RECENT MAJOR CHANGES SECTION

RECENT MAJOR CHANGES

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CLINICAL PHARMACOLOGY SECTION

12 CLINICAL PHARMACOLOGY

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 Relationship

In 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 Electrophysiology

In 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

Absorption

After 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.

Distribution

The 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.

Elimination

The 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 Populations

No 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 BSA 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 Studies

Effect 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.

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DOSAGE FORMS & STRENGTHS SECTION

Highlight: * AFINITOR: 2.5 mg, 5 mg, 7.5 mg, and 10 mg tablets (3)

• AFINITOR DISPERZ: 2 mg, 3 mg, and 5 mg tablets (3)

3 DOSAGE FORMS AND STRENGTHS

AFINITOR

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.

AFINITOR DISPERZ

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.

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CONTRAINDICATIONS SECTION

Highlight: Clinically significant hypersensitivity to everolimus or to other rapamycin derivatives. (4)

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)].

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USE IN SPECIFIC POPULATIONS SECTION

Highlight: * For breast cancer, NET, RCC, or TSC-associated renal angiomyolipoma patients with hepatic impairment, reduce the dose. (2.10, 8.6)

• 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, 2.10, 8.6)

8 USE IN SPECIFIC POPULATIONS

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.

8.2 Lactation

Risk Summary

There 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 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)].

8.4 Pediatric Use

TSC-Associated SEGA

The 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 Seizures

The 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 Indications

The safety and effectiveness of AFINITOR/AFINITOR DISPERZ in pediatric patients have not been established in:

• Hormone receptor-positive, HER2-negative breast cancer
• Neuroendocrine 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 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)].

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ADVERSE REACTIONS SECTION

Highlight: * Breast cancer, NET, RCC: Most common adverse reactions (incidence ≥ 30%) include stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, and decreased appetite. (6.1)

• TSC-Associated Renal Angiomyolipoma: Most common adverse reaction (incidence ≥ 30%) is stomatitis. (6.1)
• TSC-Associated SEGA: Most common adverse reactions (incidence ≥ 30%) are stomatitis and respiratory tract infection. (6.1)
• TSC-Associated Partial-Onset Seizures: Most common adverse reaction (incidence ≥ 30%) is stomatitis. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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)]
• Radiation Sensitization and Radiation Recall [see Warnings and Precautions (5.12)]

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

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

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

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

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

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

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

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

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

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

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

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%).

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

CLINICAL STUDIES SECTION

14 CLINICAL STUDIES

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-2

Figure 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, multicenter 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-3

Figure 2: Kaplan-Meier Curves for Progression-Free Survival by Investigator Radiological Review in PNET in RADIANT-3

Investigator-determined response rate was 4.8% in the AFINITOR arm and there were no complete responses. Overall Survival (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 Origin

A 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). The final OS analysis did not show a statistically significant difference between those patients who received AFINITOR or placebo (HR = 0.90 [95% CI: 0.66, 1.24]).

Table 22: Progression-Free Survival in Neuroendocrine Tumors of Gastrointestinal or Lung Origin in RADIANT-4

Figure 3: Kaplan-Meier Curves for Progression-Free Survival in NET of GI or Lung Origin in RADIANT-4

Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors

The 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, multicenter 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, multicenter, 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

Figure 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-2

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-1

A 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-1

Patients 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 2485

Study 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-3

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INFORMATION FOR PATIENTS SECTION

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Non-infectious Pneumonitis

Advise 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)].

Infections

Advise 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 Reactions

Advise 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 ACE Inhibitors

Advise patients to avoid 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)].

Stomatitis

Advise patients of the risk of stomatitis and to use alcohol-free mouthwashes during treatment [see Warnings and Precautions (5.5)].

Renal Impairment

Advise 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)].

Risk of Impaired Wound Healing

Advise patients that AFINITOR/AFINITOR DISPERZ may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.7)].

Geriatric Patients

Inform 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 Disorders

Advise patients of the risk of metabolic disorders and the need to monitor glucose and lipids periodically during therapy [see Warnings and Precautions (5.9)].

Myelosuppression

Advise patients of the risk of myelosuppression and the need to monitor CBCs periodically during therapy [see Warnings and Precautions (5.10)].

Risk of Infection or Reduced Immune Response with Vaccination

Advise 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 Toxicity

Advise 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 (5.13), Use in Specific Populations (8.1, 8.3)].

Radiation Sensitization and Radiation Recall

Radiation sensitization and recall can occur in patients treated with radiation prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment. Advise patients to inform their healthcare provider if they have had or are planning to receive radiation therapy [see Warnings and Precautions (5.12)].

Lactation

Advise 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)].

Infertility

Advise males and females of reproductive potential of the potential risk for impaired fertility [see Use in Specific Populations (8.3)].

