Afinitor

AFINITOR is a kinase inhibitor 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. (
  1.1     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.
  )
  
  
• Adults with progressive neuroendocrine tumors of pancreatic origin (PNET) and adults with progressive, well-differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin that are unresectable, locally advanced or metastatic.
  
  
  Limitations of Use:
  AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors. (
  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.

  Limitations of Use:

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

  [see Clinical Studies (14.2)]

  .
  )
  
  
• Adults with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. (
  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.
  )
  
  
• Adults with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. (
  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.
  )
  
  

AFINITOR and AFINITOR DISPERZ are kinase inhibitors indicated for the treatment of adult and pediatric patients aged 1 year and older with TSC who have subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected. (

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

Tablets, 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.

Tablets 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.

• For breast cancer, NET, RCC, or TSC-associated renal angiomyolipoma patients with hepatic impairment, reduce the dose. (
  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 Impairment

  Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.
  Indication	Dose 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/m2orally once daily. Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)] .
  ,
  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 class 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)]

  .
  )
  
  
• For patients with TSC-associated SEGA or TSC-associated partial-onset seizures and severe hepatic impairment, reduce the starting dose and adjust dose to attain target trough concentrations. (
  2.8     Therapeutic Drug Monitoring (TDM) 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 TDM throughout treatment.

  Table 1: Recommended Timing of Therapeutic Drug Monitoring

  Abbreviation: P-gp, P-glycoprotein.
  Event	When to Assess Trough Concentrations After Event
  Initiation of AFINITOR/AFINITOR DISPERZ	1 to 2 weeks
  Modification of AFINITOR/AFINITOR DISPERZ dose	1 to 2 weeks
  Switch between AFINITOR and AFINITOR DISPERZ	1 to 2 weeks
  Initiation or discontinuation of P-gp and moderate CYP3A4 inhibitor	2 weeks
  Initiation or discontinuation of P-gp and strong CYP3A4 inducer	2 weeks
  Change in hepatic function	2 weeks
  Stable dose with changing body surface area (BSA)	Every 3 to 6 months
  Stable dose with stable BSA	Every 6 to 12 months
  ,
  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 Impairment

  Abbreviations: NET, Neuroendocrine Tumors; RCC, Renal Cell Carcinoma; SEGA, Subependymal Giant Cell Astrocytoma; TSC, Tuberous Sclerosis Complex.
  Indication	Dose 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/m2orally once daily. Adjust dose based on everolimus trough concentrations as recommended [see Dosage and Administration (2.8)] .
  ,
  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 class 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)]

  .
  )

• Non-Infectious Pneumonitis: Monitor for clinical symptoms or radiological changes. Withhold or permanently discontinue based on severity. (
  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 Reactions

  Adverse Reaction	Severity	Dosage Modification
  Non-infectious pneumonitis [see Warnings and Precautions (5.1)]	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. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.
  	Grade 3	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. If toxicity recurs at Grade 3, permanently discontinue.
  	Grade 4	Permanently discontinue.
  Stomatitis [see Warnings and Precautions (5.5)]	Grade 2	Withhold 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 3	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 4	Permanently discontinue.
  Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)]	Grade 3	Withhold 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 4	Permanently discontinue.
  Other non-hematologic toxicities	Grade 2	If 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 3	Withhold 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 4	Permanently discontinue.
  Thrombocytopenia [see Warnings and Precautions (5.10)]	Grade 2	Withhold until improvement to Grade 0 or 1. Resume at same dose.
  	Grade 3 OR Grade 4	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.
  Neutropenia [see Warnings and Precautions (5.10)]	Grade 3	Withhold until improvement to Grade 0, 1, or 2. Resume at same dose.
  	Grade 4	Withhold 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 3	Withhold 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 4	Permanently discontinue.
  ,
  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.
  )
  
  
• Infections: Monitor for signs and symptoms of infection. Withhold or permanently discontinue based on severity. (
  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 Reactions

  Adverse Reaction	Severity	Dosage Modification
  Non-infectious pneumonitis [see Warnings and Precautions (5.1)]	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. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.
  	Grade 3	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. If toxicity recurs at Grade 3, permanently discontinue.
  	Grade 4	Permanently discontinue.
  Stomatitis [see Warnings and Precautions (5.5)]	Grade 2	Withhold 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 3	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 4	Permanently discontinue.
  Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)]	Grade 3	Withhold 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 4	Permanently discontinue.
  Other non-hematologic toxicities	Grade 2	If 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 3	Withhold 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 4	Permanently discontinue.
  Thrombocytopenia [see Warnings and Precautions (5.10)]	Grade 2	Withhold until improvement to Grade 0 or 1. Resume at same dose.
  	Grade 3 OR Grade 4	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.
  Neutropenia [see Warnings and Precautions (5.10)]	Grade 3	Withhold until improvement to Grade 0, 1, or 2. Resume at same dose.
  	Grade 4	Withhold 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 3	Withhold 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 4	Permanently discontinue.
  ,
  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.
  )
  
