NDC 0078-0566 Afinitor

Everolimus

NDC Product Code 0078-0566

NDC CODE: 0078-0566

Proprietary Name: Afinitor What is the Proprietary Name?
The proprietary name also known as the trade name is the name of the product chosen by the medication labeler for marketing purposes.

Non-Proprietary Name: Everolimus What is the Non-Proprietary Name?
The non-proprietary name is sometimes called the generic name. The generic name usually includes the active ingredient(s) of the product.

Drug Use Information

Drug Use Information
The drug use information is a summary and does NOT have all possible information about this product. This information does not assure that this product is safe, effective, or appropriate. This information is not individual medical advice and does not substitute for the advice of a health care professional. Always ask a health care professional for complete information about this product and your specific health needs.

  • Everolimus is used to treat various types of cancer (such as kidney, breast, pancreas, lung, stomach/intestinal cancers). Everolimus is also used in people with a certain genetic disorder (tuberous sclerosis complex) to treat certain types of benign tumors in the brain or kidney. It works by slowing or stopping the growth of cancer or tumor cells.

Product Characteristics

Color(s):
WHITE (C48325 - WHITE TO SLIGHTLY YELLOW)
Shape: OVAL (C48345)
Size(s):
12 MM
Imprint(s):
5;NVR
Score: 1

NDC Code Structure

  • 0078 - Novartis Pharmaceuticals Corporation

NDC 0078-0566-51

Package Description: 28 BLISTER PACK in 1 CARTON > 1 TABLET in 1 BLISTER PACK (0078-0566-61)

NDC Product Information

Afinitor with NDC 0078-0566 is a a human prescription drug product labeled by Novartis Pharmaceuticals Corporation. The generic name of Afinitor is everolimus. The product's dosage form is tablet and is administered via oral form.

Labeler Name: Novartis Pharmaceuticals Corporation

Dosage Form: Tablet - A solid dosage form containing medicinal substances with or without suitable diluents.

Product Type: Human Prescription Drug What kind of product is this?
Indicates the type of product, such as Human Prescription Drug or Human Over the Counter Drug. This data element matches the “Document Type” field of the Structured Product Listing.

Afinitor Active Ingredient(s)

What is the Active Ingredient(s) List?
This is the active ingredient list. Each ingredient name is the preferred term of the UNII code submitted.

  • EVEROLIMUS 5 mg/1

Inactive Ingredient(s)

About the Inactive Ingredient(s)
The inactive ingredients are all the component of a medicinal product OTHER than the active ingredient(s). The acronym "UNII" stands for “Unique Ingredient Identifier” and is used to identify each inactive ingredient present in a product.

  • BUTYLATED HYDROXYTOLUENE (UNII: 1P9D0Z171K)
  • CROSPOVIDONE (UNII: 68401960MK)
  • HYPROMELLOSES (UNII: 3NXW29V3WO)
  • ANHYDROUS LACTOSE (UNII: 3SY5LH9PMK)
  • LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X)
  • MAGNESIUM STEARATE (UNII: 70097M6I30)

Administration Route(s)

What are the Administration Route(s)?
The translation of the route code submitted by the firm, indicating route of administration.

  • Oral - Administration to or by way of the mouth.
  • Oral - Administration to or by way of the mouth.

Pharmacological Class(es)

What is a Pharmacological Class?
These are the reported pharmacological class categories corresponding to the SubstanceNames listed above.

  • Kinase Inhibitor - [EPC] (Established Pharmacologic Class)
  • Protein Kinase Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 3A4 Inhibitors - [MoA] (Mechanism of Action)
  • P-Glycoprotein Inhibitors - [MoA] (Mechanism of Action)
  • Cytochrome P450 2D6 Inhibitors - [MoA] (Mechanism of Action)
  • mTOR Inhibitor Immunosuppressant - [EPC] (Established Pharmacologic Class)
  • mTOR Inhibitors - [MoA] (Mechanism of Action)
  • Decreased Immunologic Activity - [PE] (Physiologic Effect)

Product Labeler Information

What is the Labeler Name?
Name of Company corresponding to the labeler code segment of the Product NDC.

Labeler Name: Novartis Pharmaceuticals Corporation
Labeler Code: 0078
FDA Application Number: NDA022334 What is the FDA Application Number?
This corresponds to the NDA, ANDA, or BLA number reported by the labeler for products which have the corresponding Marketing Category designated. If the designated Marketing Category is OTC Monograph Final or OTC Monograph Not Final, then the Application number will be the CFR citation corresponding to the appropriate Monograph (e.g. “part 341”). For unapproved drugs, this field will be null.

Marketing Category: NDA - A product marketed under an approved New Drug Application. What is the Marketing Category?
Product types are broken down into several potential Marketing Categories, such as NDA/ANDA/BLA, OTC Monograph, or Unapproved Drug. One and only one Marketing Category may be chosen for a product, not all marketing categories are available to all product types. Currently, only final marketed product categories are included. The complete list of codes and translations can be found at www.fda.gov/edrls under Structured Product Labeling Resources.

Start Marketing Date: 03-31-2009 What is the Start Marketing Date?
This is the date that the labeler indicates was the start of its marketing of the drug product.

Listing Expiration Date: 12-31-2021 What is the Listing Expiration Date?
This is the date when the listing record will expire if not updated or certified by the product labeler.

Exclude Flag: N What is the NDC Exclude Flag?
This field indicates whether the product has been removed/excluded from the NDC Directory for failure to respond to FDA’s requests for correction to deficient or non-compliant submissions. Values = ‘Y’ or ‘N’.

* Please review the disclaimer below.

Information for Patients

Everolimus

Everolimus is pronounced as (e'' ver oh' li mus)

Why is everolimus medication prescribed?
Everolimus (Afinitor) is used to treat advanced renal cell carcinoma (RCC; cancer that begins in the kidneys) that has already been treated unsuccessfully with other medi...
[Read More]

* Please review the disclaimer below.

Afinitor Product Label Images

Afinitor Product Labeling Information

The product labeling information includes all published material associated to a drug. Product labeling documents include information like generic names, active ingredients, ingredient strength dosage, routes of administration, appearance, usage, warnings, inactive ingredients, etc.

Product Labeling Index

1.1     Hormone Receptor-Positive, Her2-Negative Breast Cancer

AFINITOR® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.

1.2     Neuroendocrine Tumors (Net)

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 indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.Limitation of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)].

1.3     Renal Cell Carcinoma (Rcc)

AFINITOR is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib.

1.4     Tuberous Sclerosis Complex (Tsc)-Associated Renal Angiomyolipoma

AFINITOR is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.

1.5     Tuberous Sclerosis Complex (Tsc)-Associated Subependymal Giant Cell Astrocytoma (Sega)

AFINITOR and AFINITOR DISPERZ® are indicated in adult and pediatric patients aged 1 year and older with TSC for the treatment of SEGA that requires therapeutic intervention but cannot be curatively resected.

1.6     Tuberous Sclerosis Complex (Tsc)-Associated Partial-Onset Seizures

AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

2.1     Important Dosage Information

  • AFINITOR and AFINITOR DISPERZ are two different dosage forms. Select the recommended dosage form based on the indication [see Indications and Usage (1)]. Do not combine AFINITOR and AFINITOR DISPERZ to achieve the total dose.Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration (2.10, 2.11, 2.12)].

2.2     Recommended Dosage For Hormone Receptor-Positive, Her2-Negative Breast Cancer

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

2.3     Recommended Dosage For Neuroendocrine Tumors (Net)

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

2.4     Recommended Dosage For Renal Cell Carcinoma (Rcc)

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

2.5     Recommended Dosage For Tuberous Sclerosis Complex (Tsc)-Associated Renal Angiomyolipoma

The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.

2.6     Recommended Dosage For Tuberous Sclerosis Complex (Tsc)-Associated Subependymal Giant Cell Astrocytoma (Sega)

The recommended starting dosage of AFINITOR/AFINITOR DISPERZ is 4.5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)].

2.7     Recommended Dosage For Tuberous Sclerosis Complex (Tsc)-Associated Partial-Onset Seizures

The recommended starting dosage of AFINITOR DISPERZ is 5 mg/m2 orally once daily until disease progression or unacceptable toxicity [see Dosage and Administration (2.8)].

