Afinitor Disperz Drug Information
Generic name: EVEROLIMUS
Kinase Inhibitor [EPC] mTOR Inhibitor Immunosuppressant [EPC]
Uses of Afinitor Disperz
Hormone Receptor-Positive, HER2-Negative Breast Cancer AFINITOR ® is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole.
Neuroendocrine Tumors (NET) AFINITOR is indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. AFINITOR is indicated for the treatment of adult patients with progressive, well-differentiated, non-functional NET of gastrointestinal (GI) or lung origin with unresectable, locally advanced or metastatic disease. Limitations of Use: AFINITOR is not indicated for the treatment of patients with functional carcinoid tumors.
Renal Cell Carcinoma (RCC) AFINITOR is indicated for the treatment of adult patients with advanced RCC after failure of treatment with sunitinib or sorafenib.
Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma AFINITOR is indicated for the treatment of adult patients with renal angiomyolipoma and TSC, not requiring immediate surgery.
Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) AFINITOR and AFINITOR DISPERZ ® 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.
Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures AFINITOR DISPERZ is indicated for the adjunctive treatment of adult and pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.
Dosage & Administration of Afinitor Disperz
Recommended Dosage for Hormone Receptor-Positive, HER2-Negative Breast Cancer The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.
Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma The recommended dosage of AFINITOR is 10 mg orally once daily until disease progression or unacceptable toxicity.
Recommended Dosage for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) The recommended starting dosage of AFINITOR/AFINITOR DISPERZ is 4.5 mg/m 2 orally once daily until disease progression or unacceptable toxicity.
Therapeutic Drug Monitoring (TDM) and Dose Titration for Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) and TSC-Associated Partial-Onset Seizures 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 s Table 2 summarizes recommendations for dosage modifications of AFINITOR/AFINITOR DISPERZ for the management of adverse reactions.
Table 2: Recommended Metabolic events (e.g., hyperglycemia, dyslipidemia) s for Hepatic Impairment The recommended dosages of AFINITOR/AFINITOR DISPERZ for patients with hepatic impairment are described in Table 3: Table 3: Recommended Severe hepatic impairment (Child-Pugh class C) – 2.5 mg/m 2 orally once daily. Adjust dose based on everolimus trough concentrations as recommended.
Dosage Modifications for Drug Interactions Strong or Moderate CYP3A Inhibitor and P-glycoprotein (P-gp) Inhibitor Avoid the coadministration of a strong CYP3A inhibitor and P-gp inhibitor. Reduce the dosage for AFINITOR/AFINITOR DISPERZ with a moderate CYP3A inhibitor and P-gp as recommended in Table 4. Table 4: Recommended Dosage Modifications with a Moderate CYP3A Inhibitor and P-gp Inhibitor Reduce the daily dose by 50%.
Assess trough concentrations when initiating and discontinuing the inhibitor. Cannabidiol Oral Solution Reduce the dosage of AFINITOR/AFINITOR DISPERZ when coadministered with cannabidiol oral solution as recommended in Table 5. The effects of other cannabidiol products on everolimus exposure are unknown.
Table 5: Recommended Reduce the daily dose by 50%. Strong CYP3A Inducer and P-gp Inducer Increase the dosage for AFINITOR/AFINITOR DISPERZ with a strong CYP3A inducer and P-gp inducer as recommended in Table 6. Table 6: Recommended Dosage Modifications with a Strong CYP3A Inducer and P-gp Inducer Double the daily dose using increments of 5 mg or less.
Multiple increments may be required. Assess trough concentrations when initiating and discontinuing the inducer. Resume the dosage administered before starting any inducer, once all inducers are discontinued for 5 days.
Administration and Preparation Administer AFINITOR/AFINITOR DISPERZ at the same time each day. Administer AFINITOR/AFINITOR DISPERZ consistently either with or without food. If a dose of AFINITOR/AFINITOR DISPERZ 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, AFINITOR/AFINITOR DISPERZ should be administered at its usual time. Double doses should not be administered to make up for the dose that was missed.
AFINITOR AFINITOR should be swallowed whole with a glass of water. Do not break or crush tablets. AFINITOR DISPERZ Wear gloves to avoid possible contact with everolimus when preparing suspensions of AFINITOR DISPERZ 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. 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. 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.
If higher doses are required, prepare an additional glass. 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.
| Abbreviation: P-gp, P-glycoprotein. | |
| Event | When to Assess Trough Concentrations After Event |
| Initiation of AFINITOR/AFINITOR DISPERZ | 1 to 2 weeks |
| Modification of AFINITOR/AFINITOR DISPERZ dose | 1 to 2 weeks |
| Switch between AFINITOR and AFINITOR DISPERZ | 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 |
| Adverse Reaction | Severity | Dosage Modification |
|---|---|---|
| Non-infectious pneumonitis [see Warnings and Precautions (5.1)] | Grade 2 | Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. Permanently discontinue if toxicity does not resolve or improve to Grade 1 within 4 weeks. |
| Grade 3 | Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If toxicity recurs at Grade 3, permanently discontinue. | |
| Grade 4 | Permanently discontinue. | |
| Stomatitis [see Warnings and Precautions (5.5)] | Grade 2 | Withhold until improvement to Grade 0 or 1. Resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. |
| Grade 3 | Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. | |
| Grade 4 | Permanently discontinue. | |
| Metabolic events (e.g., hyperglycemia, dyslipidemia) [see Warnings and Precautions (5.9)] | Grade 3 | Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. |
| Grade 4 | Permanently discontinue. | |
| Other non-hematologic toxicities | Grade 2 | If toxicity becomes intolerable, withhold until improvement to Grade 0 or 1. Resume at same dose. If toxicity recurs at Grade 2, withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. |
| Grade 3 | Withhold until improvement to Grade 0 or 1. Consider resuming at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. If recurs at Grade 3, permanently discontinue. | |
| Grade 4 | Permanently discontinue. | |
| Thrombocytopenia [see Warnings and Precautions (5.10)] | Grade 2 | Withhold until improvement to Grade 0 or 1. Resume at same dose. |
| Grade 3 OR Grade 4 | Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. | |
| Neutropenia [see Warnings and Precautions (5.10)] | Grade 3 | Withhold until improvement to Grade 0, 1, or 2. Resume at same dose. |
| Grade 4 | Withhold until improvement to Grade 0, 1, or 2. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. | |
| Febrile neutropenia [see Warnings and Precautions (5.10)] | Grade 3 | Withhold until improvement to Grade 0, 1, or 2, and no fever. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength. |
| Grade 4 | Permanently discontinue. |
| Indication | Dosage Modification for AFINITOR/AFINITOR DISPERZ |
|---|---|
| Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma | Reduce dose to 2.5 mg once daily. May increase dose to 5 mg once daily if tolerated. Resume dosage administered prior to inhibitor initiation, once the inhibitor is discontinued for 3 days. |
| 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)]. |
| Indication | Dosage Modification for AFINITOR/AFINITOR DISPERZ |
|---|---|
| Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma | Reduce dose to 5 mg once daily. May increase dose to 7.5 mg once daily if tolerated. Resume dosage administered prior to cannabidiol oral solution initiation, once cannabidiol oral solution is discontinued for 3 days. |
| 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)]. |
| Indication | Dosage Modification for AFINITOR/AFINITOR DISPERZ |
|---|---|
| Breast Cancer, NET, RCC, and TSC-Associated Renal Angiomyolipoma | Avoid coadministration where alternatives exist. If coadministration cannot be avoided, double the daily dose using increments of 5 mg or less. Multiple increments may be required. Resume the dosage administered prior to inducer initiation, once an inducer is discontinued for 5 days. |
| 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. |
Side Effects of Afinitor Disperz
Clinical Trials Experience
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. Hormone Receptor-Positive, HER2-Negative Breast Cancer The safety of AFINITOR (10 mg orally once daily) in combination with exemestane (25 mg orally once daily) (n = 485) vs. placebo in combination with exemestane (n = 239) was evaluated in a randomized, controlled trial (BOLERO-2) in patients with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The median follow-up was approximately 13 months.