  
• Severe Hypersensitivity Reactions: Permanently discontinue for clinically significant hypersensitivity. (
  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.
  )
  
  
• Angioedema: Patients taking concomitant angiotensin-converting-enzyme (ACE) inhibitors may be at increased risk for angioedema. Permanently discontinue for angioedema. (
  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.
  ,
  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)]

  .
  )
  
  
• Stomatitis: Initiate dexamethasone alcohol-free mouthwash when starting treatment. (
  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.
  ,
  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 Cancer

  The 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 vs. 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-2

  Grading according to NCI CTCAE Version 3.0. aIncludes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. bIncludes 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 fibrosis. dNo Grade 4 adverse reactions were reported.
  	AFINITOR with Exemestane N = 482		Placebo with Exemestane N = 238
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Gastrointestinal
  Stomatitisa	67	8d	11	0.8
  Diarrhea	33	2	18	0.8
  Nausea	29	0.4	28	1
  Vomiting	17	1	12	0.8
  Constipation	14	0.4d	13	0.4
  Dry mouth	11	0	7	0
  General
  Fatigue	36	4	27	1d
  Edema peripheral	19	1d	6	0.4d
  Pyrexia	15	0.2d	7	0.4d
  Asthenia	13	2	4	0
  Infections
  Infectionsb	50	6	25	2d
  Investigations
  Weight loss	25	1d	6	0
  Metabolism and nutrition
  Decreased appetite	30	1d	12	0.4d
  Hyperglycemia	14	5	2	0.4d
  Musculoskeletal and connective tissue
  Arthralgia	20	0.8d	17	0
  Back pain	14	0.2d	10	0.8d
  Pain in extremity	9	0.4d	11	2d
  Nervous system
  Dysgeusia	22	0.2d	6	0
  Headache	21	0.4d	14	0
  Psychiatric
  Insomnia	13	0.2d	8	0
  Respiratory, thoracic and mediastinal
  Cough	24	0.6d	12	0
  Dyspnea	21	4	11	1
  Epistaxis	17	0	1	0
  Pneumonitisc	19	4	0.4	0
  Skin and subcutaneous tissue
  Rash	39	1d	6	0
  Pruritus	13	0.2d	5	0
  Alopecia	10	0	5	0
  Vascular
  Hot flush	6	0	14	0

  Table 7: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With Hormone Receptor-Positive Breast Cancer in BOLERO-2

  Grading 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 Parameter	AFINITOR with Exemestane N = 482		Placebo with Exemestane N = 238
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Hematologya
  Anemia	68	6	40	1
  Leukopenia	58	2b	28	6
  Thrombocytopenia	54	3	5	0.4
  Lymphopenia	54	12	37	6
  Neutropenia	31	2b	11	2
  Chemistry
  Hypercholesterolemia	70	1	38	2
  Hyperglycemia	69	9	44	1
  Increased AST	69	4	45	3
  Increased ALT	51	4	29	5b
  Hypertriglyceridemia	50	0.8b	26	0
  Hypoalbuminemia	33	0.8b	16	0.8b
  Hypokalemia	29	4	7	1b
  Increased creatinine	24	2	13	0

  Topical Prophylaxis for Stomatitis

  In 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/5 mL 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-3

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

  Table 9: Selected Laboratory Abnormalities Reported in ≥ 10% of Patients With PNET in RADIANT-3

  Grading according to NCI CTCAE Version 3.0.
  Laboratory parameter	AFINITOR N = 204		Placebo N = 203
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Hematology
  Anemia	86	15	63	1
  Lymphopenia	45	16	22	4
  Thrombocytopenia	45	3	11	0
  Leukopenia	43	2	13	0
  Neutropenia	30	4	17	2
  Chemistry
  Hyperglycemia (fasting)	75	17	53	6
  Increased alkaline phosphatase	74	8	66	8
  Hypercholesterolemia	66	0.5	22	0
  Bicarbonate decreased	56	0	40	0
  Increased AST	56	4	41	4
  Increased ALT	48	2	35	2
  Hypophosphatemia	40	10	14	3
  Hypertriglyceridemia	39	0	10	0
  Hypocalcemia	37	0.5	12	0
  Hypokalemia	23	4	5	0
  Increased creatinine	19	2	14	0
  Hyponatremia	16	1	16	1
  Hypoalbuminemia	13	1	8	0
  Hyperbilirubinemia	10	1	14	2
  Hyperkalemia	7	0	10	0.5

