Important Safety Information:

AFINITOR DISPERZ is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

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Indication: AFINITOR DISPERZ® (everolimus tablets for oral suspension) is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures.

Efficacy

EXIST-3 Results

EXIST-3 demonstrated the efficacy of adjunctive AFINITOR DISPERZ® (everolimus tablets for oral suspension) with AED therapy in patients with TSC-associated partial-onset seizures.1,2

EXIST-3 Study Design demonstrating efficacy of AFINITOR DISPERZ® (everolimus tablets for oral suspension)

AEDs, antiepileptic drugs.


EXIST-3 (EXamining everolimus In a Study of TSC) was a large (N=366), 3-arm, randomized, double-blind, placebo-controlled, phase 3 study evaluating the efficacy and safety of everolimus as adjunctive treatment in patients with TSC receiving 1 to 3 AEDs and who have recurrent seizures.

 

Patient Population

The study included a mostly pediatric population with inadequate control of partial-onset seizures.1

  • Trial population was stratified by age
  • 82% were pediatric patients; median age was 10.1 years (2 to 56)

 

Distribution of patients by age (in years)

 EXIST-3 Study Design Patient Population: Distribution of age category

 

During the baseline phase of the trial, more than 89% of enrolled patients were receiving 2 or more AEDs.2  

 

Number of AEDs in regimen during baseline

EXIST-3 Study Design Patient Population: Number of AEDs in regimen during baseline

 

  • Prior to the study, the majority of all patients (67%) had failed ≥5 AEDs 
  • All patients had at least 8 seizures per week (median) (10.5, placebo; 8.6 and 9.5, AFINITOR DISPERZ 3-7 ng/mL and 9-15 ng/mL group, respectively)
  • At baseline, 65% of patients had complex partial seizures, 52% had secondarily generalized seizures, 19% had simple partial seizures, and 2% had generalized onset seizures

 

Efficacy Outcome Measures

EXIST-3 measured the impact of AFINITOR DISPERZ + other AED therapies on seizure frequency response in patients with TSC-associated partial-onset seizures.1


Major efficacy outcome measure:

  • Percentage reduction from baseline in seizure frequency during the maintenance period of the core phase

Additional efficacy outcome measures:

  • Response rate, defined as at least a 50% reduction from baseline in seizure frequency during the maintenance period of the core phase
  • Seizure freedom rate

 

Results

AFINITOR DISPERZ + AED therapy demonstrated statistically significant percentage reductions in seizure frequency

Reduction in seizure frequency vs placebo (median, from baseline)1

Reduction in seizure frequency vs placebo (median, from baseline)

 Seizures per week (median)

Seizures per week - Median

 

Consistent results were found for the response rate, defined as ≥50% reduction from baseline in seizure frequency:

AFINITOR DISPERZ® (everolimus tablets for oral suspension) vs placebo response rate

 
Observed responses in seizure freedom outcome measures 

No SeizureThe seizure-free rate was defined as the proportion of patients who became seizure free during the maintenance period of the core phase. Results were2:

  • 3.8% (95% CI, 1.3-8.7) in the AFINITOR DISPERZ 9-15 ng/mL group
  • 5.1% (95% CI, 1.9-10.8) in the AFINITOR DISPERZ 3-7 ng/mL group
  • 0.8% (95% CI, 0-4.6) in the placebo group

 

Number of DaysThe median number of seizure-free days (per 28-day period) increased from baseline by 2.0 in the AFINITOR DISPERZ 3-7 ng/mL group and 4.0 days in the AFINITOR DISPERZ 9-15 ng/mL group, compared with 0.5 days in the placebo group.

 


Seizure freedom results reported were not prespecified and are observational in nature; as such, there was no prespecified statistical procedure controlling for type 1 error.