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

T2022-07

SPL PATIENT PACKAGE INSERT SECTION

T2022-08

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HOW SUPPLIED SECTION

16 HOW SUPPLIED/STORAGE AND HANDLING

AFINITOR

2.5 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 0078-0594-51

Each carton contains 4 blister cards of 7 tablets each

5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “5” on one side and “NVR” on the other; available in:

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0566-51

Each carton contains 4 blister cards of 7 tablets each

7.5 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “7P5” on one side and “NVR” on the other; available in:

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0620-51

Each carton contains 4 blister cards of 7 tablets each

10 mg tablets: White to slightly yellow, elongated tablets with a bevelled edge and engraved with “UHE” on one side and “NVR” on the other; available in:

Blisters of 28 tablets………………………………………………………………………………NDC 0078-0567-51

Each carton contains 4 blister cards of 7 tablets each

AFINITOR DISPERZ

2 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 0078-0626-51

Each carton contains 4 blister cards of 7 tablets each

3 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D3” on one side and “NVR” on the other; available in:

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

Each carton contains 4 blister cards of 7 tablets each

5 mg tablets for oral suspension: White to slightly yellowish, round, flat tablets with a bevelled edge and engraved with “D5” on one side and “NVR” on the other; available in:

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

Each carton contains 4 blister cards of 7 tablets each

Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F). See USP Controlled Room Temperature.

Store in the original container, protect from light and moisture.

Follow special handling and disposal procedures for anti-cancer pharmaceuticals.1

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INSTRUCTIONS FOR USE SECTION

Instructions For Use
AFINITOR (a-fin-it-or) DISPERZ**®**** (dis-perz)**
(everolimus tablets for oral suspension)

Read these Instructions for Use for AFINITOR DISPERZ before you start taking it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

Important Information:

***Take AFINITOR DISPERZ as a suspension only.**AFINITOR DISPERZ is prepared as a suspension of undissolved medicine that is mixed with water, and then it is taken by mouth. Do not chew, crush, or swallow AFINITOR DISPERZ whole. ***AFINITOR DISPERZ can cause harm to an unborn baby.**When possible, the suspension should be prepared by an adult who is not pregnant or planning to become pregnant.

• Keep AFINITOR DISPERZ and the prepared suspension out of the reach of children.
• Anyone who prepares suspensions of AFINITOR DISPERZ for another person should wear gloves to avoid possible contact with the drug.
• Only use water with AFINITOR DISPERZ to prepare the suspension. Do not prepare the suspension with juice or any other liquids.
• The suspension must be given right away. If you do not give the dose within 60 minutes after it has been prepared, throw away the dose and prepare a new dose of AFINITOR DISPERZ.
• Before starting to prepare the suspension, collect all of the supplies that you will need to prepare and take the suspension. Do not use any of these supplies for purposes other than preparing and taking the AFINITOR DISPERZ suspension.

Supplies needed to prepare the suspension in an oral syringe:

• Blister card with AFINITOR DISPERZ
• Scissors to open the blister card
• Disposable gloves (for one time use)
• 2 clean drinking glasses
• Approximately 30 mL of water
• 10 mL oral syringe (for one time use) (see Figure A)
• Paper towels

Figure A

Supplies needed to prepare the suspension in a small drinking glass:

• Blister card with AFINITOR DISPERZ
• Scissors to open the blister card
• Disposable gloves (for one time use)
• 30 mL dose cup for measuring water (you can ask your pharmacist for this)
• 1 clean drinking glass (maximum size 100 mL)
• Water to prepare the suspension
• Spoon for stirring
• Paper towels

Preparing a dose of AFINITOR DISPERZ suspension using an oral syringe:

**Step 1:**Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel.

**Step 2:**Wash and dry your hands well before preparing the medicine (see Figure B).

Figure B

**Step 3:**If preparing the AFINITOR DISPERZ suspension for another person, put on disposable gloves (see Figure C).

Figure C

**Step 4:**Take a 10 mL oral syringe and pull back on the plunger. Remove the plunger from the barrel of the syringe (see Figure D).

Figure D

**Step 5:**Use scissors to open the blister card along the dotted line (see Figure E) and remove the prescribed number of AFINITOR DISPERZ tablets for oral suspension from the blister card. Place them into the barrel of the oral syringe (see Figure F).

Figure E

Figure F

• Doses of up to 10 mg can be prepared with the oral syringe.**If your total prescribed dose is more than 10 mg, you will need to split the dose. Follow steps 4 through 17 for the first half of the dose. Then repeat steps 4 through 17 for the second half of the dose. Do not prepare a dose of more than 10 mg in one syringe.**Ask your pharmacist or healthcare provider if you are not sure what to do.

**Step 6:**Re-insert the plunger into the barrel of the oral syringe (see Figure G) and push the plunger in until it comes into contact with the AFINITOR DISPERZ tablets for oral suspension (see Figure H).

Figure G

Figure H

**Step 7:**Fill a small drinking glass with about 30 mL of water. Insert the tip of the oral syringe into the water. Then slowly pull back on the plunger until the syringe is about half full of water and all the tablets are covered by water (see Figure I).

