatitisa 78 6 0 23 0 0
  Vomiting 15 0 0 5 0 0
  Diarrhea 14 0 0 5 0 0
General disorders and administration site conditions
  Peripheral edema 13 0 0 8 0 0
Infections and infestations
  Upper respiratory tract infection 11 0 0 5 0 0
Musculoskeletal and connective tissue disorders
  Arthralgia 13 0 0 5 0 0
Respiratory, thoracic and mediastinal disorders
  Cough 20 0 0 13 0 0
Skin and subcutaneous tissue disorders
  Acne 22 0 0 5 0 0
Grading according to CTCAE Version 3.0
a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.

Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52) and 4% (1 of 26) of females in the placebo group. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).

The following additional adverse reactions occurred in less than 10% of AFINITOR -treated patients: epistaxis (9%), decreased appetite (6%), otitis media (6%), depression (5%), abnormal taste (5%), increased blood luteinizing hormone (LH) levels (4%), increased blood follicle stimulating hormone (FSH) levels (3%), hypersensitivity (3%), ovarian cyst (3%), pneumonitis (1%), and angioedema (1%).

Table 9: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with Renal Angiomyolipoma

 

AFINITOR
N=79
Placebo
N=39
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Hematology
  Anemia 61 0 0 49 0 0
  Leucopenia 37 0 0 21 0 0
  Neutropenia 25 0 1 26 0 0
  Lymphopenia 20 1 0 8 0 0
  Thrombocytopenia 19 0 0 3 0 0
Clinical chemistry
  Hypercholesterolemia 85 1 0 46 0 0
  Hypertriglyceridemia 52 0 0 10 0 0
  Hypophosphatemia 49 5 0 15 0 0
  Alkaline phosphatase increased 32 1 0 10 0 0
  Elevated aspartate transaminase (AST) 23 1 0 8 0 0
  Elevated alanine transaminase (ALT) 20 1 0 15 0 0
  Fasting hyperglycemia 14 0 0 8 0 0
Grading according to CTCAE Version 3.0

 

Clinical Study Experience In Subependymal Giant Cell Astrocytoma With Tuberous Sclerosis Complex

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (Study 1) of AFINITOR in 117 patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC). The median age of patients was 9.5 years (range 0.8 to 26 years), 93% were Caucasian, and 57% were male. The median duration of blinded study treatment was 52 weeks (range 24 to 89 weeks) for patients receiving AFINITOR and 47 weeks (range 14 to 88 weeks) for those receiving placebo.

The most common adverse reactions reported for AFINITOR (incidence ≥ 30%) were stomatitis and respiratory tract infection. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. The most common key laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia and elevated partial thromboplastin time. The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was neutropenia.

There were no adverse reactions resulting in permanent discontinuation. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 55% of AFINITOR-treated patients. The most common adverse reaction leading to AFINITOR dose adjustment was stomatitis.

Table 10 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo. Laboratory abnormalities are described separately in Table 11.

Table 10: Adverse Reactions Reported in ≥ 10% of AFINITOR-treated Patients with SEGA in Study 1

 

AFINITOR
N=78
Placebo
N=39
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Any adverse reaction 97 36 3 92 23 3
Gastrointestinal disorders
  Stomatitisa 62 9 0 26 3 0
  Vomiting 22 1 0 13 0 0
  Diarrhea 17 0 0 5 0 0
  Constipation 10 0 0 3 0 0
Infections and infestations
  Respiratory tract infectionb 31 1 1 23 0 0
  Gastroenteritisc 10 4 1 3 0 0
  Pharyngitis streptococcal 10 0 0 3 0 0
General disorders and administration site conditions
  Pyrexia 23 6 0 18 3 0
  Fatigue 14 0 0 3 0 0
Psychiatric disorders
  Anxiety, aggression or other behavioral disturbanced 21 5 0 3 0 0
Skin and subcutaneous tissue disorders
  Rashe 21 0 0 8 0 0
  Acne 10 0 0 5 0 0
Grading according to CTCAE Version 3.0
aIncludes mouth ulceration, stomatitis, and lip ulceration
bIncludes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral
cIncludes gastroenteritis, gastroenteritis viral, and gastrointestinal infection
dIncludes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder
eIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria

Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18) and none of the females in the placebo group. For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%).

