Yulithira Tablet
FDA Label NDC 82249-610

Yulithira™ tablets are 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.

Yulithira tablets are indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease.

Yulithira tablets are 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: Yulithira tablets are not indicated for the treatment of patients with functional carcinoid tumors [see Clinical Studies (14.2)].

Yulithira (everolimus) Tablets

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

Yulithira Tablets

2.5 mg tablet

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '2.5' on the other side.

5 mg tablet

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '5' on the other side.

7.5 mg tablet

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '7.5' on the other side.

10 mg tablet

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and 'NAT' on the other side.

Hormone Receptor-Positive, HER2-Negative Breast Cancer

The safety of Yulithira tablets (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 Yulithira tablets. The rate of adverse reactions resulting in permanent discontinuation was 24% for the Yulithira tablets arm. Dose adjustments (interruptions or reductions) occurred in 63% of patients in the Yulithira tablets arm.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving Yulithira tablets vs. placebo are presented in Table 6. Laboratory abnormalities are presented in Table 7. The median duration of treatment with Yulithira tablets was 23.9 weeks; 33% were exposed to Yulithira tablets for a period of ≥ 32 weeks.

Topical Prophylaxis for Stomatitis

In a single arm study (SWISH; N = 92) in postmenopausal women with hormone receptor-positive, HER2-negative breast cancer beginning Yulithira tablets (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 Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets (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 everolimus tablets 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 Yulithira tablets. Causes of death on the Yulithira tablets 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 Yulithira tablets, 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 Yulithira tablets group. Dose delay or reduction was necessary in 61% of Yulithira tablets patients. Grade 3-4 renal failure occurred in six patients in the Yulithira tablets arm. Thrombotic events included five patients with pulmonary embolus in the Yulithira tablets arm as well as three patients with thrombosis in the Yulithira tablets arm.

Table 8 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving Yulithira tablets vs. placebo. Laboratory abnormalities are summarized in Table 9. The median duration of treatment in patients who received Yulithira tablets was 37 weeks.

In female patients aged 18 to 55 years, irregular menstruation occurred in 5 of 46 (11%) Yulithira tablets-treated females.

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

In a randomized, controlled trial (RADIANT-4) of Yulithira tablets (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 Yulithira tablets was 9.3 months; 64% of patients were treated for ≥ 6 months and 39% were treated for ≥ 12 months. Yulithira tablets was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of Yulithira tablets-treated patients.

Serious adverse reactions occurred in 42% of Yulithira tablets-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.

Renal Cell Carcinoma (RCC)

The data described below reflect exposure to Yulithira tablets (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 Yulithira tablets.

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 Yulithira tablets arm. The rate of adverse reactions resulting in permanent discontinuation was 14% for the Yulithira tablets 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 Yulithira tablets treatment were for infections, anemia, and stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving Yulithira tablets vs. placebo are presented in Table 12. Laboratory abnormalities are presented in Table 13.

Other notable adverse reactions occurring more frequently with Yulithira tablets 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%)

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 Yulithira tablets 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 Yulithira tablets.

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

Adverse reactions reported with an incidence of ≥ 10% for patients receiving Yulithira tablets and occurring more frequently with Yulithira tablets than with placebo are presented in Table 14. Laboratory abnormalities are presented in Table 15.

Amenorrhea occurred in 15% of Yulithira tablets-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 Yulithira tablets-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%).

Updated safety information from 112 patients treated with Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets.

The most common adverse reactions reported for Yulithira tablets (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 Yulithira tablets-treated patients. The most common adverse reaction leading to Yulithira tablets dose adjustment was stomatitis.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving Yulithira tablets and occurring more frequently with Yulithira tablets than with placebo are reported in Table 16. Laboratory abnormalities are presented in Table 17.

Amenorrhea occurred in 17% of Yulithira tablets-treated females aged 10 to 55 years (3 of 18). For this same group of Yulithira tablets-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 Yulithira tablets-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%).

Updated safety information from 111 patients treated with everolimus tablets 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%).

Inhibitors

Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Reduce the dose for patients taking Yulithira tablets with a P-gp and moderate CYP3A4 inhibitor as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Inducers

Increase the dose for patients taking Yulithira tablets with a P-gp and strong CYP3A4 inducer as recommended [see Dosage and Administration (2.12), Clinical Pharmacology (12.3)].