A consistent effect was observed in patients taking AFINITOR DISPERZ across all subgroups2:

  • Age 
  • Gender
  • Race and ethnicity
  • Seizure types
  • Seizure frequency at baseline
  • Number of concomitant antiepileptic drugs

 

Extension Trial Results

 

Up to 2 years of observed data in EXIST-3 extension trial3

Study design3

  • After completion of the core phase, 361 patients entered an open-label extension phase and received AFINITOR DISPERZ® (everolimus tablets for oral suspension) for ≥48 weeks
  • Patients in the core phase of the trial transitioned from placebo to AFINITOR DISPERZ in the extension phase. They received 3 ng/mL to 7 ng/mL of AFINITOR DISPERZ or 9 ng/mL to 15 ng/mL of AFINITOR DISPERZ

Observed data in EXIST-3 Extension Trial design and results

Primary end points3

  • Change from baseline in average weekly seizure frequency, including response rate (≥50% reduction) and median percentage reduction in seizure frequency

 

Greater reduction in seizure frequency observed over time while on AFINITOR DISPERZ + AED therapy3

Greater reduction in seizure frequency observed over time while on AFINITOR DISPERZ + AED therapy

* Of the 361 patients enrolled in the EXIST-3 extension phase, 9 patients discontinued AFINITOR DISPERZ treatment before week 7.4

 Safety results were consistent with core phase, except that incidence and severity of infections increased.

EXIST-3 extension trial study limitations3

Limitations included lack of placebo arm and lack of assessments related to change in AEDs

  • Although a large number of patients (n=202) had achieved 2 years of treatment follow-up, there was a decreasing number of evaluable patients over time
  • Ninety-five patients discontinued everolimus before achieving 2 years of follow-up, and 103 patients did not attain the 2 years of follow-up at the time of data cutoff
  • A conservative analysis, which considered patients who discontinued treatment as nonresponders, confirmed the sustained efficacy of everolimus over time and suggested that once patients have responded, the efficacy of everolimus is typically maintained

 Safety results were consistent with core phase, except that incidence and severity of infections increased.

 

Neurologist Perspective Video

Watch Darcy A. Krueger, MD, PhD, a leading pediatric neurologist at Cincinnati Children's Hospital Medical Center, share his experience treating patients who have TSC-associated partial-onset seizures with AFINITOR DISPERZ.

References:

  1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.

  2. French JA, Lawson JA, Yapici Z, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet. 2016;388(10056):2153-2163.

  3. Franz DN, Lawson JA, Yapici Z, et al. Everolimus for treatment-refractory seizures in TSC. Neurol Clin Pract. 2018;8:1-9. doi:10.1212/CPJ.0000000000000514.

  4. Data on file. Afinitor (everolimus) Core Data Sheet: Version 3.1. Novartis Pharma AG; March 2017.

 

INDICATION

AFINITOR DISPERZ® (everolimus tablets for oral suspension) is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures.

IMPORTANT SAFETY INFORMATION

AFINITOR DISPERZ is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Noninfectious Pneumonitis: Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR; some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of grade 3 and 4 noninfectious pneumonitis was up to 4% and up to 0.2%, respectively. Fatal outcomes have been observed. Monitor for clinical symptoms or radiological changes. Consider opportunistic infections such as Pneumocystis jiroveci pneumonia (PJP) in the differential diagnosis. For grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue based on severity. Corticosteroids may be indicated until clinical symptoms resolve. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required. The development of pneumonitis has been reported even at a reduced dose.

Infections: AFINITOR DISPERZ has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoal infections, including those with opportunistic pathogens. Localized and systemic infections, including pneumonia, mycobacterial infections, other bacterial infections; invasive fungal infections, such as aspergillosis, candidiasis, or PJP; and viral infections, including reactivation of hepatitis B virus, have occurred. Some of these infections have been severe (eg, 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. Complete treatment of preexisting invasive fungal infections prior to starting treatment. Monitor for signs and symptoms of infection. Withhold or permanently discontinue AFINITOR DISPERZ based on severity of infection. Administer prophylaxis for PJP when concomitant use of corticosteroids or other immunosuppressive agents are required.

Severe Hypersensitivity Reactions: Hypersensitivity reactions to AFINITOR DISPERZ have been observed and include anaphylaxis, dyspnea, flushing, chest pain, and angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). The incidence of grade 3 hypersensitivity reactions was up to 1%. Permanently discontinue AFINITOR DISPERZ for the development of clinically significant hypersensitivity.

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitors with AFINITOR DISPERZ may be at increased risk for angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment). In a pooled analysis, the incidence of angioedema in patients taking everolimus with an ACE inhibitor was 6.8% compared to 1.3% in the control arm with an ACE inhibitor. Permanently discontinue AFINITOR DISPERZ for angioedema.