The following additional adverse reactions occurred in less than 10% of AFINITOR-treated patients: nausea (8%), pain in extremity (8%), insomnia (6%), pneumonia (6%), epistaxis (5%), hypersensitivity (3%), increased blood luteinizing hormone (LH) levels (1%) and pneumonitis (1%).

Table 11: Key Laboratory Abnormalities Reported in AFINITOR-treated Patients with SEGA in Study 1

 

AFINITOR
N=78
Placebo
N=39
All grades % Grade 3 % Grade 4 % All grades % Grade 3 % Grade 4 %
Hematology
  Elevated partial thromboplastin time 72 3 0 44 5 0
  Neutropenia 46 9 0 41 3 0
  Anemia 41 0 0 21 0 0
Clinical chemistry
  Hypercholesterolemia 81 0 0 39 0 0
  Elevated aspartate transaminase (AST) 33 0 0 0 0 0
  Hypertriglyceridemia 27 0 0 15 0 0
  Elevated alanine transaminase (ALT) 18 0 0 3 0 0
  Hypophosphatemia 9 1 0 3 0 0
Grading according to CTCAE Version 3.0

Longer-term follow-up of 34.2 months (range 4.7 to 47.1 months) from a non-randomized, open-label, 28-patient trial resulted in the following additional notable adverse reactions and key laboratory abnormalities: cellulitis (29%), hyperglycemia (25%), and elevated creatinine (14%).

Postmarketing Experience

The following adverse reactions have been identified during post approval use of AFINITOR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure: acute pancreatitis, cholecystitis, cholelithiasis, arterial thrombotic events and reflex sympathetic dystrophy.

DRUG INTERACTIONS

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.

Agents That May Increase Everolimus Blood Concentrations

CYP3A4 Inhibitors and PgP Inhibitors

In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

  • ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) – Cmax and AUC increased by 3.9- and 15.0-fold, respectively.
  • erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) – Cmax and AUC increased by 2.0- and 4.4-fold, respectively.
  • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) – Cmax and AUC increased by 2.3- and 3.5-fold, respectively.

Concomitant strong inhibitors of CYP3A4/PgP should not be used.

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

Agents That May Decrease Everolimus Blood Concentrations

CYP3A4/PgP Inducers

In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4 and an inducer of PgP, 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/PgP inducers if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided.

Drugs That May Have Their Plasma Concentrations Altered By Everolimus

Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

A study in healthy subjects demonstrated that co-administration of an oral dose of midazolam (sensitive CYP3A4 substrate) with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf).

Coadministration of everolimus and exemestane increased exemestane Cmin by 45% and C2h by 64%. However, the corresponding estradiol levels at steady state (4 weeks) were not different between the 2 treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.

Coadministration of everolimus and depot octreotide increased octreotide Cmin by approximately 50%.

PRECAUTIONS

Non-infectious Pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR in clinical trials. The incidence of Common Terminology Criteria (CTC) Grade 3 and 4 non-infectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed.

Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) should be considered in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. Imaging appears to overestimate the incidence of clinical pneumonitis.

If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at a daily dose approximately 50% lower than the dose previously administered.

For cases of Grade 3 non-infectious pneumonitis interrupt AFINITOR until resolution to less than or equal to Grade 1. AFINITOR may be re-introduced at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances. If toxicity recurs at Grade 3, consider discontinuation of AFINITOR. For cases of Grade 4 non-infectious pneumonitis, discontinue AFINITOR.

Corticosteroids may be indicated until clinical symptoms resolve. For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, prophylaxis for PJP may be considered. The development of pneumonitis has been reported even at a reduced dose.

