Everolimus Tablet, For Suspension
FDA Label NDC 70954-773

Everolimus tablets for oral suspension 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.

Everolimus tablets for oral suspension are indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.

• Do not combine AFINITOR and everolimus tablets for oral suspension to achieve the total dose.

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

The recommended starting dosage of everolimus tablets for oral suspension is 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* = current dose x (target concentration divided by current concentration)*The maximum dose increment at any titration must not exceed 5 mg. Multiple dose titrations may be required to attain the target trough concentration.
• When possible, use the same assay and laboratory for TDM throughout treatment.



Table 1: Recommended Timing of Therapeutic Drug Monitoring





Event	When to Assess Trough Concentrations After Event
Initiation of everolimus tablets for oral suspension	1 to 2 weeks
Modification of everolimus tablets for oral suspension dose	1 to 2 weeks
Switch between AFINITOR and everolimus tablets for oral suspension	1 to 2 weeks
Initiation or discontinuation of moderate CYP3A inhibitor and P-gp inhibitor	2 weeks
Initiation or discontinuation of cannabidiol oral solution	2 weeks
Initiation or discontinuation of strong CYP3A inducer and P-gp 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
Abbreviation: P-gp, P-glycoprotein.

Table 2 summarizes recommendations for dosage modifications of everolimus tablets for oral suspension for the management of adverse reactions.

Table 2: Recommended Dosage Modifications for Everolimus Tablets for Oral Suspension for Adverse Reactions

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

Table 3: Recommended Dosage Modifications for Patients With Hepatic Impairment

Strong or Moderate CYP3A Inhibitor and P-glycoprotein (P-gp) Inhibitor

• Avoid the coadministration of a strong CYP3A inhibitor and P-gp inhibitor [see Drug Interactions (7.1)].
• Reduce the dosage for everolimus tablets for oral suspension with a moderate CYP3A inhibitor and P-gp as recommended in Table 4 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].



Table 4: Recommended Dosage Modifications with a Moderate CYP3A Inhibitor and P-gp Inhibitor





Indication	Dosage Modification for Everolimus Tablets for Oral Suspension
TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures	Reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. Resume dosage 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)].




Cannabidiol Oral Solution

• Reduce the dosage of everolimus tablets for oral suspension when coadministered with cannabidiol oral solution as recommended in Table 5 [see Clinical Pharmacology (12.3)]. The effects of other cannabidiol products on everolimus exposure are unknown.



Table 5: Recommended Dosage Modifications with Cannabidiol Oral Solution




Indication	Dosage Modification for everolimus tablets for oral suspension
TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures	Reduce the daily dose by 50%. Change to every other day dosing if the reduced dose is lower than the lowest available strength. Resume dosage administered prior to cannabidiol oral solution initiation, once cannabidiol oral solution is discontinued for 3 days. Assess trough concentrations when initiating and discontinuing the inhibitor [see Dosage and Administration (2.8)].




Strong CYP3A Inducer and P-gp Inducer

• Increase the dosage for everolimus tablets for oral suspension with a strong CYP3A inducer and P-gp inducer as recommended in Table 6 [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].



Table 6: Recommended Dosage Modifications with a Strong CYP3A Inducer and P-gp Inducer

 

 

Indication

Dosage Modification for Everolimus Tablets for Oral Suspension

TSC-Associated SEGA and TSC-Associated Partial-Onset Seizures

Double the daily dose using increments of 5 mg or less. Multiple increments may be required. Addition of another strong CYP3A4 inducer in a patient already receiving treatment with a strong CYP3A4 inducer may not require additional dosage modification. Assess trough concentrations when initiating and discontinuing the inducer [see Dosage and Administration (2.8)]. Resume the dosage administered before starting any inducer, once all inducers are discontinued for 5 days.

 

• Administer everolimus tablets for oral suspension at the same time each day.
• Administer everolimus tablets for oral suspension consistently either with or without food [see Clinical Pharmacology (12.3)].
• If a dose of everolimus tablets for oral suspension 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, everolimus tablets for oral suspension should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.



Everolimus Tablets for Oral Suspension

• Wear gloves to avoid possible contact with everolimus when preparing suspensions of everolimus tablets for oral suspension for another person.
• Administer as a suspension only.
• Administer suspension immediately after preparation. Discard suspension if not administered within 60 minutes after preparation.
• Prepare suspension in water only.