Risk Summary

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], Yulithira tablets can cause fetal harm when administered to a pregnant woman. There are limited case reports of Yulithira tablets use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, Yulithira 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 Yulithira tablets 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 Yulithira 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 Yulithira tablets 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 Yulithira tablets 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), 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.

Risk Summary

There are no data on the presence of Yulithira or its metabolites in human milk, the effects of Yulithira on the breastfed infant or on milk production. Yulithira 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 Yulithira, advise women not to breastfeed during treatment with Yulithira tablets and for 2 weeks after the last dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to starting Yulithira tablets [see Use in Specific Populations(8.1)].

Contraception

Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets. Based on these findings, Yulithira tablets 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 Yulithira tablets. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of Yulithira tablets 10 mg orally once daily. Based on these findings, Yulithira tablets may impair fertility in male patients [see Nonclinical Toxicology (13.1)].

TSC-Associated SEGA

The safety and effectiveness of Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets-treated patients < 6 years had at least one infection compared to 67% of 55 Yulithira tablets-treated patients ≥ 6 years. Thirty-five percent of 23 Yulithira tablets-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 Yulithira tablets-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, Yulithira tablets did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with Yulithira tablets for a median duration of 4.1 years.

Other Indications

The safety and effectiveness of Yulithira tablets 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

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.

Cardiac Electrophysiology

In a randomized, placebo-controlled, cross-over study, 59 healthy subjects were administered a single oral dose of everolimus tablets (20 mg and 50 mg) and placebo. Everolimus tablets at single doses up to 50 mg did not prolong the QT/QTc interval.

Absorption

After administration of Yulithira (everolimus) tablets 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, C_max is dose-proportional with daily dosing between 5 mg and 10 mg. With single doses of 20 mg and higher, the increase in C_max 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 C_min 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 Yulithira tablets 10 mg (as measured by AUC) by 22% and the peak blood concentration C_max by 54%. Light-fat meals (containing approximately 500 calories and 20 grams of fat) reduced AUC by 32% and C_max by 42%.

Relative Bioavailability: The AUC_inf of everolimus was equivalent between everolimus tablets for oral suspension and everolimus tablets; the C_max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of everolimus tablets. 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 everolimus tablets 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, the mean C_min 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 everolimus tablets were coadministered with:

• ketoconazole (a P-gp and strong CYP3A4 inhibitor) - C_max and AUC increased by 3.9- and 15-fold, respectively.
• erythromycin (a P-gp and moderate CYP3A4 inhibitor) - C_max and AUC increased by 2- and 4.4-fold, respectively.
• verapamil (a P-gp and moderate CYP3A4 inhibitor) - C_max and AUC increased by 2.3- and 3.5-fold, respectively.

Effect of CYP3A4 and P-gp Inducers on Everolimus: The coadministration of everolimus tablets with rifampin, a P-gp and strong inducer of CYP3A4, decreased everolimus AUC by 63% and C_max by 58% compared to everolimus tablets alone [see Dosage and Administration (2.12)].

Effect of Everolimus on CYP3A4 Substrates: No clinically significant pharmacokinetic interactions were observed between everolimus tablets 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 everolimus tablets resulted in a 25% increase in midazolam C_max and a 30% increase in midazolam AUC_0-inf.

The coadministration of everolimus tablets with exemestane increased exemestane C_min by 45% and C_2h 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 everolimus tablets with long-acting octreotide increased octreotide C_min 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.

Pancreatic Neuroendocrine Tumors (PNET)

A randomized, double-blind, multi-center trial (RADIANT-3, NCT00510068) of everolimus tablets 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 everolimus tablets. Other outcome measures included ORR, response duration, and OS.

