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April 10, 2018–Everolimus tablets approved for oral suspension (Afinitor Disperz®, Novartis Pharmaceuticals Corp.) for the adjunctive treatment of adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures (with Pharmacist's Applications to Practice)

February 26, 2016–Everolimus (Afinitor®) approved for the treatment of adult patients with progressive, well-differentiated non-functional, neuroendocrine tumors


April 10, 2018, with PAP

https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022334s040,203985s013lbl.pdf

On April 10, 2018, the Food and Drug Administration approved everolimus tablets for oral suspension (Afinitor Disperz®, Novartis Pharmaceuticals Corp.) for the adjunctive treatment of adult and pediatric patients aged 2 years and older with tuberous sclerosis complex (TSC)-associated partial-onset seizures. Everolimus is also approved for two other manifestations of TSC: TSC-associated subependymal giant cell astrocytoma (SEGA) and TSC-associated renal angiomyolipoma.

Approval was based on EXIST-3 (NCT01713946), a randomized, double-blind, multicenter trial in 366 patients with TSC-associated partial-onset seizures, inadequate seizure control with ≥ 2 sequential anti-epileptic drug (AED) regimens, and a TSC diagnosis (modified Gomez criteria). Additionally, eligible patients were required to have ≥ 16 partial-onset seizures during the 8-week baseline phase on a stable AED regimen.

Patients were randomized (1:1.09:1) to Afinitor Disperz targeting a low trough (LT, n=117) or high trough (HT, n=130) concentration of everolimus or placebo (n=119). Patients initiated treatment with Afinitor Disperz/matching placebo at 3 to 6 mg/m2 (depending on age or further adjusted for concomitant CYP3A4/P-glycoprotein inducer use) orally once daily. Subsequent doses were titrated to achieve the targeted trough concentrations as directed by an automated system to maintain the study blind. The major efficacy measure was the percentage reduction in average weekly seizures during a 12-week treatment period compared with the average weekly seizures during the 8-week baseline period.

The trial demonstrated statistically significant reductions in seizures for each of the Afinitor Disperz arms (LT arm 29.3% [95% CI: 18.8, 41.9; p=0.003] and HT arm 39.6% [95% CI: 35, 48.7; p<0.001]) compared with the placebo arm (14.9% [95% CI: 0.1, 21.7]). The proportion of patients with 50% reduction in seizure frequency during the 12-week treatment period compared with baseline also was higher in the LT and HT Afinitor Disperz arms (28.2% and 40%, respectively) compared with the placebo arm (15.1%).

The most common adverse reactions (occurring in at least 10% of patients receiving Afinitor Disperz in EXIST-3) were stomatitis, diarrhea, vomiting, nasopharyngitis, upper respiratory tract infection, pyrexia, cough, and rash.

The recommended starting dose of Afinitor Disperz for this indication is 5 mg/m2 orally once daily with dose adjustments (in increments up to 5 mg) to achieve trough concentrations of 5-15 ng/mL. The dose of Afinitor Disperz should be reduced in patients with severe hepatic impairment or in patients taking concurrent p-glycoprotein and moderate CYP3A4 inhibitors. The dose of Afinitor Disperz should be increased in patients taking concurrent p-glycoprotein and strong CYP3A4 inducers.

Full prescribing information is available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/022334s040,203985s013lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).


Pharmacist's Applications to Practice

Everolimus as Adjunctive Treatment for Patients 2 Years and Older with Tuberous Sclerosis Complex–Associated Partial-Onset Seizures

Author: Michael J. Williams, PharmD
PGY-2 Pharmacy Resident in Oncology
Aurora Health Care
Milwaukee, WI

What is the potential role for everolimus in the treatment of tuberous sclerosis complex (TSC)–associated partial-onset seizures?1-4