Using an Oral Syringe to Prepare Oral Suspension:

• Place the prescribed dose into a 10-mL syringe. Do not exceed a total of 10 mg per syringe. If higher doses are required, prepare an additional syringe. Do not break or crush tablets.
• Draw approximately 5 mL of water and 4 mL of air into the syringe.
• Place the filled syringe into a container (tip up) for 3 minutes, until the tablets are in suspension.
• Gently invert the syringe 5 times immediately prior to administration.
• After administration of the prepared suspension, draw approximately 5 mL of water and 4 mL of air into the same syringe, and swirl the contents to suspend remaining particles. Administer the entire contents of the syringe.



Using a Small Drinking Glass to Prepare Oral Suspension:

• Place the prescribed dose into a small drinking glass (maximum size 100 mL) containing approximately 25 mL of water. Do not exceed a total of 10 mg per glass. If higher doses are required, prepare an additional glass. Do not break or crush tablets.
• Allow 3 minutes for suspension to occur.
• Stir the contents gently with a spoon, immediately prior to drinking.
• After administration of the prepared suspension, add 25 mL of water and stir with the same spoon to re-suspend remaining particles. Administer the entire contents of the glass.

Everolimus Tablets for Oral Suspension

Tablets for oral suspension, white to slightly yellowish speckled, round, flat:

• 2 mg: no score, debossed with "N 773" on one side and plain on the other side, free from physical defects.
• 3 mg: no score, debossed with "N 774" on one side and plain on the other side, free from physical defects.
• 5 mg: no score, debossed with "N 775" on one side and plain on the other side, free from physical defects.

Everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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.

Everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension for the development of clinically significant hypersensitivity.

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

Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with everolimus tablets for oral suspension 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 everolimus tablets for oral suspension, 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 AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking everolimus tablets for oral suspension [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 everolimus tablets for oral suspension 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, everolimus tablets for oral suspension have the potential to adversely affect wound healing.

Withhold everolimus tablets for oral suspension 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.

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

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

The safety of immunization with live vaccines during everolimus tablets for oral suspension 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 everolimus tablets for oral suspension. 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 everolimus tablets for oral suspension treatment [see Adverse Reactions (6.2)].

Monitor patients closely when everolimus tablets for oral suspension is administered during or sequentially with radiation treatment.

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

TSC-Associated Subependymal Giant Cell Astrocytoma (SEGA)

The data described below are based on a randomized (2:1), double-blind, placebo-controlled trial (EXIST-1) of AFINITOR in 117 patients with SEGA and TSC. The median age of patients was 9.5 years (0.8 to 26 years), 93% were white, and 57% were male. The median duration of blinded study treatment was 52 weeks (24 to 89 weeks) for patients receiving AFINITOR.

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

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

Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR and occurring more frequently with AFINITOR than with placebo are reported in Table 17. Laboratory abnormalities are presented in Table 18.

Table 17: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1

Amenorrhea occurred in 17% of AFINITOR-treated females aged 10 to 55 years (3 of 18). For this same group of AFINITOR-treated females, the following menstrual abnormalities were reported: dysmenorrhea (6%), menorrhagia (6%), metrorrhagia (6%), and unspecified menstrual irregularity (6%).

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

Table 18: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated SEGA in EXIST-1

Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions and selected laboratory abnormalities: decreased appetite (14%), hyperglycemia (13%), hypertension (11%), urinary tract infection (9%), decreased fibrinogen (8%), cellulitis (6%), abdominal pain (5%), decreased weight (5%), elevated creatinine (5%), and azoospermia (1%).

TSC-Associated Partial-Onset Seizures

The data described below are based on the 18-week Core phase of a randomized, double-blind, multicenter, three-arm trial (EXIST-3) comparing two everolimus trough levels (3-7 ng/mL and 9-15 ng/mL) to placebo as adjunctive antiepileptic therapy in patients with TSC-associated partial-onset seizures. A total of 366 patients were randomized to everolimus tablets for oral suspension low trough (LT) (n = 117), everolimus tablets for oral suspension high trough (HT) (n = 130), or placebo (n = 119). The median age of patients was 10 years (2.2 to 56 years; 28% were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years), 65% were white, and 52% were male. Patients received between one and three concomitant antiepileptic drugs.