The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, rash, fatigue, diarrhea, and decreased appetite. The most common Grade 3-4 adverse reactions (incidence ≥ 2%) were stomatitis, infections, hyperglycemia, fatigue, dyspnea, pneumonitis, and diarrhea. The most common laboratory abnormalities (incidence ≥ 50%) were hypercholesterolemia, hyperglycemia, increased aspartate transaminase (AST), anemia, leukopenia, thrombocytopenia, lymphopenia, increased alanine transaminase (ALT), and hypertriglyceridemia.
The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypokalemia, increased AST, increased ALT, and thrombocytopenia. Fatal adverse reactions occurred in 2% of patients who received AFINITOR. The rate of adverse reactions resulting in permanent discontinuation was 24% for the AFINITOR arm.
Dose adjustments (interruptions or reductions) occurred in 63% of patients in the AFINITOR arm. Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo are presented in Table 7. Laboratory abnormalities are presented in Table 8.
The median duration of treatment with AFINITOR was 23.9 weeks; 33% were exposed to AFINITOR for a period of ≥ 32 weeks. No food or drink was to be consumed for at least 1 hour after swishing and spitting the dexamethasone mouthwash. The primary objective of this study was to assess the incidence of Grade 2 to 4 stomatitis within 8 weeks.
The incidence of Grade 1 stomatitis was 19%. No cases of Grade 3 or 4 stomatitis were reported. Oral candidiasis was reported in 2% of patients in this study compared to 0.2% in the BOLERO-2 trial.
Coadministration of AFINITOR/AFINITOR DISPERZ and dexamethasone alcohol-free oral solution has not been studied in pediatric patients. Patients on the placebo arm could cross over to open-label AFINITOR upon disease progression. The most common adverse reactions (incidence ≥ 30%) were stomatitis, rash, diarrhea, fatigue, edema, abdominal pain, nausea, fever, and headache.
The most common laboratory abnormalities (incidence ≥ 50%) were anemia, hyperglycemia, increased alkaline phosphatase, hypercholesterolemia, decreased bicarbonate, and increased AST. Deaths during double-blind treatment where an adverse reaction was the primary cause occurred in seven patients on AFINITOR. Causes of death on the AFINITOR arm included one case of each of the following: acute renal failure, acute respiratory distress, cardiac arrest, death (cause unknown), hepatic failure, pneumonia, and sepsis.
After cross-over to open-label AFINITOR, there were three additional deaths, one due to hypoglycemia and cardiac arrest in a patient with insulinoma, one due to myocardial infarction with congestive heart failure, and the other due to sudden death. The rate of adverse reactions resulting in permanent discontinuation was 20% for the AFINITOR group. Dose delay or reduction was necessary in 61% of AFINITOR patients.
Grade 3-4 renal failure occurred in six patients in the AFINITOR arm. Thrombotic events included five patients with pulmonary embolus in the AFINITOR arm as well as three patients with thrombosis in the AFINITOR arm. Table 9 compares the incidence of adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR vs. placebo.
Laboratory abnormalities are summarized in Table 10. The median duration of treatment in patients who received AFINITOR was 37 weeks. Table 9: Adverse Reactions Reported in ≥: Selected Laboratory Abnormalities Reported in ≥ (GI) or Lung Origin In a randomized, controlled trial (RADIANT-4) of AFINITOR (n = 202 treated) vs. placebo (n = 98 treated) in patients with advanced non-functional NET of GI or lung origin, the median age of patients was 63 years (22-86 years), 76% were white, and 53% were female.
AFINITOR was discontinued for adverse reactions in 29% of patients, dose reduction or delay was required in 70% of AFINITOR-treated patients. Serious adverse reactions occurred in 42% of AFINITOR-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). Laboratory abnormalities are presented in Table 12.
Table 11: Adverse Reactions in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4: Selected Laboratory Abnormalities in ≥ 10% of AFINITOR-Treated Patients With Non-Functional NET of GI or Lung Origin in RADIANT-4 0 8 0 Renal Cell Carcinoma (RCC) The data described below reflect exposure to AFINITOR (n = 274) and placebo (n = 137) in a randomized, controlled trial (RECORD-1) in patients with metastatic RCC who received prior treatment with sunitinib and/or sorafenib. The median duration of blinded study treatment was 141 days (19 to 451 days) for patients receiving AFINITOR. The most common adverse reactions (incidence ≥ 30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea.
The most common Grade 3-4 adverse reactions (incidence ≥ 3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common Grade 3-4 laboratory abnormalities (incidence ≥ 3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the AFINITOR arm.
The most common adverse reactions leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.
Laboratory abnormalities are presented in Table 14. The median duration of blinded study treatment was 48 weeks (2 to 115 weeks) for patients receiving AFINITOR. The most common adverse reaction reported for AFINITOR (incidence ≥ 30%) was stomatitis.
The most common Grade 3-4 laboratory abnormality (incidence ≥ 3%) was hypophosphatemia. The rate of adverse reactions resulting in permanent discontinuation was 3.8% in the AFINITOR-treated patients. Adverse reactions leading to permanent discontinuation in the AFINITOR arm were hypersensitivity/angioedema/bronchospasm, convulsion, and hypophosphatemia.