Patients were randomized 1:1 to receive either everolimus tablets 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 everolimus tablets 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

Analysis	N	Everolimus Tablets N = 207	Placebo N = 203	Hazard Ratio (95% CI)	p-value
	410	Median progression-free survival (months) (95% CI)
Investigator radiological review		11.0 (8.4, 13.9)	4.6 (3.1, 5.4)	0.35 (0.27, 0.45)	< 0.001
Central radiological review		13.7 (11.2, 18.8)	5.7 (5.4, 8.3)	0.38 (0.28, 0.51)	< 0.001
Adjudicated radiological review Includes adjudication for discrepant assessments between investigator radiological review and central radiological review.		11.4 (10.8, 14.8)	5.4 (4.3, 5.6)	0.34 (0.26, 0.44)	< 0.001

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



Figure 2 (Yulithira 03)

Investigator-determined response rate was 4.8% in the everolimus 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets 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

	Everolimus Tablets N = 205	Placebo N = 97
Progression-Free Survival
Number of Events	113 (55%)	65 (67%)
Progressive Disease	104 (51%)	60 (62%)
Death	9 (4%)	5 (5%)
Median PFS in months (95% CI)	11.0 (9.2, 13.3)	3.9 (3.6, 7.4)
Hazard Ratio (95% CI) Hazard ratio is obtained from the stratified Cox model.	0.48 (0.35, 0.67)
p-value p-value is obtained from the stratified log-rank test.	< 0.001
Overall Response Rate	2%	1%

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



Figure 3 (Yulithira 04)

Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors

The safety and effectiveness of everolimus tablets in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated. In a randomized (1:1), double-blind, multi-center trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, everolimus tablets 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 everolimus tablets; of those randomized to placebo, 67% received open-label everolimus tablets 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.

EXIST-1

A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of everolimus tablets 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 everolimus tablets 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. Everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets-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 everolimus tablets. No patient in either treatment arm required surgical intervention.

Table 25: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1

	Everolimus Tablets N=78	Placebo N=39	p-value
Primary Analysis
SEGA response rate Per independent central radiology review - (%)	35	0	< 0.0001
95% CI	24, 46	0, 9

Patients randomized to placebo were permitted to receive everolimus tablets at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with everolimus tablets 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 everolimus tablets and 33 patients randomized to placebo) received at least one dose of everolimus tablets. Median duration of everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on everolimus tablets 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 everolimus tablets. Nine additional patients were identified as having a ≥50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating everolimus tablets, including 3 patients who had surgical resection with subsequent regrowth prior to receiving everolimus tablets.

Everolimus Tablets

2.5 mg tablets

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '2.5' on the other side; available in:

Bottles of 30 tablets

NDC 82249-610-30

5 mg tablets

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '5' on the other side; available in:

Bottles of 30 tablets

NDC 82249-611-30

7.5 mg tablets

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and '7.5' on the other side; available in:

Bottles of 30 tablets

NDC 82249-612-30

10 mg tablets

White to off-white coloured, oval, flat shaped tablets and no score, debossed with 'EVR' on one side and 'NAT' on the other side; available in:

Bottles of 30 tablets

NDC 82249-613-30

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 Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets 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:
CivicaScript, LLC
Lehi, Utah 84048

Manufactured for:
Breckenridge Pharmaceutical, Inc.
Berkeley Heights, NJ 07922 by
Natco Pharma Limited
Visakhapatnam - 531019
AP, India

PHARMACIST – DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT

Yulithira tablets are indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib.

Yulithira tablets are indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.

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

• Yulithira tablets and everolimus tablets for oral suspension are two different dosage forms. Do not combine Yulithira tablets and everolimus tablets for oral suspension to achieve the total dose.
• Modify the dosage for patients with hepatic impairment or for patients taking drugs that inhibit or induce P-glycoprotein (P-gp) and CYP3A4 [see Dosage and Administration (2.10, 2.11, 2.12)].

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

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

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

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

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

• 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

The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration.

= current dose × (target concentration divided by current concentration)
• When possible, use the same assay and laboratory for TDM throughout treatment.

Table 1: Recommended Timing of Therapeutic Drug Monitoring

Event	When to Assess Trough Concentrations After Event
Abbreviation: P-gp, P-glycoprotein.
Initiation of everolimus tablets	1 to 2 weeks
Modification of everolimus tablets dose	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

Table 2 summarizes recommendations for dosage modifications of Yulithira (everolimus) tablets for the management of adverse reactions.

The recommended dosages of Yulithira tablets for patients with hepatic impairment are described in Table 3 [see Use in Specific Populations (8.6)]:

• Avoid the concomitant use of P-gp and strong CYP3A4 inhibitors [see Drug Interactions (7.1)].
• Avoid ingesting grapefruit and grapefruit juice.
• Reduce the dose for patients taking Yulithira tablets with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 4: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with a P-gp and Moderate CYP3A4 Inhibitor

Indication	Dose Modification for Everolimus Tablets
Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma	Reduce dose to 2.5 mg once daily. May increase dose to 5 mg once daily if tolerated. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days.
TSC-Associated SEGA	Reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. Resume dose administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8)].