2.8     Therapeutic Drug Monitoring And Dose Titration For Tuberous Sclerosis Complex (Tsc)-Associated Subependymal Giant Cell Astrocytoma (Sega) And Tsc-Associated Partial-Onset Seizures

  • Monitor everolimus whole blood trough concentrations at time points recommended in Table 1.Titrate the dose to attain trough concentrations of 5 ng/mL to 15 ng/mL.Adjust the dose using the following equation:New dose* = current dose x (target concentration divided by current concentration)*The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration.When possible, use the same assay and laboratory for therapeutic drug monitoring throughout treatment.Table 1: Recommended Timing of Therapeutic Drug MonitoringEventWhen to Assess Trough Concentrations After Event
  • Initiation of AFINITOR/AFINITOR DISPERZ1 to 2 weeks
  • Modification of AFINITOR/AFINITOR DISPERZ dose1 to 2 weeks
  • Switch between AFINITOR and AFINITOR DISPERZ1 to 2 weeks
  • Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor2 weeks
  • Initiation or discontinuation of P-gp and strong CYP3A4 inducer2 weeks
  • Change in hepatic function2 weeks
  • Stable dose with changing body surface areaEvery 3 to 6 months
  • Stable dose with stable body surface areaEvery 6 to 12 months

2.9     Dosage Modifications For Adverse Reactions

Table 2 summarizes recommendations for dosage modifications of AFINITOR/AFINITOR DISPERZ for the management of adverse reactions.Table 2: Recommended Dosage Modifications for AFINITOR/AFINITOR DISPERZ for Adverse ReactionsAdverse ReactionSeverityDosage Modification
Non-infectious pneumonitis[see Warnings and Precautions (5.1)]Grade 2Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.Grade 3Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.If toxicity recurs at Grade 3, permanently discontinue.Grade 4Permanently discontinue.
Stomatitis[see Warnings and Precautions (5.5)]Grade 2Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.
Grade 3Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.Grade 4Permanently discontinue.
Metabolic events
(e.g., hyperglycemia, dyslipidemia)[see Warnings and Precautions (5.9)]Grade 3Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.
Grade 4Permanently discontinue.
Other non-hematologic toxicitiesGrade 2If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose.
If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.Grade 3Withhold until improvement to Grade 0 or 1. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.If recurs at Grade 3, permanently discontinue.Grade 4Permanently discontinue.
Thrombocytopenia[see Warnings and Precautions (5.10)]Grade 2Withhold until improvement to Grade 0 or 1. Resume at same dose.
Grade 3   OR Grade 4Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.
Neutropenia[see Warnings and Precautions (5.10)]Grade 3Withhold until improvement to Grade 0, 1 or 2. Resume at same dose.
Grade 4Withhold until improvement to Grade 0, 1 or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.
Febrile neutropenia[see Warnings and Precautions (5.10)]Grade 3Withhold until improvement to Grade 0, 1 or 2 and no fever. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.Grade 4Permanently discontinue.

2.10     Dosage Modifications For Hepatic Impairment

  • The recommended dosages of AFINITOR/AFINITOR DISPERZ for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6)]:
  • Table 3: Recommended Dosage Modifications for Patients with Hepatic ImpairmentIndicationDose Modification for AFINITOR/AFINITOR DISPERZ
  • Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma
  • Mild hepatic impairment (Child-Pugh class A) – 7.5 mg orally once daily; decrease the dose to 5 mg orally once daily if a dose of 7.5 mg once daily is not tolerated.Moderate hepatic impairment (Child-Pugh class B) – 5 mg orally once daily; decrease the dose to 2.5 mg orally once daily if a dose of 5 mg once daily is not tolerated.Severe hepatic impairment (Child-Pugh class C) – 2.5 mg orally once daily if the desired benefit outweighs the risk; do not exceed a dose of 2.5 mg once daily.
  • TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures
  • Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m2 orally once daily.Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)].

2.11     Dosage Modifications For P-Gp And Cyp3a4 Inhibitors

  • Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1)].Avoid ingesting grapefruit and grapefruit juice.Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. Table 4: Recommended Dosage Modifications for Concurrent Use of AFINITOR/AFINITOR DISPERZ with a P-gp and Moderate CYP3A4 InhibitorIndicationDose Modification for AFINITOR/AFINITOR DISPERZ
  • Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma
  • Reduce dose to 2.5 mg once daily.May increase dose to 5 mg once daily if tolerated.Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.
  • TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures
  • Reduce the daily dose by 50%.Change to every other day dosing if the reduced dose is lower than the lowest available strength.Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8)].

2.12     Dosage Modifications For P-Gp And Cyp3a4 Inducers

  • Avoid concomitant use of St. John’s Wort (Hypericum perforatum).Increase the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].Table 5: Recommended Dosage Modifications for Concurrent Use of AFINITOR/AFINITOR DISPERZ with P-gp and Strong CYP3A4 InducersIndicationDose Modification for AFINITOR/AFINITOR DISPERZ
  • Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma
  • Avoid coadministration where alternatives exist.If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days.
  • TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures
  • Double the daily dose using increments of 5 mg or less. Multiple increments may be required.Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification.Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8)].Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days.

2.13     Administration And Preparation

  • Administer AFINITOR/AFINITOR DISPERZ at the same time each day.Administer AFINITOR/AFINITOR DISPERZ consistently either with or without food [see Clinical Pharmacology (12.3)].If a dose of AFINITOR/AFINITOR DISPERZ is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, AFINITOR/AFINITOR DISPERZ should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.AFINITORAFINITOR should be swallowed whole with a glass of water. Do not break or crush tablets.AFINITOR DISPERZWear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ for another person.Administer as a suspension only.Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation.Prepare suspension in water only.Using an Oral Syringe to Prepare Oral Suspension:Place the prescribed dose 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 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 to Prepare Oral Suspension:Place the prescribed dose into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg 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.

3     Dosage Forms And Strengths

  • AFINITORTablets, white to slightly yellow and elongated with a bevelled edge:2.5 mg: engraved with “LCL” on one side and “NVR” on the other.5 mg: engraved with “5” on one side and “NVR” on the other.7.5 mg: engraved with “7P5” on one side and “NVR” on the other.10 mg: engraved with “UHE” on one side and “NVR” on the other.AFINITOR DISPERZTablets for oral suspension, white to slightly yellowish, round, and flat with a bevelled edge:2 mg: engraved with “D2” on one side and “NVR” on the other.3 mg: engraved with “D3” on one side and “NVR” on the other.5 mg: engraved with “D5” on one side and “NVR” on the other.

4     Contraindications

AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions (5.3)].

5.1     Non-Infectious Pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR/AFINITOR DISPERZ in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of Grade 3 and 4 non-infectious pneumonitis was up to 4% and up to 0.2%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed.Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms. Consider opportunistic infections such as pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. Advise patients to report promptly any new or worsening respiratory symptoms.Continue AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For Grade 2 to 4 non-infectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)]. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose.

5.2     Infections

AFINITOR/AFINITOR DISPERZ has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP) and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4)].Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity of infection [see Dosage and Administration (2.9)].
Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

5.3     Severe Hypersensitivity Reactions

Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (e.g., swelling of the airways or tongue, with or without respiratory impairment) [see Contraindications (4)]. The incidence of Grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue AFINITOR/AFINITOR DISPERZ for the development of clinically significant hypersensitivity.

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

Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ 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 AFINITOR with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR/AFINITOR DISPERZ for angioedema.

5.5     Stomatitis

Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/AFINITOR DISPERZ at an incidence ranging from 44% to 78% across clinical trials. Grades 3-4 stomatitis was reported in 4% to 9% of patients [see Adverse Reactions (6.1)]. Stomatitis most often occurs within the first 8 weeks of treatment. When starting AFINITOR/AFINITOR DISPERZ, initiating dexamethasone alcohol-free oral solution as a swish and spit mouthwash reduces the incidence and severity of stomatitis [see Adverse Reactions (6.1)]. If stomatitis does occur, mouthwashes and/or other topical treatments are recommended. Avoid alcohol-, hydrogen peroxide-, iodine-, or thyme- containing products, as they may exacerbate the condition. Do not administer antifungal agents, unless fungal infection has been diagnosed.

5.6     Renal Failure

Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR/AFINITOR DISPERZ [see Adverse Reactions (6.1)]. The incidence of Grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of Grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

5.7     Impaired Wound Healing

AFINITOR/AFINITOR DISPERZ 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/AFINITOR DISPERZ in the peri-surgical period.