  • On April 10, 2018, the U.S. Food and Drug Administration (FDA) expanded approved indications for everolimus to include its use as an adjunctive treatment of TSC-associated partial-onset seizures in both pediatric and adult patients.
  • Approximately 60% of patients with TSC-associated epilepsy may be resistant to current practice approaches, including antiepileptic drugs and nonpharmacologic therapies.
  • Everolimus targets the molecular cause of TSC-associated seizures as opposed to controlling symptoms alone.
    • The mechanism of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is able to limit signaling of mTOR, a pathway known to cause epilepsy due to dysregulation and hyperactivation in patients with TSC.
    • The role of everolimus in these patients may be two-fold: it has also been approved by the FDA for the treatment of subependymal giant-cell astrocytoma and renal angiopyolipoma, both of which are known complications of TSC.
  • The most recent TSC consensus group meeting in 2013 suggests that TSC-associated epilepsy should be treated like other partial epilepsy types, especially given the paucity of data for this indication.
  • Current American Academy of Neurology guidelines offer options for treatment in children for prevention of seizure recurrence, including but not limited to lamotrigine, zonisamide, topiramate, carbamazepine, and levitiracetam.
  • The Novartis-funded EXIST-3 trial, the largest known cause-specific epilepsy trial, evaluated pediatric and adult patients (2–65 years) with TSC who had treatment-resistant epilepsy, defined as having 16 or more seizures in an 8-week baseline phase with no 21-day continuous seizure-free period. Patients must also have been on 1–3 antiepileptic medications at a stable dose for 12 weeks prior to randomization.
    • Participants (N = 366) were randomly assigned 1:1:1 to placebo, low-exposure (trough 3–7 ng/ml), and high-exposure (trough 9–15 ng/ml) groups and stratified by age subgroup (less than 6 years, 6 to less than 12 years, 12 to less than 18 years, and 18 years or older).
    • Change from baseline in seizure frequency (response rate) during the maintenance phase for the placebo, low-exposure, and high-exposure groups was 15.1%, 28.2% (p = .0077), and 40% (p < .0001), respectively.
    • Median percent of seizure-frequency reduction between placebo, low-exposure, and high-exposure groups was 14.9%, 29.3% (p = .0028), and 39.6% (p < .0001), respectively.
  • Everolimus may serve as a safe suitable add-on option for patients who are unable to achieve seizure control despite optimization of existing antiepileptic therapy.

What role can the pharmacist play in the management of patients on everolimus? 2,5,6

  • Dosing and therapeutic drug monitoring
    • In contrast to the dosing of everolimus for other indications, dosing for patients with TSC-associated partial-onset seizures should be initiated at 5 mg/m2 once daily.
    • Goal trough concentrations, established by the EXIST-3 trial, are between 5 and 15 ng/ml.
      • A follow-up review of the everolimus exposure-response relationship suggests that an initial goal of 5-7 ng/ml is appropriate, with subsequent dose titrations as needed for response.
    • Pharmacists serve as stewards for therapeutic drug monitoring. Trough levels should be obtained 1–2 weeks after the following:
      • treatment initiation
      • dose modification
      • addition or discontinuation of concurrent CYP3A4/P-glycoprotein (P-gp) inhibitors or inducers.
    • If the patient’s body surface area (BSA) is changing significantly but all else is stable, levels should be checked every 3–6 months; if BSA is stable, levels may be checked every 6–12 months.
    • Pharmacists may use linear kinetics to best estimate dose modifications in response to a trough level.
      • In the EXIST-3 trial, dose modifications were made in increments of 2 mg for patients not on concomitant CYP3A4 inducers and 4 mg for those who were on concomitant CYP3A4 inducers.
    • Dose adjustments
      • No renal adjustments are necessary.
      • In cases of severe hepatic impairment (Child-Pugh class C), the dose should be reduced to 2.5 mg/m2 once daily, and the drug level should be monitored 2 weeks after any significant hepatic function change.
  • Pertinent drug interactions
    • Avoid concomitant use of P-gp and strong CYP3A4 inhibitors.
    • Empiric dose reductions may be required if the drug is given with concomitant moderate CYP3A4 inhibitors or inducers; recommendations can be found in the prescribing information.
  • Adverse reactions2
    • Stomatitis (59.5%) was the only adverse event of any grade and was seen in less than 20% of patients, regardless of trough goal. Recommendations for dose adjustments based on the severity of stomatitis can be found in the prescribing information.
    • Grade 3/4 adverse events were significant for stomatitis (3.5%); others occurred at an incidence of less than 2%: vomiting, headache, hypercholesterolemia, decreased appetite, hypertriglyceridemia, pharyngitis, ear infection, and influenza.

