Get your patient on Everolimus

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 is 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.
• 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 starting dosage of everolimus tablets for oral suspension is 4.5 mg/m ² 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/m ² 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 2 summarizes recommendations for dosage modifications of everolimus tablets for oral suspension for the management of 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) ] :

• 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 everolimus tablets for oral suspension with a P-gp and moderate CYP3A4 inhibitor as recommended in Table 4 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] .

• Avoid concomitant use of St. John’s Wort (Hypericum perforatum) .

• Increase the dose for patients taking everolimus tablets for oral suspension with a P-gp and strong CYP3A4 inducer as recommended in Table 5 [see Drug Interactions (7.1) , Clinical Pharmacology (12.3) ] .

• 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 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) ] .

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 has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1) ] . Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections, invasive fungal infections (e.g., aspergillosis, candidiasis, or PJP), and viral infections (e.g., reactivation of hepatitis B virus) have occurred. Some of these infections have been severe (e.g., sepsis, septic shock, or resulting in multisystem organ failure) or fatal. The incidence of Grade 3 and 4 infections was up to 10% and up to 3%, respectively. The incidence of serious infections was reported at a higher frequency in patients < 6 years of age [see Use in Specific Populations (8.4) ] .

Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue 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. 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. 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) ].

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 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

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) ] .

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 were administered a single oral dose of AFINITOR (20 mg and 50 mg) and placebo. AFINITOR at single doses up to 50 mg did not prolong the QT/QTc interval.

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/m ² /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.

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/m ² orally once daily, depending on age, in patients not receiving concomitant CYP3A4/P-gp inducers and from 5 to 9 mg/m ² 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 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 26.

Table 26: Percentage Reduction in Seizure Frequency and Response Rate in TSC-Associated Partial-Onset Seizures in EXIST-3