• Avoid concomitant use of St. John's Wort (Hypericum perforatum).
• Increase the dose for patients taking Yulithira tablets with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

Table 5: Recommended Dosage Modifications for Concurrent Use of Everolimus Tablets with P-gp and Strong CYP3A4 Inducers

Indication	Dose Modification for Everolimus Tablets
Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma	Avoid coadministration where alternatives exist. If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dose administered prior to inducer initiation, once an inducer is discontinued for 5 days.
TSC-Associated SEGA	Double the daily dose using increments of 5 mg or less. Multiple increments may be required. Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification. Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8)]. Resume the dose administered before starting any inducer, once all inducers are discontinued for 5 days.

• Administer Yulithira tablets at the same time each day.
• Administer Yulithira tablets consistently either with or without food [see Clinical Pharmacology (12.3)].
• If a dose of Yulithira tablets is missed, it can be administered up to 6 hours after the time it is normally administered. After more than 6 hours, the dose should be skipped for that day. The next day, Yulithira tablets should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.

Yulithira tablets are contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives [see Warnings and Precautions (5.3)].

Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets 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.

Yulithira tablets have 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 Yulithira tablets 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.

Hypersensitivity reactions to Yulithira tablets 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 Yulithira tablets for the development of clinically significant hypersensitivity.

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

Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with Yulithira tablets 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 Yulithira tablets, 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.

Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking Yulithira tablets. Elevations of serum creatinine and proteinuria have been reported in patients taking Yulithira tablets [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 Yulithira tablets and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

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

Withhold Yulithira tablets 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.

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 Yulithira tablets 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)].

Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking Yulithira tablets 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 Yulithira tablets and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting Yulithira tablets and annually thereafter. When possible, achieve optimal glucose and lipid control prior to starting Yulithira tablets. For Grade 3 to 4 metabolic events, withhold or permanently discontinue Yulithira tablets based on severity [see Dosage and Administration (2.9)].

Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking Yulithira tablets. 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 Yulithira tablets every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue Yulithira tablets based on severity [see Dosage and Administration (2.9)].

The safety of immunization with live vaccines during Yulithira tablets 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 Yulithira tablets. 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 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 Yulithira tablets treatment [see Adverse Reactions (6.2)].

Monitor patients closely when Yulithira tablets are administered during or sequentially with radiation treatment.

Based on animal studies and the mechanism of action, Yulithira tablets can cause fetal harm when administered to a pregnant woman. In animal studies, Yulithira 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 Yulithira tablets and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with Yulithira tablets and for 4 weeks after the last dose [see Use in Specific Populations (8.1, 8.3)].

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)].

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.

The following adverse reactions have been identified during post approval use of Yulithira tablets. 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

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

In BOLERO-2, 40% of patients with breast cancer treated with Yulithira tablets 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 Yulithira tablets 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 Yulithira tablets were ≥ 65 years of age, while 7% were ≥ 75 years of age. In RADIANT-3, 30% of patients with PNET treated with Yulithira tablets 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.

Yulithira tablets 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 Yulithira tablets dose as recommended [see Dosage and Administration (2.10)].

For patients with TSC-associated SEGA who have severe hepatic impairment (Child-Pugh class C), reduce the starting dose of Yulithira tablets as recommended and adjust the dose based on Yulithira trough concentrations [see Dosage and Administration (2.8, 2.10)].

Yulithira (everolimus) tablets are kinase inhibitors.

The chemical name of everolimus is (1R,9S,12S,15R,16E,18R,19R,21R,23S,24E,26E,28E,30S,32S,35R)-1,18-dihydroxy-12-{(1R)-2-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]-1-methylethyl}-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-aza-tricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentaone. The molecular formula is C₅₃H₈₃NO₁₄ and the molecular weight is 958.2 g/mol. The structural formula is:

Chemical Structure (Yulithira 01)

Yulithira (everolimus) tablets for oral administration contain 2.5 mg, 5 mg, 7.5 mg or 10 mg of everolimus. The tablets also contain anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, and magnesium stearate as inactive ingredients.