5.8     Geriatric Patients

In the randomized hormone receptor-positive, HER2-negative breast cancer study (BOLERO-2), 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 [see Dosage and Administration (2.9), Use in Specific Populations (8.5)].

5.9     Metabolic Disorders

Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR/AFINITOR DISPERZ at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively [see Adverse Reactions (6.1)]. In non-diabetic patients, monitor fasting serum glucose prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR/AFINITOR DISPERZ and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR/AFINITOR DISPERZ. For Grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)].

5.10     Myelosuppression

Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR/AFINITOR DISPERZ. The incidence of these Grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively [see Adverse Reactions (6.1)]. Monitor complete blood count prior to starting AFINITOR/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity [see Dosage and Administration (2.9)].

5.11     Risk Of Infection Or Reduced Immune Response With Vaccination

The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ therapy has not been studied. Due to the potential increased risk of infection, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR/AFINITOR DISPERZ. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

5.12     Embryo-Fetal Toxicity

Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

6     Adverse Reactions

  • The following serious adverse reactions are described elsewhere in the labeling:Non-Infectious Pneumonitis [see Warnings and Precautions (5.1)].Infections [see Warnings and Precautions (5.2)].Severe Hypersensitivity Reactions [see Warnings and Precautions (5.3)].Angioedema with Concomitant Use of ACE inhibitors [see Warnings and Precautions (5.4)].
  • Stomatitis [see Warnings and Precautions (5.5)].Renal Failure [see Warnings and Precautions (5.6)].Impaired Wound Healing [see Warnings and Precautions (5.7)].Metabolic Disorders [see Warnings and Precautions (5.9)].Myelosuppression [see Warnings and Precautions (5.10)].

6.1     Clinical Trials Experience

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.Hormone Receptor-Positive, HER2-Negative Breast CancerThe safety of AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median age of patients was 61 years (28 to 93 years), and 75% were White. The median follow-up was 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, hypokalemia, increased AST, increased ALT, and thrombocytopenia.Fatal adverse reactions occurred in 2% of patients who received AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm.Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR versus placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR for a period of ≥ 32 weeks.Table 6: Adverse Reactions Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2Grading according to NCI CTCAE Version 3.0aIncludes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulcerationbIncludes all reported infections including, but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections.cIncludes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosisdNo Grade 4 adverse reactions were reported.
AFINITOR with ExemestaneN = 482Placebo with Exemestane
N = 238All GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal
     
Stomatitisa678d110.8
     
Diarrhea332180.8
     
Nausea290.4281
     
Vomiting171120.8
     
Constipation140.4d130.4
     
Dry mouth11070General
     
Fatigue364271d
     
Edema peripheral191d60.4d
     
Pyrexia150.2d70.4d
     
Asthenia13240Infections
     
Infectionsb506252dInvestigations
     
Weight loss251d60Metabolism and nutrition
     
Decreased appetite301d120.4d
     
Hyperglycemia14520.4dMusculoskeletal and connective tissue
     
Arthralgia200.8d170
     
Back pain140.2d100.8d
     
Pain in extremity90.4d112dNervous system
     
Dysgeusia220.2d60
     
Headache210.4d140Psychiatric
     
Insomnia130.2d80Respiratory, thoracic and mediastinal
     
Cough240.6d120
     
Dyspnea214111
     
Epistaxis17010
     
Pneumonitisc1940.40Skin and subcutaneous tissue
     
Rash391d60
     
Pruritus130.2d50
     
Alopecia10050Vascular
     
Hot flush60140Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with Hormone Receptor-Positive Breast Cancer in BOLERO-2Grading according to NCI CTCAE Version 3.0 aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency.bNo Grade 4 laboratory abnormalities were reported.Laboratory ParameterAFINITOR with ExemestaneN = 482Placebo with Exemestane N = 238All GradesGrade 3-4All GradesGrade 3-4%%%%Hematologya
     
Anemia686401
     
Leukopenia582b286
     
Thrombocytopenia54350.4
     
Lymphopenia5412376
     
Neutropenia312b112Chemistry
     
Hypercholesterolemia701382
     
Hyperglycemia699441
     
Increased aspartate transaminase (AST)694453
     
Increased alanine transaminase (ALT)514295b
     
Hypertriglyceridemia500.8b260
     
Hypoalbuminemia330.8b160.8b
     
Hypokalemia29471b
     
Increased creatinine 242130Topical Prophylaxis for StomatitisIn a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily), patients started dexamethasone 0.5 mg/5mL alcohol-free mouthwash (10 mL swished for 2 minutes and spat, 4 times daily for 8 weeks) concurrently with AFINITOR and exemestane. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks. The incidence of Grade 2 to 4 stomatitis within 8 weeks was 2%, which was lower than the 33% reported in the BOLERO-2 trial. The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial.Coadministration of AFINITOR/AFINITOR DISPERZ and dexamethasone alcohol-free oral solution has not been studied in pediatric patients.Pancreatic Neuroendocrine Tumors (PNET)In a randomized, controlled trial (RADIANT-3) of AFINITOR (n = 204) vs. placebo (n = 203) in patients with advanced PNET the median age of patients was 58 years (20 to 87 years), 79% were White, 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 anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were hyperglycemia, lymphopenia, anemia, hypophosphatemia, increased alkaline phosphatase, neutropenia, increased AST, hypokalemia, and thrombocytopenia.Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on AFINITOR. 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. 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 rate of adverse reactions resulting in permanent discontinuation was 20% for the AFINITOR group. Dose delay or reduction was necessary in 61% of AFINITOR patients. Grade 3-4 renal failure occurred in six patients in the AFINITOR arm. Thrombotic events included five patients with pulmonary embolus in the AFINITOR arm as well as three patients with thrombosis in the AFINITOR arm.Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received AFINITOR was 37 weeks.In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) AFINITOR-treated females.Table 8: Adverse Reactions Reported in ≥ 10% of Patients with PNET in RADIANT-3Grading according to NCI CTCAE Version 3.0aIncludes 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.dNo Grade 4 adverse reactions were reported.
AFINITORN = 204PlaceboN = 203All GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal
     
Stomatitisa707d200
     
Diarrheab506253d
     
Abdominal pain364d327
     
Nausea322d332d
     
Vomiting291d212d
     
Constipation140130.5d
     
Dry mouth11040General
     
Fatigue/malaise454273
     
Edema (general and peripheral)392121d
     
Fever 311130.5d
     
Asthenia193d203dInfections
     
Nasopharyngitis/rhinitis/URI250130
     
Urinary tract infection16060.5dInvestigations
     
Weight loss280.5d110Metabolism and nutrition
     
Decreased appetite301d181d
     
Diabetes mellitus102d0.50Musculoskeletal and connective tissue
     
Arthralgia15170.5d
     
Back pain151d111d
     
Pain in extremity140.5d61d
     
Muscle spasms10040Nervous system
     
Headache/migraine300.5d151d
     
Dysgeusia19050
     
Dizziness120.5d70Psychiatric
     
Insomnia14080Respiratory, thoracic and mediastinal
     
Cough/productive cough250.5d130
     
Epistaxis22010
     
Dyspnea/dyspnea exertional20370.5d
     
Pneumonitisc17400
     
Oropharyngeal pain11060Skin and subcutaneous
     
Rash590.5190
     
Nail disorders220.520
     
Pruritus/pruritus generalized210130
     
Dry skin/xeroderma13060Vascular
     
Hypertension13161dTable 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients with PNET in RADIANT-3Grading according to NCI CTCAE Version 3.0Laboratory parameterAFINITORN = 204PlaceboN = 203All GradesGrade 3-4All GradesGrade 3-4%%%%Hematology
     