Figure I

**Step 8:**Hold the oral syringe with the tip pointing up. Pull back on the plunger to draw back about 4 mL of air (see Figure J).

Figure J

Step 9:Place the filled oral syringe in the clean, empty glass with the tip pointing up. Wait3 minutesto allow AFINITOR DISPERZ to break apart (see Figure K).

Figure K

**Step 10:**Slowly turn the oral syringe up and down five times just before giving the dose (see Figure L).Do not shakethe syringe.

Figure L

**Step 11:**Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure M).

Figure M

**Step 12:**Give the full contents of the oral syringe slowly and gently into the mouth right away, within 60 minutes of preparing it (see Figure N). Carefully remove the syringe from the mouth. Continue with steps 13 through 17 to make sure that the entire dose of medicine is given.

Figure N

**Step 13:**Insert the tip of the oral syringe into the drinking glass that is filled with water, and pull up about 5 mL of water by slowly pulling back on the plunger (see Figure O).

Figure O

**Step 14:**Hold the oral syringe with the tip pointing up and use the plunger to draw back about 4 mL of air (see Figure P).

Figure P

**Step 15:**With the tip of the syringe still pointing up, swirl the contents by gently rotating the syringe in a circular motion (see Figure Q).

Figure Q

**Step 16:**Hold the oral syringe in an upright position (with the tip up). Carefully remove most of the air by pushing up gently on the plunger (see Figure R).

Figure R

**Step 17:**Give the full contents of the oral syringe slowly and gently into the mouth by pushing on the plunger (see Figure S). Carefully remove the syringe from the mouth.

Figure S

If the total prescribed dose is more than 10 mg, repeat steps 4 through 17 to finish giving the dose.

**Step 18:**Throw away the oral syringe, paper towel, and used gloves in your household trash.

**Step 19:**Wash your hands.

Preparing a dose of AFINITOR DISPERZ suspension using a small drinking glass:

**Step 1:**Prepare a clean, flat work surface that is away from where you prepare and eat food. Place a clean paper towel on the work surface. Place the needed supplies on the paper towel.

**Step 2:**Wash and dry your hands before preparing the medicine (see Figure T).

Figure T

**Step 3:**If preparing the AFINITOR DISPERZ suspension for another person, put on disposable gloves (see Figure U).

Figure U

**Step 4:**Add about 25 mL of water to the 30 mL dose cup. The amount of water added does not need to be exact (see Figure V).

Figure V

**Step 5:**Pour the water from the dose cup into a small drinking glass (maximum size 100 mL) (see Figure W).

Figure W

• Doses up to 10 mg can be prepared in the small drinking glass.**If your total prescribed dose is more than 10 mg, you will need to split the dose. Follow steps 4 through 10 for the first half of the dose. Then repeat steps 4 through 10 for the second half of the dose.**Ask your pharmacist or healthcare provider if you are not sure what to do.

**Step 6:**Use scissors to open the blister card along the dotted line (see Figure X) and remove the prescribed number of AFINITOR DISPERZ tablets for oral suspension from the blister card.

Figure X

**Step 7:**Add the prescribed number of AFINITOR DISPERZ tablets for oral suspension into the water (see Figure Y).

Figure Y

Step 8:Wait3 minutes to allow AFINITOR DISPERZ tablets for oral suspension to break apart (see Figure Z).

Figure Z

**Step 9:**Gently stir the contents of the glass with a spoon and place the spoon back on the paper towel (see Figure AA). Drink the full amount of the suspension right away, within 60 minutes of preparing it (see Figure BB).

Figure AA

Figure BB

**Step 10:**Refill the glass with the same amount of water (about 25 mL). Stir the contents with the same spoon and place the spoon back on the paper towel (see Figure CC). Drink the full amount right away so that you take any remaining medicine (see Figure DD).

Figure CC

Figure DD

If your total prescribed dose is more than 10 mg, repeat steps 4 through 10 to finish taking your dose.

**Step 11:**Wash the glass and the spoon thoroughly with water. Wipe the glass and spoon with a clean paper towel and store them in a dry and clean place until your next dose of AFINITOR DISPERZ (see Figure EE).

Figure EE

**Step 12:**Throw away the used paper towel and gloves in your household trash.

**Step 13:**Wash your hands.

How should I store AFINITOR DISPERZ?

• Store AFINITOR DISPERZ at room temperature, between 68°F to 77°F (20°C to 25°C).
• Keep AFINITOR DISPERZ in the pack it comes in.
• Open the blister pack just before taking AFINITOR DISPERZ.
• Keep AFINITOR DISPERZ dry and away from light.
• Do not use AFINITOR DISPERZ that is out of date or no longer needed.

Keep AFINITOR DISPERZ and all medicines out of the reach of children.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.

Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936

T2018-82
June 2018

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REFERENCES SECTION

15 REFERENCES

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

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