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.

Administration of everolimus for up to 2 years did not indicate oncogenic potential in mice and rats up to the highest doses tested (0.9 mg/kg) corresponding, respectively to 3.9 and 0.2 times the estimated human exposure based on AUC at the recommended dose of everolimus tablets 10 mg orally once daily.

Everolimus was not genotoxic in a battery of in vitro assays (Ames mutation test in Salmonella, mutation test in L5178Y mouse lymphoma cells, and chromosome aberration assay in V79 Chinese hamster cells). Everolimus was not genotoxic in an in vivo mouse bone marrow micronucleus test at doses up to 500 mg/kg/day (1500 mg/m²/day, approximately 255-fold the recommended dose of everolimus tablets 10 mg orally once daily, and approximately 200-fold the median dose administered to patients with TSC-associated SEGA, based on the BSA), administered as 2 doses, 24 hours apart.

Based on non-clinical findings, everolimus tablets may impair male fertility. In a 13-week male fertility study in rats, testicular morphology was affected at doses of 0.5 mg/kg and above. Sperm motility, sperm count, and plasma testosterone levels were diminished in rats treated with 5 mg/kg. The exposures at these doses (52 ng•hr/mL and 414 ng•hr/mL, respectively) were within the range of human exposure at the recommended dose of everolimus tablets 10 mg orally once daily (560 ng•hr/mL) and resulted in infertility in the rats at 5 mg/kg. Effects on male fertility occurred at AUC_0-24h values 10% to 81% lower than human exposure at the recommended dose of everolimus tablets 10 mg orally once daily. After a 10-13 week non-treatment period, the fertility index increased from zero (infertility) to 60%.

Oral doses of everolimus in female rats at doses ≥ 0.1 mg/kg (approximately 4% the human exposure based on AUC at the recommended dose of everolimus tablets 10 mg orally once daily) resulted in increased incidence of pre-implantation loss, suggesting that the drug may reduce female fertility.

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

A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets in combination with exemestane arm and the placebo in combination with exemestane arm [HR 0.89 (95% CI: 0.73, 1.10)].

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

Figure 1 (Yulithira 02)

An international, multi-center, randomized, double-blind trial (RECORD-1, NCT00410124) comparing everolimus tablets 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 everolimus tablets. Other outcome measures included OS.

In total, 416 patients were randomized 2:1 to receive everolimus tablets (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).

Everolimus tablets were 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 everolimus tablets occurred in 80% of the 139 patients and may have confounded the OS benefit.

Figure 4: Kaplan-Meier Curves for Progression-Free Survival in RCC in RECORD-1

Figure 4 (Yulithira 05)

A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets 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 everolimus tablets-treated patients (Table 24). The median response duration was 5.3+ months (2.3+ to 19.6+ months).

There were 3 patients in the everolimus tablets 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 everolimus tablets arm (HR 0.08 [95% CI: 0.02, 0.37]; p < 0.0001).

Skin lesion response rates were assessed by local investigators for 77 patients in the everolimus tablets 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 everolimus tablets 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 everolimus tablets at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with everolimus tablets 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 everolimus tablets and 33 randomized to placebo) received at least one dose of everolimus tablets. The median duration of everolimus tablets 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 everolimus tablets 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 everolimus tablets.

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

Store Yulithira Tablets 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

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

YULITHIRA™ (YUL-ee-thir-ah) (everolimus) TABLETS

Read this Patient Information leaflet that comes with Yulithira tablets 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.

What is the most important information I should know about Yulithira tablets?

Yulithira tablets can cause serious side effects, including:

1. You may develop lung or breathing problems. In some people lung or breathing problems may be severe and can lead to death. Tell your healthcare provider right away if you have any of these symptoms:

• New or worsening cough
• Shortness of breath
• Chest pain
• Difficulty breathing or wheezing

2. You may be more likely to develop an infection, such as pneumonia, or a bacterial, fungal or viral infection. Viral infections may include active hepatitis B in people who have had hepatitis B in the past (reactivation). In some people (including adults and children) these infections may be severe and can lead to death. You may need to be treated as soon as possible.

Tell your healthcare provider right away if you have a temperature of 100.5°F or above, chills, or do not feel well.