Anemia8615631
     
Lymphopenia4516224
     
Thrombocytopenia453110
     
Leukopenia432130
     
Neutropenia304172Chemistry
     
Hyperglycemia (fasting)7517536
     
Increased alkaline phosphatase748668
     
Hypercholesterolemia660.5220
     
Bicarbonate decreased560400
     
Increased AST564414
     
Increased ALT482352
     
Hypophosphatemia4010143
     
Hypertriglyceridemia390100
     
Hypocalcemia370.5120
     
Hypokalemia23450
     
Increased creatinine 192140
     
Hyponatremia161161
     
Hypoalbuminemia13180
     
Hyperbilirubinemia101142
     
Hyperkalemia70100.5Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung OriginIn a randomized, controlled trial (RADIANT-4) of AFINITOR (n = 202 treated) vs. placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were White, and 53% were female. The median duration of exposure to AFINITOR was 9.3 months; 64% of patients were treated for > 6 months and 39% were treated for > 12 months. AFINITOR was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of AFINITOR-treated patients.Serious adverse reactions occurred in 42% of AFINITOR-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Adverse reactions occurring at an incidence of ≥ 10% and at > 5% absolute incidence over placebo (all Grades) or > 2% higher incidence over placebo (Grade 3 and 4) are presented in Table 10. Laboratory abnormalities are presented in Table 11.Table 10: Adverse Reactions in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4Grading according to NCI CTCAE Version 4.03aIncludes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation.bUrinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis.cIncludes pneumonitis and interstitial lung disease.dNo Grade 4 adverse reactions were reported.
AFINITORN = 202PlaceboN = 98All GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal
     
Stomatitisa639d220
     
Diarrhea419312d
     
Nausea263171d
     
Vomiting154d122dGeneral
     
Peripheral edema393d61d
     
Fatigue375361d
     
Asthenia23380
     
Pyrexia23280Infections
     
Infectionsb5811292Investigations
     
Weight loss222d111dMetabolism and nutrition
     
Decreased appetite221d171dNervous system
     
Dysgeusia181d40Respiratory, thoracic and mediastinal
     
Cough270200
     
Dyspnea203d112
     
Pneumonitisc162d20
     
Epistaxis131d30Skin and subcutaneous
     
Rash301d90
     
Pruritus171d90Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients with Non-Functional NET of GI or Lung Origin in RADIANT-4Grading according to NCI CTCAE Version 4.03aNo Grade 4 laboratory abnormalities were reported.AFINITORN = 202PlaceboN = 98All GradesGrade 3-4All GradesGrade 3-4%%%%Hematology
     
Anemia815a412a
     
Lymphopenia6616322a
     
Leukopenia492a170
     
Thrombocytopenia332110
     
Neutropenia322a153aChemistry
     
Hypercholesterolemia710370
     
Increased AST572342a
     
Hyperglycemia (fasting)556a361a
     
Increased ALT465391a
     
Hypophosphatemia434a152a
     
Hypertriglyceridemia30381a
     
Hypokalemia276123a
     
Hypoalbuminemia18080Renal Cell Carcinoma (RCC)The data described below reflect exposure to AFINITOR (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (27 to 85 years), 88% were White, and 78% were male. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving AFINITOR.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. The rate of adverse reactions resulting in permanent discontinuation was 14% for the AFINITOR group. The most common adverse reactions 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.Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR versus placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13.Table 12: Adverse Reactions Reported in ≥ 10% of Patients with RCC and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm in RECORD-1Grading according to NCI CTCAE Version 3.0aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.bIncludes all reported infections including, but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections.cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.dNo Grade 4 adverse reactions were reported.
AFINITORN = 274PlaceboN = 137All GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal
     
Stomatitisa44480
     
Diarrhea302d70
     
Nausea262d190
     
Vomiting202d120Infectionsb3710182General
     
Asthenia334234
     
Fatigue316d274
     
Edema peripheral25< 1d8< 1d
     
Pyrexia20< 1d90
     
Mucosal inflammation192d10Respiratory, thoracic and mediastinal
     
Cough30< 1d160
     
Dyspnea248153d
     
Epistaxis18000
     
Pneumonitisc144d00Skin and subcutaneous tissue
     
Rash291d70
     
Pruritus14< 1d70
     
Dry skin13< 1d50Metabolism and nutrition
     
Anorexia252d14< 1dNervous system
     
Headache1919< 1d
     
Dysgeusia10020Musculoskeletal and connective tissue
     
Pain in extremity101d70Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of < 10% include:
     
Gastrointestinal: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)
     
General: Weight loss (9%), chest pain (5%), chills (4%), impaired wound healing (< 1%)
     
Respiratory, thoracic and mediastinal: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%)
     
Skin and subcutaneous tissue: 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: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (< 1%)
     
Psychiatric: Insomnia (9%)
     
Nervous system: Dizziness (7%), paresthesia (5%)
     
Ocular: Eyelid edema (4%), conjunctivitis (2%)
     
Vascular: Hypertension (4%), deep vein thrombosis (< 1%)
     
Renal and urinary: Renal failure (3%)
     
Cardiac: Tachycardia (3%), congestive cardiac failure (1%)
     
Musculoskeletal and connective tissue: Jaw pain (3%)
     
Hematologic: Hemorrhage (3%)Table 13: Selected Laboratory Abnormalities Reported in Patients with RCC at a Higher Rate in the AFINITOR Arm than the Placebo Arm in RECORD-1Grading according to NCI CTCAE Version 3.0 aReflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency.bNo Grade 4 laboratory abnormalities were reported.Laboratory parameterAFINITORN = 274PlaceboN = 137All GradesGrade 3-4All GradesGrade 3-4%%%%Hematologya
     
Anemia9213796
     
Lymphopenia5118285b
     
Thrombocytopenia231b2< 1
     
Neutropenia14< 140Chemistry
     
Hypercholesterolemia774b350
     
Hypertriglyceridemia73< 1b340
     
Hyperglycemia5716252b
     
Increased creatinine increased502b340
     
Hypophosphatemia376b80
     
Increased AST25170
     
Increased ALT211b40
     
Hyperbilirubinemia3120Tuberous Sclerosis Complex (TSC)-Associated Renal AngiomyolipomaThe data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-2) 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 (18 to 61 years), 89% were White, and 34% were male. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving AFINITOR.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.Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15.Table 14: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2Grading according to NCI CTCAE Version 3.0aIncludes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia.bNo Grade 4 adverse reactions were reported.
AFINITORN = 79PlaceboN = 39All GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal
     
Stomatitisa786b230
     
Vomiting15050
     
Diarrhea14050General
     
Peripheral edema13080Infections
     
Upper respiratory tract infection11050Musculoskeletal and connective tissue
     
Arthralgia13050Respiratory, thoracic and mediastinal
     
Cough200130Skin and subcutaneous tissue
     
Acne22050Amenorrhea occurred in 15% of AFINITOR-treated females (8 of 52). 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 15: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated Renal Angiomyolipoma in EXIST-2Grading according to NCI CTCAE Version 3.0aNo Grade 4 laboratory abnormalities were reported.AFINITORN = 79PlaceboN = 39All GradesGrade 3-4All GradesGrade 3-4%%%%Hematology
     
Anemia610490
     
Leukopenia370210
     
Neutropenia251260
     
Lymphopenia201a80
     
Thrombocytopenia19030Chemistry
     
Hypercholesterolemia851a460
     
Hypertriglyceridemia520100
     
Hypophosphatemia495a150
     
Increased alkaline phosphatase321a100
     
Increased AST231a80
     
Increased ALT201a150
     
Hyperglycemia (fasting)14080Updated safety information from 112 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time (63%), increased prothrombin time (40%), decreased fibrinogen (38%), urinary tract infection (31%), proteinuria (18%), abdominal pain (16%), pruritus (12%), gastroenteritis (12%), myalgia (11%), and pneumonia (10%).TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA)The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were White, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR.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 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.Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17.Table 16: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1Grading according to NCI CTCAE Version 3.0aIncludes mouth ulceration, stomatitis, and lip ulcerationbIncludes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viralcIncludes gastroenteritis, gastroenteritis viral, and gastrointestinal infectiondIncludes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disordereIncludes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticariafNo Grade 4 adverse reactions were reported.
AFINITORN = 78PlaceboN = 39All GradesGrade 3-4All GradesGrade 3-4%%%%Gastrointestinal
     
Stomatitisa629f263f
     
Vomiting221f130
     
Diarrhea17050
     
Constipation10030Infections
     
Respiratory tract infectionb313230
     
Gastroenteritisc10530
     
Pharyngitis streptococcal10030General
     
Pyrexia236f183f
     
Fatigue14030Psychiatric
     
Anxiety, aggression or other behavioral disturbanced215f30Skin and subcutaneous tissue
     
Rashe21080
     
Acne10050Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). 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 17: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients with TSC-Associated SEGA in EXIST-1Grading according to NCI CTCAE Version 3.0aNo Grade 4 laboratory abnormalities were reported.AFINITORN = 78PlaceboN = 39All GradesGrade 3-4All GradesGrade 3-4%%%%Hematology
     