  Neuroendocrine Tumors (NET) of Gastrointestinal (GI) or Lung Origin

  In 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-4

  Grading according to NCI CTCAE Version 4.03. aIncludes 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.
  	AFINITOR N = 202		Placebo N = 98
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Gastrointestinal
  Stomatitisa	63	9d	22	0
  Diarrhea	41	9	31	2d
  Nausea	26	3	17	1d
  Vomiting	15	4d	12	2d
  General
  Peripheral edema	39	3d	6	1d
  Fatigue	37	5	36	1d
  Asthenia	23	3	8	0
  Pyrexia	23	2	8	0
  Infections
  Infectionsb	58	11	29	2
  Investigations
  Weight loss	22	2d	11	1d
  Metabolism and nutrition
  Decreased appetite	22	1d	17	1d
  Nervous system
  Dysgeusia	18	1d	4	0
  Respiratory, thoracic and mediastinal
  Cough	27	0	20	0
  Dyspnea	20	3d	11	2
  Pneumonitisc	16	2d	2	0
  Epistaxis	13	1d	3	0
  Skin and subcutaneous
  Rash	30	1d	9	0
  Pruritus	17	1d	9	0

  Table 11: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4

  Grading according to NCI CTCAE Version 4.03. aNo Grade 4 laboratory abnormalities were reported.
  	AFINITOR N = 202		Placebo N = 98
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Hematology
  Anemia	81	5a	41	2a
  Lymphopenia	66	16	32	2a
  Leukopenia	49	2a	17	0
  Thrombocytopenia	33	2	11	0
  Neutropenia	32	2a	15	3a
  Chemistry
  Hypercholesterolemia	71	0	37	0
  Increased AST	57	2	34	2a
  Hyperglycemia (fasting)	55	6a	36	1a
  Increased ALT	46	5	39	1a
  Hypophosphatemia	43	4a	15	2a
  Hypertriglyceridemia	30	3	8	1a
  Hypokalemia	27	6	12	3a
  Hypoalbuminemia	18	0	8	0

  Renal 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 vs. 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-1

  Grading according to NCI CTCAE Version 3.0. aStomatitis (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.
  	AFINITOR N = 274		Placebo N = 137
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Gastrointestinal
  Stomatitisa	44	4	8	0
  Diarrhea	30	2d	7	0
  Nausea	26	2d	19	0
  Vomiting	20	2d	12	0
  Infectionsb	37	10	18	2
  General
  Asthenia	33	4	23	4
  Fatigue	31	6d	27	4
  Edema peripheral	25	< 1d	8	< 1d
  Pyrexia	20	< 1d	9	0
  Mucosal inflammation	19	2d	1	0
  Respiratory, thoracic and mediastinal
  Cough	30	< 1d	16	0
  Dyspnea	24	8	15	3d
  Epistaxis	18	0	0	0
  Pneumonitisc	14	4d	0	0
  Skin and subcutaneous tissue
  Rash	29	1d	7	0
  Pruritus	14	< 1d	7	0
  Dry skin	13	< 1d	5	0
  Metabolism and nutrition
  Anorexia	25	2d	14	< 1d
  Nervous system
  Headache	19	1	9	< 1d
  Dysgeusia	10	0	2	0
  Musculoskeletal and connective tissue
  Pain in extremity	10	1d	7	0

  Other 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-1

  Grading 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 parameter	AFINITOR N = 274		Placebo N = 137
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Hematologya
  Anemia	92	13	79	6
  Lymphopenia	51	18	28	5b
  Thrombocytopenia	23	1b	2	< 1
  Neutropenia	14	< 1	4	0
  Chemistry
  Hypercholesterolemia	77	4b	35	0
  Hypertriglyceridemia	73	< 1b	34	0
  Hyperglycemia	57	16	25	2b
  Increased creatinine	50	2b	34	0
  Hypophosphatemia	37	6b	8	0
  Increased AST	25	1	7	0
  Increased ALT	21	1b	4	0
  Hyperbilirubinemia	3	1	2	0

  Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma

  The 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-2

  Grading according to NCI CTCAE Version 3.0. aIncludes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. bNo Grade 4 adverse reactions were reported.
  	AFINITOR N = 79		Placebo N = 39
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Gastrointestinal
  Stomatitisa	78	6b	23	0
  Vomiting	15	0	5	0
  Diarrhea	14	0	5	0
  General
  Peripheral edema	13	0	8	0
  Infections
  Upper respiratory tract infection	11	0	5	0
  Musculoskeletal and connective tissue
  Arthralgia	13	0	5	0
  Respiratory, thoracic and mediastinal
  Cough	20	0	13	0
  Skin and subcutaneous tissue
  Acne	22	0	5	0

  Amenorrhea 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-2

  Grading according to NCI CTCAE Version 3.0. aNo Grade 4 laboratory abnormalities were reported.
  	AFINITOR N = 79		Placebo N = 39
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Hematology
  Anemia	61	0	49	0
  Leukopenia	37	0	21	0
  Neutropenia	25	1	26	0
  Lymphopenia	20	1a	8	0
  Thrombocytopenia	19	0	3	0
  Chemistry
  Hypercholesterolemia	85	1a	46	0
  Hypertriglyceridemia	52	0	10	0
  Hypophosphatemia	49	5a	15	0
  Increased alkaline phosphatase	32	1a	10	0
  Increased AST	23	1a	8	0
  Increased ALT	20	1a	15	0
  Hyperglycemia (fasting)	14	0	8	0

  Updated 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-1

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

  Amenorrhea 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-1

  Grading according to NCI CTCAE Version 3.0. aNo Grade 4 laboratory abnormalities were reported.
  	AFINITOR N = 78		Placebo N = 39
  	All Grades	Grade 3-4	All Grades	Grade 3-4
  	%	%	%	%
  Hematology
  Elevated partial thromboplastin time	72	3a	44	5a
  Neutropenia	46	9a	41	3a
  Anemia	41	0	21	0
  Chemistry
  Hypercholesterolemia	81	0	39	0
  Elevated AST	33	0	0	0
  Hypertriglyceridemia	27	0	15	0
  Elevated ALT	18	0	3	0
  Hypophosphatemia	9	1a	3	0

  Updated 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 Seizures

  The 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-3

  Grading according to NCI CTCAE Version 4.03. aIncludes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain. bNo Grade 4 adverse reactions were reported.
  	AFINITOR DISPERZ				Placebo
  	Target of 3-7 ng/mL N = 117		Target of 9-15 ng/mL N = 130		N = 119
  	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
  Gastrointestinal
  Stomatitisa	55	3b	64	4b	9	0
  Diarrhea	17	0	22	0	5	0
  Vomiting	12	0	10	2b	9	0
  Infections
  Nasopharyngitis	14	0	16	0	16	0
  Upper respiratory tract infection	13	0	15	0	13	0.8b
  General
  Pyrexia	20	0	14	0.8b	5	0
  Respiratory, thoracic and mediastinal
  Cough	11	0	10	0	3	0
  Skin and subcutaneous tissue
  Rash	6	0	10	0	3	0

  The 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 Seizures

  Grading according to NCI CTCAE version 4.03. aNo Grade 4 laboratory abnormalities were reported.
  	AFINITOR DISPERZ				Placebo
  	Target of 3-7 ng/mL N = 117		Target of 9-15 ng/mL N = 130		N = 119
  	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %	All Grades %	Grade 3-4 %
  Hematology
  Neutropenia	25	4a	37	6	23	7a
  Anemia	27	0.9a	30	0	21	0.8a
  Thrombocytopenia	12	0	15	0	6	0
  Chemistry
  Hypercholesterolemia	86	0	85	0.8a	58	0
  Hypertriglyceridemia	43	2a	39	2	22	0
  Increased ALT	17	0	22	0	6	0
  Increased AST	13	0	19	0	4	0
  Hyperglycemia	19	0	18	0	17	0
  Increased alkaline phosphatase	24	0	16	0	29	0
  Hypophosphatemia	9	0.9a	16	2	3	0

  Updated 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%).
  )
  
  
• Renal Failure: Monitor renal function prior to treatment and periodically thereafter. (
  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.
  )
  
  
• Risk of Impaired Wound Healing: Withhold for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment after resolution of wound healing complications has not been established. (
  5.7     Risk of Impaired Wound Healing

  Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, AFINITOR/AFINITOR DISPERZ have the potential to adversely affect wound healing.