Symptoms of hepatitis B or infection may include the following:

• Fever
• Chills
• Skin rash
• Joint pain and swelling
• Tiredness
• Loss of appetite
• Nausea
• Pale stools or dark urine
• Yellowing of the skin
• Pain in the upper right side of the stomach

3. Severe allergic reactions. Call your healthcare provider or get medical help right away if you get signs and symptoms of a severe allergic reaction including: rash, itching, hives, flushing, trouble breathing or swallowing, chest pain or dizziness.

4. Possible increased risk for a type of allergic reaction called angioedema, in people who take an Angiotensin-Converting Enzyme (ACE) inhibitor medicine during treatment with Yulithira tablets. Talk with your healthcare provider before taking Yulithira tablets if you are not sure if you take an ACE inhibitor medicine. Get medical help right away if you have trouble breathing or develop swelling of your tongue, mouth, or throat during treatment with Yulithira tablets.

5. Mouth ulcers and sores. Mouth ulcers and sores are common during treatment with Yulithira tablets but can also be severe. When you start treatment with Yulithira tablets, your healthcare provider may tell you to also start a prescription mouthwash to reduce the likelihood of getting mouth ulcers or sores and to reduce their severity. Follow your healthcare provider's instructions on how to use this prescription mouthwash. If you develop pain, discomfort, or open sores in your mouth, tell your healthcare provider. Your healthcare provider may tell you to restart this mouthwash or to use a special mouthwash or mouth gel that does not contain alcohol, peroxide, iodine, or thyme.

6. You may develop kidney failure. In some people this may be severe and can lead to death. Your healthcare provider should do tests to check your kidney function before and during your treatment with Yulithira tablets.

If you have any of the serious side effects listed above, you may need to stop taking Yulithira tablets for a while or use a lower dose. Follow your healthcare provider's instructions.

What are Yulithira tablets?

Yulithira tablets are a prescription medicine used to treat:

• advanced hormone receptor-positive, HER2-negative breast cancer, along with the medicine exemestane, in postmenopausal women who have already received certain other medicines for their cancer.
• adults with a type of pancreatic cancer known as pancreatic neuroendocrine tumor (PNET), that has progressed and cannot be treated with surgery.
• adults with a type of cancer known as neuroendocrine tumor (NET) of the stomach and intestine (gastrointestinal), or lung that has progressed and cannot be treated with surgery.

Yulithira tablets are not for use in people with carcinoid tumors that actively produce hormones.

• adults with advanced kidney cancer (renal cell carcinoma or RCC) when certain other medicines have not worked.
• people with the following types of tumors that are seen with a genetic condition called tuberous sclerosis complex (TSC):
  • adults with a kidney tumor called angiomyolipoma, when their kidney tumor does not require surgery right away.
  • adults and children 1 year of age and older with a brain tumor called subependymal giant cell astrocytoma (SEGA) when the tumor cannot be removed completely by surgery.

  It is not known if Yulithira tablets are safe and effective in children to treat:

  • hormone receptor-positive, HER-2 negative breast cancer
  • a type of cancer called neuroendocrine tumors (NET)
  • kidney cancer (renal cell carcinoma)
  • a kidney tumor called angiomyolipoma, that can happen in children with a genetic condition called tuberous sclerosis complex (TSC).

  Do not take Yulithira tablets if you have had a severe allergic reaction to everolimus.

  Talk to your healthcare provider before taking this medicine if you are allergic to:

  • a medicine that contains sirolimus
  • a medicine that contains temsirolimus

  Ask your healthcare provider if you do not know.

  Before taking Yulithira tablets, tell your healthcare provider about all of your medical conditions, including if you:

  • Have or have had kidney problems
  • Have or have had liver problems
  • Have diabetes or high blood sugar
  • Have high blood cholesterol levels
  • Have any infections
  • Previously had hepatitis B
  • Are scheduled to receive any vaccinations. You should not receive a "live vaccine" or be around people who have recently received a "live vaccine" during your treatment with Yulithira tablets. If you are not sure about the type of immunization or vaccine, ask your healthcare provider. For children with TSC and SEGA, work with your healthcare provider to complete the recommended childhood series of vaccines before your child starts treatment with Yulithira tablets.
  • Are pregnant, can become pregnant, or have a partner who can become pregnant. Yulithira tablets can cause harm to your unborn baby.
    Females who are able to become pregnant:
    • Your healthcare provider will give you a pregnancy test before you start treatment with Yulithira tablets.
    • You should use effective birth control during treatment and for 8 weeks after your last dose of Yulithira tablets.
    Males with a female partner, you should use effective birth control during treatment and for 4 weeks after your last dose of Yulithira tablets.
    Talk to your healthcare provider about birth control methods that may be right for you during this time. If you become pregnant or think you are pregnant, tell your healthcare provider right away.
    • Are breastfeeding or plan to breastfeed. It is not known if everolimus passes into your breast milk. Do not breastfeed during treatment and for 2 weeks after your last dose of Yulithira tablets.
    • Are planning to have surgery or if you have had a recent surgery. You should stop taking Yulithira at least 1 week before planned surgery. See "What are the possible side effects of Yulithira tablets?"
    • Have received radiation therapy or are planning to receive radiation therapy in the future. See "What are the possible side effects of Yulithira tablets?"

    Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

    Yulithira tablets may affect the way other medicines work, and other medicines can affect how Yulithira tablets work. Taking Yulithira tablets with other medicines can cause serious side effects.

    Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine. Especially tell your healthcare provider if you take:

    • St. John's Wort (Hypericum perforatum)
    • Medicine for:
      • Fungal infections
      • Bacterial infections
      • Tuberculosis
      • Seizures
      • HIV-AIDS
      • Heart conditions or high blood pressure
      • Medicines that weaken your immune system (your body's ability to fight infections and other problems)

      Ask your healthcare provider or pharmacist if you are not sure if your medicine is one of those taken for the conditions listed above. If you are taking any medicines for the conditions listed above, your healthcare provider might need to prescribe a different medicine or your dose of Yulithira tablets may need to be changed. You should also tell your healthcare provider before you start taking any new medicine.

      How should I take Yulithira tablets?

      • Your healthcare provider will prescribe the dose of Yulithira tablets that is right for you.
      • Take Yulithira tablets exactly as your healthcare provider tells you to.
      • Your healthcare provider may change your dose of Yulithira tablets or tell you to temporarily interrupt dosing, if needed.
      • Take only Yulithira tablets or everolimus tablets for oral suspension. Do not mix Yulithira tablets and everolimus tablets for oral suspension together.
      • Swallow Yulithira tablets whole with a glass of water. Do not take any tablet that is broken or crushed.
      • Take Yulithira tablets 1 time each day at about the same time.
      • Take Yulithira tablets the same way each time, either with food or without food.
      • If you take too much Yulithira tablets contact your healthcare provider or go to the nearest hospital emergency room right away. Take the pack of Yulithira tablets with you.
      • If you miss a dose of Yulithira tablets, you may take it if it is less than 6 hours after the time you normally take it. If it is more than 6 hours after you normally take your Yulithira tablets, skip the dose for that day. The next day, take Yulithira tablets at your usual time. Do not take 2 doses to make up for a missed dose. If you are not sure about what to do, call your healthcare provider.
      • You should have blood tests before you start Yulithira tablets and as needed during your treatment. These will include tests to check your blood cell count, kidney and liver function, cholesterol, and blood sugar levels.
      • If you take Yulithira tablets to treat SEGA, you will also need to have blood tests regularly to measure how much medicine is in your blood. This will help your healthcare provider decide how much Yulithira tablets you need to take.

      What should I avoid while taking Yulithira tablets?

      You should not drink grapefruit juice or eat grapefruit during your treatment with Yulithira tablets. It may make the amount of Yulithira tablets in your blood increase to a harmful level.

      What are the possible side effects of Yulithira tablets?

      Yulithira tablets can cause serious side effects, including:

      • See "What is the most important information I should know about Yulithira tablets?" for more information.
      • Risk of wound healing problems. Wounds may not heal properly during Yulithira tablets treatment. Tell your healthcare provider if you plan to have any surgery before starting or during treatment with Yulithira tablets.
        • You should stop taking Yulithira tablets at least 1 week before planned surgery.
        • Your healthcare provider should tell you when you may start taking Yulithira tablets again after surgery.
        • Increased blood sugar and fat (cholesterol and triglyceride) levels in the blood. Your healthcare provider should do blood tests to check your fasting blood sugar, cholesterol, and triglyceride levels in the blood before you start and during treatment with Yulithira tablets.
        • Decreased blood cell counts. Everolimus tablets can cause you to have decreased red blood cells, white blood cells, and platelets. Your healthcare provider should do blood tests to check your blood cell counts before you start and during treatment with Yulithira tablets.
        • Worsening side effects from radiation treatment, that can sometimes be severe. Tell your healthcare provider if you have had or are planning to receive radiation therapy.