Infections

AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections, such as aspergillosis, candidiasis, or pneumocystis jiroveci pneumonia (PJP) and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR, be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

Pneumocystis jiroveci pneumonia, some with a fatal outcome, has been reported in patients who received everolimus. This may be associated with concomitant use of corticosteroids or other immunosuppressive agents. Prophylaxis for PJP should be considered when concomitant use of corticosteroids or other immunosuppressive agents are required.

Angioedema With Concomitant Use Of Angiotensin-Converting Enzyme (ACE) Inhibitors

Patients taking concomitant ACE inhibitor therapy may be at increased risk for angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis of randomized double-blind oncology clinical trials, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor.

Oral Ulceration

Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR at an incidence ranging from 44%-78% across the clinical trial experience. Grade 3 or 4 stomatitis was reported in 4%-9% of patients. In such cases, topical treatments are recommended, but alcohol-, hydrogen peroxide-, iodine-, or thyme- containing mouthwashes should be avoided as they may exacerbate the condition. 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.

Impaired Wound Healing

Everolimus delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR in the peri-surgical period.

Geriatric Patients

In the randomized advanced hormone receptor-positive, HER2-negative breast cancer study, the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.

Laboratory Tests And Monitoring

Renal Function

Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR. Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein, or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Blood Glucose and Lipids

Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in patients taking AFINITOR. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter as well as management with appropriate medical therapy. More frequent monitoring is recommended when AFINITOR is co-administered with other drugs that may induce hyperglycemia. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR.

Hematologic Parameters

Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in patients taking AFINITOR. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Drug-drug Interactions

Due to significant increases in exposure of everolimus, co-administration with strong CYP3A4/PgP inhibitors should be avoided.

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4/PgP inhibitor.

An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4/PgP inducer.

Hepatic Impairment

Exposure to everolimus was increased in patients with hepatic impairment.

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC 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.

For patients with SEGA and mild or moderate hepatic impairment, adjust the dose of AFINITOR Tablets or AFINITOR DISPERZ based on therapeutic drug monitoring. For patients with SEGA and severe hepatic impairment, reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50% and adjust subsequent doses based on therapeutic drug monitoring.

Vaccinations

During AFINITOR treatment, avoid the use of live vaccines and avoid close contact with individuals who have received live vaccines (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines).

For pediatric patients with SEGA that do not require immediate treatment, complete the recommended childhood series of live virus vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Embryo-fetal Toxicity

Based on the mechanism of action, AFINITOR can cause fetal harm. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

Advise female patients of reproductive potential to avoid becoming pregnant and to use highly effective contraception while using AFINITOR and for up to 8 weeks after ending treatment.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling

Non-infectious Pneumonitis

Warn patients of the possibility of developing non-infectious pneumonitis. In clinical studies, some non-infectious pneumonitis cases have been severe and occasionally fatal. Advise patients to report promptly any new or worsening respiratory symptoms.

Infections

Inform patients that they are more susceptible to infections while being treated with AFINITOR and that cases of hepatitis B reactivation have been associated with AFINITOR treatment. In clinical studies, some of these infections have been severe (e.g., leading to sepsis, respiratory or hepatic failure) and occasionally fatal. Patients should be aware of the signs and symptoms of infection and should report any such signs or symptoms promptly to their physician.

Angioedema with Concomitant use of Angiotensin-Converting Enzyme (ACE) Inhibitors

Inform patients that they are more susceptible to angioedema if concomitantly taking angiotensin-converting enzyme (ACE) inhibitors. Patients should be aware of any signs or symptoms of angioedema and seek prompt medical attention.

Oral Ulceration

Inform patients of the possibility of developing mouth ulcers, stomatitis, and oral mucositis. In such cases, mouthwashes and/or topical treatments are recommended, but these should not contain alcohol, peroxide, iodine, or thyme.