The most common adverse reaction reported for everolimus tablets for oral suspension in both arms (incidence ≥ 30%) was stomatitis. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, pneumonia, and irregular menstruation. The most common laboratory abnormality (incidence ≥ 50%) was hypercholesterolemia. The most common Grade 3-4 laboratory abnormality (incidence ≥ 2%) was neutropenia.

Adverse reactions leading to study drug discontinuation occurred in 5% and 3% of patients in the LT and HT arms, respectively. The most common adverse reaction (incidence ≥ 1%) leading to discontinuation was stomatitis. Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 24% and 35% of patients in the LT and HT arms, respectively. The most common adverse reactions (incidence ≥ 3%) leading to dose adjustments in the everolimus tablets for oral suspension arms were stomatitis, pneumonia, and pyrexia.

Adverse reactions reported with an incidence of ≥ 10% for patients receiving everolimus tablets for oral suspension are presented in Table 19. Laboratory abnormalities are presented in Table 20.

Table 19: Adverse Reactions Reported in ≥ 10% of Everolimus Tablets for Oral Suspension-Treated Patients With TSC-Associated Partial-Onset Seizures in EXIST-3

Table-19 (Table 19)

The following additional adverse reactions occurred in < 10% of everolimus tablets for oral suspension treated patients (%everolimus tablets for oral suspension LT, % everolimus tablets for oral suspension HT): decreased appetite (9%, 7%), pneumonia (2%, 4%), aggression (2%, 0.8%), proteinuria (0%, 2%), menorrhagia (0.9%, 0.8%), and pneumonitis (0%, 0.8%).

Table 20: Selected Laboratory Abnormalities Reported in ≥ 10% Everolimus Tablets for Oral Suspension-Treated Patients With TSC-Associated Partial-Onset Seizures

Updated safety information from 357 patients treated with everolimus tablets for oral suspension for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

The following adverse reactions have been identified during postapproval use of everolimus tablets for oral suspension. 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

Strong or Moderate CYP3A Inhibitor and P-gp Inhibitor

Avoid the coadministration of a strong CYP3A inhibitor and P-gp inhibitor [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Reduce the dosage for everolimus tablets for oral suspension with a moderate CYP3A inhibitor and Pg-p inhibitor as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

Cannabidiol Oral Solution

Reduce the dosage of everolimus tablets for oral suspension when coadministered with cannabidiol oral solution [see Dosage and Administration (2.11)].

Coadministration with cannabidiol oral solution increases everolimus exposure [see Clinical Pharmacology (12.3)], which may increase the risk of everolimus adverse reactions. The effects of other cannabidiol productson everolimus exposure are unknown.

Strong CYP3A Inducer and P-gp Inducer

Increase the dosage for everolimus tablets for oral suspension with a strong CYP3A inducer and Pg-p inducer as recommended [see Dosage and Administration (2.11), Clinical Pharmacology (12.3)].

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

Risk Summary

Based on animal studies and the mechanism of action [see Clinical Pharmacology (12.1)], everolimus tablets for oral suspension can cause fetal harm when administered to a pregnant woman. There are limited case reports of AFINITOR use in pregnant women; however, these reports are not sufficient to inform about risks of birth defects or miscarriage. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the recommended dose of AFINITOR 10 mg orally once daily (see Data). Advise pregnant women of the potential risk to the fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage is 2% to 4% and 15% to 20% of clinically recognized pregnancies, respectively.

Data

Animal Data

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft), and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities in rats occurred at doses ≥ 0.1 mg/kg (0.6 mg/m²) with resulting exposures of approximately 4% of the human exposure at the recommended dose of AFINITOR 10 mg orally once daily based on area under the curve (AUC). In rabbits, embryo-toxicity evident as an increase in resorptions occurred at an oral dose of 0.8 mg/kg (9.6 mg/m²), approximately 1.6 times the recommended dose of AFINITOR 10 mg orally once daily or the median dose administered to patients with tuberous sclerosis complex (TSC)-associated subependymal giant cell astrocytoma (SEGA), and 1.3 times the median dose administered to patients with TSC-associated partial-onset seizures based on BSA. The effect in rabbits occurred in the presence of maternal toxicities.

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

Risk Summary

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

Pregnancy Testing

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

Contraception

Everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension. Based on these findings, everolimus tablets for oral suspension may impair fertility in female patients [see Adverse Reactions (6.1), Nonclinical Toxicology (13.1)].