  Withhold AFINITOR/AFINITOR DISPERZ for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of treatment upon resolution of wound healing complications has not been established.
  )
  
  
• Geriatric Patients: Monitor and adjust dose for adverse reactions. (
  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)]

  .
  )
  
  
• Metabolic Disorders: Monitor serum glucose and lipids prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (
  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 Reactions

  Adverse Reaction	Severity	Dosage Modification
  Non-infectious pneumonitis [see Warnings and Precautions (5.1)]	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. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.
  	Grade 3	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. If toxicity recurs at Grade 3, permanently discontinue.
  	Grade 4	Permanently discontinue.
  Stomatitis [see Warnings and Precautions (5.5)]	Grade 2	Withhold 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 3	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 4	Permanently discontinue.
  Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)]	Grade 3	Withhold 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 4	Permanently discontinue.
  Other non-hematologic toxicities	Grade 2	If 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 3	Withhold 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 4	Permanently discontinue.
  Thrombocytopenia [see Warnings and Precautions (5.10)]	Grade 2	Withhold until improvement to Grade 0 or 1. Resume at same dose.
  	Grade 3 OR Grade 4	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.
  Neutropenia [see Warnings and Precautions (5.10)]	Grade 3	Withhold until improvement to Grade 0, 1, or 2. Resume at same dose.
  	Grade 4	Withhold 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 3	Withhold 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 4	Permanently discontinue.
  ,
  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)]

  .
  )
  
  
• Myelosuppression: Monitor hematologic parameters prior to treatment and periodically thereafter. Withhold or permanently discontinue based on severity. (
  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 Reactions

  Adverse Reaction	Severity	Dosage Modification
  Non-infectious pneumonitis [see Warnings and Precautions (5.1)]	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. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks.
  	Grade 3	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. If toxicity recurs at Grade 3, permanently discontinue.
  	Grade 4	Permanently discontinue.
  Stomatitis [see Warnings and Precautions (5.5)]	Grade 2	Withhold 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 3	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 4	Permanently discontinue.
  Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)]	Grade 3	Withhold 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 4	Permanently discontinue.
  Other non-hematologic toxicities	Grade 2	If 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 3	Withhold 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 4	Permanently discontinue.
  Thrombocytopenia [see Warnings and Precautions (5.10)]	Grade 2	Withhold until improvement to Grade 0 or 1. Resume at same dose.
  	Grade 3 OR Grade 4	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.
  Neutropenia [see Warnings and Precautions (5.10)]	Grade 3	Withhold until improvement to Grade 0, 1, or 2. Resume at same dose.
  	Grade 4	Withhold 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 3	Withhold 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 4	Permanently discontinue.
  ,
  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 (CBC) 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)]

  .
  )
  
  
• Risk of Infection or Reduced Immune Response with Vaccination: Avoid live vaccines and close contact with those who have received live vaccines. Complete recommended childhood vaccinations prior to starting treatment. (
  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.
  )
  
• Radiation Sensitization and Radiation Recall: Severe radiation reactions may occur. (
  5.12     Radiation Sensitization and Radiation Recall

  Radiation sensitization and recall, in some cases severe, involving cutaneous and visceral organs (including radiation esophagitis and pneumonitis) have been reported in patients treated with radiation prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment

  [see Adverse Reactions (6.2)]

  .

  Monitor patients closely when AFINITOR/AFINITOR DISPERZ is administered during or sequentially with radiation treatment.
  ,
  6.2     Postmarketing Experience

  The following adverse reactions have been identified during postapproval 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:

  • Blood and lymphatic disorders:
    Thrombotic microangiopathy
  • Cardiac:
    Cardiac failure with some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event
  • Gastrointestinal:
    Acute pancreatitis
  • Hepatobiliary:
    Cholecystitis and cholelithiasis
  • Infections:
    Sepsis and septic shock
  • Nervous system:
    Reflex sympathetic dystrophy
  • Vascular:
    Arterial thrombotic events, lymphedema
  • Injury, poisoning and procedural complications:
    Radiation Sensitization and Radiation Recall
  )
  
• Embryo-Fetal Toxicity: Can cause fetal harm. Advise patients of reproductive potential of the potential risk to a fetus and to use effective contraception. (
  5.13     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)]

  .
  ,
  8.1     Pregnancy

  Risk Summary

  Based 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.

  Data

  Animal Data

  In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m²) with resulting exposures of approximately 4% of the 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 BSA. 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.
  ,
  8.3     Females and Males of Reproductive Potential

  Pregnancy Testing

  Verify the pregnancy status of females of reproductive potential prior to starting AFINITOR/AFINITOR DISPERZ

  [see Use in Specific Populations (8.1)]

  .

  Contraception

  AFINITOR/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.

  Infertility

  Females:

  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)]

  .
  )