Elevated partial thromboplastin time723a445a
     
Neutropenia469a413a
     
Anemia410210Chemistry
     
Hypercholesterolemia810390
     
Elevated aspartate transaminase (AST)33000
     
Hypertriglyceridemia270150
     
Elevated alanine transaminase (ALT)18030
     
Hypophosphatemia91a30Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%).TSC-Associated Partial-Onset SeizuresThe data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to AFINITOR DISPERZ low trough (LT) (n = 117), AFINITOR DISPERZ high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were White, and 52% were male. Patients received between one and three concomitant antiepileptic drugs.The most common adverse reaction reported for AFINITOR DISPERZ in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia.Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the AFINITOR DISPERZ arms were stomatitis, pneumonia, and pyrexia.Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR DISPERZ are presented in Table 18. Laboratory abnormalities are presented in Table 19.Table 18: Adverse Reactions Reported in ≥ 10% of AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset Seizures in EXIST-3aIncludes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival painbNo Grade 4 adverse reactions were reported.
AFINITOR DISPERZPlaceboTarget of3-7 ng/mLN = 117Target of9-15 ng/mLN = 130N=119All Grades%Grade 3-4%All Grades%Grade 3-4%All Grades%Grade 3-4%Gastrointestinal
     
Stomatitisa553b644b90
     
Diarrhea17022050
     
Vomiting120102b90Infections
     
Nasopharyngitis
140160160
     
Upper respiratory tract infection
130150130.8bGeneral
     
Pyrexia200140.8b50Respiratory, thoracic and mediastinal
     
Cough
11010030Skin and subcutaneous tissue
     
Rash
6010030The following additional adverse reactions occurred in < 10% of AFINITOR DISPERZ treated patients (% AFINITOR DISPERZ LT, % AFINITOR DISPERZ HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%).Table 19: Selected Laboratory Abnormalities Reported in ≥ 10% AFINITOR DISPERZ-Treated Patients with TSC-Associated Partial-Onset SeizuresGrading according to NCI CTCAE version 4.03aNo Grade 4 laboratory abnormalities were reported.
AFINITOR DISPERZPlaceboTarget of3-7 ng/mLN = 117Target of9-15 ng/mLN = 130N=119All Grades%Grade 3-4%All Grades%Grade 3-4%All Grades%Grade 3-4%Hematology
     
Neutropenia
254a376237a
     
Anemia270.9a300210.8a
     
Thrombocytopenia12015060Chemistry
     
Hypercholesterolemia
860850.8a580
     
Hypertriglyceridemia
432a392220
     
Increased ALT
17022060
     
Increased AST
13019040
     
Hyperglycemia
190180170
     
Increased alkaline phosphatase
240160290
     
Hypophosphatemia
90.9a16230Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

6.2     Postmarketing Experience

  • The following adverse reactions have been identified during post approval use of AFINITOR/AFINITOR DISPERZ. 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:Gastrointestinal: Acute pancreatitisHepatobiliary: Cholecystitis and cholelithiasisVascular: Arterial thrombotic eventsNervous System: Reflex sympathetic dystrophyCardiac: Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary eventInfections: Sepsis and septic shock

7.1     Effect Of Other Drugs On Afinitor/Afinitor Disperz

InhibitorsAvoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].Reduce the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and moderate CYP3A4 inhibitor as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].InducersIncrease the dose for patients taking AFINITOR/AFINITOR DISPERZ with a P-gp and strong CYP3A4 inducer as recommended [see Dosage and Administration (2.12), Clinical Pharmacology (12.3)].

7.2     Effects Of Combination Use Of Angiotensin Converting Enzyme (Ace) Inhibitors

Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ [see Warnings and Precautions (5.4)].

8.1     Pregnancy

Risk SummaryBased on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], AFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily (see Data). Advise pregnant women of the potential risk to the fetus.In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.DataAnimal DataIn 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 human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m2), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on body surface area. 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.

8.2     Lactation

Risk SummaryThere are no data on the presence of everolimus or its metabolites in human milk, the effects of everolimus on the breastfed infant or on milk production. Everolimus and its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because of the potential for serious adverse reactions in breastfed infants from everolimus, advise women not to breastfeed during treatment with AFINITOR/AFINITOR DISPERZ and for 2 weeks after the last dose.

8.3     Females And Males Of Reproductive Potential

Pregnancy TestingVerify the pregnancy status of females of reproductive potential prior to starting AFINITOR/AFINITOR DISPERZ [see Use in Specific Population (8.1)].ContraceptionAFINITOR/AFINITOR DISPERZ can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)].
Females: Advise female patients of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 8 weeks after the last dose.
Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR/AFINITOR DISPERZ and for 4 weeks after the last dose.
InfertilityFemales: Menstrual irregularities, secondary amenorrhea, and increases in luteinizing hormone (LH) and follicle stimulating hormone (FSH) occurred in female patients taking AFINITOR/AFINITOR DISPERZ. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in female patients [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)].
Males: Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, AFINITOR/AFINITOR DISPERZ may impair fertility in male patients [see Nonclinical Toxicology (13.1)].

8.4     Pediatric Use

  • TSC-Associated SEGAThe safety and effectiveness of AFINITOR/AFINITOR DISPERZ have been established in pediatric patients age 1 year and older with TSC-associated SEGA that requires therapeutic intervention but cannot be curatively resected. Use of AFINITOR/AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-1); an open-label, single-arm trial in adult and pediatric patients (Study 2485); and additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.5)]. The safety and effectiveness of AFINITOR/AFINITOR DISPERZ have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA. In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years. Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients ≥ 6 years.Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years.TSC-Associated Partial-Onset SeizuresThe safety and effectiveness of AFINITOR DISPERZ has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of AFINITOR DISPERZ for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6)]. The safety and effectiveness of AFINITOR DISPERZ and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures.The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 AFINITOR DISPERZ-treated patients < 6 years had at least one infection, compared to 53% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years. Sixteen percent of 70 AFINITOR DISPERZ-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 AFINITOR DISPERZ-treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients.Other IndicationsThe safety and effectiveness of AFINITOR/AFINITOR DISPERZ in pediatric patients have not been established in:Hormone receptor-positive, HER2-negative breast cancerNeuroendocrine tumors (NET)Renal cell carcinoma (RCC)TSC-associated renal angiomyolipoma

8.5     Geriatric Use

In BOLERO-2, 40% of patients with breast cancer treated with AFINITOR were ≥ 65 years of age, while 15% were ≥ 75 years of age. 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 RECORD-1, 41% of patients with renal cell carcinoma treated with AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age. In RADIANT-3, 30% of patients with PNET treated with AFINITOR were ≥ 65 years of age, while 7% were ≥ 75 years of age. No overall differences in safety or effectiveness were observed between elderly and younger patients.

8.6     Hepatic Impairment

AFINITOR/AFINITOR DISPERZ exposure may increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)].For patients with breast cancer, NET, RCC, and TSC-associated renal angiomyolipoma who have hepatic impairment, reduce the AFINITOR dose as recommended [see Dosage and Administration (2.10)].For patients with TSC-associated SEGA and TSC-associated partial-onset seizures who have severe hepatic impairment (Child-Pugh C), reduce the starting dose of AFINITOR/AFINITOR DISPERZ as recommended and adjust the dose based on everolimus trough concentrations [see Dosage and Administration (2.8, 2.10)].

11     Description

AFINITOR (everolimus) and AFINITOR DISPERZ (everolimus tablets for oral suspension) are kinase inhibitors.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-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C53H83NO14 and the molecular weight is 958.2. The structural formula is:AFINITOR for oral administration contains 2.5 mg, 5 mg, 7.5 mg, or 10 mg of everolimus and the following inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, lactose monohydrate, and magnesium stearate.AFINITOR DISPERZ for oral administration contains 2 mg, 3 mg, or 5 mg of everolimus and the following inactive ingredients: butylated hydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.