Males: Cases of reversible azoospermia have been reported in male patients taking AFINITOR. In male rats, sperm motility, sperm count, plasma testosterone levels and fertility were diminished at AUC similar to those of the clinical dose of AFINITOR 10 mg orally once daily. Based on these findings, everolimus tablets for oral suspension may impair fertility in male patients [see Nonclinical Toxicology (13.1)].

TSC-Associated SEGA

The safety and effectiveness of everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension have not been established in pediatric patients less than 1 year of age with TSC-associated SEGA.

In EXIST-1, the incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age. Ninety-six percent of 23 AFINITOR-treated patients < 6 years had at least one infection compared to 67% of 55 AFINITOR-treated patients ≥ 6 years. Thirty-five percent of 23 AFINITOR-treated patients < 6 years of age had at least 1 serious infection compared to 7% of 55 AFINITOR-treated patients ≥ 6 years.

Although a conclusive determination cannot be made due to the limited number of patients and lack of a comparator arm in the open label follow-up periods of EXIST-1 and Study 2485, AFINITOR did not appear to adversely impact growth and pubertal development in the 115 pediatric patients treated with AFINITOR for a median duration of 4.1 years.

TSC-Associated Partial-Onset Seizures

The safety and effectiveness of everolimus tablets for oral suspension has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures. Use of everolimus tablets for oral suspension for this indication is supported by evidence from a randomized, double-blind, placebo-controlled trial in adult and pediatric patients (EXIST-3) with additional pharmacokinetic data in pediatric patients [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), Clinical Studies (14.6)]. The safety and effectiveness of everolimus tablets for oral suspension and AFINITOR have not been established for the adjunctive treatment of pediatric patients less than 2 years of age with TSC-associated partial-onset seizures.

The incidence of infections and serious infections were reported at a higher frequency in patients < 6 years of age compared to patients ≥ 6 years old. Seventy-seven percent of 70 everolimus tablets for oral suspension-treated patients < 6 years had at least one infection, compared to 53% of 177 everolimus tablets for oral suspension-treated patients ≥ 6 years. Sixteen percent of 70 everolimus tablets for oral suspension-treated patients < 6 years of age had at least 1 serious infection, compared to 4% of 177 everolimus tablets for oral suspension -treated patients ≥ 6 years of age. Two fatal cases due to infections were reported in pediatric patients.

Everolimus tablets for oral suspension exposure may increase in patients with hepatic impairment [see Clinical Pharmacology (12.3)].

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

Everolimus tablets for oral suspension are a 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[30.3.1.0^4,9]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:

Structure (Structure)

Everolimus tablets for oral suspension for oral administration contains 2 mg, 3 mg, or 5 mg of everolimus and the following inactive ingredients: butylhydroxytoluene, colloidal silicon dioxide, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, mannitol, and microcrystalline cellulose.

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.

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.

Exposure-Response Relationship

In patients with TSC-associated subependymal giant cell astrocytoma (SEGA), the magnitude of the reduction in SEGA volume was correlated with the everolimus trough concentration.

In patients with TSC-associated partial-onset seizures, the magnitude of the reduction in absolute seizure frequency was correlated with the everolimus trough concentration.

Cardiac Electrophysiology

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

Absorption

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 who received 9 mg of everolimus tablets for oral suspension, high-fat meals (containing approximately 1000 calories and 55 grams of fat) reduced everolimus AUC by 12% and C_max by 60% and low-fat meals (containing approximately 500 calories and 20 grams of fat) reduced everolimus AUC by 30% and C_max by 50%.

Relative Bioavailability: The AUC_inf of everolimus was equivalent between everolimus tablets for oral suspension and AFINITOR; the C_max of everolimus in the everolimus tablets for oral suspension dosage form was 20% to 36% lower than that of AFINITOR. The predicted trough concentrations at steady-state were similar after daily administration.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5000 ng/mL, is 17% to 73%. The amount of everolimus confined to plasma is approximately 20% at blood concentrations observed in cancer patients given AFINITOR 10 mg orally once daily. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment.

Elimination

The mean elimination half-life of everolimus is approximately 30 hours.

Metabolism: Everolimus is a substrate of CYP3A4. Following oral administration, everolimus is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100-times less activity than everolimus itself.

Excretion: No specific elimination studies have been undertaken in cancer patients. Following the administration of a 3 mg single dose of radiolabeled everolimus in patients who were receiving cyclosporine, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine. The parent substance was not detected in urine or feces.