Dose adjustments (interruptions or reductions) due to adverse reactions occurred in 52% 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 presented in Table 15.
Laboratory abnormalities are presented in Table 16. Table 15: Adverse Reactions Reported in ≥ 10% of AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2. Other adverse reactions involving the female reproductive system were menorrhagia (10%), menstrual irregularities (10%), and vaginal hemorrhage (8%).
Table 16: Selected Laboratory Abnormalities Reported in AFINITOR-Treated Patients With TSC-Associated Renal Angiomyolipoma in EXIST-2 patients treated with AFINITOR for a median duration of 3.9 years identified the following additional adverse reactions and selected laboratory abnormalities: increased partial thromboplastin time ( %). 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 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.
There were no adverse reactions resulting in permanent discontinuation. 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.
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 % were male. Patients received between one and three concomitant antiepileptic drugs.
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. 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 AFINITOR DISPERZ arms were stomatitis, pneumonia, and pyrexia.
Adverse reactions reported with an incidence of ≥ 10% for patients receiving AFINITOR DISPERZ are presented in Table 19. Laboratory abnormalities are presented in Table 20. 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
| Grading according to NCI CTCAE Version 3.0. a Includes stomatitis, mouth ulceration, aphthous stomatitis, glossodynia, gingival pain, glossitis, and lip ulceration. b Includes all reported infections, including but not limited to, urinary tract infections, respiratory tract (upper and lower) infections, skin infections, and gastrointestinal tract infections. c Includes pneumonitis, interstitial lung disease, lung infiltration, and pulmonary fibrosis. d No Grade 4 adverse reactions were reported. | ||||
| AFINITOR with Exemestane N = 482 | Placebo with Exemestane N = 238 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Gastrointestinal | ||||
| Stomatitis a | 67 | 8 d | 11 | 0.8 |
| Diarrhea | 33 | 2 | 18 | 0.8 |
| Nausea | 29 | 0.4 | 28 | 1 |
| Vomiting | 17 | 1 | 12 | 0.8 |
| Constipation | 14 | 0.4 d | 13 | 0.4 |
| Dry mouth | 11 | 0 | 7 | 0 |
| General | ||||
| Fatigue | 36 | 4 | 27 | 1 d |
| Edema peripheral | 19 | 1 d | 6 | 0.4 d |
| Pyrexia | 15 | 0.2 d | 7 | 0.4 d |
| Asthenia | 13 | 2 | 4 | 0 |
| Infections | ||||
| Infections b | 50 | 6 | 25 | 2 d |
| Investigations | ||||
| Weight loss | 25 | 1 d | 6 | 0 |
| Metabolism and nutrition | ||||
| Decreased appetite | 30 | 1 d | 12 | 0.4 d |
| Hyperglycemia | 14 | 5 | 2 | 0.4 d |
| Musculoskeletal and connective tissue | ||||
| Arthralgia | 20 | 0.8 d | 17 | 0 |
| Back pain | 14 | 0.2 d | 10 | 0.8 d |
| Pain in extremity | 9 | 0.4 d | 11 | 2 d |
| Nervous system | ||||
| Dysgeusia | 22 | 0.2 d | 6 | 0 |
| Headache | 21 | 0.4 d | 14 | 0 |
| Psychiatric | ||||
| Insomnia | 13 | 0.2 d | 8 | 0 |
| Respiratory, thoracic and mediastinal | ||||
| Cough | 24 | 0.6 d | 12 | 0 |
| Dyspnea | 21 | 4 | 11 | 1 |
| Epistaxis | 17 | 0 | 1 | 0 |
| Pneumonitis c | 19 | 4 | 0.4 | 0 |
| Skin and subcutaneous tissue | ||||
| Rash | 39 | 1 d | 6 | 0 |
| Pruritus | 13 | 0.2 d | 5 | 0 |
| Alopecia | 10 | 0 | 5 | 0 |
| Vascular | ||||
| Hot flush | 6 | 0 | 14 | 0 |
| Grading according to NCI CTCAE Version 3.0. a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively as pancytopenia), which occurred at lower frequency. b No Grade 4 laboratory abnormalities were reported. | ||||
| Laboratory Parameter | AFINITOR with Exemestane N = 482 | Placebo with Exemestane N = 238 | ||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Hematology a | ||||
| Anemia | 68 | 6 | 40 | 1 |
| Leukopenia | 58 | 2 b | 28 | 6 |
| Thrombocytopenia | 54 | 3 | 5 | 0.4 |
| Lymphopenia | 54 | 12 | 37 | 6 |
| Neutropenia | 31 | 2 b | 11 | 2 |
| Chemistry | ||||
| Hypercholesterolemia | 70 | 1 | 38 | 2 |
| Hyperglycemia | 69 | 9 | 44 | 1 |
| Increased AST | 69 | 4 | 45 | 3 |
| Increased ALT | 51 | 4 | 29 | 5 b |
| Hypertriglyceridemia | 50 | 0.8 b | 26 | 0 |
| Hypoalbuminemia | 33 | 0.8 b | 16 | 0.8 b |
| Hypokalemia | 29 | 4 | 7 | 1 b |
| Increased creatinine | 24 | 2 | 13 | 0 |
| Grading according to NCI CTCAE Version 3.0. a Includes stomatitis, aphthous stomatitis, gingival pain/swelling/ulceration, glossitis, glossodynia, lip ulceration, mouth ulceration, tongue ulceration, and mucosal inflammation. b Includes diarrhea, enteritis, enterocolitis, colitis, defecation urgency, and steatorrhea. c Includes pneumonitis, interstitial lung disease, pulmonary fibrosis, and restrictive pulmonary disease. d No Grade 4 adverse reactions were reported. | ||||
| AFINITOR N = 204 | Placebo N = 203 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Gastrointestinal | ||||
| Stomatitis a | 70 | 7 d | 20 | 0 |
| Diarrhea b | 50 | 6 | 25 | 3 d |
| Abdominal pain | 36 | 4 d | 32 | 7 |
| Nausea | 32 | 2 d | 33 | 2 d |
| Vomiting | 29 | 1 d | 21 | 2 d |
| Constipation | 14 | 0 | 13 | 0.5 d |