12.1     Mechanism Of Action

Everolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway. The mTOR pathway is dysregulated in several human cancers and in tuberous sclerosis complex (TSC). Everolimus binds to an intracellular protein, FKBP-12, resulting in an inhibitory complex formation with mTOR complex 1 (mTORC1) and thus inhibition of mTOR kinase activity. Everolimus reduced the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic initiation factor 4E-binding protein (4E-BP1), downstream effectors of mTOR, involved in protein synthesis. S6K1 is a substrate of mTORC1 and phosphorylates the activation domain 1 of the estrogen receptor which results in ligand-independent activation of the receptor. In addition, everolimus inhibited the expression of hypoxia-inducible factor (e.g., HIF-1) and reduced the expression of vascular endothelial growth factor (VEGF). Inhibition of mTOR by everolimus has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.Constitutive activation of the PI3K/Akt/mTOR pathway can contribute to endocrine resistance in breast cancer. In vitro studies show that estrogen-dependent and HER2+ breast cancer cells are sensitive to the inhibitory effects of everolimus, and that combination treatment with everolimus and Akt, HER2, or aromatase inhibitors enhances the anti-tumor activity of everolimus in a synergistic manner.Two regulators of mTORC1 signaling are the oncogene suppressors tuberin-sclerosis complexes 1 and 2 (TSC1, TSC2). Loss or inactivation of either TSC1 or TSC2 leads to activation of downstream signaling. In TSC, a genetic disorder, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body as well as seizures and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal development and function. Treatment with an mTOR inhibitor in animal models of mTOR dysregulation in the brain resulted in seizure suppression, prevention of the development of new-onset seizures, and prevention of premature death.

12.2     Pharmacodynamics

Exposure-Response RelationshipIn patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration.In patients with TSC-associated partial-onset seizures, the magnitude of the reduction in absolute seizure frequency was correlated with the everolimus trough concentration.Cardiac ElectrophysiologyIn a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval.

12.3     Pharmacokinetics

  • AbsorptionAfter administration of AFINITOR in patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in Cmax is less than dose-proportional; however, AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing.In patients with TSC-associated SEGA, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.Effect of Food: In healthy subjects, a high-fat meal (containing approximately 1000 calories and 55 grams of fat) reduced systemic exposure to AFINITOR 10 mg (as measured by AUC) by 22% and the peak blood concentration Cmax by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and Cmax by 42%.In healthy subjects who received 9 mg of AFINITOR DISPERZ, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and Cmax by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and Cmax by 50%.Relative Bioavailability: The AUCinf of everolimus was equivalent between AFINITOR DISPERZ and AFINITOR; the Cmax of everolimus in the AFINITOR DISPERZ dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady-state were similar after daily administration.DistributionThe blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to the plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.EliminationThe mean elimination half-life of everolimus is approximately 30 hours.
  • Metabolism: Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.
  • Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces.
  • Specific PopulationsNo relationship was apparent between oral clearance and age or sex in patients with cancer.
  • Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.
  • Patients with Hepatic Impairment: Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage and Administration (2.10), Use in Specific Populations (8.6)].
  • Pediatric Patients: In patients with TSC-associated SEGA or TSC-associated partial-onset seizures, the mean Cmin values normalized to mg/m2 dose in pediatric patients (< 18 years of age) were lower than those observed in adults, suggesting that everolimus clearance adjusted to body surface area was higher in pediatric patients as compared to adults.
  • Race or Ethnicity: Based on a cross-study comparison, Japanese patients had on average exposures that were higher than non-Japanese patients receiving the same dose. Oral clearance (CL/F) is on average 20% higher in Black patients than in White patients.Drug Interaction StudiesEffect of CYP3A4 and P-glycoprotein (P-gp) Inhibitors on Everolimus: Everolimus exposure increased when AFINITOR was coadministered with:ketoconazole (a P-gp and strong CYP3A4 inhibitor) - Cmax and AUC increased by 3.9- and 15-fold, respectively.
  • Erythromycin (a P-gp and moderate CYP3A4 inhibitor) - Cmax and AUC increased by 2- and 4.4-fold, respectively.
  • Verapamil (a P-gp and moderate CYP3A4 inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively.
  • Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of AFINITOR with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and Cmax by 58% compared to AFINITOR alone [see Dosage and Administration (2.12)].Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate).The coadministration of an oral dose of midazolam (sensitive CYP3A4 substrate) with AFINITOR resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC0-inf.The coadministration of AFINITOR with 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 reactions related to exemestane was observed in patients with hormone receptor-positive, HER2-negative advanced breast cancer receiving the combination.The coadministration of AFINITOR with long acting octreotide increased octreotide Cmin by approximately 50%.Effect of Everolimus on Antiepileptic drugs (AEDs): Everolimus increased pre-dose concentrations of the carbamazepine, clobazam, oxcarbazepine, and clobazam’s metabolite N-desmethylclobazam by about 10%. Everolimus had no impact on pre-dose concentrations of AEDs that are substrates of CYP3A4 (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin.

13.1     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 human exposure based on area under the curve (AUC) at the recommended dose of AFINITOR 10 mg orally once daily.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 255-fold the recommended dose of AFINITOR 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA and TSC-associated partial-onset seizures, based on the body surface area), administered as 2 doses, 24 hours apart.Based on non-clinical findings, AFINITOR/AFINITOR DISPERZ may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng•hr/mL and 414 ng•hr/mL, respectively) were within the range of human exposure at the recommended dose of AFINITOR 10 mg orally once daily (560 ng•hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC0-24h values 10% to 81% lower than human exposure at the recommended dose of AFINITOR 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%.Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of AFINITOR 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

13.2     Animal Toxicology And/Or Pharmacology

In juvenile rat toxicity studies, dose-related delayed attainment of developmental landmarks including delayed eye-opening, delayed reproductive development in males and females and increased latency time during the learning and memory phases were observed at doses as low as 0.15 mg/kg/day.

14.1     Hormone Receptor-Positive, Her2-Negative Breast Cancer

A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of AFINITOR in combination with exemestane vs. placebo in combination with exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes vs. no). Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease. The major efficacy outcome measure was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment. Other outcome measures included overall survival (OS) and objective response rate (ORR).Patients were randomized 2:1 to AFINITOR 10 mg orally once daily in combination with exemestane 25 mg once daily (n = 485) or to placebo in combination with exemestane 25 mg orally once daily (n = 239). The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. Patients were not permitted to cross over to AFINITOR at the time of disease progression.The trial demonstrated a statistically significant improvement in PFS by investigator assessment (Table 20 and Figure 1). The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy.ORR was higher in the AFINITOR in combination with exemestane arm vs. the placebo in combination with exemestane arm (Table 20). There were 3 complete responses (0.6%) and 58 partial responses (12%) in the AFINITOR arm. There were no complete responses and 4 partial responses (1.7%) in the placebo in combination with exemestane arm.After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the AFINITOR in combination with exemestane arm and the placebo in combination with exemestane arm [HR 0.89 (95% CI: 0.73, 1.10)].Table 20: Efficacy Results in Hormone-Receptor Positive, HER-2 Negative Breast Cancer in BOLERO-2aHazard ratio is obtained from the stratified Cox proportional-hazards model by sensitivity to prior hormonal therapy and presence of visceral metastasisbp-value is obtained from the one-sided log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasiscObjective response rate = proportion of patients with CR or PRdNot applicableAnalysisAFINITORwith Exemestane
N = 485Placebowith Exemestane
N = 239Hazard ratiop-valueMedian progression-free survival (months, 95% CI)Investigator radiological review7.8(6.9, 8.5)3.2(2.8, 4.1)0.45a(0.38, 0.54)< 0.0001bIndependent radiological review11.0(9.7, 15.0)4.1(2.9, 5.6)0.38a(0.3, 0.5)< 0.0001bBest overall response (%, 95% CI)Objective response rate (ORR)c12.6%(9.8, 15.9)1.7%(0.5, 4.2)n/adFigure 1: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in Hormone Receptor-Positive, HER-2 Negative Breast Cancer in BOLERO-2