Renal Failure

Inform patients of the possibility of developing kidney failure. In some cases kidney failure has been severe and occasionally fatal. Inform patients of the need for the healthcare provider to monitor kidney function, especially in patients with risk factors that may impair kidney function.

Impaired Wound Healing

Inform patients of the possibility of impaired wound healing or dehiscence while being treated with AFINITOR.

Laboratory Tests and Monitoring

Inform patients of the need to monitor blood chemistry and hematology prior to the start of AFINITOR therapy and periodically thereafter.

Drug-drug Interactions

Advise patients to inform their healthcare providers of all concomitant medications, including over-the-counter medications and dietary supplements. Inform the patients to avoid concomitant administration of strong CYP3A4/PgP inhibitors or inducers while on AFINITOR treatment.

Vaccinations

Advise patients to avoid the use of live vaccines and close contact with those who have received live vaccines.

Embryo-fetal Toxicity

Advise female patients of childbearing potential that AFINITOR may cause fetal harm and that a highly effective method of contraception should be used during therapy with AFINITOR and for up to 8 weeks after ending treatment.

Safe Handling Practices for AFINITOR DISPERZ

Advise patients and their caregivers to read and carefully follow the FDA approved AFINITOR DISPERZ “Instructions for Use”.

Dosing Instructions

Inform patients to take AFINITOR Tablets orally once daily at the same time every day, either consistently with food or consistently without food. Inform patients that AFINITOR Tablets should be swallowed whole with a glass of water.

Inform patients to take AFINITOR DISPERZ orally once daily at the same time every day as a suspension. Refer patients to the “Instructions for Use” pamphlet for additional information regarding these procedures.

Instruct patients that if they miss a dose of AFINITOR, they may still take it up to 6 hours after the time they would normally take it. If more than 6 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take AFINITOR at the usual time. Warn patients to not take 2 doses to make up for the one that they missed.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding respectively to 3.9 and 0.2 times the estimated clinical exposure (AUC0-24h) at the 10 mg daily human dose.

Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m²/day, approximately 255fold the 10 mg daily human dose, and 103-fold the maximum dose administered to patients with SEGA, based on the body surface area), administered as 2 doses, 24 hours apart.

Based on non-clinical findings, male fertility may be compromised by treatment with AFINITOR. In a 13-week male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. These doses result in exposures which are within the range of therapeutic exposure (52 ng•hr/mL and 414 ng•hr/mL respectively compared to 560 ng•hr/mL human exposure at 10 mg/day), and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at the AUC 0-24h values below that of therapeutic exposure (approximately 10%-81% of the AUC0-24h in patients receiving the 10 mg daily dose). After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60% (12/20 mated females were pregnant).

Oral doses of everolimus in female rats at ≥ 0.1 mg/kg (approximately 4% the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Risk Summary

Based on the mechanism of action, AFINITOR can cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, apprise the patient of the potential hazard to the fetus.

Animal Data

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m²) with resulting exposures of approximately 4% of the exposure (AUC0-24h) achieved in patients receiving the 10 mg daily dose of everolimus. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m²), approximately 1.6 times either the 10 mg daily dose or the median dose administered to SEGA patients on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At the dose of 0.1 mg/kg (0.6 mg/m²), there were no adverse effects on delivery and lactation or signs of maternal toxicity; however, there were reductions in body weight (up to 9% reduction from the control) and in survival of offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring.

Nursing Mothers

It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Pediatric use of AFINITOR Tablets and AFINITOR DISPERZ is recommended for patients 1 year of age and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected. The safety and effectiveness of AFINITOR Tablets and AFINITOR DISPERZ have not been established in pediatric patients with renal angiomyolipoma with TSC in the absence of SEGA.

The effectiveness of AFINITOR in pediatric patients with SEGA was demonstrated in two clinical trials based on demonstration of durable objective response, as evidenced by reduction in SEGA tumor volume. Improvement in disease-related symptoms and overall survival in pediatric patients with SEGA has not been demonstrated. The long term effects of AFINITOR on growth and pubertal development are unknown.