| Dry mouth | 11 | 0 | 4 | 0 |
| General | ||||
| Fatigue/malaise | 45 | 4 | 27 | 3 |
| Edema (general and peripheral) | 39 | 2 | 12 | 1 d |
| Fever | 31 | 1 | 13 | 0.5 d |
| Asthenia | 19 | 3 d | 20 | 3 d |
| Infections | ||||
| Nasopharyngitis/rhinitis/URI | 25 | 0 | 13 | 0 |
| Urinary tract infection | 16 | 0 | 6 | 0.5 d |
| Investigations | ||||
| Weight loss | 28 | 0.5 d | 11 | 0 |
| Metabolism and nutrition | ||||
| Decreased appetite | 30 | 1 d | 18 | 1 d |
| Diabetes mellitus | 10 | 2 d | 0.5 | 0 |
| Musculoskeletal and connective tissue | ||||
| Arthralgia | 15 | 1 | 7 | 0.5 d |
| Back pain | 15 | 1 d | 11 | 1 d |
| Pain in extremity | 14 | 0.5 d | 6 | 1 d |
| Muscle spasms | 10 | 0 | 4 | 0 |
| Nervous system | ||||
| Headache/migraine | 30 | 0.5 d | 15 | 1 d |
| Dysgeusia | 19 | 0 | 5 | 0 |
| Dizziness | 12 | 0.5 d | 7 | 0 |
| Psychiatric | ||||
| Insomnia | 14 | 0 | 8 | 0 |
| Respiratory, thoracic and mediastinal | ||||
| Cough/productive cough | 25 | 0.5 d | 13 | 0 |
| Epistaxis | 22 | 0 | 1 | 0 |
| Dyspnea/dyspnea exertional | 20 | 3 | 7 | 0.5 d |
| Pneumonitis c | 17 | 4 | 0 | 0 |
| Oropharyngeal pain | 11 | 0 | 6 | 0 |
| Skin and subcutaneous | ||||
| Rash | 59 | 0.5 | 19 | 0 |
| Nail disorders | 22 | 0.5 | 2 | 0 |
| Pruritus/pruritus generalized | 21 | 0 | 13 | 0 |
| Dry skin/xeroderma | 13 | 0 | 6 | 0 |
| Vascular | ||||
| Hypertension | 13 | 1 | 6 | 1 d |
| Grading according to NCI CTCAE Version 3.0. | ||||
| Laboratory parameter | AFINITOR N = 204 | Placebo N = 203 | ||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Hematology | ||||
| Anemia | 86 | 15 | 63 | 1 |
| Lymphopenia | 45 | 16 | 22 | 4 |
| Thrombocytopenia | 45 | 3 | 11 | 0 |
| Leukopenia | 43 | 2 | 13 | 0 |
| Neutropenia | 30 | 4 | 17 | 2 |
| Chemistry | ||||
| Hyperglycemia (fasting) | 75 | 17 | 53 | 6 |
| Increased alkaline phosphatase | 74 | 8 | 66 | 8 |
| Hypercholesterolemia | 66 | 0.5 | 22 | 0 |
| Bicarbonate decreased | 56 | 0 | 40 | 0 |
| Increased AST | 56 | 4 | 41 | 4 |
| Increased ALT | 48 | 2 | 35 | 2 |
| Hypophosphatemia | 40 | 10 | 14 | 3 |
| Hypertriglyceridemia | 39 | 0 | 10 | 0 |
| Hypocalcemia | 37 | 0.5 | 12 | 0 |
| Hypokalemia | 23 | 4 | 5 | 0 |
| Increased creatinine | 19 | 2 | 14 | 0 |
| Hyponatremia | 16 | 1 | 16 | 1 |
| Hypoalbuminemia | 13 | 1 | 8 | 0 |
| Hyperbilirubinemia | 10 | 1 | 14 | 2 |
| Hyperkalemia | 7 | 0 | 10 | 0.5 |
| Grading according to NCI CTCAE Version 4.03. a Includes stomatitis, mouth ulceration, aphthous stomatitis, gingival pain, glossitis, tongue ulceration, and mucosal inflammation. b Urinary tract infection, nasopharyngitis, upper respiratory tract infection, lower respiratory tract infection (pneumonia, bronchitis), abscess, pyelonephritis, septic shock and viral myocarditis. c Includes pneumonitis and interstitial lung disease. d No Grade 4 adverse reactions were reported. | ||||
| AFINITOR N = 202 | Placebo N = 98 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Gastrointestinal | ||||
| Stomatitis a | 63 | 9 d | 22 | 0 |
| Diarrhea | 41 | 9 | 31 | 2 d |
| Nausea | 26 | 3 | 17 | 1 d |
| Vomiting | 15 | 4 d | 12 | 2 d |
| General | ||||
| Peripheral edema | 39 | 3 d | 6 | 1 d |
| Fatigue | 37 | 5 | 36 | 1 d |
| Asthenia | 23 | 3 | 8 | 0 |
| Pyrexia | 23 | 2 | 8 | 0 |
| Infections | ||||
| Infections b | 58 | 11 | 29 | 2 |
| Investigations | ||||
| Weight loss | 22 | 2 d | 11 | 1 d |
| Metabolism and nutrition | ||||
| Decreased appetite | 22 | 1 d | 17 | 1 d |
| Nervous system | ||||
| Dysgeusia | 18 | 1 d | 4 | 0 |
| Respiratory, thoracic and mediastinal | ||||
| Cough | 27 | 0 | 20 | 0 |
| Dyspnea | 20 | 3 d | 11 | 2 |
| Pneumonitis c | 16 | 2 d | 2 | 0 |
| Epistaxis | 13 | 1 d | 3 | 0 |
| Skin and subcutaneous | ||||
| Rash | 30 | 1 d | 9 | 0 |
| Pruritus | 17 | 1 d | 9 | 0 |
| Grading according to NCI CTCAE Version 4.03. a No Grade 4 laboratory abnormalities were reported. | ||||
| AFINITOR N = 202 | Placebo N = 98 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Hematology | ||||
| Anemia | 81 | 5 a | 41 | 2 a |
| Lymphopenia | 66 | 16 | 32 | 2 a |
| Leukopenia | 49 | 2 a | 17 | 0 |
| Thrombocytopenia | 33 | 2 | 11 | 0 |
| Neutropenia | 32 | 2 a | 15 | 3 a |
| Chemistry | ||||
| Hypercholesterolemia | 71 | 0 | 37 | 0 |
| Increased AST | 57 | 2 | 34 | 2 a |
| Hyperglycemia (fasting) | 55 | 6 a | 36 | 1 a |
| Increased ALT | 46 | 5 | 39 | 1 a |
| Hypophosphatemia | 43 | 4 a | 15 | 2 a |
| Hypertriglyceridemia | 30 | 3 | 8 | 1 a |
| Hypokalemia | 27 | 6 | 12 | 3 a |
| Hypoalbuminemia | 18 | 0 | 8 | 0 |
| Grading according to NCI CTCAE Version 3.0. a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all reported infections, including but not limited to, respiratory tract (upper and lower) infections, urinary tract infections, and skin infections. c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. d No Grade 4 adverse reactions were reported. | ||||
| AFINITOR N = 274 | Placebo N = 137 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Gastrointestinal | ||||
| Stomatitis a | 44 | 4 | 8 | 0 |
| Diarrhea | 30 | 2 d | 7 | 0 |
| Nausea | 26 | 2 d | 19 | 0 |
| Vomiting | 20 | 2 d | 12 | 0 |
| Infections b | 37 | 10 | 18 | 2 |
| General | ||||
| Asthenia | 33 | 4 | 23 | 4 |
| Fatigue | 31 | 6 d | 27 | 4 |