        The most common side effects of Yulithira tablets in people with advanced hormone receptor-positive, HER2-negative breast cancer, advanced neuroendocrine tumors of the pancreas, stomach and intestine (gastrointestinal) or lung, and advanced kidney cancer include:

        • Infections
        • Rash
        • Feeling weak or tired
        • Diarrhea
        • Swelling of arms, hands, feet, ankles, face, or other parts of the body
        • Stomach-area (abdominal) pain
        • Nausea
        • Fever
        • Cough
        • Headache
        • Decreased appetite

        The most common side effects of Yulithira tablets in people who have SEGA or renal angiomyolipoma include respiratory tract infections.

        Other side effects that may occur with Yulithira tablets:

        • Absence of menstrual periods (menstruation). You may miss 1 or more menstrual periods. Tell your healthcare provider if this happens.
        • Yulithira tablets may affect fertility in females and may affect your ability to become pregnant. Talk to your healthcare provider if this is a concern for you.
        • Yulithira tablets may affect fertility in males and may affect your ability to father a child. Talk to your healthcare provider if this is a concern for you.

        Tell your healthcare provider if you have any side effect that bothers you or does not go away.

        These are not all the possible side effects of Yulithira tablets. For more information, ask your healthcare provider or pharmacist.

        Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

        How should I store Yulithira tablets?

        • Store Yulithira tablets at room temperature, between 68°F to 77°F (20°C to 25°C).
        • Keep Yulithira tablets in the pack it comes in.
        • Keep Yulithira tablets dry and away from light.
        • Do not use Yulithira tablets that are out of date or no longer needed.

        Keep Yulithira tablets and all medicines out of the reach of children.

        General information about the safe and effective use of Yulithira tablets

        Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use Yulithira tablets for a condition for which it was not prescribed. Do not give Yulithira tablets to other people, even if they have the same problem you have. It may harm them.

        This leaflet summarizes the most important information about Yulithira tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information written for healthcare professionals.

        What are the ingredients in everolimus tablets?

        Active ingredient: everolimus.

        Inactive ingredients: anhydrous lactose, butylated hydroxytoluene, crospovidone, hypromellose, and magnesium stearate.

        Distributed by:
        CivicaScript, LLC
        Lehi, Utah 84048

        Manufactured for:
        Breckenridge Pharmaceutical, Inc.
        Berkeley Heights, NJ 07922 by:
        Natco Pharma Limited
        Visakhapatnam - 531019
        AP, India

        The brands listed are the trademarks or register marks of their respective owners and are not trademarks or register marks of Breckenridge Pharmaceutical, Inc.

        This Patient Information has been approved by the U.S. Food and Drug Administration.

        Revised: 03/2026

NDC 82249-610-30
Rx Only

Yulithira™
(everolimus) tablets

2.5 mg

Each tablet contains
2.5 mg everolimus

For oral use.

30 Tablets

CIVICASCRIPT^®

Principal Display Panel (2.5 mg Tablet Bottle Label)

NDC 82249-611-30
Rx Only

Yulithira™
(everolimus) tablets

5 mg

Each tablet contains
5 mg everolimus

For oral use.

30 Tablets

CIVICASCRIPT^®

Principal Display Panel (5 mg Tablet Bottle Label)

NDC 82249-612-30
Rx Only

Yulithira™
(everolimus) tablets

7.5 mg

Each tablet contains
7.5 mg everolimus

For oral use.

30 Tablets

CIVICASCRIPT^®

Principal Display Panel (7.5 mg Tablet Bottle Label)

NDC 82249-613-30
Rx Only

Yulithira™
(everolimus) tablets

10 mg

Each tablet contains
10 mg everolimus

For oral use.

30 Tablets

CIVICASCRIPT^®

Principal Display Panel (10 mg Tablet Bottle Label)