Specific Populations

No relationship was apparent between oral clearance and age or sex in patients with cancer.

Patients with Renal Impairment: No significant influence of creatinine clearance (25 to 178 mL/min) was detected on oral clearance (CL/F) of everolimus.

Patients with Hepatic Impairment: Compared to normal subjects, there was a 1.8-fold, 3.2-fold, and 3.6-fold increase in AUC for subjects with mild (Child-Pugh class A), moderate (Child-Pugh class B), and severe (Child-Pugh class C) hepatic impairment, respectively. In another study, the average AUC of everolimus in subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in subjects with normal hepatic function [see Dosage and Administration (2.10), Use in Specific Populations (8.6)].

Pediatric Patients: In patients with TSC-associated SEGA or TSC-associated partial-onset seizures, the mean 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

Strong or Moderate CYP3A Inhibitor and P-gp Inhibitor: Everolimus exposure increased when AFINITOR was coadministered with:
• ketoconazole (strong CYP3A inhibitor and P-gp inhibitor) - Cmax and AUC increased 3.9- and 15-fold, respectively.
• erythromycin (moderate CYP3A inhibitor and P-gp inhibitor) - Cmax and AUC increased 2- and 4.4-fold, respectively.
• verapamil (moderate CYP3A inhibitor and P-gp inhibitor) - Cmax and AUC increased 2.3- and 3.5-fold, respectively.

Cannabidiol Oral Solution: Everolimus C_max and AUC increased 2.5-fold when coadministered with cannabidiol oral solution (12.5 mg/kg twice daily).

Strong CYP3A Inducer and P-gp Inducer: Everolimus AUC decreased to 37% and C_max decreased to 42% when AFINITOR was coadministered with rifampin (strong CYP3A inducer and P-gp inducer).

CYP3A Substrates: No clinically significant pharmacokinetic interactions were observed between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate), pravastatin (a non-CYP3A4 substrate), and simvastatin (a CYP3A4 substrate).

Midazolam (sensitive CYP3A substrate) C_max increased 1.2-fold and AUC increased 1.3-fold when oral midazolam was coadministered with AFINITOR.

Exemestane C_min increased 1.4-fold and C_2h increased 1.6-fold when coadministered with AFINITOR; 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.

Octreotide Cmin increased 1.5-fold when long-acting octreotide was coadministered with AFINITOR.

Antiepileptic Drugs (AEDs): Pre-dose concentrations of carbamazepine, clobazam, oxcarbazepine, and clobazam’s metabolite N-desmethylclobazam increased 1.1-fold when coadministered with everolimus. No significant interactions were observed on pre-dose concentrations of AEDs that are substrates of CYP3A (e.g., clonazepam and zonisamide) or other AEDs, including valproic acid, topiramate, phenobarbital, and phenytoin, when coadministered with everolimus.

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 AFINITOR 10 mg orally once daily.

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

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

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

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.

EXIST-1

A randomized (2:1), double-blind, placebo-controlled trial (EXIST-1, NCT00789828) of AFINITOR was conducted in 117 pediatric and adult patients with SEGA and TSC. Eligible patients had at least one SEGA lesion ≥ 1 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥ 1 cm in longest diameter, or new or worsening hydrocephalus. Patients randomized to the treatment arm received AFINITOR at a starting dose of 4.5 mg/m² daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated. AFINITOR or matched placebo continued until disease progression or unacceptable toxicity. MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter.

The main efficacy outcome measure was SEGA response rate based on independent central radiology review. SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus. The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).

Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo. The median age was 9.5 years (0.8 to 26 years); a total of 20 patients were < 3 years, 54 patients were 3 to < 12 years, 27 patients were 12 to < 18 years, and 16 patients were ≥ 18 years; 57% were male, and 93% were white. At baseline, 18% of patients were receiving EIAEDs. Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥ 1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥ 2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus. The median values for the sum of all target SEGA lesions at baseline were 1.63 cm³ (0.18 to 25.15 cm³) and 1.30 cm³ (0.32 to 9.75 cm³) in the AFINITOR and placebo arms, respectively. Eight (7%) patients had prior SEGA-related surgery. The median duration of follow-up was 8.4 months (4.6 to 17.2 months) at the time of primary analysis.

The SEGA response rate was statistically significantly higher in AFINITOR-treated patients (Table 26). At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (2.1 to 8.4 months).