Study 1 was a randomized, double-blind, multicenter trial comparing AFINITOR (n=78) to placebo (n=39) in pediatric and adult patients. The median age was 9.5 years (range 0.8 to 26 years). At the time of randomization, a total of 20 patients were < 3 years of age, 54 patients were 3 to < 12 years of age, 27 patients were 12 to < 18 years of age, and 16 patients were ≥ 18 years of age. The overall nature, type, and frequency of adverse reactions across the age groups evaluated were similar, with the exception of a higher per patient incidence of infectious serious adverse events in patients < 3 years of age. A total of 6 of 13 patients (46%) < 3 years of age had at least 1 serious adverse event due to infection, compared to 2 of 7 patients (29%) treated with placebo. No patient in any age group discontinued AFINITOR due to infection. Subgroup analyses showed reduction in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Study 2 was an open-label, single-arm, single-center trial of AFINITOR (N=28) in patients aged ≥ 3 years; median age was 11 years (range 3 to 34 years). A total of 16 patients were 3 to < 12 years, 6 patients were 12 to < 18 years, and 6 patients were ≥ 18 years. The frequency of adverse reactions across the age groups was generally similar. Subgroup analyses showed reductions in SEGA volume with AFINITOR treatment in all pediatric age subgroups.

Everolimus clearance normalized to body surface area was higher in pediatric patients than in adults with SEGA.The recommended starting dose and subsequent requirement for therapeutic drug monitoring to achieve and maintain trough concentrations of 5 to 15 ng/mL are the same for adult and pediatric patients with SEGA.

Geriatric Use

In the randomized advanced hormone receptor positive, HER2-negative breast cancer study, 40% of AFINITOR-treated patients were ≥ 65 years of age, while 15% were 75 years and over. No overall differences in effectiveness were observed between elderly and younger patients. The incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Adverse reactions leading to permanent treatment discontinuation occurred in 33% of patients ≥ 65 years of age compared to 17% in patients < 65 years of age.

In two other randomized trials (advanced renal cell carcinoma and advanced neuroendocrine tumors of pancreatic origin), no overall differences in safety or effectiveness were observed between elderly and younger patients. In the randomized advanced RCC study, 41% of AFINITOR treated patients were ≥ 65 years of age, while 7% were 75 years and over. In the randomized advanced PNET study, 30% of AFINITOR-treated patients were ≥ 65 years of age, while 7% were 75 years and over.

Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

No dosage adjustment in initial dosing is required in elderly patients, but close monitoring and appropriate dose adjustments for adverse reactions is recommended.

Females And Males Of Reproductive Potential

Contraception

Females

AFINITOR can cause fetal harm when administered to a pregnant woman. Advise female patients of reproductive potential to use highly effective contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Infertility

Females

Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR. Based on these clinical findings and findings in animals, female fertility may be compromised by treatment with AFINITOR.

Males

AFINITOR treatment may impair fertility in male patients based on animal findings.

Renal Impairment

No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment.

Hepatic Impairment

The safety, tolerability and pharmacokinetics of AFINITOR were evaluated in a 34 subject single oral dose study of everolimus in subjects with impaired hepatic function relative to subjects with normal hepatic function. Exposure was increased in patients with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment.

For advanced HR+ BC, advanced PNET, advanced RCC, and renal angiomyolipoma with TSC patients with severe hepatic impairment, 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.

For patients with SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of AFINITOR Tablets or AFINITOR DISPERZ by approximately 50%. For patients with SEGA who have mild (Child-Pugh class A) or moderate (Child-Pugh class B) hepatic impairment, adjustment to the starting dose may not be needed. Subsequent dosing should be based on therapeutic drug monitoring.

OVERDOSE

In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity was observed in either mice or rats given single oral doses of 2000 mg/kg (limit test).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

CONTRAINDICATIONS

AFINITOR is contraindicated in patients with hypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients. Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

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