Clinical Pearls2,5

  • Everolimus for TSC-associated partial-onset seizures is available under the brand name Afinitor Disperz (everolimus tablets for oral suspension).
    • It is available as 2-mg, 3-mg, and 5-mg tablets.
    • Doses should be administered at the same time each day and may be given with or without food.
    • If a dose is missed, it may be made up within 6 hours of the usual administration time; otherwise the dose should be skipped and taken at the next scheduled time.
    • Preparation
      • The drug should be administered in suspension only and taken immediately after preparation.
      • The tablets should not be crushed or broken.
      • When using an oral syringe:
        • Place prescribed dose into a 10-ml syringe (maximum 10 mg per syringe).
        • Draw 5 ml of water and 4 ml of air into the syringe.
        • Place the syringe tip up in a container for 3 minutes until contents are in suspension.
        • Invert the syringe gently 5 times immediately prior to administration.
        • After administration, again draw 5 ml of water and 4 ml of air into the same syringe, swirl contents, and administer the remaining contents of the syringe.
      • When using a small drinking glass:
        • Place the prescribed dose into a small drinking glass containing 25 ml of water (maximum 10 mg per glass).
        • Allow 3 minutes for the tablet to suspend.
        • Stir the contents gently with a spoon immediately prior to administration.
        • After administration, add 25 ml of water and stir with the same spoon to resuspend the remaining contents and administer.
  • The duration of treatment may be prolonged or indefinite; long-term studies may better describe safety and efficacy with chronic use.

References

  1. U.S. Food and Drug Administration. FDA approves everolimus for tuberous sclerosis complex-associated partial-onset seizures. April 10, 2018. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm604351.htm.
    Accessed May 23, 2018.
  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. Krueger DA, Northrup H. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013;49(4):255-265.
  4. Hirtz D, Berg A, Bettis D, et al. Practice parameter: treatment of the child with a first unprovoked seizure: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2003;60(2):166-175.
  5. Afinitor Disperz (everolimus) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; April 2018.
  6. Franz DN, Lawson JA, Yapici Z, et al. Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures. Epilepsia. 2018. doi:10.1111/epi.14085. [Epub ahead of print].

February 26, 2016

http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s036lbl.pdf

On February 26, 2016, the U. S. Food and Drug Administration approved everolimus (Afinitor® , Novartis) for the treatment of adult patients with progressive, well-differentiated non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease.

Today’s approval was based on demonstration of improvement in progression-free survival (PFS) in a multicenter, randomized (2:1), placebo-controlled trial of everolimus 10 mg orally once daily plus best supportive care (BSC) to placebo plus BSC.

The clinical trial enrolled 302 patients with unresectable, locally advanced or metastatic, well differentiated (low or intermediate grade), non-functional (no current or prior history of carcinoid symptoms), neuroendocrine tumors (NET) of gastrointestinal or lung origin. All patients were required to have evidence of disease progression within 6 months prior to randomization. The major efficacy outcome measure was progression-free survival (PFS) based on independent radiological assessment per RECIST. Median PFS were 11 months and 3.9 months in the everolimus and placebo arms, respectively [HR 0.48 (95% CI: 0.35, 0.67), p <0.001, stratified log rank test]. Overall response rates were 2% in the everolimus arm and 1% in the placebo arm. At the planned interim analysis, there was no statistically significant difference in overall survival between arms.

Safety data were evaluated in 300 patients who received at least one dose of investigational drug. The median exposure duration to everolimus was 9.3 months; 64% of patients were treated for greater than or equal to 6 months and 39% were treated for greater than or equal to12 months.

Everolimus was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of everolimus-treated patients. Serious adverse reactions occurred in 42% of everolimus-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash. The most common laboratory abnormalities (incidence greater than or equal to 50%) were anemia, hypercholesterolemia, lymphopenia, elevated aspartate transaminase (AST) and fasting hyperglycemia.

The recommended dose and schedule for everolimus is 10 mg orally once daily.

Full prescribing information is available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022334s036lbl.pdf

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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