With a median follow-up of 8.4 months, SEGA progression was detected in 15.4% of the 39 patients randomized to receive placebo and none of the 78 patients randomized to receive AFINITOR. No patient in either treatment arm required surgical intervention.

Table 26: Subependymal Giant Cell Astrocytoma Response Rate in TSC-Associated SEGA in EXIST-1

Patients randomized to placebo were permitted to receive AFINITOR at the time of SEGA progression or after the primary analysis, whichever occurred first. After the primary analysis, patients treated with AFINITOR underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized. A total of 111 patients (78 patients randomized to AFINITOR and 33 patients randomized to placebo) received at least one dose of AFINITOR. Median duration of AFINITOR treatment and follow-up was 3.9 years (0.2 to 4.9 years).

By four years after the last patient was enrolled, 58% of the 111 patients treated with AFINITOR had a ≥ 50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis. The median time to SEGA response was 5.3 months (2.5 to 33.1 months). Twelve percent of the 111 patients treated with AFINITOR had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the study.

Study 2485

Study 2485 (NCT00411619) was an open-label, single-arm trial conducted to evaluate the antitumor activity of AFINITOR 3 mg/m²/orally once daily in patients with SEGA and TSC. Serial radiological evidence of SEGA growth was required for entry. Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier. The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review. Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥ 25% over the nadir observed on study.

A total of 28 patients received AFINITOR for a median duration of 5.7 years (5 months to 6.9 years); 82% of the 28 patients remained on AFINITOR for at least 5 years. The median age was 11 years (3 to 34 years), 61% male, 86% white.

At the primary analysis, 32% of the 28 patients (95% CI: 16%, 52%) had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion. At the completion of the study, the median duration of durable response was 12 months (3 months to 6.3 years).

By 60 months after the last patient was enrolled, 11% of the 28 patients had documented disease progression. No patient developed a new SEGA lesion while on AFINITOR. Nine additional patients were identified as having a ≥ 50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating AFINITOR, including 3 patients who had surgical resection with subsequent regrowth prior to receiving AFINITOR.

The efficacy of everolimus tablets for oral suspension as an adjunctive anti-epileptic drug (AED) was evaluated in a randomized, double-blind, multicenter, placebo-controlled study conducted in patients with TSC-associated partial-onset seizures (EXIST-3, NCT01713946). Patients with a history of inadequate control of partial-onset seizures despite treatment with ≥ 2 sequential AED regimens were randomized to receive placebo or everolimus tablets for oral suspension once daily at a dose to achieve a low trough (LT) level (3-7 ng/mL) or a high trough (HT) level (9-15 ng/mL). Randomization was stratified by age group (1 to < 6, 6 to < 12, 12 to < 18, ≥ 18 years). The study consisted of 3 phases: an 8-week Baseline observation phase; an 18-week double-blind, placebo-controlled Core phase (6-week titration period and a 12-week maintenance period), and an Extension phase of ≥ 48 weeks. Patients were required to have a diagnosis of TSC per the modified Gomez criteria, and ≥ 16 partial-onset seizures during the Baseline phase while receiving a stable dose of 1 to 3 concomitant AEDs. The starting doses for everolimus tablets for oral suspension in the Core phase ranged from 3 to 6 mg/m² orally once daily, depending on age, in patients not receiving concomitant CYP3A4/P-gp inducers and from 5 to 9 mg/m² orally once daily, depending on age, in patients receiving concomitant CYP3A4/P-gp inducers. During the 6-week titration period, everolimus trough levels were assessed every 2 weeks and up to 3 dose adjustments were allowed to attempt to reach the targeted everolimus trough concentration range.

The major efficacy outcome measure was the percentage reduction in seizure frequency from the Baseline phase, during the maintenance period of the Core phase. Additional efficacy outcome measures included response rate, defined as at least a 50% reduction in seizure frequency from the Baseline phase during the maintenance period of the Core phase, and seizure freedom rate during the maintenance period of the Core phase.