| Edema peripheral | 25 | < 1 d | 8 | < 1 d |
| Pyrexia | 20 | < 1 d | 9 | 0 |
| Mucosal inflammation | 19 | 2 d | 1 | 0 |
| Respiratory, thoracic and mediastinal | ||||
| Cough | 30 | < 1 d | 16 | 0 |
| Dyspnea | 24 | 8 | 15 | 3 d |
| Epistaxis | 18 | 0 | 0 | 0 |
| Pneumonitis c | 14 | 4 d | 0 | 0 |
| Skin and subcutaneous tissue | ||||
| Rash | 29 | 1 d | 7 | 0 |
| Pruritus | 14 | < 1 d | 7 | 0 |
| Dry skin | 13 | < 1 d | 5 | 0 |
| Metabolism and nutrition | ||||
| Anorexia | 25 | 2 d | 14 | < 1 d |
| Nervous system | ||||
| Headache | 19 | 1 | 9 | < 1 d |
| Dysgeusia | 10 | 0 | 2 | 0 |
| Musculoskeletal and connective tissue | ||||
| Pain in extremity | 10 | 1 d | 7 | 0 |
| Grading according to NCI CTCAE Version 3.0. a Reflects corresponding adverse drug reaction reports of anemia, leukopenia, lymphopenia, neutropenia, and thrombocytopenia (collectively pancytopenia), which occurred at lower frequency. b No Grade 4 laboratory abnormalities were reported. | ||||
| Laboratory parameter | AFINITOR N = 274 | Placebo N = 137 | ||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Hematology a | ||||
| Anemia | 92 | 13 | 79 | 6 |
| Lymphopenia | 51 | 18 | 28 | 5 b |
| Thrombocytopenia | 23 | 1 b | 2 | < 1 |
| Neutropenia | 14 | < 1 | 4 | 0 |
| Chemistry | ||||
| Hypercholesterolemia | 77 | 4 b | 35 | 0 |
| Hypertriglyceridemia | 73 | < 1 b | 34 | 0 |
| Hyperglycemia | 57 | 16 | 25 | 2 b |
| Increased creatinine | 50 | 2 b | 34 | 0 |
| Hypophosphatemia | 37 | 6 b | 8 | 0 |
| Increased AST | 25 | 1 | 7 | 0 |
| Increased ALT | 21 | 1 b | 4 | 0 |
| Hyperbilirubinemia | 3 | 1 | 2 | 0 |
| Grading according to NCI CTCAE Version 3.0. a Includes stomatitis, aphthous stomatitis, mouth ulceration, gingival pain, glossitis, and glossodynia. b No Grade 4 adverse reactions were reported. | ||||
| AFINITOR N = 79 | Placebo N = 39 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Gastrointestinal | ||||
| Stomatitis a | 78 | 6 b | 23 | 0 |
| Vomiting | 15 | 0 | 5 | 0 |
| Diarrhea | 14 | 0 | 5 | 0 |
| General | ||||
| Peripheral edema | 13 | 0 | 8 | 0 |
| Infections | ||||
| Upper respiratory tract infection | 11 | 0 | 5 | 0 |
| Musculoskeletal and connective tissue | ||||
| Arthralgia | 13 | 0 | 5 | 0 |
| Respiratory, thoracic and mediastinal | ||||
| Cough | 20 | 0 | 13 | 0 |
| Skin and subcutaneous tissue | ||||
| Acne | 22 | 0 | 5 | 0 |
| Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported. | ||||
| AFINITOR N = 79 | Placebo N = 39 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Hematology | ||||
| Anemia | 61 | 0 | 49 | 0 |
| Leukopenia | 37 | 0 | 21 | 0 |
| Neutropenia | 25 | 1 | 26 | 0 |
| Lymphopenia | 20 | 1 a | 8 | 0 |
| Thrombocytopenia | 19 | 0 | 3 | 0 |
| Chemistry | ||||
| Hypercholesterolemia | 85 | 1 a | 46 | 0 |
| Hypertriglyceridemia | 52 | 0 | 10 | 0 |
| Hypophosphatemia | 49 | 5 a | 15 | 0 |
| Increased alkaline phosphatase | 32 | 1 a | 10 | 0 |
| Increased AST | 23 | 1 a | 8 | 0 |
| Increased ALT | 20 | 1 a | 15 | 0 |
| Hyperglycemia (fasting) | 14 | 0 | 8 | 0 |
| Grading according to NCI CTCAE Version 3.0. a Includes mouth ulceration, stomatitis, and lip ulceration. b Includes respiratory tract infection, upper respiratory tract infection, and respiratory tract infection viral. c Includes gastroenteritis, gastroenteritis viral, and gastrointestinal infection. d Includes agitation, anxiety, panic attack, aggression, abnormal behavior, and obsessive compulsive disorder. e Includes rash, rash generalized, rash macular, rash maculo-papular, rash papular, dermatitis allergic, and urticaria. f No Grade 4 adverse reactions were reported. | ||||
| AFINITOR N = 78 | Placebo N = 39 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Gastrointestinal | ||||
| Stomatitis a | 62 | 9 f | 26 | 3 f |
| Vomiting | 22 | 1 f | 13 | 0 |
| Diarrhea | 17 | 0 | 5 | 0 |
| Constipation | 10 | 0 | 3 | 0 |
| Infections | ||||
| Respiratory tract infection b | 31 | 3 | 23 | 0 |
| Gastroenteritis c | 10 | 5 | 3 | 0 |
| Pharyngitis streptococcal | 10 | 0 | 3 | 0 |
| General | ||||
| Pyrexia | 23 | 6 f | 18 | 3 f |
| Fatigue | 14 | 0 | 3 | 0 |
| Psychiatric | ||||
| Anxiety, aggression or other behavioral disturbance d | 21 | 5 f | 3 | 0 |
| Skin and subcutaneous tissue | ||||
| Rash e | 21 | 0 | 8 | 0 |
| Acne | 10 | 0 | 5 | 0 |
| Grading according to NCI CTCAE Version 3.0. a No Grade 4 laboratory abnormalities were reported. | ||||
| AFINITOR N = 78 | Placebo N = 39 | |||
| All Grades | Grade 3-4 | All Grades | Grade 3-4 | |
| % | % | % | % | |
| Hematology | ||||
| Elevated partial thromboplastin time | 72 | 3 a | 44 | 5 a |
| Neutropenia | 46 | 9 a | 41 | 3 a |
| Anemia | 41 | 0 | 21 | 0 |
| Chemistry | ||||
| Hypercholesterolemia | 81 | 0 | 39 | 0 |
| Elevated AST | 33 | 0 | 0 | 0 |
| Hypertriglyceridemia | 27 | 0 | 15 | 0 |
| Elevated ALT | 18 | 0 | 3 | 0 |
| Hypophosphatemia | 9 | 1 a | 3 | 0 |
| Grading according to NCI CTCAE Version 4.03. a Includes stomatitis, mouth ulceration, aphthous ulcer, lip ulceration, tongue ulceration, mucosal inflammation, gingival pain. b No Grade 4 adverse reactions were reported. | ||||||
| AFINITOR DISPERZ | Placebo | |||||
| Target of 3-7 ng/mL N = 117 | Target of 9-15 ng/mL N = 130 | N = 119 | ||||