Stomatitis: Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR or AFINITOR DISPERZ at an incidence ranging from 44% to 78% across the clinical trial experience. Grade 3/4 stomatitis was reported in 4% to 9% of patients. Stomatitis most often occurs within the first 8 weeks of treatment. When starting AFINITOR DISPERZ, 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, but alcohol-, hydrogen peroxide-, iodine-, or thyme-containing products should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Renal Failure: Cases of renal failure (including acute renal failure), some with a fatal outcome, have occurred in patients taking AFINITOR. Elevations of serum creatinine and proteinuria have been reported in patients taking AFINITOR or AFINITOR DISPERZ. The incidence of grade 3 and 4 elevations of serum creatinine was up to 2% and up to 1%, respectively. The incidence of grade 3 and 4 proteinuria was up to 1% and up to 0.5%, respectively. Monitor renal function prior to starting AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

Risk of Impaired Wound Healing: Impaired wound healing can occur in patients who receive drugs that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. Therefore, AFINITOR DISPERZ has the potential to adversely affect wound healing. Withhold AFINITOR DISPERZ for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing occurs. The safety of resuming treatment upon resolution of wound healing complications has not been established.

Metabolic Disorders: Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR or AFINITOR DISPERZ at an incidence up to 75%, 86%, and 73%, respectively. The incidence of these grade 3 and 4 laboratory abnormalities was up to 15% and up to 0.4%, respectively. In nondiabetic patients, monitor fasting serum glucose prior to starting AFINITOR DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR DISPERZ and once yearly thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR DISPERZ. For grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR DISPERZ based on severity.

Myelosuppression: Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR or AFINITOR DISPERZ. The incidence of these grade 3 and 4 laboratory abnormalities was up to 16% and up to 2%, respectively. Monitor complete blood count prior to starting AFINITOR DISPERZ, every 6 months for the first year of treatment, and annually thereafter. Withhold or permanently discontinue AFINITOR DISPERZ based on severity.

Risk of Infection or Reduced Immune Response With Vaccinations: The safety of immunization with live vaccines during AFINITOR DISPERZ therapy has not been studied. Due to the potential increased risk of infection and/or reduced immune response to the vaccine, avoid the use of live vaccines and close contact with individuals who have received live vaccines during treatment with AFINITOR DISPERZ. Due to the potential increased risk of infection or reduced immune response with vaccination, complete the recommended childhood series of live vaccinations according to American Council on Immunization Practices (ACIP) guidelines prior to the start of therapy. An accelerated vaccination schedule may be appropriate.

Radiation Sensitization and Radiation Recall: 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 before, during, or after AFINITOR DISPERZ treatment. Monitor patients closely when administering AFINITOR DISPERZ during, or sequentially with, radiation treatment.

Embryo-Fetal Toxicity: Based on animal studies and the mechanism of action, AFINITOR DISPERZ can cause fetal harm when administered to a pregnant woman. In animal studies, everolimus caused embryo-fetal toxicities in rats when administered during the period of organogenesis at maternal exposures that were lower than human exposures at the clinical dose of 10 mg once daily. Advise pregnant women of the potential risk to a fetus. Advise female patients of reproductive potential to avoid becoming pregnant and to use effective contraception during treatment with AFINITOR DISPERZ and for 8 weeks after the last dose. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with AFINITOR DISPERZ and for 4 weeks after the last dose.

Adverse Reactions: The most common adverse reaction reported for AFINITOR DISPERZ (incidence ≥30%, all grades) was stomatitis (55% low trough, 64% high trough). The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis, pneumonia, and irregular menstruation. Updated safety information from 357 patients treated with AFINITOR DISPERZ for a median duration of 48 weeks identified the following additional notable adverse reactions: hypersensitivity (0.6%), angioedema (0.3%), and ovarian cyst (0.3%).

Laboratory Abnormalities: The most common laboratory abnormality (incidence ≥50%, all grades) was hypercholesterolemia (86% low trough, 85% high trough). The most common grade 3/4 laboratory abnormality (incidence ≥2%) was neutropenia.

Please see full Prescribing Information.