A total of 366 patients were randomized to everolimus tablets for oral suspension LT (n = 117), everolimus tablets for oral suspension HT (n = 130) or placebo (n = 119). Median age was 10.1 years (2.2 to 56 years); 28% of patients were < 6 years, 31% were 6 to < 12 years, 22% were 12 to < 18 years, and 18% were ≥ 18 years). The majority were white (65%) and male (52%). The most common major features of TSC were cortical tubers (92%), hypomelanotic macules (84%), and subependymal nodules (83%). While 17% of the patients had SEGA, 42% had renal angiomyolipoma, and 9% had both SEGA and renal angiomyolipoma; no patients were receiving treatment with AFINITOR or everolimus tablets for oral suspension for these manifestations of TSC. During the Baseline phase, 65% of patients had complex partial seizures, 52% had secondarily generalized seizures, 19% had simple partial seizures, and 2% had generalized onset seizures. The median seizure frequency per week during the Baseline phase was 9.4 for all patients and 47% of patients were receiving 3 AEDs during the Baseline phase. The efficacy results are summarized in Table 27.

Table 27: Percentage Reduction in Seizure Frequency and Response Rate in TSC-Associated Partial-Onset Seizures in EXIST-3

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

Everolimus Tablets for Oral Suspension

• 2 mg tablets for oral suspension: White to slightly yellowish speckled, round flat tablets, no score, debossed with "N 773" on one side and plain on the other side, free from physical defects; available in:

Blisters of 28 tablets.......................................................................................NDC 70954-773-20

Each carton contains 4 blister cards of 7 tablets each



• 3 mg tablets for oral suspension: White to slightly yellowish speckled, round flat tablets, no score, debossed with "N 774" on one side and plain on the other side, free from physical defects; available in:

Blisters of 28 tablets.......................................................................................NDC 70954-774-20

Each carton contains 4 blister cards of 7 tablets each



• 5 mg tablets for oral suspension: White to slightly yellowish speckled, round flat tablets, no score, debossed with "N 775" on one side and plain on the other side, free from physical defects; available in:

Blisters of 28 tablets.......................................................................................NDC 70954-775-20

Each carton contains 4 blister cards of 7 tablets each




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




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




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

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

Non-infectious Pneumonitis

Advise patients of the risk of developing non-infectious pneumonitis and to immediately report any new or worsening respiratory symptoms to their healthcare provider [see Warnings and Precautions (5.1)].

Infections

Advise patients that they are more susceptible to infections and that they should immediately report any signs or symptoms of infections to their healthcare provider [see Warnings and Precautions (5.2)].

Hypersensitivity Reactions

Advise patients of the risk of clinically significant hypersensitivity reactions and to promptly contact their healthcare provider or seek emergency care for signs of hypersensitivity reaction, including rash, itching, hives, difficulty breathing or swallowing, flushing, chest pain, or dizziness [see Contraindications (4), Warnings and Precautions (5.3)].

Angioedema with Concomitant Use of ACE Inhibitors

Advise patients to avoid ACE inhibitors and to promptly contact their healthcare provider or seek emergency care for signs or symptoms of angioedema [see Warnings and Precautions (5.4)].

Stomatitis

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

Renal Impairment

Advise patients of the risk of developing kidney failure and the need to monitor their kidney function periodically during treatment [see Warnings and Precautions (5.6)].

Risk of Impaired Wound Healing

Advise patients that everolimus tablets for oral suspension may impair wound healing. Advise patients to inform their healthcare provider of any planned surgical procedure [see Warnings and Precautions (5.7)].

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 everolimus tablets for oral suspension 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 everolimus tablets for oral suspension 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)].

All trademarks are the property of their respective owners.

Distributed by:

ANI Pharmaceuticals, Inc.

Baudette, MN 56623

Issued: 06/2026

LB4872-00

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

Revised: 06/2026
LB4872-00

Everolimus (e″ ver oh′ li mus)

Tablets For Oral Suspension

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

Important Information:

• Take everolimus tablets for oral suspensionas a suspension only. Everolimus tablets for oral suspension is prepared as a suspension of undissolved medicine that is mixed with water, and then it is taken by mouth. Do not chew, crush, or swallow everolimus tablets for oral suspension whole.
• Everolimus tablets for oral suspensioncan cause harm to an unborn baby. When possible, the suspension should be prepared by an adult who is not pregnant or planning to become pregnant.
• Keep everolimus tablets for oral suspensionand the prepared suspension out of the reach of children.
• Anyone who prepares suspensions of everolimus tablets for oral suspensionfor another person should wear gloves to avoid possible contact with the drug.
• Only use water with everolimus tablets for oral suspensionto prepare the suspension. Do not prepare the suspension with juice or any other liquids.
• The suspension must be given right away. If you do not give the dose within 60 minutes after it has been prepared, throw away the dose and prepare a new dose of everolimus tablets for oral suspension.
• Before starting to prepare the suspension, collect all of the supplies that you will need to prepare and take the suspension. Do not use any of these supplies for purposes other than preparing and taking the everolimus tablets for oral suspension.