14.2     Neuroendocrine Tumors (Net)

Pancreatic Neuroendocrine Tumors (PNET)A randomized, double-blind, multi-center trial (RADIANT-3, NCT00510068) of AFINITOR in combination with best supportive care (BSC) compared to placebo in combination with BSC was conducted in patients with locally advanced or metastatic advanced PNET and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes vs. no) and WHO performance status (0 vs. 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC. The major efficacy outcome was PFS evaluated by RECIST. After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR. Other outcome measures included ORR, response duration, and OS.Patients were randomized 1:1 to receive either AFINITOR 10 mg once daily (n = 207) or placebo (n = 203). Demographics were well balanced (median age 58 years, 55% male, 79% White). Of the 203 patients randomized to BSC, 172 patients (85%) received AFINITOR following documented radiologic progression.The trial demonstrated a statistically significant improvement in PFS (Table 21 and Figure 2). PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use. The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 21.Table 21: Progression-Free Survival Results in PNET in RADIANT-3aIncludes adjudication for discrepant assessments between investigator radiological review and central radiological reviewAnalysisNAFINITORN = 207PlaceboN = 203Hazard Ratio (95% CI)p-value410Median progression-free survival (months) (95% CI)Investigator radiological review11.0(8.4, 13.9)4.6(3.1, 5.4)0.35(0.27, 0.45)< 0.001Central radiological review13.7(11.2, 18.8)5.7(5.4, 8.3)0.38(0.28, 0.51)< 0.001Adjudicated radiological reviewa11.4(10.8, 14.8)5.4(4.3, 5.6)0.34(0.26, 0.44)< 0.001Figure 2: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in PNET in RADIANT-3Investigator-determined response rate was 4.8% in the AFINITOR arm and there were no complete responses. OS was not statistically significantly different between arms [HR = 0.94 (95% CI 0.73, 1.20); p = 0.30].NET of Gastrointestinal (GI) or Lung OriginA randomized, double-blind, multicenter study (RADIANT-4, NCT01524783) of AFINITOR in combination with BSC compared to placebo in combination with BSC was conducted in patients with unresectable, locally advanced or metastatic, well differentiated, non-functional NET of GI (excluding pancreatic) or lung origin. The study required that patients had well-differentiated (low or intermediate grade) histology, no prior or current history of carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization. Patients were randomized 2:1 to receive either AFINITOR 10 mg once daily or placebo, and stratified by prior somatostatin analog use (yes vs. no), tumor origin and WHO performance status (0 vs. 1). The major efficacy outcome measure was PFS based on independent radiological assessment evaluated by RECIST. Additional efficacy outcome measures were OS and ORR.A total of 302 patients were randomized, 205 to the AFINITOR arm and 97 to the placebo arm. The median age was 63 years (22 to 86 years); 47% were male; 76% were White; 74% had WHO performance status of 0 and 26% had WHO performance status of 1. The most common primary sites of tumor were lung (30%), ileum (24%), and rectum (13%).The study demonstrated a statistically significant improvement in PFS per independent radiological review (Table 22 and Figure 3). There was no statistically significant difference in OS at the planned interim analysis.Table 22: Progression-Free Survival in NET of GI or Lung Origin in RADIANT-4a Hazard ratio is obtained from the stratified Cox model.b p-value is obtained from the stratified log-rank test.AFINITORN = 205PlaceboN = 97Progression-Free SurvivalNumber of Events113 (55%)65 (67%)Progressive Disease104 (51%)60 (62%)Death9 (4%)5 (5%)Median PFS in months (95% CI)11.0 (9.2, 13.3)3.9 (3.6, 7.4)Hazard Ratio (95% CI)a0.48 (0.35, 0.67)p-valueb< 0.001Overall Response Rate2%1%Figure 3: Kaplan-Meier Curves for Progression-Free Survival in NET of GI or Lung Origin in RADIANT-4Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid TumorsThe safety and effectiveness of AFINITOR in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated. In a randomized (1:1), double-blind, multi-center trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, AFINITOR in combination with long-acting octreotide (Sandostatin LAR®) was compared to placebo in combination with long-acting octreotide. After documented radiological progression, patients on the placebo arm could receive AFINITOR; of those randomized to placebo, 67% received open-label AFINITOR in combination with long-acting octreotide. The study did not meet its major efficacy outcome measure of a statistically significant improvement in PFS and the final analysis of OS favored the placebo in combination with long-acting octreotide arm.

14.3     Renal Cell Carcinoma (Rcc)

An international, multi-center, randomized, double-blind trial (RECORD-1, NCT00410124) comparing AFINITOR 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy. The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on a blinded, independent, central radiologic review. After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR. Other outcome measures included OS.In total, 416 patients were randomized 2:1 to receive AFINITOR (n = 277) or placebo (n = 139). Demographics were well balanced between the arms (median age 61 years; 77% male, 88% White, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).AFINITOR was superior to placebo for PFS (Table 23 and Figure 4). The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final OS results yield a hazard ratio of 0.90 (95% CI: 0.71, 1.14), with no statistically significant difference between the arms. Planned cross-over from placebo due to disease progression to open-label AFINITOR occurred in 80% of the 139 patients and may have confounded the OS benefit.Table 23: Progression-Free Survival and Objective Response Rate by Central Radiologic Review in RCC in RECORD-1 aLog-rank test stratified by prognostic score.bNot applicable.AFINITORN = 277PlaceboN = 139Hazard Ratio(95% CI)p-valueaMedian Progression-free Survival(95% CI)4.9 months(4.0, 5.5)1.9 months(1.8, 1.9)0.33(0.25, 0.43)< 0.0001Objective Response Rate2%0%n/abn/abFigure 4: Kaplan-Meier Curves for Progression-Free Survival in RCC in RECORD-1

14.4     Tuberous Sclerosis Complex (Tsc)-Associated Renal Angiomyolipoma

A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of AFINITOR was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. Patients received AFINITOR 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity. CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2. Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).Of the 118 patients enrolled, 79 were randomized to AFINITOR and 39 to placebo. The median age was 31 years (18 to 61 years), 34% were male, and 89% were White. At baseline, 17% of patients were receiving EIAEDs. On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥ 3 cm in longest diameter, 29% had angiomyolipomas ≥ 8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions. The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm3 (9 to 1612 cm3) and 120 cm3 (3 to 4520 cm3) in the AFINITOR and placebo arms, respectively. Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (0.7 to 24.8 months) at the time of the primary analysis.The renal angiomyolipoma response rate was statistically significantly higher in AFINITOR-treated patients (Table 24). The median response duration was 5.3+ months (2.3+ to 19.6+ months).There were 3 patients in the AFINITOR arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥ 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥ 1 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥ 2 angiomyolipoma-related bleeding). The time to angiomyolipoma progression was statistically significantly longer in the AFINITOR arm (HR 0.08 [95% CI: 0.02, 0.37]; p < 0.0001).Table 24: Angiomyolipoma Response Rate in TSC-Associated Renal Angiomyolipoma in EXIST-2aPer independent central radiology reviewAFINITORPlacebop-valueN = 79N = 39Primary analysis
     
Angiomyolipoma response ratea - %41.80< 0.0001
     
95% CI(30.8, 53.4)(0.0, 9.0)Skin lesion response rates were assessed by local investigators for 77 patients in the AFINITOR arm and 37 patients in the placebo arm who presented with skin lesions at study entry. The skin lesion response rate was statistically significantly higher in the AFINITOR arm (26% vs. 0, p = 0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50% to 99% of all skin lesions durable for at least 8 weeks (Physician's Global Assessment of Clinical Condition). Patients randomized to placebo were permitted to receive AFINITOR at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with AFINITOR underwent additional follow-up CT or MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 112 patients (79 randomized to AFINITOR and 33 randomized to placebo) received at least one dose of AFINITOR. The median duration of AFINITOR treatment was 3.9 years (0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (0.9 months to 5.4 years). During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review. Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (2.6 to 33.8 months). Fourteen percent of the 112 patients treated with AFINITOR had angiomyolipoma progression by the end of the follow-up period. No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with AFINITOR.