| All Grades % | Grade 3-4 % | All Grades % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Gastrointestinal | ||||||
| Stomatitis a | 55 | 3 b | 64 | 4 b | 9 | 0 |
| Diarrhea | 17 | 0 | 22 | 0 | 5 | 0 |
| Vomiting | 12 | 0 | 10 | 2 b | 9 | 0 |
| Infections | ||||||
| Nasopharyngitis | 14 | 0 | 16 | 0 | 16 | 0 |
| Upper respiratory tract infection | 13 | 0 | 15 | 0 | 13 | 0.8 b |
| General | ||||||
| Pyrexia | 20 | 0 | 14 | 0.8 b | 5 | 0 |
| Respiratory, thoracic and mediastinal | ||||||
| Cough | 11 | 0 | 10 | 0 | 3 | 0 |
| Skin and subcutaneous tissue | ||||||
| Rash | 6 | 0 | 10 | 0 | 3 | 0 |
| Grading according to NCI CTCAE version 4.03. a No Grade 4 laboratory abnormalities were reported. | ||||||
| AFINITOR DISPERZ | Placebo | |||||
| Target of 3-7 ng/mL N = 117 | Target of 9-15 ng/mL N = 130 | N = 119 | ||||
| All Grades % | Grade 3-4 % | All Grades % | Grade 3-4 % | All Grades % | Grade 3-4 % | |
| Hematology | ||||||
| Neutropenia | 25 | 4 a | 37 | 6 | 23 | 7 a |
| Anemia | 27 | 0.9 a | 30 | 0 | 21 | 0.8 a |
| Thrombocytopenia | 12 | 0 | 15 | 0 | 6 | 0 |
| Chemistry | ||||||
| Hypercholesterolemia | 86 | 0 | 85 | 0.8 a | 58 | 0 |
| Hypertriglyceridemia | 43 | 2 a | 39 | 2 | 22 | 0 |
| Increased ALT | 17 | 0 | 22 | 0 | 6 | 0 |
| Increased AST | 13 | 0 | 19 | 0 | 4 | 0 |
| Hyperglycemia | 19 | 0 | 18 | 0 | 17 | 0 |
| Increased alkaline phosphatase | 24 | 0 | 16 | 0 | 29 | 0 |
| Hypophosphatemia | 9 | 0.9 a | 16 | 2 | 3 | 0 |
Warnings & Cautions for Afinitor Disperz
Non-infectious Pneumonitis
Non-infectious pneumonitis is a class effect of rapamycin derivatives. Non-infectious pneumonitis was reported in up to 19% of patients treated with AFINITOR/AFINITOR DISPERZ in clinical trials, some cases were reported with pulmonary hypertension (including pulmonary arterial hypertension) as a secondary event. 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 AFINITOR/AFINITOR DISPERZ 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 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 infections with opportunistic pathogens. 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 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.
Severe Hypersensitivity Reactions
Hypersensitivity reactions to AFINITOR/AFINITOR DISPERZ 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). 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 inhibitors with AFINITOR/AFINITOR DISPERZ 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 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 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 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. 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.
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. 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.
Risk of Impaired Wound Healing
Impaired wound healing can occur in patients who receive drugs that inhibit the VEGF signaling pathway. Therefore, AFINITOR/AFINITOR DISPERZ have the potential to adversely affect wound healing. Withhold AFINITOR/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. The safety of resumption of treatment upon resolution of wound healing complications has not been established.
Geriatric Patients In the randomized hormone receptor-positive, HER2-negative breast cancer study (BOLERO-2), the incidence of deaths due to any cause within 28 days of the last AFINITOR dose was 6% in patients ≥ 65 years of age compared to 2% in patients < 65 years of age. Careful monitoring and appropriate dose adjustments for adverse reactions are recommended.
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. In non-diabetic 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 annually 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. Monitor complete blood count (CBC) prior to starting AFINITOR/AFINITOR DISPERZ every 6 months for the first year of treatment and annually thereafter.
Risk of Infection or Reduced Immune Response With Vaccination The safety of immunization with live vaccines during AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ. 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 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 prior to, during, or subsequent to AFINITOR/AFINITOR DISPERZ treatment. Monitor patients closely when AFINITOR/AFINITOR DISPERZ is administered during or sequentially with radiation treatment.
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.
Drug Interactions with Afinitor Disperz
Effect of Other Drugs on AFINITOR/AFINITOR DISPERZ Strong or Moderate CYP3A Inhibitor and P-gp Inhibitor Avoid the coadministration of a strong CYP3A inhibitor and P-gp inhibitor. Reduce the dosage for AFINITOR/AFINITOR DISPERZ with a moderate CYP3A inhibitor and Pg-p inhibitor as recommended. Cannabidiol Oral Solution Reduce the dosage of AFINITOR/AFINITOR DISPERZ when coadministered with cannabidiol oral solution.
Coadministration with cannabidiol oral solution increases everolimus exposure, which may increase the risk of everolimus adverse reactions. The effects of other cannabidiol products on everolimus exposure are unknown. Strong CYP3A Inducer and P-gp Inducer Increase the dosage for AFINITOR/AFINITOR DISPERZ with a strong CYP3A inducer and Pg-p inducer as recommended.