Supplies needed to prepare the suspension in an oral syringe:

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




Figure A (Figure A)

                            Figure A

 

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

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



Preparing a dose of everolimus tablets for oralsuspension using an oral syringe:




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

 

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



Figure-b (Figure B)

                        Figure B

 

Step 3: If preparing the everolimus tablets for oral suspension for another person, put on disposable gloves (see Figure C).



Figure-c (Figure C)

                        Figure C

 

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





Figure-d (Figure D)

                        Figure D

 

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



Figure-e (Figure E)

                        Figure E





Figure-f (Figure F)

                        Figure F

 

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



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



Figure-g (Figure G)

                             Figure G





Figure-h (Figure H)

                             Figure H

 

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



Figure-i (Figure I)




                            Figure I

 

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



Figure-j (Figure J)

                        Figure J

 

Step 9: Place the filled oral syringe in the clean, empty glass with the tip pointing up. Wait 3 minutes to allow everolimus tablets for oral suspension to break apart (see Figure K).



Figure-k (Figure K)




                        Figure K

 

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



Figure-l (Figure L)

                             Figure L

 

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



Figure-m (Figure M)

                             Figure M

 

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



Figure-n (Figure N)

                             Figure N

 

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



Figure-o (Figure O)

                             Figure O

 

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



Figure-p (Figure P)

                             Figure P

 

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



Figure-q (Figure Q)

                        Figure Q

 

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



Figure-r (Figure R)

                        Figure R

 

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



Figure-s (Figure S)

                   Figure S

 

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

 

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

 

Step 19: Wash your hands.

 

Preparing a dose of everolimus tablets for oral suspension using a small drinking glass:

 

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

 

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



Figure-t (Figure T)




                        Figure T

 

Step 3: If preparing the everolimus tablets for oral suspension for another person, put on disposable gloves (see Figure U).



Figure-u (Figure U)




                        Figure U

 

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



Figure-v (Figure V)

                        Figure V

 

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



Figure-w (Figure W)

                        Figure W

 

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

 

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



Figure-x (Figure X)

                        Figure X

 

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



Figure-y (Figure Y)

                        Figure Y

 

Step 8: Wait 3 minutes to allow everolimus tablets for oral suspension to break apart (see Figure Z).



Figure-z (Figure Z)

                            Figure Z

 

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



Figure-aa (Figure Aa)




                        Figure AA





Figure-bb (Figure Bb)




                        Figure BB

 

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



Figure-cc (Figure Cc)

                        Figure CC





Figure-dd (Figure Dd)

                        Figure DD

 

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

 

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



Figure-ee (Figure Ee)

                        Figure EE

 

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

 

Step 13: Wash your hands.

 

How should I store everolimus tablets for oral suspension?

• Store everolimus tablets for oral suspensionat room temperature, between 68°F to 77°F (20°C to 25°C).
• Keep everolimus tablets for oral suspensionin the pack it comes in.
• Open the blister pack just before taking everolimus tablets for oral suspension.
• Keep everolimus tablets for oral suspensiondry and away from light.
• Do not use everolimus tablets for oral suspensionthat is out of date or no longer needed.



Keep everolimus tablets for oral suspension and all medicines out of the reach of children.




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




Distributed by:

ANI Pharmaceuticals, Inc.

Baudette, MN 56623




Issued: 06/2026

LB4915-00

Everolimus Tablets for Oral Suspension, 2 mg

Blister Label

NDC 70954-773-10

Blister-2mg (Blister 2mg)

Carton Label

NDC 70954-773-20 - 28 Tablets (4 individual blister cards of 7 tablets)

Carton-2mg (Carton 2mg)

Everolimus Tablets for Oral Suspension, 3 mg

Blister Label

NDC 70954-774-10

Blister-3mg (Blister 3mg)

Carton Label

NDC 70954-774-20  - 28 Tablets (4 individual blister cards of 7 tablets)

Carton-3mg (Carton 3mg)

Everolimus Tablets for Oral Suspension, 5 mg

Blister Label

NDC 70954-775-10

Blister-5mg (Blister 5mg)

Carton Label

NDC 70954-775-20  - 28 Tablets (4 individual blister cards of 7 tablets)

Carton-5mg (Carton 5mg)