14.5     Tuberous Sclerosis Complex (Tsc)-Associated Subependymal Giant Cell Astrocytoma (Sega)

EXIST-1A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of AFINITOR was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received AFINITOR at a starting dose of 4.5 mg/m2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. AFINITOR or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter.The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years, and 16 patients were ≥ 18 years; 57% were male, and 93% were White. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm3 (0.18 to 25.15 cm3) and 1.30 cm3 (0.32 to 9.75 cm3) in the AFINITOR and placebo arms respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis.The SEGA response rate was statistically significantly higher in AFINITOR-treated patients (Table 25). At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months).With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive AFINITOR. No patient in either treatment arm required surgical intervention.Table 25: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1aPer independent central radiology reviewAFINITORPlacebop-valueN = 78N = 39Primary analysis
     
SEGA response ratea - (%)350< 0.0001
     
95% CI24, 460, 9Patients randomized to placebo were permitted to receive AFINITOR at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with AFINITOR underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 111 patients (78 patients randomized to AFINITOR and 33 patients randomized to placebo) received at least one dose of AFINITOR. Median duration of AFINITOR treatment and follow-up was 3.9 years (0.2 to 4.9 years). By four years after the last patient was enrolled, 58% of the 111 patients treated with AFINITOR had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis. The median time to SEGA response was 5.3 months (2.5 to 33.1 months). Twelve percent of the 111 patients treated with AFINITOR had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study.Study 2485Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of AFINITOR 3 mg/m2/orally once daily in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier. The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review. Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study.A total of 28 patients received AFINITOR for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on AFINITOR for at least 5 years. The median age was 11 years (3 to 34 years), 61% male, 86% White.At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion. At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years).By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression. No patient developed a new SEGA lesion while on AFINITOR. Nine additional patients were identified as having a > 50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating AFINITOR including 3 patients who had surgical resection with subsequent regrowth prior to receiving AFINITOR.

14.6     Tuberous Sclerosis Complex (Tsc)-Associated Partial-Onset Seizures

The efficacy of AFINITOR DISPERZ as an adjunctive anti-epileptic drug (AED) was evaluated in a randomized, double-blind, multicenter, placebo-controlled study conducted in patients with TSC-associated partial-onset seizures (EXIST-3, NCT01713946). Patients with a history of inadequate control of partial-onset seizures despite treatment with ≥ 2 sequential AED regimens were randomized to receive placebo or AFINITOR DISPERZ once daily at a dose to achieve a low trough (LT) level (3-7 ng/mL) or a high trough (HT) level (9-15 ng/mL). Randomization was stratified by age group (1 to < 6, 6 to < 12, 12 to < 18, ≥ 18 years). The study consisted of 3 phases: an 8-week Baseline observation phase; an 18-week double-blind, placebo-controlled Core phase (6-week titration period and a 12-week maintenance period), and an Extension phase of ≥ 48 weeks. Patients were required to have a diagnosis of TSC per the modified Gomez criteria, and ≥ 16 partial-onset seizures during the Baseline phase while receiving a stable dose of 1 to 3 concomitant AEDs. The starting doses for AFINITOR DISPERZ in the Core phase ranged from 3 to 6 mg/m2 orally once daily, depending on age, in patients not receiving concomitant CYP3A4/P-gp inducers and from 5 to 9 mg/m2 orally once daily, depending on age, in patients receiving concomitant CYP3A4/P-gp inducers. During the 6-week titration period, everolimus trough levels were assessed every 2 weeks and up to 3 dose adjustments were allowed to attempt to reach the targeted everolimus trough concentration range.The major efficacy outcome measure was the percentage reduction in seizure frequency from the Baseline phase, during the maintenance period of the Core phase. Additional efficacy outcome measures included response rate, defined as at least a 50% reduction in seizure frequency from the Baseline phase during the maintenance period of the Core phase, and seizure freedom rate during the maintenance period of the Core phase. A total of 366 patients were randomized to AFINITOR DISPERZ LT (n = 117), AFINITOR DISPERZ HT (n = 130) or placebo (n = 119). Median age was 10.1 years (2.2 to 56 years); 28% of patients were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years). The majority were White (65%) and male (52%). The most common major features of TSC were cortical tubers (92%), hypomelanotic macules (84%), and subependymal nodules (83%). While 17% of the patients had SEGA, 42% had renal angiomyolipoma, and 9% had both SEGA and renal angiomyolipoma; no patients were receiving treatment with AFINITOR or AFINITOR DISPERZ for these manifestations of TSC. During the Baseline phase, 65% of patients had complex partial seizures, 52% had secondarily generalized seizures, 19% had simple partial seizures, and 2% had generalized onset seizures. The median seizure frequency per week during the Baseline phase was 9.4 for all patients and 47% of patients were receiving 3 AEDs during the Baseline phase. The efficacy results are summarized in Table 26.Table 26: Percentage Reduction in Seizure Frequency and Response Rate in TSC-Associated Partial-Onset Seizures in EXIST-3aIf patient discontinued before starting the Maintenance period, then the Titration period is usedb95% CI of the median based on bootstrap percentilescp-values were for superiority vs. placebo, and obtained from rank ANCOVA with Baseline seizure frequency as covariate, stratified by age subgroupdExact 95% CI obtained using Clopper-Pearson method
AFINITOR DISPERZPlaceboTarget of3-7 ng/mLN = 117Target of9-15 ng/mLN = 130N = 119Seizures per week
     
Median at Baseline (Min, Max)
8.6 (1.4, 192.9)9.5 (0.3, 218.4)10.5 (1.3, 231.7)
     
Median at Core phasea (Min, Max)6.8 (0.0, 193.5)4.9 (0.0, 133.7)8.5 (0.0, 217.7)Percentage reduction from Baseline to Core phase (Maintenance a)
     
Median
29.339.614.9
     
95% CIb18.8, 41.935.0, 48.70.1, 21.7
     
p-valuec0.003< 0.001 Response rate
     
Responders, n (%)
28.24015.1
     
95% CId20.3, 37.331.5, 49.09.2, 22.8

15     References

  • OSHA Hazardous Drugs. OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

16     How Supplied/Storage And Handling

AFINITOR2.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “LCL” on one side and “NVR” on the other; available in:Blisters of 28 tablets………………………………………………………………………………NDC 0078-0594-51Each carton contains 4 blister cards of 7 tablets each5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the other; available in:Blisters of 28 tablets………………………………………………………………………………NDC 0078-0566-51Each carton contains 4 blister cards of 7 tablets each7.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5” on one side and “NVR” on the other; available in:Blisters of 28 tablets………………………………………………………………………………NDC 0078-0620-51Each carton contains 4 blister cards of 7 tablets each10 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “UHE” on one side and “NVR” on the other; available in:Blisters of 28 tablets………………………………………………………………………………NDC 0078-0567-51Each carton contains 4 blister cards of 7 tablets eachAFINITOR DISPERZ2 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D2” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0626-51Each carton contains 4 blister cards of 7 tablets each3 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D3” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0627-51Each carton contains 4 blister cards of 7 tablets each5 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D5” on one side and “NVR” on the other; available in: Blisters of 28 tablets………………………………………………………………………………NDC 0078-0628-51Each carton contains 4 blister cards of 7 tablets eachStore at 25°C (77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). See USP Controlled Room Temperature.Store in the original container, protect from light and moisture.
Follow special handling and disposal procedures for anticancer pharmaceuticals.1

17     Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Non-infectious PneumonitisAdvise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.1)].InfectionsAdvise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions (5.2)].Hypersensitivity ReactionsAdvise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.3)].Angioedema with Concomitant Use of Angiotensin-Converting Enzyme (ACE) InhibitorsAdvise patients to avoid angiotensin-converting enzyme (ACE) inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions (5.4)].StomatitisAdvise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions (5.5)].Renal ImpairmentAdvise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions (5.6)].Impaired Wound HealingAdvise patients of the risk of impaired wound healing or dehiscence during treatment [see Warnings and Precautions (5.7)].Geriatric PatientsInform patients that in a study conducted in patients with breast cancer, the incidence of deaths and adverse reactions leading to permanent discontinuation was higher in patients ≥ 65 years compared to patients < 65 years [see Warnings and Precautions (5.8), Use in Specific Populations (8.5)].Metabolic DisordersAdvise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions (5.9)].MyelosuppressionAdvise patients of the risk of myelosuppression and the need to monitor complete blood counts periodically during therapy [see Warnings and Precautions (5.10)].Risk of Infection or Reduced Immune Response with VaccinationAdvise patients to avoid the use of live vaccines and close contact with those who have received live vaccines [see Warnings and Precautions (5.11)].Embryo-Fetal ToxicityAdvise females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 8 weeks after the last dose. Advise patients to inform their healthcare provider of a known or suspected pregnancy. Advise males with female partners of reproductive potential to use effective contraception during treatment and for 4 weeks after the last dose [see Warnings and Precautions (5.12) and Use in Specific Populations (8.1, 8.3)].LactationAdvise women not to breastfeed during treatment with AFINITOR/AFINITOR DISPERZ and for 2 weeks after the last dose [see Use in Specific Populations (8.2)].InfertilityAdvise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)].Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936T2018-50

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