Effects of Combination Use of Angiotensin Converting Enzyme (ACE) Inhibitors Patients taking concomitant ACE inhibitors with AFINITOR/AFINITOR DISPERZ may be at increased risk for angioedema. Avoid the concomitant use of ACE inhibitors with AFINITOR/AFINITOR DISPERZ.
Pregnancy Safety for Afinitor Disperz
Pregnancy Risk Summary Based on animal studies and the mechanism of action, AFINITOR/AFINITOR DISPERZ 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 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/m 2 ) 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/m 2 ), 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/m 2 ), 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.
Pediatric Use of Afinitor Disperz
Pediatric Use TSC-Associated SEGA The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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 AFINITOR/AFINITOR DISPERZ 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. The safety and effectiveness of AFINITOR/AFINITOR DISPERZ 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. 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 AFINITOR DISPERZ has been established for the adjunctive treatment of pediatric patients aged 2 years and older with TSC-associated partial-onset seizures.
The safety and effectiveness of AFINITOR DISPERZ 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. Two fatal cases due to infections were reported in pediatric patients.
Other Indications The safety and effectiveness of AFINITOR/AFINITOR DISPERZ in pediatric patients have not been established in: Hormone receptor-positive, HER2-negative breast cancer Neuroendocrine tumors (NET) Renal cell carcinoma (RCC) TSC-associated renal angiomyolipoma
Contraindications for Afinitor Disperz
AFINITOR/AFINITOR DISPERZ is contraindicated in patients with clinically significant hypersensitivity to everolimus or to other rapamycin derivatives.
Clinical Studies of Afinitor Disperz
Hormone Receptor-Positive, HER2-Negative Breast Cancer
A randomized, double-blind, multicenter study (BOLERO-2, NCT00863655) of AFINITOR in combination with exemestane vs. placebo in combination with exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomization was stratified by documented sensitivity to prior hormonal therapy (yes vs. no) and by the presence of visceral metastasis (yes vs. no). Sensitivity to prior hormonal therapy was defined as either documented clinical benefit (complete response, partial response, stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or at least 24 months of adjuvant hormonal therapy prior to recurrence.
Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease. The major efficacy outcome measure was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on investigator (local radiology) assessment. Other outcome measures included overall survival (OS) and objective response rate (ORR).
The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics. Patients were not permitted to cross over to AFINITOR at the time of disease progression. The trial demonstrated a statistically significant improvement in PFS by investigator assessment (Table 21 and Figure 1).
The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment. PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy. ORR was higher in the AFINITOR in combination with exemestane arm vs. the placebo in combination with exemestane arm (Table 21).
There were no complete responses and 4 partial responses (1.7%) in the placebo in combination with exemestane arm. After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the AFINITOR in combination with exemestane arm and the placebo in combination with exemestane arm. Table 21: Efficacy Results in Hormone-Receptor Positive, HER-2 Negative Breast Cancer in BOLERO-2 by Investigator Radiological Review in Hormone Receptor-Positive, HER-2 Negative Breast Cancer in BOLERO-2
Neuroendocrine Tumors (NET) Pancreatic Neuroendocrine Tumors (PNET) A randomized, double-blind, multicenter trial (RADIANT-3, NCT00510068) of AFINITOR in combination with best supportive care (BSC) compared to placebo in combination with BSC was conducted in patients with locally advanced or metastatic advanced PNET and disease progression within the prior 12 months. Patients were stratified by prior cytotoxic chemotherapy (yes vs. no) and WHO performance status (0 vs. 1 and 2). Treatment with somatostatin analogs was allowed as part of BSC.
After documented radiological progression, patients randomized to placebo could receive open-label AFINITOR. Other outcome measures included ORR, response duration, and OS. Demographics were well balanced (median age 58 years, 55% male, 79% white).
Of the 203 patients randomized to BSC, 172 patients (85%) received AFINITOR following documented radiologic progression. The trial demonstrated a statistically significant improvement in PFS (Table 22 and Figure 2). PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use.
The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 22. Table 22: by Investigator Radiological Review in PNET in RADIANT-3 Investigator-determined response rate was 4.8% in the AFINITOR arm and there were no complete responses. Overall Survival (OS) was not statistically significantly different between arms.
NET of Gastrointestinal (GI) or Lung Origin A randomized, double-blind, multicenter study (RADIANT-4, NCT01524783) of AFINITOR in combination with BSC compared to placebo in combination with BSC was conducted in patients with unresectable, locally advanced or metastatic, well differentiated, non-functional NET of GI (excluding pancreatic) or lung origin. The study required that patients had well-differentiated (low or intermediate grade) histology, no prior or current history of carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization. The major efficacy outcome measure was PFS based on independent radiological assessment evaluated by RECIST.
Additional efficacy outcome measures were OS and ORR. A total of 302 patients were randomized, 205 to the AFINITOR arm and 97 to the placebo arm. The most common primary sites of tumor were lung (30%), ileum (24%), and rectum (13%).
The study demonstrated a statistically significant improvement in PFS per independent radiological review (Table 23 and Figure 3). The final OS analysis did not show a statistically significant difference between those patients who received AFINITOR or placebo (HR = 0.90 ). Table 23: Progression-Free Survival in Neuroendocrine Tumors of Gastrointestinal or Lung Origin in RADIANT-4 in NET of GI or Lung Origin in RADIANT-4 Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors The safety and effectiveness of AFINITOR in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated.
In a randomized (1:1), double-blind, multicenter trial (RADIANT-2, NCT00412061) in 429 patients with carcinoid tumors, AFINITOR in combination with long-acting octreotide (Sandostatin LAR ® ) was compared to placebo in combination with long-acting octreotide. The study did not meet its major efficacy outcome measure of a statistically significant improvement in PFS and the final analysis of OS favored the placebo in combination with long-acting octreotide arm.
Renal Cell Carcinoma (RCC)
An international, multicenter, randomized, double-blind trial (RECORD-1, NCT00410124) comparing AFINITOR 10 mg once daily and placebo, both in conjunction with BSC, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially. Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted. Randomization was stratified according to prognostic score and prior anticancer therapy.
The major efficacy outcome measure for the trial was PFS evaluated by RECIST, based on a blinded, independent, central radiologic review. Other outcome measures included OS. AFINITOR was superior to placebo for PFS (Table 24 and Figure 4).
The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib. Final OS results yield a hazard ratio of with no statistically significant difference between the arms. Planned cross-over from placebo due to disease progression to open-label AFINITOR occurred in 80% of the 139 patients and may have confounded the OS benefit.
