Important Safety Information

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

Noninfectious Pneumonitis:...

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Indication

AFINITOR® (everolimus) Tablets and AFINITOR DISPERZ® (everolimus tablets for oral suspension) are indicated in adult and pediatric patients 1 year and older with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.

Efficacy

Phase 3 Study (EXIST-1) and 4-Year Data

AFINITOR® (everolimus) Tablets demonstrated reduction in SEGA volume.

EXIST-1 (EXamining everolimus In a Study of TSC-1) was a phase 3, randomized (2:1), double-blind, placebo-controlled trial of AFINITOR conducted in 117 pediatric and adult patients with SEGA and TSC.

STUDY DESIGN

The first and only double-blind, randomized, placebo-controlled clinical trial in SEGA with TSC1

EXIST-1 Study Design

SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis complex.

  • Median duration of AFINITOR treatment and follow-up was 3.9 years (range, 0.2-4.9 years)1

 

Baseline Characteristics1:

  • 98% of patients had at least 1 SEGA lesion ≥1 cm in longest diameter
  • 79% of patients had bilateral SEGAs
  • 43% of patients had ≥2 target SEGA lesions
  • 26% of patients had growth in or into the inferior surface of the ventricle
  • 9% of patients had evidence of growth beyond the subependymal tissue adjacent to the ventricle
  • 7% of patients had radiographic evidence of hydrocephalus
  • Median age of patients enrolled in the trial was 9.5 years (range, 0.8-26 years)

RESULTS

AFINITOR statistically significantly improved SEGA response rate at 6 months (P<0.0001)1

SEGA response rate

Per independent central radiology review. Primary analysis for double-blind period. Final analysis includes patients who crossed over from the placebo group; median duration of exposure to everolimus was 47 months.

  • SEGA response rate based on independent central radiology review was the primary end point of EXIST-1 and was defined as all of the following1:
    • Reduction in the sum of SEGA volume ≥50% relative to baseline
    • No unequivocal worsening of nontarget SEGA lesions
    • No new SEGA lesion ≥1 cm
    • No new or worsening hydrocephalus

 

Disease progressionBy the end of the follow-up period, 13 of the 111 patients treated with AFINITOR had documented disease progression.

Disease Progression 2

Phase 2 Study and 5-Year Data

STUDY DESIGN1

This phase 2 study was an open-label, single-arm trial conducted to evaluate the safety and efficacy of AFINITOR in patients with SEGA with TSC.

Key eligibility requirements...
  • The median age of patients was 11 years (range, 3-34 years)1
  • Median duration of treatment was 5.7 years (range, 5 months-6.9 years)1

RESULTS

SEGA reduction

Patients with ≥50% reduction of largest SEGA lesion

 

Disease progression 5 years

Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥25% over the nadir observed on study. By the end of the study, 11% of patients (3/28) had documented disease progression.

 

Patient Scans

SEGA reduction in an actual patient

Baseline vs. After 6 months of AFINITOR

The scans above are from an actual patient enrolled in the AFINITOR registration trial who represents the 32% of patients with a ≥50% reduction in the volume of the largest SEGA lesion seen in the trial. Results may vary.

References:

  1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
  2. Data on file. Study CRAD001M2301. Novartis Pharmaceuticals Corp; September 14, 2011.

IMPORTANT SAFETY INFORMATION

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

Noninfectious Pneumonitis: Noninfectious pneumonitis is a class effect of rapamycin derivatives. Noninfectious pneumonitis was reported in up to 19% of patients treated with AFINITOR/AFINITOR DISPERZ in clinical trials, some cases reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. The incidence of grade 3 and 4 noninfectious pneumonitis was up to 4.0% and up to 0.2%, respectively. Fatal outcomes have been observed. Consider a diagnosis of noninfectious pneumonitis in patients presenting with nonspecific 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 AFINITOR/AFINITOR DISPERZ without dose alteration in patients who develop radiological changes suggestive of noninfectious pneumonitis and have few or no symptoms. Imaging appears to overestimate the incidence of clinical pneumonitis. For grade 2 to 4 noninfectious pneumonitis, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ 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/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, sepsis 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/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/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/AFINITOR DISPERZ for the development of clinically significant hypersensitivity.

Angioedema With Concomitant Use of Angiotensin-Converting Enzyme (ACE) Inhibitors: Patients taking concomitant ACE inhibitor with AFINITOR/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/AFINITOR DISPERZ for angioedema.

Stomatitis: Stomatitis, including mouth ulcers and oral mucositis, has occurred in patients treated with AFINITOR/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/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/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/AFINITOR DISPERZ and annually thereafter. Monitor renal function at least every 6 months in patients who have additional risk factors for renal failure.

Impaired Wound Healing: AFINITOR/AFINITOR DISPERZ delays wound healing and increases the occurrence of wound-related complications like wound dehiscence, wound infection, incisional hernia, lymphocele, and seroma. These wound-related complications may require surgical intervention. Exercise caution with the use of AFINITOR/AFINITOR DISPERZ in the perisurgical period.

Metabolic Disorders: Hyperglycemia, hypercholesterolemia, and hypertriglyceridemia have been reported in patients taking AFINITOR/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/AFINITOR DISPERZ and annually thereafter. In diabetic patients, monitor fasting serum glucose more frequently as clinically indicated. Monitor lipid profile prior to starting AFINITOR/AFINITOR DISPERZ and once yearly thereafter. When possible, achieve optimal glucose and lipid control prior to starting AFINITOR/AFINITOR DISPERZ. For grade 3 to 4 metabolic events, withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity.

Myelosuppression: Anemia, lymphopenia, neutropenia, and thrombocytopenia have been reported in patients taking AFINITOR/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/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter. Withhold or permanently discontinue AFINITOR/AFINITOR DISPERZ based on severity.

Risk of Infection or Reduced Immune Response With Vaccinations: The safety of immunization with live vaccines during AFINITOR/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/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.

Embryo-Fetal Toxicity: Based on animal studies and the mechanism of action, AFINITOR/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/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/AFINITOR DISPERZ and for 4 weeks after the last dose.

Adverse Reactions: In patients with TSC-associated SEGA the most common adverse reactions (incidence ≥30%, all grades) were stomatitis (62%) and respiratory tract infection (31%). The most common grade 3/4 adverse reactions (incidence ≥2%) were stomatitis, pyrexia, pneumonia, gastroenteritis, aggression, agitation, and amenorrhea. Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional notable adverse reactions: decreased appetite (14%), hypertension (11%), urinary tract infection (9%), cellulitis (6%), abdominal pain (5%), and decreased weight (5%).

Laboratory Abnormalities: In patients with TSC-associated SEGA, the most common key laboratory abnormalities (incidence ≥50%, all grades) were hypercholesterolemia (81%) and elevated partial thromboplastin time (72%). The most common grade 3/4 laboratory abnormality (incidence ≥3%) was neutropenia (9%). Updated safety information from 111 patients treated with AFINITOR for a median duration of 47 months identified the following additional key laboratory abnormalities: hyperglycemia (13%), decreased fibrinogen (8%), elevated creatinine (5%), and azoospermia (1%).

Please see full Prescribing Information.

Indication

AFINITOR® (everolimus) Tablets and AFINITOR DISPERZ® (everolimus tablets for oral suspension) are indicated in adult and pediatric patients 1 year and older with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.