Table 24: Progression-Free Survival and Objective Response Rate by Central Radiologic Review in RCC in RECORD-1 in RCC in RECORD-1
Tuberous Sclerosis Complex (TSC)-Associated Renal Angiomyolipoma A randomized (2:1), double-blind, placebo-controlled trial (EXIST-2, NCT00790400) of AFINITOR was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n = 113) or sporadic lymphangioleiomyomatosis (n = 5). The key eligibility requirements for this trial were at least one angiomyolipoma of ≥ 3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥ 18 years. Patients received AFINITOR 10 mg or matching placebo orally once daily until disease progression or unacceptable toxicity.
CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter. Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation. The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥ 50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥ 1 cm, absence of kidney volume increase ≥ 20%, and no angiomyolipoma related bleeding of ≥ Grade 2.
Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate. The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized. The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes vs. no).
Of the 118 patients enrolled, 79 were randomized to AFINITOR and 39 to placebo. At baseline, 17% of patients were receiving EIAEDs. The median values for the sum of all target renal angiomyolipoma lesions at baseline were and in the AFINITOR and placebo arms, respectively.
Forty-six (39%) patients had prior renal embolization or nephrectomy. The median duration of follow-up was 8.3 months (0.7 to 24.8 months) at the time of the primary analysis. The renal angiomyolipoma response rate was statistically significantly higher in AFINITOR-treated patients (Table 25).
The median response duration was 5.3+ months (2.3+ to 19.6+ months). There were 3 patients in the AFINITOR arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥ 25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥ 1 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥ 2 angiomyolipoma-related bleeding). The time to angiomyolipoma progression was statistically significantly longer in the AFINITOR arm (HR 0.08; p < 0.0001).
Table 25: Angiomyolipoma Response Rate in TSC-Associated Renal Angiomyolipoma in EXIST-2 Skin lesion response rates were assessed by local investigators for 77 patients in the AFINITOR arm and 37 patients in the placebo arm who presented with skin lesions at study entry. Patients randomized to placebo were permitted to receive AFINITOR at the time of angiomyolipoma progression or after the time of the primary analysis. After the primary analysis, patients treated with AFINITOR underwent additional follow-up CT or 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 112 patients (79 randomized to AFINITOR and 33 randomized to placebo) received at least one dose of AFINITOR. During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review. Fourteen percent of the 112 patients treated with AFINITOR had angiomyolipoma progression by the end of the follow-up period.
No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with AFINITOR.
Tuberous Sclerosis Complex (TSC)-Associated Subependymal Giant Cell Astrocytoma (SEGA) 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/m 2 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. 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. Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo. At baseline, 18% of patients were receiving EIAEDs.
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). No patient in either treatment arm required surgical intervention. 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. 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.
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. 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.
Tuberous Sclerosis Complex (TSC)-Associated Partial-Onset Seizures The efficacy of AFINITOR DISPERZ 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 AFINITOR DISPERZ 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). 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. 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. 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 AFINITOR DISPERZ for these manifestations of TSC. 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
| a Includes adjudication for discrepant assessments between investigator radiological review and central radiological review. | |||||
| Analysis | N | AFINITOR N = 207 | Placebo N = 203 | Hazard Ratio (95% CI) | p-value |
| 410 | Median progression-free survival (months) (95% CI) | ||||
| Investigator radiological review | 11.0 (8.4, 13.9) | 4.6 (3.1, 5.4) | 0.35 (0.27, 0.45) | < 0.001 | |
| Central radiological review | 13.7 (11.2, 18.8) | 5.7 (5.4, 8.3) | 0.38 (0.28, 0.51) | < 0.001 | |
| Adjudicated radiological review a | 11.4 (10.8, 14.8) | 5.4 (4.3, 5.6) | 0.34 (0.26, 0.44) | < 0.001 | |
| a Hazard ratio is obtained from the stratified Cox model. b p-value is obtained from the stratified log-rank test. | ||
| AFINITOR N = 205 | Placebo N = 97 | |
| Progression-Free Survival | ||
| Number of Events | 113 (55%) | 65 (67%) |
| Progressive Disease | 104 (51%) | 60 (62%) |
| Death | 9 (4%) | 5 (5%) |
| Median PFS in months (95% CI) | 11.0 (9.2, 13.3) | 3.9 (3.6, 7.4) |
| Hazard Ratio (95% CI) a | 0.48 (0.35, 0.67) | |
| p-value b | < 0.001 | |
| Overall Response Rate | 2% | 1% |
| a Log-rank test stratified by prognostic score. b Not applicable. | ||||
| AFINITOR N = 277 | Placebo N = 139 | Hazard R atio (95% CI) | p-value a | |
| Median P rogression- free S urvival (95% CI) | 4.9 months (4.0, 5.5) | 1.9 months (1.8, 1.9) | 0.33 (0.25, 0.43) | < 0.0001 |
| Objective R esponse R ate | 2% | 0% | n/a b | n/a b |
| a Per independent central radiology review. | |||
| AFINITOR | Placebo | p-value | |
| N = 79 | N = 39 | ||
| Primary analysis | |||
| Angiomyolipoma response rate a - (%) | 41.8 | 0 | < 0.0001 |
| 95% CI | (30.8, 53.4) | (0.0, 9.0) | |
| a Per independent central radiology review. | |||
| AFINITOR | Placebo | p-value | |
| N = 78 | N = 39 | ||
| Primary analysis | |||
| SEGA response rate a - (%) | 35 | 0 | < 0.0001 |
| 95% CI | 24, 46 | 0, 9 | |
| a If patient discontinued before starting the Maintenance period, then the Titration period is used. b 95% CI of the median based on bootstrap percentiles. c p-values were for superiority vs. placebo, and obtained from rank ANCOVA with Baseline seizure frequency as covariate, stratified by age subgroup. d Exact 95% CI obtained using Clopper-Pearson method. | |||
| AFINITOR DISPERZ | Placebo | ||
| Target of 3-7 ng/mL N = 117 | Target of 9-15 ng/mL N = 130 | N = 119 | |
| Seizures per week | |||
| Median at Baseline (Min, Max) | 8.6 (1.4, 192.9) | 9.5 (0.3, 218.4) | 10.5 (1.3, 231.7) |
| Median at Core phase a (Min, Max) | 6.8 (0.0, 193.5) | 4.9 (0.0, 133.7) | 8.5 (0.0, 217.7) |
| Percentage reduction from Baseline to Core phase (Maintenance a ) | |||
| Median | 29.3 | 39.6 | 14.9 |
| 95% CI b | 18.8, 41.9 | 35.0, 48.7 | 0.1, 21.7 |
| p-value c | 0.003 | < 0.001 | |
| Response rate | |||
| Responders, n (%) | 28.2 | 40 | 15.1 |
| 95% CI d | 20.3, 37.3 | 31.5, 49.0 | 9.2, 22.8 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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